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Nanotechnology and Heart Disease

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, BioSimilars, Cardiac & Vascular Repair Tools Subsegment, Cardiovascular Pharmacogenomics, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Frontiers in Cardiology and Cardiovascular Disorders, Medical Devices R&D Investment, Nanotechnology for Drug Delivery, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Stents & Tools, Valves & Tools, tagged Artherosclerosis, artificial artery, cardiovascular, Heart Attack, Heart disease, nanotechnology, plaque on March 4, 2013| 3 Comments »

Nanotechnology and Heart Disease

Author and Curator: Tilda Barliya PhD

Cardiovascular disease is the most common cause of death worldwide and will become even more prevalent as the population ages. New therapeutic targets are being identified as a result of emerging insights into disease mechanisms, and new strategies are also being tested, possibly leading to new treatment options. Improving diagnosis is also crucial, because by detecting disease early, the focus could be shifted from treatment to prevention (1).

Mortality rates for cardiovascular disease have improved, but there are inequalities across the UK

The World Health Organization estimates that more than 17 million people died from cardiovascular diseases in 2008. In the U.S., about 785,000 people will have new heart attacks this year and 470,000 will suffer recurrent ones. While more patients are surviving such events, about two-thirds don’t make complete recoveries and are vulnerable to heart failure (2).

Heart and vascular disease is the number one killer in most industrialized nations, and costs countries billions in health care, and lost wages. Nanotechnology, biotechnology, robotics, and stem cells are reinvigorating the development of artificial components of the cardiovascular system. We’ve seen hearts grown from stem cells in labs, artificial mechanical hearts, companies spending millions to develop artificial blood, and now even artificial vascular tubes which act more like the real thing. Combined with upcoming advances in robotic and micro-surgery, medicine could be on the path to conquering its public enemy number one.

Nanotechnology offers several tools and advantages in cardiovascular science which are in the areas of diagnosis, imaging, and tissue engineering.

including:

treating defective heart valves
detecting and treat arterial plaque
understanding at a sub-cellular level how heart tissue functions in both healthy and damaged organs, which can help researchers design better treatments

Examples:

Robert Langer, Omid Farokhzad and colleagues have developed nanoparticles that can cling to artery walls and slowly release medicine, an advance that potentially provides an alternative to drug-releasing stents in some patients with cardiovascular disease. The particles, dubbed “nanoburrs” because they are coated with tiny protein fragments that allow them to stick to target proteins, can be designed to release their drug payload over several days (3, 4). The nanoburrs are targeted to a specific structure, known as the basement membrane, which lines the arterial walls and is only exposed when those walls are damaged. Therefore, the nanoburrs could be used to deliver drugs to treat atherosclerosis and other inflammatory cardiovascular diseases. In the current study, the team used paclitaxel, a drug that inhibits cell division and helps prevent the growth of scar tissue that can clog arteries

Prof. Erkki Ruoslahti and other researchers from UC Santa Barbara have developed a nanoparticle that can attack plaque –– a major cause of cardiovascular disease (5). These lipid-based micelles target the p32 receptors known to overexpress in plaques. To accomplish the research, the team induced atherosclerotic plaques in mice by keeping them on a high-fat diet. They then intravenously injected these mice with the micelles, which were allowed to circulate for three hours.

Clinical Trials:

“Nanotechnology creates artificial artery for clinical trials”

Researchers at London Royal Free Hospital are hoping to save limbs and lives with the creation of their new artificial artery. Unlike current artery replacements, this grafting substance was created using nanotechnology and can pulse with the natural movements of the body. That pulsing will allow the polymer tube to be used in very small grafts (<8mm), giving hope that damaged arteries which would normally lead to amputations or heart attacks can now be treated (6). The clinical study should have started by the end of 2010. No further information is currently available on this clinical trial.

The new artificial artery material was developed by Professors George Hamilton (vascular surgery) and Alexander Seifalian (nanotechnology and tissue repair). The substance is a polymer which has been embedded with different types of special molecules. Some of these molecules aid circulation, others encourage stem cells to coat its walls. That coating is very important and may allow the artificial tissue to bond better with the body and promote long term health. Most importantly though, the design of the artificial vascular tissue is resistant to clotting and can pulse.

Summary:

Research of heart disease is progressing on several levels simultaniously. It is believed that nanotechnology may offer several advantages in detecting and treating several heart conditions, however, they have yet to progressed into the clinical trials.

Quoting Dr. Tal Dvir: ” Many current experimental approaches to heart attack involve supplying growth factors, drugs, stem cells and other therapeutic agents to the scarred, dying tissue. Some of these compounds, such as periostin and neuregulin, have been shown in animal models to enhance heart regeneration and improve cardiac function. But the existing delivery approaches are all invasive, involving direct injections into the heart, catheter procedures, or surgical placement of implants that release the necessary factors.

The ultimate goal is to have the particles release compounds that promote regeneration. One approach is to release factors that attract the patient’s own stem cells, avoiding the need for tissue-engineered patches. But to date, no one’s gotten stem cells to differentiate efficiently into cardiomyocytes”

REFERENCES

1. http://www.nature.com/nature/supplements/insights/cardiovascular/index.html

2. Novel Cure for Ailing Hearts. http://online.wsj.com/article/SB10000872396390443537404577577002440205144.html

3. Chan JM., Zhang L., Tong R., Ghosh D., Gao W., Liao G., Yuet KP., Gray D., Rhee JW., Cheng J., Golomb G., Libby P, Langer R and Farokhzad OC. Spatiotemporal controlled delivery of nanoparticles to injured vasculature. Proc Natl Acad Sci U S A. 2010 Feb 2;107(5):2213-8. http://www.pnas.org/content/107/5/2213.long

4. Chan JM., Rhee JW., Drum CL., Bronson RT., Golomb G., Langer R and Farokhzad OC. In vivo prevention of arterial restenosis with paclitaxel-encapsulated targeted lipid-polymeric nanoparticles. Proc Natl Acad Sci U S A. 2011 Nov 29;108(48):19347-52.

http://www.pnas.org/content/108/48/19347.long

5. Hamzah J., Kotamraju VR., Seo JW., Agemy L., Fogel V., Mahakian LM., Peters D., Roth L., Gagnon MK., Ferrara KW and Ruoslahti E. Specific penetration and accumulation of a homing peptide within atherosclerotic plaques of apolipoprotein E-deficient mice. Proc Natl Acad Sci U S A. 2011 Apr 26;108(17):7154-9. http://www.pnas.org/content/108/17/7154.long

6. Written By: Aaron Saenz: http://singularityhub.com/2010/01/05/nanotechnology-creates-artificial-artery-for-clinical-trials/

7. Ikaria® Commences Global Registration Trial for Bioabsorbable Cardiac Matrix. http://www.prnewswire.com/news-releases/ikaria-commences-global-registration-trial-for-bioabsorbable-cardiac-matrix-136581753.html.

8. Posted by: Prof. Lev-Ari :”Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel” http://pharmaceuticalintelligence.com/2013/02/27/arteriogenesis-and-cardiac-repair-two-biomaterials-injectable-thymosin-beta4-and-myocardial-matrix-hydrogel/

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Nanotechnology and Ocular Drug Delivery: Part I

Posted in Advanced Drug Manufacturing Technology, BioSimilars, Disease Biology, Drug Delivery Platform Technology, Nanotechnology for Drug Delivery, Pharmaceutical R&D Investment, Small Molecules in Development of Therapeutic Drugs, Technology Transfer: Biotech and Pharmaceutical, tagged anterior chamber, Ciprofloxacin, colloidal carriers, Drug delivery, Human eye, liposome, liposomes, nanoparticles, nanotechnology, Ocular drug delivery, Ophthalmology, posterior chamber, prodrug, Tilda Barliya, Time release technology, Topical on February 23, 2013| Leave a Comment »

Author: Tilda Barliya PhD

Ocular drug delivery is a very challenging field for pharmaceutical scientists. The unique structure of the eye restricts the entry of drug molecules at the required site of action. The eye and its drugs are classically divided into : Anterior and Posterior segments (1).

Conventional systems like eye drops, suspensions and ointments cannot be considered optimal in the treatment of vision threatening ocular diseases yet more than 90% of the marketed ophthalmic formulations are in the form of eye drops.

In the majority of these topical formulations which target the anterior chamber (the front of the eye) are washed off from the eye by various mechanisms:

lacrimation,
tear dilution
tear turnover
Moreover, human cornea comprising of epithelium, substantia propria and endothelium also restricts the ocular entry of drug molecules

Under normal condition the human eye can hold about 25–30 μl of an ophthalmic solution; however after a single blink the volume is reduced to 7–10 μl through nasolacrimal drainage which cause the drug to be systemically absorbed across the nasal mucosa or the gastrointestinal tract. A significant systemic loss from topically applied drugs also occurs from conjunctival absorption into the local circulation (4)

Thus resulting in low ocular bioavailability of drugs with less than 5% of the drugs entering the eye. Recently many drug efflux pumps have been identified and significant enhancement in ocular drug absorption was achieved following their inhibition or evasion. But prolonged use of such inhibitors may result in undesirable effects.

Targeting the posterior chamber is even more difficult due to the tight junctions of blood retinal barrier (BRB) restrict the entry of systemically administered drugs into the retina. Drugs are therefore delivered to the posterior chamber via:

Intravitreal injections
Implants
periocular injections

Here’s an illustration of the several ocular drug and their administration path

The success of nanoparticle systems for ocular drug delivery may depend on optimizing lipophilic-hydrophilic properties of the polymer-drug system, optimizing rates of biodegradation, and safety. Polymers used for the preparation of nanoparticles should be mucoadhesive and biocompatible. The choice of polymer plays an important role in the release kinetics of the drug from a nanoparticle system (4).

The choice of polymer plays an important role in the release kinetics of the drug from a nanoparticle system. Ocular bioavailability from a mucoadhesive dosage form will depend on the polymer’s bioadhesion characteristics, which are affected by its swelling properties, hydration time, molecular weight, and degree of crosslinking. The binding of drug depends on the physicochemical properties of the molecule as well as of the nanoparticle polymer, and also on the manufacturing process for these nanoparticle systems (4).

Other areas in which nanotechnology may be used is the use as biosensors, cell delivery and scaffolds etc (2)

Delivery of a drug via nanotechnology based product fulfills mainly three objectives as follows:

enhances drug permeation
controls the release of drug
targets drug

Tiwari et al (1) nicely covered different ocular delivery systems available. In this section we’ll review only few of the these drug products:

Viscosity improver:

The viscosity enhancers used are hydrophilic polymers such as cellulose, polyalcohol and polyacrylic acid. Sodium carboxy methyl cellulose is one of the most important mucoadhesion polymers having mono adhesive strength. Viscosity vehicles increases the contact time and no marked sustaining effect are seen.

Prodrugs:

Prodrugs enhance comeal drug permeability through modification of the hydrophilic or lipophilicity of the drug . The method includes modification of chemical structure of the drug molecule, thus making it selective, site specific and a safe ocular drug delivery system. Drugs with increased penetrability through prodrug formulations are epinephrine1, phenylephrine, timolol, and pilocarpine. The main indication of these drugs is to treat glaucoma thought epinephrine1 and phenylephrine are also being used to treat redness of the eye and/or part of dialing eye-drops.

Colloidal Carriers:
Nanoparticles provide sustained release-and prolonged therapeutic activity when retained in the cul-de-sac after topical administration and the entrapped drug must be released from the particles at an appropriate rate. Most commonly used polymers are venous poly (alkyl cyanoacrylates), poly Scaprolactone and polylactic-co-glycolic acid, which undergo hydrolysis in tears. Enhanced permeation across the cornea was also observed when poly (epsilon-caprolactone) nanoparticles were coated with polyethylene glycol.

Liposomes:

Liposomes are lipid vesicles containing aqueous core which have been widely exploited in ocular delivery for various drug molecules.Liposomes are favorable for lipophilic drugs and not for-hydrophilic drugs. liposomes has an affinity to bind to, ocular surfaces, and release contents at optimal rates. Coating with bioadhesive polymers to liposomes, prolong the precomea retention of liposomes. Carbopol 1342-coated pilocarpine containing liposomes were shown to produce a longer duration of action. Ciprofloxacin (CPFX) was also formulated in liposomal environmental which lowered tear-driven dilution in the conjunctival sac. Multilamellar vesicles from lecithin and alpha-L-dipalmithoyl-phosphatidylcholine were used to prepare liposome containing CPFX. This approach produced sustained release of the drug depending on the nature of the lipid composition selected.

There are many other known forms used in the industry to enhance drug penetration and bioavailability such as dendrimers, bioadhesive polymers, niosomes and microemulsions which will be discussed elsewhere.

