Posts Tagged ‘CXCR4’

Are CXCR4 Antagonists Making a Comeback in Cancer Chemotherapy?

Reporter: Stephen J. Williams, Ph.D.

Biospace News reported that Massachusetts based X4 Pharmaceuticals is using $34B to launch two clinical trials on its CXCR4 inhibitor X4P-001 in refractory clear cell renal cell carcinoma and refractory epithelial ovarian cancer.

The full report is below:

X4 Pharma Uses $37.5 Million to Push Cancer Therapies into Human Trials


December 14, 2015
By Alex Keown, Breaking News Staff

CAMBRIDGE, Mass. – Massachusetts based X4 Pharmaceuticals is beginning human trials for its oncology program using CXCR4 inhibitors, the Boston Business Journal reported this morning.

After spending years in stealth mode, the company, helmed by former Genzyme executives, is launching two clinical two clinical studies initiating in 2016 in refractory clear cell renal cell carcinoma and refractory epithelial ovarian cancer with its lead drug candidate, X4P-001.

The company’s pipeline is based on drug compounds that originate from a portfolio of oral CXCR4 inhibitors exclusively licensed from Sanofi (SNY), X4 said in a statement. Inhibition of CXCR4, a receptor over-expressed in many cancers, is designed to block non-cancerous immuno-suppressive and pro-angiogenic cells from populating the tumor, thereby disrupting the cancer microenvironment and restoring normal immune surveillance functions. The novel mechanism of CXCR4 inhibition increases the ability of T-Cells to track and destroy cancer. X4 is leveraging its CXCR4 research against past experience working with Genzyme’s plerixafor, which is also a CXCR4 blocker.

In an interview with the Journal, Paula Ragan, X4’s chief executive officer, said the CXCR4 protein “acts as a beacon to attract cells to surround a tumor, effectively hiding the tumor from the body’s T cells that would otherwise destroy them.” Developing a therapy to block the protein will prevent the tumors from hiding and allow it to be treated.

Ragan said the Phase Ia trial for X4P-001 will test safety and dosage in a small trial of about 20 people, the Journal reported. If all goes well the company would start a Phase 2a trial by the end of 2016 in around 50 or 60 patients, the Journal said.

In September, Ragan said a CXCR4 antagonist could potentially be paired with promising oncology drugs like Merck & Co. (MRK)’s Keytruda, or Bristol-Myers Squibb (BMY)’s Opdivo. Keytruda has been shown to be effective in treating patients with three types of cancer, melanoma, lung cancer and mesothelioma. Opdivo is a treatment of patients with metastatic squamous non-small cell lung cancer (NSCLC) with progression on or after platinum-based chemotherapy.

The cytokines and cytokine receptors have been investigated before for their utility as a chemotherapeutic target as they are highly expressed on tumors and promote metastasis. The general idea was that tumor cells secrete cytokines which promote their growth and metastases and attract immune cells which also secrete growth-promoting cytokines. Many tumor types have shown increased expression of these cytokines and cytokine receptors. However only some development efforts have shown promise, there have been no approved drugs in this class. As written in a previous post (Tumor Associated Macrophages: The Double-Edged Sword Resolved?), there could be many biological reasons for this, as well as difficulties in interpreting preclinical results in immunocompromised mice.

CXCR4: from the review by Ori Wald, Oz M. Shapira, Uzi Izha


Source: Wald O, Shapira OM, Izhar U. CXCR4/CXCL12 Axis in Non Small Cell Lung Cancer (NSCLC) Pathologic Roles and Therapeutic Potential. Theranostics 2013; 3(1):26-33. doi:10.7150/thno.4922. Available from


Chemokines, a family of 48 chemotactic cytokines interact with their 7 transmembrane G-protein-coupled receptors to guide immune cell trafficking in the body under both physiologic and pathologic conditions (20, 21). Tumor cells, which express a relatively restricted repertoire of chemokine and chemokine receptors, utilize and manipulate the chemokine system in a manner that benefits both local tumor growth and distant dissemination (20, 22, 23). In the tumor microenvironment autocrine and paracrine chamokine/chemokine receptor loops interact to promote tumor cell survival and growth, and also to enhance tumor neo-angiogenesis (20, 22, 23). At distant sites, it is the tissue-produced chemokine which guide/attracts the metastasis of chemokine receptor expressing tumor cells (20).

Among the 19 chemokine receptors, CXCR4 is the receptor most widely expressed by malignant tumors and whose role in tumor biology is most thoroughly studied (20). The chemokine CXCL12 is the sole ligand of CXCR4 and the majority of research that focus on the role of CXCR4 in cancer relates to this chemokine/chemokine receptor pair (24, 25). Nevertheless, in 2006 another receptor for CXCL12 was identified and named CXCR7 (26). CXCR7 is expressed during embriogenesis, angiogenesis and in various malignant tissues including NSCLC. CXCR7 is thought to act in part as a scavenger of CXCL12 however additional functions for this receptor have also been reported (2628). In distinct form CXCR4, CXCR7 binds not only CXCL12 but also the chemokine CXCL11 (26, 27). Moreover, the signaling cascades that are generated upon binding of CXCL12 to CXCR4 or CXCR7 vary at least partly, depending on which of the receptors is engaged (26, 27). This review focuses mainly on data collected regarding the expression and function of CXCR4 in NSCLC, nevertheless it is important to keep in mind that whenever CXCL12 is mentioned the effects related to its expression may be attributed in part to CXCR7 expression and function.

