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Posts Tagged ‘Tilda Barliya’


CD47: Target Therapy for Cancer

Author/Curator: Tilda Barliya

“A research team from Stanford University’s School of Medicine is now one step closer to uncovering a cancer treatment that could be applicable across the board in killing every kind of cancer tumor” (1). It appeared that their antibody-drug against the CD47 protein, enabled the shrinking of all tumor cells. After completing their animal studies the researchers now move into a human phase clinical trials. CD47 has been previously studied and evaluated for its role in multiple cells, some of this data however, is somewhat controversy. So where do we stand?

CD47

CD47 (originally named integrin-associated protein (IAP)) is a cell surface protein of the immunoglobulin (Ig) superfamily, which is heavily glycosylated and expressed by virtually all cells in the body and overexpressed in many types of cancer  including breast, ovarian, colon, prostate and others (3). CD47 was first recognized as a 50 kDa protein associated and copurified with the  Alpha-v-Beta-3 integrin in placenta and neutrophil granulocytes and later shown to have the capacity to regulate integrin function and the responsiveness of leukocytes to RGD-containing extracellular matrix proteins. CD47 has also been shown to be identical to the OA-3/OVTL3 antigen highly expressed on most ovarian carcinomas (4,5).

CD47 consists of an extracellular IgV domain, a five times transmembrane-spanning domain, and a short alternatively spliced cytoplasmic tail. In both humans and mice, the cytoplasmic tail can be found as four different splice isoforms ranging from 4 to 36 amino acids, showing different tissue expression patterns (3).

CD47 interactions (3, 6):

  • Thrombospondin-1 (TSP-1) – a secreted glycoprotein that plays a role in vascular development and angiogenesis. Binding of TSP-1 to CD47 influences several fundamental cellular functions including cell migration and adhesion, cell proliferation or apoptosis, and plays a role in the regulation of angiogenesis and inflammation.
  • Signal-regulatory protein-alpha (SIRPα) – an inhibitory transmembrane receptor present on myeloid cells. The CD47/SIRPα interaction leads to bidirectional signaling, resulting in different cell-to-cell responses including inhibition of phagocytosis, stimulation of cell-cell fusion, and T-cell activation.
  • Integrins – several membrane integrins, most commonly integrin avb3. These interactions result in CD47/integrin complexes that effect a range of cell functions including adhesion, spreading and migration

These interactions with multiple proteins and cells types create several important functions, which include:

  • Cell proliferation – cell proliferation is heavily dependent on cell type as both activation and loss of CD47 can result in enhanced proliferation. For example, activation of CD47 with TSP-1 in wild-type cells inhibits proliferation and reduces expression of stem cell transcription factors. In cancer cells however, activation of CD47 with TSP-1 increases proliferation of human U87 and U373 astrocytoma. it is likely that CD47 promotes proliferation via the PI3K/Akt pathway in cancerous cells but not normal cells (7).  Loss of CD47 allows sustained proliferation of primary murine endothelial cells and enables these cells to spontaneously reprogram to form multipotent embryoid body-like clusters (8).
  • Apoptosis – Ligation of CD47 by anti-CD47 mAbs was found to induce apoptosis in a number of different cell types (3). For example: Of the two SIRP-family members known to bind the CD47 IgV domain (SIRPα and SIRPγ), SIRPα as a soluble Fc-fusion protein does not induce CD47-dependent apoptosis, hile SIRPα or SIRPγ bound onto the surface of beads induces apoptosis through CD47 in Jurkat T cells and the myelomonocytic cell line U937.
  • Migration – CD47  role on cell migration was first demonstrated in neutrophils, these effects were shown to be dependent on avb3 integrins, which interact with and are activated by CD47 at the plasma membrane. In cancer, Blocking CD47 function has been shown to inhibit migration and metastasis in a variety of tumor models. Blockade of CD47 by neutralizing antibodies reduced migration and chemotaxis in response to collagen IV in melanomaprostate cancer and ovarian cancer-derived cells (9).
  • Angiogenesis – The mechanism of the anti-angiogenic activity of CD47 is not fully understood, but introduction of CD47 antibodies and TSP-1 have been shown to inhibit nitric oxide (NO)-stimulated responses in both endothelial and vascular smooth muscle cells (10). More so, CD47 signaling influences the SDF-1 chemokine pathway, which plays a role in angiogenesis (11). (12)
  • Inflammatory response – Interactions between endothelial cell CD47 and leukocyte SIRPγ regulate T cell transendothelial migration (TEM) at sites of inflammation. CD47 also functions as a marker of self on murine red blood cells which allows RBC to avoid phagocytosis. Tumor cells can also evade macrophage phagocytosis through the expression of CD47 (2, 13).