Summary:

Drug delivery by topical and intravitreal routes cannot always be considered safe, effective and patient friendly. Drug delivery by periocular route can potentially overcome many of these limitations and also can provide sustained drug levels in ocular pathologies affecting both segments. Transporter targeted delivery can be a promising strategy for many drug molecules. Colloidal carriers can substantially improve the current therapy and may emerge as an alternative following their periocular administration. Ophthalmic drug delivery, more than any other route of administration, may benefit to a full extent from the characteristics of nano-sized drug particles. Other aspect of nanotechnology and ocular drug delivery will be discussed in the next chapter.

REFERENCES

1. Tiwari A and Shukla KR. Novel ocular drug delivery systems: An overview. J. Chem. Pharm. Res., 2010, 2(3):348-355

Click to access JOCPR-2010-2-3-348-355.pdf

2. Kalishwaralal K., Barathmanikanth S., Pandian SR, Deepak V and Gurunathan S. Silver nano-a trove for retinal therapies. J Control Release 2010 Jul 14;145(2):76-90. http://www.ncbi.nlm.nih.gov/pubmed/20359511

3.Cholkar K., Patel SP., Vadlapudi AD and Mitra AK. Novel Strategies for Anterior Segment Ocular Drug Delivery. J Ocul Pharmaco Ther 2012 Dec 5. [Epub ahead of print]

4. Bucolo C., Drago F and Salomone S. Ocular drug delivery: a clue from nanotechnology. Front Pharmacol. 2012; 3: 188.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3486627/

5. Vega E., Gamisans F., García M. L., Chauvet A., Lacoulonche F., Egea M. A. (2008). PLGA nanospheres for the ocular delivery of flubiprofen: drug release and interactions. J. Pharm. Sci.97, 5306–5317.

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Prostate Cancer and Nanotechnology

Author, Curator: Tilda Barliya, PhD

Prostate cancer is common and a frequent cause of cancer death. In the United States, prostate cancer is the most commonly diagnosed visceral cancer. In 2012, there were expected to be about 242,000 new prostate cancer diagnoses and about 28,000 prostate cancer deaths. Prostate cancer is second only to nonmelanoma skin cancer and lung cancer as the leading cause of cancer and cancer death, respectively, in US men. Worldwide, in 2008 there were estimated to be 903,000 new cases of prostate cancer and 258,000 prostate cancer deaths making it the second most commonly diagnosed cancer in men and the sixth leading cause of male cancer death (1).

Prostate cancer survival is related to many factors, especially the extent of tumor at the time of diagnosis. The five-year relative survival among men with cancer confined to the prostate (localized) or with just regional spread is 100 percent compared with 31.9 percent among those diagnosed with distant metastases . While men with advanced stage disease may benefit from palliative treatment, their tumors are generally not curable

Prostate-specific antigen (PSA) testing revolutionized prostate cancer screening. Although PSA was originally introduced as a tumor marker to detect cancer recurrence or disease progression following treatment, it became widely adopted for cancer screening by the early 1990s. Subsequently, professional societies issued guidelines supporting prostate cancer screening with PSA. PSA testing led to a dramatic increase in the incidence of prostate cancer, the majority of these newly-diagnosed cancers were clinically localized which led to an increase in radical prostatectomy and radiation therapy, aggressive treatments intended to cure these early-stage cancers (2). However, PSA is also elevated in a number of benign conditions, particularly benign prostatic hyperplasia (BPH) and prostatitis

So what is PSA?

PROSTATE SPECIFIC ANTIGEN (PSA) — PSA is a glycoprotein produced by prostate epithelial cells. PSA levels may be elevated in men with prostate cancer because PSA production is increased and because tissue barriers between the prostate gland lumen and the capillary are disrupted, releasing more PSA into the serum.

A research team led by Prof. Langer and Prof. Farokhzad from MIT and and Brigham and Women’s Hospital in Boston have developed a nanotechnology strategies adopted for the management of prostate cancer. In particular, the combination of targeted and controlled-release polymer nanotechnologies has recently resulted in the clinical development of BIND-14, a promising targeted Docetaxel-loaded nanoprototype, which can be validated for use in the prostate cancer therapy and entered clinical trials in January 2011

The BIND-014 nanoparticles have three components: one that carries the drug (docetaxel), one that targets PSMA, and one that helps evade macrophages and other immune-system cells.

Clinical results

The Phase I clinical trial involved 17 patients with advanced or metastatic tumors who had already gone through traditional chemotherapy. In Phase I trials, researchers evaluate a potential drug’s safety and study its effects in the body. To determine safe dosages, patients were given escalating doses of the nanoparticles. So far, doses of BIND-014 have reached the amount of docetaxel usually given without nanoparticles, with no new side effects. The known side effects of docetaxel have also been milder.

In the 48 hours after treatment, the researchers found that docetaxel concentration in the patients’ blood was 100 times higher with the nanoparticles as compared to docetaxel administered in its conventional form. Higher blood concentration of BIND-014 facilitated tumor targeting resulting in tumor shrinkage in patients, in some cases with doses of BIND-014 that correspond to as low as 20 percent of the amount of docetaxel normally given. The nanoparticles were also effective in cancers in which docetaxel usually has little activity, including cervical cancer and cancer of the bile ducts.

Summary:

Early detection of prostate cancer increased dramatically the five-year survival of patients. “This study demonstrates for the first time that it is possible to generate medicines with both targeted and programmable properties that can concentrate the therapeutic effect directly at the site of disease, potentially revolutionizing how complex diseases such as cancer are treated”. The Phase I clinical trial is still ongoing and continued dose escalation is underway; BIND Biosciences is now planning Phase II trials, which will further investigate the treatment’s effectiveness in a larger number of patients.

REFERENCES

1. Richard M Hoffman. Screening for prostate cancer. http://www.uptodate.com/contents/screening-for-prostate-cancer

2. http://web.mit.edu/newsoffice/2012/cancer-particle-0404.html

3. http://www.bindbio.com/content/pages/news/news_detail.jsp/q/news-id/70

4. State of the art in oncologic imaging of Prostate

http://pharmaceuticalintelligence.com/2013/01/28/state-of-the-art-in-oncologic-imaging-of-prostate/

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Introducing Dr. Tim Wu – Interventional Cardiologist, Inventor and Entrepreneur

Posted in Cardiac & Vascular Repair Tools Subsegment, Drug Delivery Platform Technology, Frontiers in Cardiology and Cardiovascular Disorders, Interviews with Scientific Leaders, Medical Devices R&D and Inventions, Medical Devices R&D Investment, PCI, Pharmaceutical R&D Investment, Pharmacotherapy of Cardiovascular Disease, Stents & Tools, tagged Beth Israel Medical Center, Biology, Cardiovascular disease, Cardiovascular Disorders, Cell Biology, Conditions and Diseases, Conventional PCI, Coronary circulation, DES, Drug-eluting stent, Endothelium, Food and Drug Administration, Heart disease, myocardial infarction, nanotechnology, Personalized medicine, research, Small Business Innovation Research, United States, University of Massachusetts Lowell, VasoTech on January 14, 2013| 2 Comments »

Introducing Dr. Tim Wu – Interventional Cardiologist, Inventor and Entrepreneur

Author: Ed Kislauskis, PhD

Article ID #18: Introducing Dr. Tim Wu – Interventional Cardiologist, Inventor and Entrepreneur. Published on 1/14/2013

WordCloud Image Produced by Adam Tubman

Welcome readers to the first in a series of interviews with future scientific leaders in biotechnology and medicine. In this post I interview a close colleague and clinical scientist who appears to be on a fast-track to achieving his vision for the future of interventional cardiology – at the very vanguard of applied nanotechnology.

Tim (Tiangen) Wu, M.D has graciously accepted my invitation to answer a few questions about how his career path and primary goal to develop and commercialize his first product, a fully-biodegradable drug-eluting stent he calls the PowerStent® Absorb (see insert). This technology combines three especially innovations: a unique balloon-expandable stent design (PowerStent®), a bioabsorbable nanoparticle composition (BioDe®), and a formulation of two commercially-available anti-restenosis drugs (Combo®).

About the Subject

Dr. Wu received his clinical education in China and research training in the USA. In 1988, he graduated with an MD from the prestigious Linyli Medical School and completed a fellowship in clinical cardiology at the Tonji Medical University. In 1993, presented with an opportunity to travel to the US, he uprooted to accept a position as visiting scholar, and ultimately post-doctoral fellow,in Jeffrey Isner’s lab at St. Elizabeth Hospital (Tufts University) and the Beth Israel Medical Center (Harvard Medical). There he investigated the biology of stenosis, and directed sponsored research projects to evaluate the safety and efficacy of the latest commercially-developed drug-coated stents (DES) in animals.

After a decade in academia, Dr. Wu made the successful transition to industry and joined Nitromed Inc. as a Research Scientist. His next stop was as a Research Director at Biomedical Research Models, Inc (2000-2006) where we met and collaborated on developing and characterizing macrovascular disease in an inbred, type 2 diabetic rat model. After a 20 year career, and upon gaining additional qualification in Mechanical Engineering (Wentworth Institute), Business Administration (MIT), Clinical Research Affairs (Mass. Biotech Council), and Medical Device Regulatory Affairs (North Eastern Univ.), he was ready to take the entrepreneurial leap. His first company, VasoTech would aim to re-engineer the clinical standards of stent design and drug delivery.

In 2007, Dr. Wu founded VasoTech, Inc. from inside his home garage. Less than a year later, VasoTech received a $1.5M SBIR fast-track grant award from the NIH. With funding, VasoTech joined the newly announced M2D2 facility on the University of Massachusetts Lowell campus, and expanded operations in China. With the support of one of his closest advisors, Dr. Stephen McCarthy and other research faculty, Dr. Wu was appointed as an adjunct faculty in the Dept. of BioMedical Engineering at the UMass/Lowell where he mentored a number of talented graduate students. Dr. Wu is recognized as a senior reviewer on the NIH Bioengineering, Surgical Science and Technology Study Section, and Biomaterials, Delivery Systems and Nanotechnology Special Emphasis Panels servicing the Small Business Innovation Research (SBIR) grant program.

Dr. Wu’s work at Vasotech is devoted to developing a 3^rd generation of fully biodegradable DES coronary stents to solve two major complications associated with stenting, restenosis and late-stage thrombosis. Thusfar, his ideas have attracted well over $1.5 Million (USD) in Small Business Innovation Research (SBIR) grant awards from the National Institute of Diabetes and Digestive and Kidney Diseases, and $1million (USD) from China Innovative Talent Leadership Program. Through his efforts VasoTech is well positioned to attract the strategic partnerships and venture capital investments necessary to translate his research through clinical stages of development both in China and the US.

The Interview

Kislauskis: Please help our readers understand the current clinical approach to CAD.

Wu: Most patients with advanced atherosclerosis diseases are at risk for occlusive coronary arterial disease and stroke. Consequently, it is recommended they undergo a percutaneous intervention (PCI); essentially, balloon angioplasty followed by instillation of one or more expandable metal stents. A properly expanded stent will dilate the vessel and increase blood flow to cardiac muscle tissue. Current 2^nd generation drug-eluting-stents (DES) release drugs to inhibit the process of vascular remodeling leading to restenosis. Because the DES approach is remarkably successful and lowers the rate of restenosis to < 10%, DESs is now performed in 85% of the 2 million percutaneous coronary interventions (PCI) procedures annually in the U.S.

Kislauskis: What is your impression of the recent 5 yr update of the FREEDOM trial comparing effectiveness of coronary artery bypass grafting (CABG) to PCI among diabetics? ¹

Wu: It makes perfect sense. There are other reports evaluating PCI in patients within high risk categories, including those with small diameter vessels, diabetes, and extensive, systemic vascular disease, showing unacceptably high rates of restenosis with bare metal stents (30%-60%) and DESs (6%-18%) ^2-4. We also know first-hand using an inbred rat strain that develops macrovascular disease 4 months after onset of spontaneous diabetes. In our experiment model, just 4weeks following balloon-induced injury to the coratid artery (PTCA), we observed 2x greater restenosis in female obese rats, and 4x greater stenosis in obese, diabetic rats littermates (syndrome X) relative to the non-obese, non-diabetic littermates. These results predicted that obesity (dyslipidemia) and diabetes (severe hyperglycemia) were major risk factors promoting the complication of restenosis (Wu and Kislauskis, unpublished).

Kislauskis: Can you tell our readers a bit more about the significance of restenosis and thrombosis and the concept behind your approach.

Wu: Two significant drawbacks to conventional PCI are the need for costly, long-term anti-platelet therapy; and having a metal artifact within the coronary vessel. In fact, once installed, the purpose of DES is to maintain patency and provide a scaffold until remodeling is complete, maybe 6 months. The period of drug elution is typically shorter in duration. In the event of restenosis, a second DES procedure is recommended and performed with satisfactory results. However, leaving another metal artifact is problematic.