Relative to normal cells in the tumor’s tissue of origin, malignant cells often over express CXCR4, this phenotype can be induced by multiple oncogenic alternations and appears to promote tumor cell survival, proliferation, invasion and metastasis (20, 2935).





Potential roles for CXCR4/CXCL12 in NSCLC. NSCLC tumor cells express CXCR4 and produce CXCL12. Tumor expressed CXCR4 guides metastatic spread to sights such as the brain, bone marrow and liver that express high levels of CXCL12. In addition, CXCR4/CXCL12 interactions act locally in autocrine and paracrine manners to enhance primary tumor growth and to alter its inflammatory milieu. Tumor and tumor microenvironment secreted CXCL12 enhance tumor cell survival and growth and may also guide trafficking of immune and bone marrow derived cells into the tumor microenvironment. Furthermore, alternations in the tumor microenvironment result from the stimulation of tumor cells with CXCL12 that in turn enhance the production of additional chemokines such as the pro-inflammatory and pro-proliferative chemokine CCL20) pro-angiogenic and pro-proliferative chemokine (CXCL1 – IL-8). Figure from Wald O, Shapira OM, Izhar U. CXCR4/CXCL12 Axis in Non Small Cell Lung Cancer (NSCLC) Pathologic Roles and Therapeutic Potential. Theranostics 2013; 3(1):26-33. doi:10.7150/thno.4922. Available from

For further reference on CXCR4 and development of CXCR4 inhibitors please see the following references:

  1. Peled A, Wald O, Burger J. Development of novel CXCR4-based therapeutics. Expert Opin Investig Drugs. 2012Mar;21(3):341-53
  2. Balkwill FR. The chemokine system and cancer. J Pathol. 2012Jan;226(2):148-57
  3. Burger JA, Kipps TJ. CXCR4: a key receptor in the crosstalk between tumor cells and their microenvironment. Blood. 2006Mar1;107(5):1761-7
  4. Burger JA, Peled A. CXCR4 antagonists: targeting the microenvironment in leukemia and other cancers. Leukemia. 2009Jan;23(1):43-52
  5. Otsuka S, Bebb G. The CXCR4/SDF-1 chemokine receptor axis: a new target therapeutic for non-small cell lung cancer. J Thorac Oncol. 2008Dec;3(12):1379-83


Current CXCR4 inhibitors in development


Figure. Structures of Representative Small Molecule CXCR4 Antagonists and CXCL12 Inhibitors. From JJ Zariek et al. Fragment-Based Optimization of Small Molecule CXCL12 Inhibitors for Antagonizing the CXCL12/CXCR4 Interaction. Curr Top Med Chem. 2012; 12(24): 2727–2740.


A Phase 1 Trial of LY2510924, a CXCR4 Peptide Antagonist, in Patients with Advanced Cancer

This manuscript reports the results of a phase I study designed to evaluate the safety and tolerability of the C-X-C motif receptor 4 (CXCR4) inhibitor LY2510924 in patients with advanced cancer. LY2510924 is a peptide antagonist, which blocks stromal cell-derived factor-1 (SDF-1) from CXCR4 binding. CXCR4 is often overexpressed in many cancers and involved in the metastasis of solid tumors. LY2510924 was tolerated with mostly Grade 1/2 adverse events, revealed favorable pharmacokinetics, and demonstrated evidence of target engagement as indicated by dose dependent increases in CD34+ cells.

Anti-CXCR4 (BMS-936564) Alone and in Combination With Lenalidomide/Dexamethasone or Bortezomib/Dexamethasone in Relapsed/Refractory Multiple Myeloma

The purpose of this study is to determine 1) the safety and tolerability of multiple intravenous doses of anti-CXCR4 (BMS-936564) as monotherapy and as combination, and 2) the maximum tolerated dose (MTD) of BMS-936564 in combination with Lenalidomide/Dexamethasone or Bortezomib/Dexamethasone in subjects with relapsed or refractory multiple myeloma.


Novel CXCR4 Antagonist BL-8040 Enters Clinical Testing for CML – See more at:


Other posts on this Open Access Journal on CXCR4 and Chemokines in Cancer Include

Assessing effects of antimetastatic treatment

Understanding the Stem Cell Niche: A Webinar by The Scientist

Protein regulator of HIV replication

Immunotherapy in Cancer: A Series of Twelve Articles in the Frontier of Oncology by Larry H Bernstein, MD, FCAP

Humanized Mice May Revolutionize Cancer Drug Discovery

Tumor Associated Macrophages: The Double-Edged Sword Resolved?









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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 [3638]
Stavudine Mannose- and galactose-targeted liposome Preclinical [3941]
Zidovudine Mannose-targeted liposome Preclinical [42]
Efavirenz Mannose-targeted dendrimer Preclinical [43,45]
Lamivudine Mannose-targeted dendrimer Preclinical [46]
Nanomaterials Fullerene derivatives Preclinical [4955]
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 [7781]
Immunotherapy P24 protein Poly (D,L-lactide) nanoparticles/dendritic cells Preclinical [98]
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 [108111]
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 [126127]
Microbicides L-lysine dendrimer L-lysine dendrimer Phase I/II [136138]
PLGA nanoparticles
PSC-RANTES PLGA Preclinical [139]
siRNA Nanoparticles, lipids, cholesterol conjugation Preclinical [141144]

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.



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.



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.

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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