Most concerning to PCI patients, however, should be an increased risk of sudden death from heart attack from a clot (thrombosis) and tissue ischemia (myocardial infarction). No available DES technology (eg. Cypher®or Taxus® DES) demonstrates any advantage over bare metal stents in this regard ^5-7. So the thinking is a metal artifact create an irregular vessel surface and micro-eddys in blood flow which ultimately result in late-stage thrombosis, particularly in patients who go off anti-their platelet therapy too soon ⁸. Therefore and conceptually, by combining potent DES technology with a fully-biodegradable scaffold, designed to be absorbed fully into the tissue, likely will reduce the rate in-stent stenosis and prevents late-stage thrombosis.

Kislauskis: How did you come up with your unique polymer formulation?

Wu: It turns out that through a process of trial and error in the lab I was able to identify a biodegradable formulation which reduces the local inflammatory response common to all DES formulations while improving the stent’s radial strength. With a stable drug delivery platform (BioDe®), the process of remodeling will contribute far less to restenosis. Furthermore, and unlike all prior art, my BioDe® formulation can neutralize acidic intermediates generated during stent degradation that induce inflammation. The combination of anti-restenosis drugs (Combo®) also is effective at inhibiting signaling pathways that contribute to restenosis.

Kislauskis: How did you come to design the PowerStent®?

Wu: Again, a long process of trial and error, initially using computer applied design (CAD) principals I learned while earning attending a mechanical engineering certificate program at Wentworth Institute of Technology in Boston. Elements behind my concept for BioDe® came to me while I was involved in a home renovation project, working with grout. Although the formulation is simple and may be duplicated, the process of manufacturing is complicated.

Kislauskis: So it’s your trade secret.

Wu: Absolutely.

Kislauskis: Can you summary its other advantages and your plans to commercialize the PowerStent®?

Wu: Preclinical, short duration (30 day) studies in porcine models with the PowerStent® Absorb deployed indicate that it will be non-inferior to the current metal DES and competing biodegradable stent technologies. Important functional attributes of the BioDe® polymer include better biocompatibility (less inflammatory), excellent radial strength, potent anti-restenosis activity, and a unique microporous surface that promotes integration into neointimal layer of stented vessel. Ongoing and much longer duration studies may also support our contention that this design can reduce risks of late-stage in-stent thrombosis.

Kislauskis: What path and difficulties to you foresee in obtaining a regulatory approval to conduct clinical trials with the PowerStent® Absorb?

Wu: FDA Guidance to commercialize conventional DES technology is available. Unfortunately, no guidance is published for a fully-biodegradable stent. Therefore, I anticipate seeking advice from the regulatory bodies prior to petitioning for approval to perform clinical trials. It will no doubt be a complicated process as this technology involves a novel drug combination (albeit FDA-approved drugs), and a novel formulation (albeit FDA-approved components), and a novel indwelling and bioabsorbable medical device (stent). We are presently completing several required engineering studies for the final phase of pre-clinical safety and efficacy testing, in China. The goals are to obtain FDA pre-market and NDA approvals, and to receive a CE mark from major international markets including Europe and the BRICK nations.

Kislauskis: How will you commercialize this 3^rd generation, fully-biodegradable stent?

Wu: There are likely 3 scenarios to complete development and commercialization. One involves securing bridge funding from the NIH SBIR program, supplemented with angel financing to complete preclinical program. I project that a minimum of $6 Million (USD) will be required to complete regulatory approval and pivotal clinical trials. Therefore, it is conceivable that a Series A round of equity financing from venture capitalists, in either US or China, will be required. A third scenario is to partner or sell the technology to a major player in this space to complete clinical testing and commercialization. Potential partners include Boston Scientific Company, J&J, etc. Any of these partners could facilitate the processes of regulatory approval, manufacturing, global distribution and marketing. Discussions are underway with one such prospective partner and with several VC groups.

Kislauskis: What is its likely impact of this product on patient care and the field of interventional cardiology?

Wu: According to US statistics, approximately 14 million Americans suffer from CAD, and 500,000 people die from acute myocardial infarction. One million more survive but with a 1.5 to 15 times greater risk of mortality or morbidity than the rest of the population each year. In the U.S., the annual health care costs of CAD are estimated to be in excess of $112 billion, and the estimated annual total direct cost associated with PCI with stents is over $2 billion. I anticipate that our PowerStent® Absorb stent will be competitive in a marketplace estimated to be over $5 billion in 2010. Although CAD patients are the primary market, other related applications for our PowerStent Absorb technology include peripheral arteries, intracerebral vascular and small vessels which are also significant.

Kislauskis: Thank you for your contribution to this site. For more information about MMG, LLC and Dr. Wu’s technology please refer to his publications ^9-13 or contact him directly at tiangenwu@yahoo.com.

REFERENCES

1. Mark A. Hlatky, M.D. Compelling Evidence for Coronary-Bypass Surgery in Patients with Diabetes. N Engl J Med 2012; 367:2437-2438.

2. Stamler, J. (1989) Epidemiology. Established major risk factors, and the primary prevention of coronary heart disease. In: Chatterjee K, Karliner J, Rapaport E, Cheitlin MD, Parmlee WW, Sheinman, M eds. Cardiology, Philadelphia Penn: JB Lippincott, 1991, 7.2-7.35. (volume 2).

3. Tanabe, K, Regar, E et al. Sirolimus-eluting stent for treatment of in-stentrestenosis: One-year angiographic and intravascular ultrasound follow-up. J. Am Col.Cardi. (2003) 41: 12A.

4. Grube, Eberhard; Silber, Sigmund. Six- and twelve-month results from a randomized, double-blind trial on a slow-release paclitaxel-eluting stent for de novo coronary lesions. Circulation 2003: 107, 38-42.

5. Iakovou I, Schmidt T, Bonizzoni E, et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. JAMA 2005;293:2126–2130.

6. Ong AT, McFadden EP, Regar E, et al. Late angiographic stent thrombosis (LAST) events with drug-eluting stents. J Am Coll Cardiol 2005;45:2088–2092.

7. Wang F, Stouffer GA, Waxman S, et al. Late coronary stent thrombosis: Early vs late stent thrombosis in the stent era. Catheter Cardiovasc Interven 2002;55:142–147.

8. McFadden EP, Stabile E, Regar E, et al. Late thrombosis in drug-eluting coronary stents after discontinuation of antiplatelet therapy. Lancet 2004;364:1519–1521.

9. Ma X, Oyamada S, Wu T, Robich MP, Wu H, Wang X, Buchholz B, McCarthy S, Bianchi CF, Sellke FW, Laham R. In vitro and in vivo degradation of poly(D, L-lactide-co-glycolide)/amorphous calcium phosphate copolymer coated on metal stents. J Biomed Mater Res A. 2011 Mar 15;96(4):632-8. doi: 10.1002/jbm.a.33016. Epub 2011 Jan 25.

10. Oyamada S, Ma X, Wu T, Robich MP, Wu H, Wang X, Buchholz B, McCarthy S, Bianchi CF, Sellke FW, Laham R. Trans-iliac rat aorta stenting: a novel high throughput preclinical stent model for restenosis and thrombosis. J Surg Res. 2011 Mar;166(1):e91-5. Erratum in: J Surg Res. 2012 May 1;174(1):184.

11. Ma X, Oyamada S, Gao F, Wu T, Robich MP, Wu H, Wang X, Buchholz B, McCarthy S, Gu Z, Bianchi CF, Sellke FW, Laham R Paclitaxel/sirolimus combination coated drug-eluting stent: in vitro and in vivo drug release studies. J Pharm Biomed Anal. 2011 Mar 25;54(4):807-11. Erratum in: J Pharm Biomed Anal. 2012 Feb 5;59:217.

12. Ma X, Wu T, Robich MP, Wang X, Wu H, Buchholz B, McCarthy S. Drug-eluting stents. Int J Clin Exp Med. 2010 Jul 15;3(3):192-201.

Nanotechnology, personalized medicine and DNA sequencing

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Genome Biology, Genomic Testing: Methodology for Diagnosis, Medical Devices R&D Investment, Molecular Genetics & Pharmaceutical, Nanotechnology for Drug Delivery, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Technology Transfer: Biotech and Pharmaceutical, tagged Clinical trial, DNA, DNA Sequencing, Graphene, nanopore, Nanopore sequencing, nanotechnology, National Institutes of Health, Personalized medicine on January 9, 2013| 9 Comments »

Nanotechnology, personalized medicine and DNA sequencing

Author, reporter, Curator: Tilda Barliya PhD

Dr. Ritu Saxena’s exciting report on the fascinating work of Dr. Apostolia M. Tsimberidou “personalized medicine gearing up to tackle cancer”, inspired me to go back and review this topic and see how nanotechnology can be applied in personalized medicine.

To read the Dr. Saxena’s post, please see http://pharmaceuticalintelligence.com/2013/01/07/personalized-medicine-gearing-up-to-tackle-cancer/

It is based on an interview with Dr. A. M. Tsimberidou based on her paper:

Personalized medicine in a phase I clinical trials program: the MD Anderson Cancer Center initiative.

http://www.ncbi.nlm.nih.gov/pubmed?term=22966018

In March 2011 Nature Reviews issued a special issue features discussions of the advances, challenges and progress in the field of personalized cancer medicine by key opinion leaders who presented at the Worldwide Innovative Networking (WIN) symposium (**).

So what is personalized medicine?

Personalized medicine is a huge movement in the modern medical world. It aims to move away from the traditional practice of prescribing standard doses of standard drugs for a condition to every patient, and shifts the focus onto targeting the precise drug and dose required according to the patient’s physiology.

This is achieved by detecting and tracking molecular biomarkers, which indicate the presence and level of activity of a particular biological system in a patient’s body, whether inherent or foreign.

Another major part of the emerging field of personalized medicine is pharmacogenomics – analyzing the genetic makeup of the patient to determine whether a particular medication will be successful, or if it will have any adverse effects. (1). This is particularly important in cancer treatment, where the chemotherapy drugs used can be very damaging to healthy cells as well as cancerous ones, and the exact genetics of the tumor cells can vary widely between patients, and even between locations in one patient’s body.

Personalized medicine involves:

Detection (DNA polymorphism, RNA and protein expression, metabolits, Lipids etc)
Diagnosis (imaging)
Prognosis and
Treatment (targeted-therapy)

Given the size symmetry, nanomaterials offer unprecedented sensitivity, capable of sensing biological markers and processes at the single-molecule or single-cell level either in vitro or in vivo. Techniques are being developed for high-throughput DNA sequencing using nanopores, to obtain genetic information from a patient so that targeted medication can be selected as rapidly as possible.

Cancer, a very complex disease, is propagated by various types of molecular aberrations which drive the development and progression of malignancies. Large-scale screenings of multiple types of molecular aberrations (e.g., mutations, copy number variations, DNA methylations, gene expressions) become increasingly important in the prognosis and study of cancer. Consequently, a computational model integrating multiple types of information is essential for the analysis of the comprehensive data.

One of the greatest promises of near-term nanotechnoloogy is cheaper DNA sequencing to speed the development of personalized medicine. (3)

Nanotechnology and DNA sequencing

Tumors are known to be highly heterogenetic, due to the many acquired aberration in the cancer cells. Therefore, there are not only genetic differences between different patients, but also genetic differences within the same patient; for example from different locations in the same patient, that can greatly affect the success of a therapy. Therefore, sensitive and extensive yet inexpensive whole-genome sequencing is of major medical need to enable the application personalized medicine. A review of the potential of this emerging nanotechnology “Nanopore sensors for nucleic acid analysis ” was published recently in Nature Nanotechnology (4).

The growing need for cheaper and faster genome sequencing has prompted the development of new technologies that surpass conventional Sanger chain-termination methods in terms of speed and cost. These second- and third-generation sequencing technologies — inspired by the $1,000 genome challenge proposed by the National Institutes of Health in 2004 (ref. 5) — are expected to revolutionize genomic medicine. Nanopore sensors are one of a number of DNA sequencing technologies that are currently poised to meet this challenge.

Nanopore Sequencing:

Nanopore-based sensing is attractive for DNA sequencing applications because it is a

label-free,
amplification-free,
single-molecule
requires low reagent volumes

approach that can be scaled for high-throughput DNA analysis.

This approach can be scaled up for high-throughput DNA analysis, it typically requires low reagent volumes, benefits from
relatively low cost and supports long read lengths, so it could potentially enable de novo sequencing and long-range haplotype mapping. Although, nanopore technology is not conceptually new and raised many skeptical opinions it has made major progress in the past few years and are thus worth sharing.

The principle of nanopore sensing is analogous to that of a Coulter counter. A nanoscale aperture (the nanopore) is formed in an insulating membrane separating two chambers filled with conductive electrolyte. Charged molecules (A,G,C,T) are driven through the pore under an applied electric potential (a process known as electrophoresis), thereby modulating the ionic current through the nanopore. This current reveals useful information about the structure and dynamic motion of the molecule.

Here’s an example for a nanopore-based sequencing device is a Graphene- chip that is used as trans-electrode membrane (5).

Electrical measurements on graphene membranes in which a single nanopore has been drilled show that the membrane’s effective insulating thickness is less than one nanometer. This small effective thickness makes graphene an ideal substrate for very high-resolution, high throughput nanopore-based single molecule detectors. The sensitivity of graphene’s in-plane electronic conductivity to its immediate surface environment, as influenced by trans-electrode potential, will offer new insights into atomic surface processes and sensor development opportunities. (4-6).

A nanopore-based diagnostic tool could offer various advantages:

it could detect target molecules at very low concentrations from very small sample volumes;
it could simultaneously screen panels of biomarkers or genes (which is important in disease diagnosis,
monitoring progression and prognosis);
it could provide rapid analysis at relatively low cost; and
it could eliminate cumbersome amplification and conversion steps such as PCR, bisulphite conversion and Sanger sequencing

Nanopores are likely to have an increasing role in medical diagnostics and DNA sequencing in years to come, but they will face competition from a number of other techniques. These include

single-molecule evanescent field detection of sequencing-by-synthesis in arrays of nanochambers (Pacific Biosciences),
sequencing by ligation on self-assembled DNA nanoarrays (Complete Genomics), and the
detection of H+ ions released during sequencing-by-synthesis on silicon field-effect transistors from multiple polymerase-template reactions (Ion Torrent).

However, the possibility of using nanopore-based sensors to perform long base reads on unlabelled ssDNA molecules in a rapid and costeffective manner could revolutionize genomics and personalized medicine.

Current trends suggest that many challenges in sequencing with biological nanopores

the high translocation velocity and the
lack of nucleotide specificity

have been resolved. Similarly, given the progress with solid-state nanopores, if the

translocation velocity could be reduced to a single nucleotide (which is ~3Å long) per millisecond, and if
nucleotides could be identified uniquely with an electronic signature (an area of intense research),

it would be possible to sequence a molecule containing one million bases in less than 20 minutes. Furthermore, if this technology could be scaled to an array of 100,000 individually addressed nanopores operating in parallel, it would be possible to sequence an entire human genome (some three billion base pairs) with 50-fold coverage in less than one hour.

Although, none of the nanopore-solid base sequencing technique have been used as a tool in a clinical trial, one UK-based biotechnology company has its way, nanopore sequencing may soon be available to the public. Earlier this year 2012 Oxford Nanopore Technologies (ONT) announced that it was on the verge of manufacturing a commercial nanopore sensor. [The company said that by year’s end it would release a $900 handheld model, which it claims can sequence a virus genome 48 000 bases long, and a larger, scalable model that could decode a human genome in as little as 15 minutes. In contrast, conventional systems cost upward of $500 000 and take weeks to sequence a human genome (7).]

REFERENCES

** http://www.nature.com/nrclinonc/focus/personalized-medicine/index.html

1. http://www.azonano.com/article.aspx?ArticleID=3078

2. G.E. Marchant. Small is Beautiful: What Can Nanotechnology Do for Personalized Medicine?. Current Pharmacogenomics and Personalized Medicine, 2009, 7, 231-237. http://www.benthamscience.com/cppm/Sample/cppm7-4/002AF.pdf

3. http://www.foresight.org/nanodot/?p=4992

4. Venkatesan BM and Bashi R. Nanopore sensors for nucleic acid analysis. Nature Nanotechnology 2011; 18: http://libna.mntl.illinois.edu/pdf/publications/127_venkatesan.pdf

5. Garaj S., Hubbard W., Reina A., King J., Branton D and Golovchenko JA. Graphene as a sub-nanometer trans-electrode membrane. Nature 2010 (9) 467(7312): 190-193. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2956266/

6. Min SK., Kim WY., Cho Y and Kim KS. Fast DNA sequencing with a graphene-based nanochannel device. Nature Nanotechnology 2011; 6: 162-165. http://biophy.nju.edu.cn/lablog/wp-content/uploads/2011/10/Fast-DNA-sequencing-with-a-graphene-based.pdf

7. http://www.physicstoday.org/resource/1/phtoad/v65/i11/p29_s1?bypassSSO=1

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Nanotechnology and HIV/AIDS Treatment

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, BioSimilars, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Human Immune System in Health and in Disease, Infectious Disease & New Antibiotic Targets, Nanotechnology for Drug Delivery, Pharmaceutical R&D Investment, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Uncategorized, tagged AIDS, antiretroviral drugs, CD4, CD4+ T cells, CD8, CD8+ T cells, Clinical tr, Clinical Trials, CXCR4, gene therapy, HAART, highly active antiretroviral therapy (HAART), HIV, immunoresponse, liposome, macrophages, nanosuspension, nanotechnology, nanotherapeutic, PEG, PLGA, polymeric system, retroviral, RNAi, siRNA, T cells on December 25, 2012| 5 Comments »

Nanotechnology and HIV/AIDS Treatment

Author: Tilda Barliya, PhD

AIDS was first reported in 1981 followed by the identification of HIV as the cause of the disease in 1983 and is now a global pandemic that has become the leading infectious killer of adults worldwide. By 2006, more than 65 million people had been infected with the HIV virus worldwide and 25 million had died of AIDS (Merson MH. The HIV-AIDS pandemic at 25 – the global response. (1, 2). This has caused tremendous social and economic damage worldwide, with developing countries, particularly Sub-Saharan Africa, heavily affected.

A cure for HIV/AIDS has been elusive in almost 30 years of research. Early treatments focused on antiretroviral drugs that were effective only to a certain degree. The first drug, zidovudine, was approved by the US FDA in 1987, leading to the approval of a total of 25 drugs to date, many of which are also available in fixed-dose combinations and generic formulations for use in resource-limited settings (to date, only zidovudine and didanosine are available as true generics in the USA).

However, it was the advent of a class of drugs known as protease inhibitors and the introduction of triple-drug therapy in the mid-1990s that revolutionized HIV/AIDS treatment (3,4). This launched the era of highly active antiretroviral therapy (HAART), where a combination of three or more different classes of drugs are administered simultaneously.

Challenges of HIV/AIDS treatment

HIV resides in latent cellular and anatomical reservoirs where current drugs are unable to completely eradicate the virus.
Macrophages are major cellular reservoirs, which also contribute to the generation of elusive mutant viral genotypes by serving as the host for viral genetic recombination.
Anatomical latent reservoirs include secondary lymphoid tissue, testes, liver, kidney, lungs, the gut and the brain.
The major challenge facing current drug regimens is that they do not fully eramacrdicate the virus from these reservoirs; requiring patients take medications for life. Under current treatment, pills are taken daily, resulting in problems of patient adherence. The drugs also have side effects and in some people the virus develops resistance against certain drugs.

Current treatment in HIV/AIDS

The use of the HAART regimen, particularly in the developed world, has resulted in tremendous success in improving the expectancy and quality of lives for patients. However, some HAART regimens have serious side effects and, in all cases, HAART has to be taken for a lifetime, with daily dosing of one or more pills. Due to the need to take the medication daily for a lifetime, patients fail to adhere to the treatment schedule, leading to ineffective drug levels in the body and rebound of viral replication.Some patients also develop resistance to certain combinations of drugs, resulting in failure of the treatment. The absence of complete cure under current treatment underscores the great need for continued efforts in seeking innovative approaches for treatment of HIV/AIDS.

Drug resistance is mainly caused by the high genetic diversity of HIV-1 and the continuous mutation it undergoes. This problem is being addressed with individualized therapy, whereby resistance testing is performed to select a combination of drugs that is most effective for each patient (5). In addition, side effects due to toxicities of the drugs are also a concern. There are reports that patients taking HAART experience increased rates of heart disease, diabetes, liver disease, cancer and accelerated aging. Most experts agree that these effects could be due to the HIV infection itself or co-infection with another virus, such as co-infection with hepatitis C virus resulting in liver disease. However, the toxicities resulting from the drugs used in HAART could also contribute to these effects.

Under current treatment, complete eradication of the virus from the body has not been possible. The major cause for this is that the virus resides in ‘latent reservoirs’ within memory CD4⁺ T cells and cells of the macrophage–monocyte lineage. A major study recently found that, in addition to acting as latent reservoirs, macrophages significantly contribute to the generation of elusive mutant viral genotypes by serving as the host for viral genetic recombination (6). The cells that harbor latent HIV are typically concentrated in specific anatomic sites, such as secondary lymphoid tissue, testes, liver, kidney, lungs, gut and the CNS. The eradication of the virus from such reservoirs is critical to the effective long-term treatment of HIV/AIDS patients.

Therefore, there is a great need to explore new approaches for developing nontoxic, lower-dosage treatment modalities that provide more sustained dosing coverage and effectively eradicate the virus from the reservoirs, avoiding the need for lifetime treatments.

Nanotechnology for HIV/AIDS treatment

The use of nanotechnology platforms for delivery of drugs is revolutionizing medicine in many areas of disease treatment.

Nanotechnology-based platforms for systemic delivery of antiretroviral drugs could have similar advantages.

Controlled-release delivery systems can enhance their half-lives, keeping them in circulation at therapeutic concentrations for longer periods of time. This could have major implications in improving adherence to the drugs.
Nanoscale delivery systems also enhance and modulate the distribution of hydrophobic and hydrophilic drugs into and within different tissues due to their small size. This particular feature of nanoscale delivery systems appears to hold the most promise for their use in clinical treatment and prevention of HIV. Specifically, targeted delivery of antiretroviral drugs to CD4⁺ T cells and macrophages as well as delivery to the brain and other organ systems could ensure that drugs reach latent reservoirs
Moreover, by controlling the release profiles of the delivery systems, drugs could be released over a longer time and at higher effective doses to the specific targets. Figure 1. Various nanoscale drug delivery systems.

Optional treatments:

Antiretroviral drugs
Gene Therapy
Immune Therapy
Prevention

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The use of nanotechnology systems for delivery of antiretroviral drugs has been extensively reviewed by Nowacek et al. and Amiji et al. (7,8).

In a recent study based on polymeric systems, nanosuspensions (200 nm) of the drug rilpivirine (TMC278) stabilized by polyethylene. A series of experiments by Dou et al. showed that nanosuspension of the drug indinavir can be stabilized by a surfactant system comprised of Lipoid E80 for effective delivery to various tissues. The indinavir nanosuspensions were loaded into macrophages and their uptake was investigated. Macrophages loaded with indinavir nanosuspensions were then injected intravenously into mice, resulting in a high distribution in the lungs, liver and spleen. More significantly, the intravenous administration of a single dose of the nanoparticle-loaded macrophages in a rodent mouse model of HIV brain infection resulted in significant antiviral activity in the brain and produced measureable drug levels in the blood up to 14 days post-treatment.polypropylene glycol (poloxamer 338) and PEGylated tocopheryl succinate ester (TPGS 1000) were studied in dogs and mice. A single-dose administration of the drug in nanosuspensions resulted in sustained release over 3 months in dogs and 3 weeks in mice, compared with a half-life of 38 h for free drug. These results serve as a proof-of-concept that nanoscale drug delivery may potentially lower dosing frequency and improve adherence.

Active targeting strategies have also been employed for antiretroviral drug delivery. Macrophages, which are the major HIV reservoir cells, have various receptors on their surface such as formyl peptide, mannose, galactose and Fc receptors, which could be utilized for receptor-mediated internalization. The drug stavudine was encapsulated using various liposomes (120–200 nm) conjugated with mannose and galactose, resulting in increased cellular uptake compared with free drug or plain liposomes, and generating significant level of the drug in liver, spleen and lungs. Stavudine is a water-soluble drug with a very short serum half-life (1 h). Hence, the increased cellular uptake and sustained release in the tissues afforded by targeted liposomes is a major improvement compared with free drug. The drug zidovudine, with half-life of 1 h and low solubility, was also encapsulated in a mannose-targeted liposome made from stearylamine, showing increased localization in lymph node and spleen. An important factor to consider here is that although most of the nucleoside drugs such as stavudine and zidovudine have short serum half-lives, the clinically relevant half-life is that of the intracellular triphosphate form of the drug. For example, despite zidovudine’s 1 h half-life in plasma, it is dosed twice daily based on intracellular pharmacokinetic and clinical efficacy data. Therefore, future nanotechnology-based delivery systems will have to focus in showing significant increase of the half-lives of the encapsulated drugs to achieve a less frequent dosing such as once weekly, once-monthly or even less.

Gene Therapy for HIV/AIDS

In addition to improving existing antiretroviral therapy, there are ongoing efforts to discover alternative approaches for treatment of HIV/AIDS. One promising alternative approach is gene therapy, in which a gene is inserted into a cell to interfere with viral infection or replication. Other nucleic acid-based compounds, such as DNA, siRNA, RNA decoys, ribozymes and aptamers or protein-based agents such as fusion inhibitors and zinc-finger nucleases can also be used to interfere with viral replication.

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RNAi is also considered to have therapeutic potential for HIV/AIDS. Gene silencing is induced by double stranded siRNA, which targets for destruction

he mRNA of the gene of interest. For HIV/AIDS, RNAi can either target the various stages of the viral replication cycle or various cellular targets involved in viral infection such as CD4, CCR5, and/or CXCR4, the major cell surface co-receptors responsible for viral entry. HIV replicates by reverse transcription to form DNA and uses the DNA to produce copies of its mRNA for protein synthesis; siRNA therapy could be used to knock down this viral mRNA. As with other gene therapy techniques, delivery of siRNA to specific cells and tissues has been the major challenge in realizing the potential of RNAi.

New nanotechnology platforms are tackling this problem by providing nonviral alternatives for effective and safe delivery. The first nontargeted delivery of siRNA in humans via self-assembling, cyclodextrin polymer-based nanoparticles for cancer treatment have recently entered Phase I clinical trials.

Although at an early stage, nonviral delivery of siRNA for treatment of HIV infection is also gaining ground. A fusion protein, with a peptide transduction domain and a double stranded RNA-binding domain, was used to encapsulate and deliver siRNA to T cells in vivo. CD4- and CD8-specific siRNA delivery caused RNAi responses with no adverse effects such as cyto-toxicity or immune stimulation. Similarly, a protamine-antibody fusion protein-based siRNA delivery demonstrated that siRNA knockdown of the gag gene can inhibit HIV replication in primary T cells.

Single-walled nanotubes were shown to deliver CXCR4 and CD4 specific siRNA to human T cells and peripheral blood mononuclear cells. Up to 90% knockdown of CXCR4 receptors and up to 60% knockdown of CD4 expression on T cells was observed while the knockdown of CXCR4 receptors on peripheral blood mononuclear cells was as high as 60%. In a separate study, amino-terminated carbosilane dendrimers (with interior carbon-silicon bonds) were used for delivery of siRNA to HIV-infected lymphocytes.

These pioneering studies demonstrate that nonviral siRNA delivery is possible for HIV/AIDS treatment. However, more work needs to be done in optimizing the delivery systems and utilizing designs for efficient targeting and intracellular delivery. The recent developments in polymer- and liposome-based siRNA delivery systems could be optimized for targeting cells that are infected with HIV, such as T cells and macrophages. Moreover, since HIV mutates and has multiple strains with different genetic sequences, combination siRNA therapy targeting multiple genes should be pursued. For these applications, nanotechnology platforms with capability for co-delivery and targeting need to be developed specifically for HIV-susceptible cells. A macrophage and T-cell-targeted and nanotechnology-based combination gene therapy may be a promising platform for efficient HIV/AIDS treatment.

Immunotherapy for HIV/AIDS

The various treatment approaches described above focus on treating HIV/AIDS by directly targeting HIV at the level of the host cell or the virus itself. An alternative approach is immunotherapy aimed at modulating the immune response against HIV. CD8⁺ cytotoxic T-cell responses to acute HIV infection appear to be relatively normal, while neutralizing antibody production by B cells is delayed or even absent.

Immunotherapy is a treatment approach involving the use of immunomodulatory agents to modulate the immune response against a disease. Similar to vaccines, it is based on immunization of individuals with various immunologic formulations; however, the purpose is to treat HIV-infected patients as opposed to protect healthy individuals (preventive vaccines will be discussed in an upcoming section). The various immunotherapy approaches for HIV/AIDS could be based on delivering cytokines (such as IL-2, IL-7 and IL-15) or antigens. The development of cellular immunity, and to a large degree humoral immunity, requires antigen-presenting cells (APCs) to process and present antigens to CD4⁺and CD8⁺ T cells. Dendritic cells (DCs) are the quintessential professional APCs responsible for initiating and orchestrating the development of cellular and humoral (antibody) immunity.

Various polymeric systems have been explored for in vivo targeting of DCs and delivery of small molecules, proteins or DNAs showing potential for immunotherapy. Poly(ethylene glycol) (PEG) stabilized poly(propylene sulfide) polymer nanoparticles accumulated in DCs in lymph nodes. Following nanoparticle injection, DCs containing nanoparticles accumulated in lymph nodes, peaking at 4 days with 40–50% of DCs and other APCs having internalized nanoparticles.

In another study, nanoparticles of the copolymer poly(D,L-lacticide-co-glycolide) (PLGA) showed efficient delivery of antigens to murine bone marrow-derived DCs in vitro, suggesting their potential use in immunotherapy. More recently, a very interesting work showed that HIV p24 protein adsorbed on the surface of surfactant-free anionic poly(D,L-lactide) (PLA) nanoparticles were efficiently taken-up by mouse DCs, inducing DC maturation. he p24-nanoparticles induced enhanced cellular and mucosal immune responses in mice. Although this targeting is seen in ex vivo-generated DCs and not in vivo DCs, the efficient delivery of the antigen to DCs through the nanoparticles is an important demonstration that may eventually be applied to in vivo DC targeting.

Clinical Trial

he most clinically advanced application of nanotechnology for immunotherapy of HIV/AIDS is the DermaVir patch that has reached Phase II clinical trials (9). DermaVir is a targeted nanoparticle system based on polyethyleimine mannose (PEIm), glucose and HIV antigen coding DNA plasmid formulated into nanoparticles (~100 nm) and administered under a patch after a skin preparation. The nanoparticles are delivered to epidermal Langerhans cells that trap the nanoparticles and mature to become highly immunogenic on their way to the lymph nodes. Mature DCs containing the nanoparticles present antigens to T cells inducing cellular immunity. Preclinical studies and Phase I clinical trials showed safety and tolerability of the DermaVir patch, which led the progression to Phase II trials. This is the first nanotechnology-based immunotherapy for HIV/AIDS that has reached the clinic and encourages further work in this area.

Table 1

Summary of nanotechnology-based treatment approaches for HIV/AIDS.

Type of therapy	Therapeutic agent (drug or gene)	Nanotechnology delivery platform	Development stage	Refs.
Antiretroviral therapy	Rilpivirine (TMC278)	Poloxamer 338/TPGS 1000	Preclinical	[35]
	Indinavir	Liposome-laden macrophages	Preclinical	[36–38]
	Stavudine	Mannose- and galactose-targeted liposome	Preclinical	[39–41]
	Zidovudine	Mannose-targeted liposome	Preclinical	[42]
	Efavirenz	Mannose-targeted dendrimer	Preclinical	[43,45]
	Lamivudine	Mannose-targeted dendrimer	Preclinical	[46]
Nanomaterials	Fullerene derivatives	–	Preclinical	[49–55]
	Dendrimers	–	Preclinical	[56,57]
	Silver nanoparticles	–	Preclinical	[58,59]
	SDC-1721/gold nanoparticles	Gold nanoparticles	Preclinical	[60]
Gene therapy	siRNA	Peptide fusion proteins, protamine–antibody fusion proteins, dendrimers, single walled carbon nanotubes, peptide–antibody conjugates	Preclinical	[77–81]
Immunotherapy	P24 protein	Poly (D,L-lactide) nanoparticles/dendritic cells	Preclinical	[98]
Immunotherapy	Plasmid DNA	Mannose-targeted polyethyleimine polymers	Phase II clinical trials	[99]

Note: to open the references in the table 1, please go to ref 1 in this post to see full ref info.

Nanotechnology for HIV/AIDS prevention

The search for a safe and effective HIV/AIDS vaccine has been challenging in the almost three decades since the discovery of the disease. Recently, high-profile clinical trial failures have prompted great debate over the vaccine research, with some suggesting the need for a major focus on fundamental research, with fewer efforts on clinical trials.

The major challenges in the development of a preventive HIV/AIDS vaccine have been the extensive viral strain and sequence diversity, viral evasion of humoral and cellular immune responses, coupled with the lack of methods to elicit broadly reactive neutralizing antibodies and cytotoxic T cells. The challenge associated with delivery of any exogenous antigen (such as nanoparticles) to APCs, is that exogenous antigens require specialized ‘cross-presentation’ in order to be presented by MHC class I and activate CD8⁺cytotoxic T cells.

his requirement for cytosolic delivery of antigens and cross-presentation represents yet another hurdle for HIV intracellular antigen vaccine, but potentially an advantage of nanodelivery. Humoral responses (neutralizing antibodies produced by B cells) are generated to intact antigen presented on the surface for the virus, or nanoparticles, but these humoral responses typically require ‘help’ from CD4⁺ T cells, but rather both. Nanoparticles have potential as adjuvants and delivery systems for vaccines. Table 2 present the different approaches.

Table 2

Summary of nanotechnology developments for prevention of HIV/AIDS.

Type of preventive agent	Antigen/adjuvant or drug	Nanotechnology platform	Development stage	Refs.
Protein or peptide vaccine	gp41, gp120, gp160, p24, Env, Gag, Tat	Liposomes, nanoemulsion, MF59, PLA nanoparticles, poly(γ-glutamic acid) nanoparticles	Preclinical	[108–111] [119–120] [122–125] [128–130]
DNA vaccine	env, rev, gag, tat, CpG ODN	Liposomes, nanoemulsion, PLA nanoparticles	Preclinical	[115,121]
Inactivated viral particle	Inactivated HIV viral particle	Polystyrene nanospheres	Preclinical	[126–127]
Microbicides	L-lysine dendrimer	L-lysine dendrimer	Phase I/II	[136–138]
		PLGA nanoparticles
	PSC-RANTES	PLGA	Preclinical	[139]
	siRNA	Nanoparticles, lipids, cholesterol conjugation	Preclinical	[141–144]

ODN: Oligonucleotides; PLA: Poly(D,L-lactide); PLGA: Poly(D,L-lacticide-co-glycolide).

Note: to open the references in the table 2, please go to ref 1 in this post to see full ref info.

Summary

Nanotechnology can impact the treatment and prevention of HIV/AIDS with various innovative approaches. Treatment options may be improved using nanotechnology platforms for delivery of antiretroviral drugs. Controlled and sustained release of the drugs could improve patient adherence to drug regimens, increasing treatment effectiveness.

While there is exciting potential for nanomedicine in the treatment of HIV/AIDS, challenges remain to be overcome before the potential is realized. These include toxicity of nanomaterials, stability of nanoparticles in physiological conditions and their scalability for large-scale production. These are challenges general to all areas of nanomedicine and various works are underway to tackle them.

Another important consideration in investigating nanotechnology-based systems for HIV/AIDS is the economic aspect, as the hardest hit and most vulnerable populations reside in underdeveloped and economically poor countries. In the case of antiretroviral therapy, nanotherapeutics may increase the overall cost of treatment, reducing the overall value. However, if the nanotherapeutics could improve patient adherence by reducing dosing frequency as expected, and furthermore, if they can eradicate viral reservoirs leading to a sterile immunity, these advantages may effectively offset the added cost.

Ref:

1. Mamo T, Moseman EA., Kolishetti N., Salvadoe-Morales C., Shi J., Kuritzkes DR., Langer R., von-Adrian U and Farokhzad OF. Emerging nanotechnology approaches for HIV/AIDS treatment and prevention. Nanomedicine (Lond) 2010; 5(2): 269-295.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2861897/

2. Merson MH. The HIV-AIDS pandemic at 25 – the global response. N Engl J Med.2006;354(23):2414–2417

3. Walensky RP, Paltiel AD, Losina E, et al. The survival benefits of AIDS treatment in the United States. J Infect Dis. 2006;194(1):11–19

4. Richman DD, Margolis DM, Delaney M, Greene WC, Hazuda D, Pomerantz RJ. The challenge of finding a cure for HIV infection. Science. 2009;323(5919):1304–1307)

5.Sax PE, Cohen CJ, Kuritzkes DR. HIV Essentials. Physicians’ Press; Royal Oak, MI, USA: 2007.

6. Lamers SL, Salemi M, Galligan DC, et al. Extensive HIV-1 intra-host recombination is common in tissues with abnormal histopathology. PLoS One. 2009;4(3):E5065.

7. Vyas TK, Shah L, Amiji MM. Nanoparticulate drug carriers for delivery of HIV/AIDS therapy to viral reservoir sites. Expert Opin Drug Deliv. 2006;3(5):613–628.

8. Amiji MM, Vyas TK, Shah LK. Role of nanotechnology in HIV/AIDS treatment: Potential to overcome the viral reservoir challenge. Discov Med. 2006;6(34):157–162

9. Lori F, Calarota SA, Lisziewicz J. Nanochemistry-based immunotherapy for HIV-1. Curr Med Chem. 2007;14(18):1911–1919

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Nanotechnology: Detecting and Treating metastatic cancer in the lymph node

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Imaging-based Cancer Patient Management, Nanotechnology for Drug Delivery, Pharmaceutical R&D Investment, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Technology Transfer: Biotech and Pharmaceutical, tagged Cancer - General, Cancer cell, cancer cell spread, Clinical Trials, contrast agents, Drug delivery, Fluorescence, ICG, imaging, indocyanine green (ICG), Lung cancer, Lymph node, lymph nodes, mapping, metastasis, nanoparticles, nanotechnology, near-Infrared Light (NIR), NIR, QDs, Quantom dots (QDs), Sentinel lymph node, sentinel lymph node (SLN), SLN on December 19, 2012| 6 Comments »

Author: Tilda Barliya PhD

Metastasis, the spread of cancer cells from a primary tumour to seed secondary tumours in distant sites, is one of the greatest challenges in cancer treatment today. For many patients, by the time cancer is detected, metastasis has already occurred. Over 80% of patients diagnosed with lung cancer, for example, present with metastatic disease. Few patients with metastatic cancer are cured by surgical intervention, and other treatment modalities are limited. Across all cancer types, only one in five patients diagnosed with metastatic cancer will survive more than 5 years. (1,2).

Metastatic Cancer

Metastatic cancer is cancer that has spread from the place where it first started to another place in the body.
Metastatic cancer has the same name and same type of cancer cells as the original cancer.
The most common sites of cancer metastasis are the lungs, bones, and liver.
Treatment for metastatic cancer usually depends on the type of cancer and the size, location, and number of metastatic tumors.

How do cancer cells spread (3)

Local invasion: Cancer cells invade nearby normal tissue.
Intravasation: Cancer cells invade and move through the walls of nearby lymph vessels or blood vessels.
Circulation: Cancer cells move through the lymphatic system and the bloodstream to other parts of the body.

The ability of a cancer cell to metastasize successfully depends on its individual properties; the properties of the noncancerous cells, including immune system cells, present at the original location; and the properties of the cells it encounters in the lymphatic system or the bloodstream and at the final destination in another part of the body. Not all cancer cells, by themselves, have the ability to metastasize. In addition, the noncancerous cells at the original location may be able to block cancer cell metastasis. Furthermore, successfully reaching another location in the body does not guarantee that a metastatic tumor will form. Metastatic cancer cells can lie dormant (not grow) at a distant site for many years before they begin to grow again, if at all.

Although cancer therapies are improving, many drugs are not reaching the sites of metastases, and doubt remains over the efficacy of those that do. Methods that are effective for treating large, well-vascularized tumours may be inadequate when dealing with small clusters of disseminated malignant cells.

We expect that the expanding capabilities of nanotechnology, especially in targeting, detection and particle trafficking, will enable novel approaches to treat cancers even after metastatic dissemination.

Lymph nodes, which are linked by lymphatic vessels, are distributed throughout the body and have an integral role in the immune response. Dissemination of cancer cells through the lymph network is thought to be an important route for metastatic spread. Tumor proximal lymph nodes are often the first site of metastases, and the presence of lymph node metastases signifies further metastatic spread and poor patient survival.

As such, lymph nodes have been targeted using cell-based nanotechnologies

Lymph nodes are small, bean-shaped organs that act as filters along the lymph fluid channels. As lymph fluid leaves the organ (such as breast, lung etc) and eventually goes back into the bloodstream, the lymph nodes try to catch and trap cancer cells before they reach other parts of the body. Having cancer cells in the lymph nodes suggests an increased risk of the cancer spreading. It is thus very important to evaluate the involvement of lymph nodes when choosing the best possible treatment for the patient.

Although current mapping methods are available such as CT and MRI scans, PET scan, Endobronchial Ultrasound, Mediastinoscopy and lymph node biopsy, sentinel lymph node (SLN) mapping and nodal treatment in lung cancer remain inadequate for routine clinical use.

Certain characteristics are associated with preferential (but not exclusive) nanoparticle trafficking to lymph nodes following intravenous administration.

Targeting is often an indirect process, as receptors on the surface of leukocytes bind nanoparticles and transfer them to lymph nodes as part of a normal immune response. Several strategies have been used to enhance nanoparticle uptake by leukocytes in circulation. Coating iron-oxide nanoparticles with carbohydrates, such as dextran, results in the increased accumulation of these nanoparticles in lymph nodes. Conjugating peptides and antibodies, such as immunoglobulin G (IgG), to the particle surface also increases their accumulation in the lymphatic network. In general, negatively charged particles are taken up at faster rates than positively charged or uncharged particles. Conversely, ‘stealth’ polymers, such as polyethylene glycol (PEG), on the surface of nanoparticles, can inhibit uptake by leukocytes, thereby reducing accumulation in the lymph nodes.

Lymph node targeting may be achieved by other routes of administration. Tsuda and co-workers reported that non-cationic particles with a size range of 6–34nm, when introduced to the lungs (intrapulmonary administration), are trafficked rapidly (<1 hour) to local lymph nodes. Administering particles <80 nm in size subcutaneously also results in trafficking to lymph nodes. Interestingly, some studies have indicated that non-pegylated particles exhibit enhanced accumulation in the lymphatics and that pegylated particles tend to appear in the circulation several hours after administration.

Over the last twenty years, sentinel lymph node (SLN) imaging has revolutionized the treatment of several malignancies, such has melanoma and breast cancer, and has the potential to drastically improve treatment in other malignancies, including lung cancer. Several attempts at developing an easy, reliable, and effective method for SLN mapping in lung cancer have been unsuccessful due to unique difficulties inherent to the lung and to operating in the thoracic cavity.

An inexpensive method offering rapid, intraoperative identification of SLNs, with minimal risk to both patient and provider, would allow for improved staging in patients. This, in turn, would permit better selection of patients for adjuvant therapy, thus reducing morbidity in those patients for whom adjuvant treatment is inappropriate, and ensuring that those who need this added therapy actually receive it. (http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109504/)

Current methods for SLN identification involve the use of radioactivity-guided mapping with technetium-99m sulfur colloid and/or visual mapping using vital blue dyes. Unfortunately these methods can be inadequate for SLN mapping in non-small cell lung cancer (NSCLC) The use of vital blue dyes is limited in vivo by poor visibility, particularly in the presence of anthracotic mediastinal nodes, thereby decreasing the signal-to-background ratio (SBR) that enables nodal detection. Similarly, results with technetium-99m sulfur colloid have been mixed when used in the thoracic cavity, where hilar structures and aberrant patterns of lymphatic drainage make detection more difficult.

Although Nomori et al. have reported an 83% nodal identification rate following a preoperative injection of technetium-99 colloid, there is an associated increased risk of pneumothorax and bleeding with this method. Further, the recently completed CALGB 140203 multicenter Phase 2 trial investigating the use of intraoperative technetium-99m colloid found an identification rate of only 51% with this technique. Clearly a technology with greater accuracy, improved SBR, and less potential risk to surgeon and patient would be welcome in the field of thoracic oncology.

Near-infrared (NIR) fluorescence imaging has the potential to meet this difficult challenge.

Near-Infrared Light

NIR light is defined as that within the wavelength range of 700 to 1000 nm. Although NIR light is invisible to the naked eye, it can be thought of as “redder” than UV and visible light.

Absorption, scatter, and autofluorescence are all significantly reduced at redder wavelengths. For instance, Hemoglobin, water, lipids, and other endogenous chromophores, such as melanin, have their lowest absorption within the NIR spectrum, which permits increased photon depth penetration into tissues
In addition, imaging can also be affected by photon scatter, which describes the reflection and/or deflection of light when it interacts with tissue. Scatter, on an absolute scale, is often ten-times higher than absorption. However, the two major types of scatter, Mie and Rayleigh, are both reduced in the NIR, making the use of NIR wavelengths especially important for the reduction of photon attenuation.
living tissue has extremely high “autofluorescence” in the UV and visible wavelength ranges due to endogenous fluorophores, such as NADH and the porphyrins. Therefore, UV/visible fluorescence imaging of the intestines, bladder, and gallbladder is essentially precluded. However, in the NIR spectrum, autofluorescence is extremely low, providing the black imaging background necessary for optimal detection of a NIR fluorophore within the surgical field
Additionally, optical imaging techniques, such as NIR fluorescence, eliminate the need for ionizing radiation. This, combined with the availability of a NIR fluorophore already FDA-approved for other indications and having extremely low toxicity (discussed below), make this a potentially safe imaging modality.

The main disadvantage is that it’s invisible to the human eye, requiring special imaging-systems to “see” the NIR fluorescence.

Currently there are three intraoperative NIR imaging systems in various stages of development:

The SPY system^™ (Novadaq, Canada) – utilizes laser light excitation in order to obtain fluorescent images. The Spy^™ system has been studied for imaging patency of vascular anastamoses following CABG and organ transplantation
The Photodynamic Eye^™(Hamamatsu, Japan) – is presently available only in Japan
The Fluorescence-Assisted Resection and Exploration (FLARE^™) system ()- developed by the authors’ laboratory utilizes NIR light-emitting diode (LED) excitation, eliminating the need for a potentially harmful laser. Additionally, the FLARE^™system has the advantage of being able to provide simultaneous color imaging, NIR fluorescence imaging, and color-NIR merged images, allowing the surgeon to simultaneously visualize invisible NIR fluorescence images within the context of surgical anatomy.

Near-Infrared Fluorescent Nanoparticle Contrast Agents

The ideal contrast agent for SLN mapping would be anionic and within 10–50 nm in size in order to facilitate rapid uptake into lymphatic vessels with optimal retention within the SLN.

Due to the lack of endogenous NIR tissue fluorescence, exogenous contrast agents must be administered for in vivo studies. The most important contrast agents that emit within the NIR spectrum are the heptamethine cyanines fluorophores, of which indocyanine green (ICG) is the most widely used, and fluorescent semiconductor nanocrystals, also known as quantum dots (QDs).

ICG is an extremely safe NIR fluorophore, with its only known toxicity being rare anaphylaxis. The dye was FDA approved in 1958 for systemic administration for indicator-dilution studies including measurements of cardiac output and hepatic function. Additionally, it is commonly used in ophthalmic angiography. When given intravenously, ICG is rapidly bound to plasma albumin and cleared from the blood via the biliary system. Peak absorption and emission of ICG occur at 780 nm and 830 nm respectively, within the window where in vivo tissue absorption is at its minimum. ICG has a relatively neutral charge, has a hydrodynamic diameter of only 1.2 nm, and is relatively hydrophobic. Unfortunately, this results in rapid transport out of the SLN and relatively low fluorescence yield, thereby decreasing its efficacy in mapping techniques. However, noncovalent adsorption of ICG to human serum albumin (HSA), as occurs within plasma, results in an anionic nanoparticle with a diameter of 7.3 nm and a three-fold increase in fluorescence yield markedly improving its utility in SLN mapping.
QDs consist of an inorganic heavy metal core and shell which emit within the NIR spectrum. This structure is then surrounded by a hydrophilic organic coating which facilitates aqeuous solubility and lymphatic distrubtion. QDs have been extensively studied and are ideal for SLN mapping as their hydrodynamic diameter can be customized to the appropriate size within a narrow distribution (15–20 nm), they can be engineered to have an anionic surface charge, and exhibit an extremely high SBRs with significant photostability. Unfortunately, safety concerns due to the presence of heavy metals within the QDs so far have precluded clinical application

Human Clinical Trials and NIR SLN mapping

Several studies have investigated the clinical use of indocyanine green without adsorption to HSA for NIR fluorescence-guided SLN mapping in breast and gastric cancer with good success (9-13).

Kitai et al. first examined this technique in 2005 in breast cancer patients, and was able to identify a SLN node in 17 of 18 patients using NIR fluorescence rather than the visible green color of ICG (9). Sevick-Muraca et al. reported similar results using significantly lower microdoses of ICG (10 – 100 μg), successfully identifying the SLN in 8 of 9 patients (11). Similar to these subcutaneous studies, 56 patients with gastric cancer underwent endoscopic ICG injection into the submucosa around the tumor 1 to 3 days preoperatively or injection directly into the subserosa intraoperatively with identification of the SLN in 54 patients (13).

Recently, Troyan et al. have completed a pilot phase I clinical trial examining the utility of NIR imaging the ICG:HSA nanoparticle fluorophore for SLN mapping/biopsy in breast cancer using the FLARE^™system. In this study, 6 patients received both ^99mTc-sulfur colloid lymphoscintigraphy along with ICG:HSA at micromolar doses. SLNs were identified in all patients using both methods. In 4 of 6 patients the SLNs identified were the same, while in the remaining two, lymphoscintigraphy identified an additional node in one patient and ICG:HSA identified an additional SLN in the other. Irrespective, this study demonstrates that NIR SLN mapping with low dose ICG:HSA is a viable method for intraoperative SLN identification.

Nanotechnology and Drug Delivery in Lung cancer

We previously explored Lung cancer and nanotechnology aspects as polymer nanotechnology has been an area of significant research over the past decade as polymer nanoparticle drug delivery systems offer several advantages over traditional methods of chemotherapy delivery

see: (15) http://pharmaceuticalintelligence.com/2012/11/08/lung-cancer-nsclc-drug-administration-and-nanotechnology/ (16) http://pharmaceuticalintelligence.com/2012/12/01/diagnosing-lung-cancer-in-exhaled-breath-using-gold-nanoparticles/

As the importance of micrometastatic lymphatic spread of tumor becomes clearer, there has been much interest in the use of nanoparticles for lymphatic drug delivery. The considerable focus on developing an effective method for SLN mapping for lung cancer is indicative of the importance of nodal spread on overall survival.

Our lab is investigating the use of image-guided nanoparticles engineered for lymphatic drug delivery. We have previously described the synthesis of novel, pH-responsive methacrylate nanoparticle systems (14). Following a simple subcutaneous injection of NIR fluorophore-labeled nanoparticles 70 nm in size, we have shown that we can deliver paclitaxel loaded within the particles to regional draining lymph nodes in several organ systems of Yorkshire pigs while simultaneously confirming nodal migration using NIR fluorescent light. Future studies will need to investigate the ability of nanoparticles to treat and prevent nodal metastases in animal cancer models. Additionally, the development of tumor specific nanoparticles will potentially allow for targeting of chemotherapy to small groups of metastatic tumor cells further limiting systemic toxicities by narrowing the delivery of cytotoxic drugs.

Ref:

1. http://www.nature.com.rproxy.tau.ac.il/nrc/journal/v12/n1/pdf/nrc3180.pdf

2. http://www.nature.com/nrc/focus/metastasis/index.html

3. http://www.cancer.gov/cancertopics/factsheet/Sites-Types/metastatic

4. http://www.cancerresearchuk.org/cancer-help/about-cancer/what-is-cancer/body/the-lymphatic-system

5. http://www.macmillan.org.uk/Cancerinformation/Cancertypes/Lymphnodessecondary/Secondarycancerlymphnodes.aspx

6. Khullar O, Frangioni JV and Colson YL. Image-Guided Sentinel Lymph Node Mapping and Nanotechnology-Based Nodal Treatment in Lung Cancer using Invisible Near-Infrared Fluorescent Light. Semi Thorac Cardiovasc Surg 2009 :21 (4); 309-315. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3109504/

7. Stacker SA, Achen MG, Jussila L, Baldwin ME and Alitalo K. Metastasis: Lymphangiogenesis and cancer metastasis. Nature Reviews Cancer 2002 2, 573-583. http://www.nature.com/nrc/journal/v2/n8/full/nrc863.html

8. Schroeder A., Heller DA., Winslow MM., Dahlman JE., Pratt GW., Langer R., Jacks T and Anderson DG.. Nature Reviews Cancer 2012; 12(1), 39-50. Treating metastatic cancer with nanotechnology. http://www.nature.com.rproxy.tau.ac.il/nrc/journal/v12/n1/pdf/nrc3180.pdf

http://www.nature.com.rproxy.tau.ac.il/nrc/journal/v12/n1/full/nrc3180.html

9. Kitai T, Inomoto T, Miwa M, et al. Fluorescence navigation with indocyanine green for detecting sentinel lymph nodes in breast cancer. Breast Cancer. 2005;12:211–215.

10. Ogasawara Y, Ikeda H, Takahashi M, et al. Evaluation of breast lymphatic pathways with indocyanine green fluorescence imaging in patients with breast cancer. World journal of surgery.2008;32:1924–1929.

11. Sevick-Muraca EM, Sharma R, Rasmussen JC, et al. Imaging of lymph flow in breast cancer patients after microdose administration of a near-infrared fluorophore: feasibility study. Radiology.2008;246:734–741.

12. Miyashiro I, Miyoshi N, Hiratsuka M, et al. Detection of sentinel node in gastric cancer surgery by indocyanine green fluorescence imaging: comparison with infrared imaging. Ann Surg Oncol.2008;15:1640–1643.

13. Tajima Y, Yamazaki K, Masuda Y, et al. Sentinel node mapping guided by indocyanine green fluorescence imaging in gastric cancer. Ann Surg. 2009;249:58–62.

14. Griset AP, Walpole J, Liu R, et al. Expansile nanoparticles: synthesis, characterization, and in vivo efficacy of an acid-responsive drug delivery system. J Am Chem Soc. 2009;131:2469–2471

15. http://pharmaceuticalintelligence.com/2012/11/08/lung-cancer-nsclc-drug-administration-and-nanotechnology/

16. http://pharmaceuticalintelligence.com/2012/12/01/diagnosing-lung-cancer-in-exhaled-breath-using-gold-nanoparticles/

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Nanotech Therapy for Breast Cancer

Posted in Biomarkers & Medical Diagnostics, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Cell Biology, Signaling & Cell Circuits, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Nanotechnology for Drug Delivery, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Technology Transfer: Biotech and Pharmaceutical, tagged breast cancer, Clinical trial, CYT-6091, nanotechnology, PEG-Thiol, phase I, TNFalpha, Tumor necrosis factors on December 9, 2012| 16 Comments »

Nanotech Therapy for Breast Cancer

Author/ Curator ; Tilda Barliya PhD

Breast cancer is the second most common cancer worldwide after lung cancer, the fifth most common cause of cancer death, and the leading cause of cancer death in women. The global burden of breast cancer exceeds all other cancers and the incidence rates of breast cancer are increasing (Jemel. A CA cancer J Clin 2010:60; 277-300). (Nature Reviews Clinical Oncology to coincide with the 2010 San Antonio Breast Cancer Symposiumhttp://www.nature.com/nrclinonc/focus/breast-cancer/index.html).

The heterogeneity of breast cancers makes them both a fascinating and challenging solid tumor to diagnose and treat. Triple-negative breast cancers in particular are difficult to define—this tumor subgroup lacks expression of HER2, the estrogen receptor and progesterone receptor and do not respond to hormonal therapies or HER2-targeted therapies (owing to the lack of expression of these targets)—and these tumors are associated with a poor prognosis; thus, new systemic therapies are desperately needed. Luca Gianni and coauthors review the evidence for the biology of this subtype, which shares genetic and morphologic similarities with the basal-like breast cancer subtype but also represents a biologically distinct subtype that is heterogeneous. They also discuss potential treatment options, including poly(ADP ribose) polymerase (PARP) inhibitors, which have shown promising efficacy and safety profiles in phase I and II clinical trials in patients with triple-negative breast cancer.

Breast cancers with a BRCA mutation leave the cell susceptible such that PARP inhibition combined with this genetic defect cannot repair DNA breaks resulting in cell death—an effect not observed in normal cells because the BRCA function compensates for PARP inhibition. Importantly, BRCA deficiency and sensitivity to PARP inhibition does not seem to be restricted to a particular histology but rather the BRCA genotype.

One of the greatest issues in oncology is tumor heterogeneity as well as the detection and validation of biomarkers that can aid in treatment decisions. As breast cancers represent a multitude of different diseases with intratumoral and intertumoral genetic and epigenetic alterations, the next challenge will be to understand how these defects arise during disease progression and learn more about the development of mechanisms of resistance to therapies. (Nature Reviews Clinical Oncology to coincide with the 2010 San Antonio Breast Cancer Symposiumhttp://www.nature.com/nrclinonc/focus/breast-cancer/index.html).

Generally, breast tumors are categorized into four different stages based upon their size, location, and evidence of metastasis (www.cancer.org). Treatment options are also determined by the stage, hormone (ER/PR), human epidermal growth factor receptor 2 (HER-2/neu) and gene (BRCA1) Status of breast tumors.

Many different types of nano-delivery systems with different materials and physio-chemical properties have been developed for application in breast cancer. We previously discussed in depth the application of liposomal doxorubicin, albumin-bound paclitaxel (Abraxane) and I’d like to shift the discussion to a completely different player in breast cancer progression TNF alpha.

TNF-α

Tumor necrosis factor-α (TNF-α) is an important pro-inflammatory cytokine in the development and progress in human cancer and was shown to induce mammary tumors through through the activation of p42/p44 MAPK, JNK, PI3-K/Akt pathways (http://www.ncbi.nlm.nih.gov/pubmed/18061162), (http://www.ncbi.nlm.nih.gov/pubmed/21476000). Among its roles, TNF-α is thought to be pro-angiogenic. Paradoxically, it is also a potent anti-vascular cytokine at higher doses (it was named for its anti-tumor activity) and can be used clinically to destroy tumor vasculature. More so TNF-alpha is able to initiate cellular apoptosis and it is possible that these apoptotic pathways are deactivated in tumor cells (http://jbiol.com/content/8/9/85)

Unfortunately, TNF-α has powerful and toxic systemic side effects and has only limited uses at present. Much work is under way to devise ways of targeting TNF-α specifically to tumors.

A nanoparticle delivery system, consisting of PEG coated gold nanoparticle loaded with TNF-α, was constructed to maximize the tumor damage and minimize the systemic toxicity of TNF-α (Visaria et al 2006; Visaria RK, Griffi n RJ, Williams BW, et al. 2006. Enhancement of tumor thermal therapy using gold nanoparticle-assisted tumor necrosis factoralpha delivery. Mol Cancer Ther, 5:1014–20). Combination of local heating and nanoparticle-based delivery of TNF-α resulted in enhanced therapeutic effi cacy than either treatment alone.

Thermally-induced tumor growth delay was enhanced by pretreatment with the nanoparticle, when given intravenously at the proper dosage and timing. Tumor blood fl ow suppression, as well as tumor perfusion defects, suggested vascular damage-mediated tumor cell killing. Surprisingly, following intravenous administration, little to no accumulation in the RES (eg, liver and spleen) or other healthy organs of the animals was observed (Paciotti et al 2004).

Phase I clinical trials of this conjugate, subsequently termed “CYT-6091” also known as Aurmine (CytImmune Scientific Inc)(http://www.cytimmune.com/go.cfm?do=page.view&pid=26) are currently ongoing to evaluate its safety, pharmacokinetics, and clinical efficacy.(Visaria et al 2007; Visaria R, Bischof JC, Loren M, et al. 2007. Nanotherapeutics for enhancing thermal therapy of cancer. Int J Hyperthermia, 23:501–11.), (www.cytimmune.com/download/posters/ASCO_Poster.pdf)

Both TNF-a and thiolated polyethylene glycol (PEG-Thiol) are independently bound to the surface of 27 nm colloidal gold particles.

Clinical Trial Protocol:

Aim: CYT-6091 was tested in a phase I open label trial in solid tumor, advanced stage patients.

Patients (n = 3/dose), admitted to the NIH Clinical Center ICU, received two IV injections of CYT-6091 on day 0 and 14. Dosing started at 50 µg/m2 of TNF, up to 600 µg/m2. Vital signs were monitored and blood samples were drawn over 48 h.

The primary endpoint of the study was to determine the MTD for CYT-6091.
Secondary endpoints included PK, disease response (staged 45 days post treatment by RECIST), and the detection of gold nanoparticles in tumors and in adjacent healthy tissue.

Results:

Twenty-nine patients were treated. Even at the lowest dose (50 µg/m2), patients exhibited a febrile response, which was mitigated by acetaminophen and indomethacin pretreatment. None of the 29 patients treated with doses of 50-600 µg/m2 showed a DLT hypotensive response, and in fact, no DLT was seen.
T1/2 estimates for TNF, administered as CYT-6091, are 120, 131, 127, 146, 112, 113, 266, 371, and 160 minutes for 50, 100, 150, 200, 250, 300, 400, 500, 600 µg/m2, respectively (published T1/2 for native TNF is ~27 minutes).
In the 28 patients eligible for response assessment, there was 1 PR (100 µg/m2 dose, 7 months duration) and 3 SD (2, 2, and 3 months duration). Electron micrographs show gold nanoparticles in tumor biopsies

Conclusions:

CYT-6091 is well tolerated at doses up to 600 µg/m2 of TNF, levels 3-times greater than the published MTD for native TNF. CYT-6091 targets tumors in humans. Efficacy studies in combination with chemotherapy are planned.

In summary, the phase I clinical trial used solid tumor patients to evaluate the safety of its use, breast cancer oncologists however, set their eyes on the target.

Ref:

1. Jemel. A CA cancer J Clin 2010:60; 277-300

2. Nature Reviews Clinical Oncology to coincide with the 2010 San Antonio Breast Cancer Symposiumhttp://www.nature.com/nrclinonc/focus/breast-cancer/index.html

3. Visaria RK, Griffi n RJ, Williams BW, et al. 2006. Enhancement of tumor thermal therapy using gold nanoparticle-assisted tumor necrosis factoralpha delivery. Mol Cancer Ther, 5:1014–20

4. Visaria R, Bischof JC, Loren M, et al. 2007. Nanotherapeutics for enhancing thermal therapy of cancer. Int J Hyperthermia, 23:501–11.

5. http://nano.gov/sites/default/files/nanomedicine_-_tamarkin.pdf

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Diagnosing Lung Cancer in Exhaled Breath using Gold Nanoparticles

Posted in Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, BioSimilars, CANCER BIOLOGY & Innovations in Cancer Therapy, Chemical Biology and its relations to Metabolic Disease, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Medical Devices R&D Investment, Nanotechnology for Drug Delivery, Personalized and Precision Medicine & Genomic Research, Population Health Management, Genetics & Pharmaceutical, Technology Transfer: Biotech and Pharmaceutical, tagged biomarkers, diagnostics, exhaled breath, Gas chromatography, gold nanoparticles, Lung cancer, nanotechnology, sensors, tests, volatile organic compounds (VOCs) on December 1, 2012| 8 Comments »

Diagnosing Lung Cancer in Exhaled Breath using Gold Nanoparticles

Reporter-curator: Tilda Barliya PhD

Authors: Gang Peng, Ulrike Tisch, Orna Adams¹, Meggie Hakim, Nisrean Shehada, Yoav Y. Broza, Salem Billan, Roxolyana Abdah-Bortnyak, Abraham Kuten & Hossam Haick. (NATURE NANOTECHNOLOGY | VOL 4 | OCTOBER 2009 |)

Abstract:

Conventional diagnostic methods for lung cancer1,2 are unsuitable for widespread screening, because they are expensive and occasionally miss tumours. Gas chromatography/mass spectrometry studies have shown that several volatile organic compounds, which normally appear at levels of 1–20 ppb in healthy human breath, are elevated to levels between 10 and 100 ppb in lung cancer patients. Here we show that an array of sensors based on gold nanoparticles can rapidly distinguish the breath of lung cancer patients from the breath of healthy individuals in an atmosphere of high humidity. In combination with solidphase microextraction, gas chromatography/mass spectrometry was used to identify 42 volatile organic compounds that represent lung cancer biomarkers. Four of these were used to train and optimize the sensors, demonstrating good agreement between patient and simulated breath samples. Our results show that sensors based on gold nanoparticles could form the basis of an inexpensive and non-invasive diagnostic tool for lung cancer. (http://www.nature.com/nnano/journal/v4/n10/abs/nnano.2009.235.html) (lnbd.technion.ac.il/NanoChemistry/SendFile.asp?DBID=1…1…)

Introduction:

Lung cancer accounts for 28% of cancer-related deaths. Approximately 1.3 million people die worldwide every year. Breath testing is a fast, non-invasive diagnostic method that links specific volatile organic compounds (VOCs) in exhaled breath to medical conditions. Gas chromatography/mass spectrometry (GC-MS), ion flow tube mass spectrometry10, laser absorption spectrometry,infrared spectroscopy, polymer-coated surface acoustic wave sensors and coated quartz crystal microbalance sensors have been used for this purpose. However, these techniques are expensive, slow, require complex instruments and, furthermore, require pre-concentration of the biomarkers (that is, treating the biomarkers by a process to increase the relative concentration of the biomarkers to a level that can be detected by the specific technique) to improve detection.

Here, we report a simple, inexpensive, portable sensing technology to distinguish the breath of lung cancer patients from healthy subjects without the need to pre-treat the exhaled breath in any way (see also refs 14–16 for the diagnosis of lung cancer by sensing technology that is based on arrays of polymer/carbon black sensors). Our study consisted of four phases and included volunteers aged 28–60 years. Samples were collected from 56 healthy controls and 40 lung cancer patients after clinical diagnosis using conventional methods and before chemotherapy or other treatment.

In the first phase, we collected exhaled alveolar breath of lung cancer patients and healthy subjects using an ‘offline’ method. This method was designed to avoid potential errors arising from the failure to distinguish endogenous compounds from exogenous ones in the breath and to exclude nasal entrainment of the gas. Exogenous VOCs can be either directly absorbed through the lung via the inhaled breath or indirectly through the blood or skin. Endogenous VOCs are generated by cellular biochemical processes in the body and may provide insight into the body’s function

In the second phase, we identified the VOCs that can serve as biomarkers for lung cancer in the breath samples and determined their relative compositions, using GC-MS in combination with solidphase microextraction (SPME). GC-MS analysis identified over 300–400 different VOCs per breath sample, with .87% reproducibility for a specific volunteer examined multiple times over a period of six months. Forward stepwise discriminant analysis identified 33 common VOCs that appear in at least 83% of the patients but in fewer than 83% of the healthy subjects

The compounds that were observed in both healthy breath and lung cancer breath were presented not only at different concentrations but also in distinctively different mixture compositions.

Further forward stepwise discriminant analysis revealed nine uncommon VOCs that appear in at least 83% of the patients but not in the majority (83%) of healthy subjects. This additional class of VOCs has not been recognized in earlier GC-MS studies.

In spite of these advances in the GC-MS analysis, these data certainly do not account for all the VOCs present in the exhaled breath samples, because the pre-concentration technique can be thought of as a solid phase that extracts only part of the analytes present in the examined phase and, subsequently, releases only part of the extracted analytes.

So, it is likely that the actual mixture of VOCs to which, for example, an array of gold nanoparticle sensors would be responding is different from that obtained by GC-MS.

In the third phase of this study we designed an array of nine crossreactive chemiresistors, in which each sensor was widely responsive to a variety of odorants for the detection of lung cancer by means of breath testing. We used chemiresistors based on assemblies of 5-nm gold nanoparticles with different organic functionalities (dodecanethiol, decanethiol, 1-butanethiol, 2-ethylhexanethiol, hexanethiol, tert-dodecanethiol, 4-methoxy-toluenethiol, 2-mercaptobenzoxazole and 11-mercapto-1-undecanol).

Chemiresistors based on functionalized gold nanoparticles combine the advantages of organic specificity with the robustness and processability of inorganic materials.

The response of the nine-sensor array to both healthy and lung cancer breath samples was analysed using principal component analysis . It can be seen that there is no overlap of the lung cancer and healthy patterns.

The PCA of the healthy control group revealed that the set of gold nanoparticles sensors was not influenced by characteristics such as gender, age or smoking habits, thus strengthening the ability of the sensors to discriminate between healthy and cancerous breath. Experiments with a wider population of volunteers to thoroughly probe the influence of diet, alcohol consumption,metabolic state and genetics are under way and will be published elsewhere.

Summary:

To summarize, we have demonstrated that an array of chemiresistors based on functionalized gold nanoparticles in combination with pattern recognition methods can distinguish between the breath of lung cancer patients and healthy controls, without the need for dehumidification or pre-concentration of the lung cancer biomarkers. Our results show great promise for fast, easy and cost-effective diagnosis and screening of lung cancer. The developed devices are expected to be relatively inexpensive, portable and amenable to use in widespread screening, making them potentially valuable in saving millions of lives every year. Given the impact of the rising incidence of cancer on health budgets worldwide, the proposed technology will be a significant saving for both private and public health expenditures. The potential exists for using the proposed technology to diagnose other conditions and diseases, which could mean additional cost reductions and enhanced opportunities to save lives.

Ref:

1. Gang Peng, Ulrike Tisch, Orna Adams, Meggie Hakim, Nisrean Shehada, Yoav Y. Broza, Salem Billan, Roxolyana Abdah-Bortnyak, Abraham Kuten& Hossam Haick. Diagnosing lung cancer in exhaled breath using gold nanoparticles. Nature Nanotechnology 4, 669 – 673 (2009) http://www.nature.com/nnano/journal/v4/n10/abs/nnano.2009.235.html

2. http://lungcancer.about.com/od/diagnosisoflungcancer/a/diagnosislungca.htm

3. http://metabolomx.com/2011/12/15/metabolomx-test-detects-lung-cancer-from-breath/

4. http://www.chestnet.org/accp/pccsu/medical-applications-exhaled-breath-analysis-and-testing?page=0,3

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Nanotechnology Tackles Brain Cancer

Author: Tilda Barliya PhD

Primary malignant central nervous system (CNS) tumors only represent about 2% of all cancers. But treatment is elusive. Tumors may be embedded in regions of the brain that are critical to orchestrating the body’s vital functions, while they shed cells to invade other parts of the brain, forming more tumors too small to detect using conventional imaging techniques. Brain cancer’s location and ability to spread quickly makes treatment with surgery or radiation like fighting an enemy hiding out among minefields and caves, and explains why the term “brain cancer” is all too often associated with the word “inoperable.” Nanotechnology may alter this situation. It offers a new promise for cancer diagnosis and treatment. This emerging technology, by developing and manufacturing materials using atomic and molecular elements, can provide a platform for the combination of diagnostics, therapeutics and delivery to the tumor, with subsequent monitoring of the response. This review focuses on recent developments in cancer nanotechnology with particular attention to nanoparticle systems, important tools for the improvement of drug delivery in brain tumor.

Making treatment even more challenging, there is a system of blood vessels and protective cells in the brain — the blood brain barrier — that admits only essential nutrients and oxygen, and keeps out everything else, including about 95 percent of all drugs. This natural barrier puts serious limits on how much a patient can benefit from traditional chemotherapy and new cancer drugs.

The blood-brain barrier permits the exchange of essential nutrients and gases between the bloodstream and the brain, while blocking larger entities such as microbes, immune cells and most drugs from entering. This barrier system is a perfectly logical arrangement, since the brain is the most sensitive and complex organ in the human body and it would not make sense for it to become the battleground of infection and immune response.

This biological “demilitarization zone” is enforced by an elaborate and dense network of capillary vessels that feeds the brain and removes waste products. Each capillary vessel is bound by a single layer of endothelial cells, connected by “tight junctions,” thereby making it very difficult for most molecules to exit the capillaries and permeate into the brain. Instead of “leaking” material, brain capillary walls closely regulate the flow of material using molecular pumps and receptors that recognize and transport nutrients such as glucose, nucleosides, and specific proteins into the brain. In other words, substances need to be pre-recognized to enter.

Since most drugs. including old-school chemotherapy, can not cross the BBB it very hard to treat brain-tumor patients. In certain conditions such as grade IV glioblastoma, the BBB is loosened up (becomes more permeable due to changes in the gene expression and tight-junction protein expression, making the cross over of materials much easier. Having said that, the loosened up BBB represent a double-edge sword as it not only allows the transfer of drugs but allow the escape of metastatic tumor cells.

Therefore, in order to enable drugs to enter the brain regardless of the presence of the BBB, nanotechnology has designed drugs that used the already-existing transporters located at the barrier. Among them are: glucose transporter, transferrin transporter and LDL receptor.

Trojan Horse approach:

Nanoparticles have excellent potential as carriers of drugs, because if they are small enough, they can penetrate the BBB. That way, a treatment could be injected into the bloodstream rather than performing surgery to insert it. Many researchers are exploring using nanoparticles in the manner of a Trojan horse, to carry treatments including chemotherapy, gene therapy, or immune boosters into the brain. As impressive as it may sound, receptor uptake of nanocarriers (Trojan horses) have also limitations; this can limit the amount of therapy one person can have—if all of the receptors are taken up (filled) no more of the drug could get in.

Some of these extensive beautiful work conducted by several research labs including Dr. Raoul Kopleman, Dr. Miqin Zhang and Dr. Panos Fatouros are summaried in this article “Nanotechnology Tackles Brain Tumors” (http://www.fightplga.org/files/monthly_feature_2005_dec.pdf).

I’d like to shift the discussion to FDA/EU-approved nanomedicine to treat brain tumors.

Using nanomedicines to treat brain tumors was first proposed more than three decades ago . Currently there is one nanoparticle treatment available to people with hard brain tumors: Nano-Therm therapy. Available at a clinic in Berlin, the treatment has been through trials in humans to demonstrate its safety and effectiveness. (http://www.dana.org/news/brainwork/detail.aspx?id=35524)

In the study, 59 patients with recurring glioblastoma treated with Nano-Therm therapy survived a median time of more than 13 months—more than double the control group, published in Neuro-Oncology in 2010. The EU approved the treatment developed by Magforce, in July 2010.

Nano-Therm uses “thermotherapy,” which involves surgery to insert a liquid containing 15 nanometer-wide magnetic particles into the brain tumor. Next, the patient being treated lies in a machine that emits an alternating magnetic field. This causes the nanoparticles, which have an iron oxide core, to oscillate, penetrating the tumor cells. The longer the magnetic field is on, the warmer the nanoparticles grow. Doctors can take the heat up to about 45 degrees Celsius, where the tumor cells are primed for chemotherapy or radiotherapy, or even higher, which can destroy the tumor cells. It important thought to ensure that normal brain cells are not affected.

The main aim is to build a multifunctional nano-carrier; one that contains 3 aspects :

A target moiety- that will guide the nanoparticle (NP) to the brain tumors. Preferably will use a specific receptor to penetrate through the BBB.
An imaging agent- that will enable visualization of the target ” i.e brain rumor” . MRI contrast agent are good such as gadolinium, fluorescent probes and quantum dots are good candidates.
A destructive drug/toxin- that will eliminate the tumor cells.

In summary:

Nanotechnology has huge potential and a long way to go, thought there is a growing consensus that brain cancer is a problem in need of a radically different solution, and that nanotechnology fits the bill. Functionalized nanoparticles could provide precision detection, targeted treatment, and real-time tracking that conventional technology lacks. For a disease in which only 5 percent to 32 percent of patients are likely to survive after five years, large hope is riding on the potential success of “small” technology.

Ref:

Click to access monthly_feature_2005_dec.pdf

http://www.nanowerk.com/spotlight/spotid=6269.php#axzz2D4yx1btl

Click to access amiji.pdf

http://www.dana.org/news/brainwork/detail.aspx?id=35524

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