It appears that CD47 ligation induce different responses, depending on cell type and partner for ligation.

Therapeutic and clinical aspect of CD47 in human cancer:

CD47 is overexpressed in many types of human cancers  and its known function as a “don’t eat me” signal, suggests the potential for targeting the CD47-SIRPα pathway as a common therapy for human malignancies (2,13). Upregulation of CD47 expression in human cancers also appears to influence tumor growth and dissemination. First, increased expression of CD47 in several hematologic malignancies was found to be associated with a worse clinical prognosis, and in ALL to predict refractoriness to standard chemotherapies (13, 14-16). Second, CD47 was demonstrated to regulate tumor metastasis and dissemination in both MM and NHL (13, 17).

Efforts have been made to develop therapies inhibiting the CD47-SIRPα pathway, principally through blocking monoclonal antibodies directed against CD47, but also possibly with a recombinant SIRPα protein that can also bind and block CD47.

Figure 2

Chao MP et al. 2012 Combination strategies targeting CD47 in cancer

While monotherapies targeting CD47 were efficacious in several pre-clinical tumor models, combination strategies involving inhibition of the CD47-SIRPα pathway offer even greater therapeutic potential. Specifically, antibodies targeting CD47-SIRPα can be included in combination therapies with other therapeutic antibodies, macrophage-enhancing agents, chemo-radiation therapy, or as an adjuvant therapy to inhibit metastasis (13).

For example, anti-SIRPα antibody was found to potentiate  antibody-dependent cellular cytotoxicity (ADCC) mediated by the anti-Her2/Neu antibody trastuzumab against breast cancer cells (18).  CD47–SIRPα interactions and SIRPα signaling negatively regulate trastuzumab-mediated ADCC in vitro and antibody-dependent elimination of tumor cells in vivo

More so, chemo-radiation therapy-mediated upregulation of cell surface calreticulin may potentially augment the activity of anti-CD47 antibody. However, this approach may also lead to increased toxicity as cell surface calreticulin is expressed on non-cancerous cells undergoing apoptosis, a principle effect of chemo-radiation therapy (19).

Highlights:

  • Phagocytic cells, macrophages, regulate tumor growth through phagocytic clearance
  • CD47 binds SIRPα on phagocytes which delivers an inhibitory signal for phagocytosis
  • A blocking anti-CD47 antibody enabled phagocytic clearance of many human cancers
  • Phagocytosis depends on a balance of anti-(CD47) and pro-(calreticulin) signals
  • Anti-CD47 antibody synergized with an FcR-engaging antibody, such as rituximab

Summary

Evasion of immune recognition is a major mechanism by which cancers establish and propagate disease. Recent data has demonstrated that the innate immune system plays a key role in modulating tumor phagocytosis through the CD47-SIRPα pathway. Careful development of reagents that can block the CD47/SIRPα interaction may indeed be useful to treat many forms of cancer without having too much of a negative side effect in terms of inducing clearance of host cells. Therapeutic approaches inhibiting this pathway have demonstrated significant efficacy, leading to the reduction and elimination of multiple tumor types.

Dr. Weissman says: “We are now hopeful that the first human clinical trials of anti-CD47 antibody will take place at Stanford in mid-2014, if all goes wellClinical trials may also be done in the United Kingdom”. These clinical trials must be designed so that the data they generate will produce a valid scientific result!!!

REFERENCES

1. By Sara Gates:  Cancer Drug That Shrinks All Tumors Set To Begin Human Clinical Trials. http://www.huffingtonpost.com/2013/03/28/cancer-drug-shrinks-tumors_n_2972708.html

2. Willingham SB, Volkmer JP, Gentles AJ, Sahoo D, Dalerba P, Mitra SS, Wang J, Contreras-Trujillo H, Martin R, Cohen JD, Lovelace P, Scheeren FA, Chao MP, Weiskopf K, Tang C, Volkmer AK, Naik TJ, Storm TA, Mosley AR, Edris B, Schmid SM, Sun CK, Chua MS, Murillo O, Rajendran P, Cha AC, Chin RK, Kim D, Adorno M, Raveh T, Tseng D, Jaiswal S, Enger PØ, Steinberg GK, Li G, So SK, Majeti R, Harsh GR, van de Rijn M, Teng NN, Sunwoo JB, Alizadeh AA, Clarke MF, Weissman IL. The CD47-signal regulatory protein alpha (SIRPa) interaction is a therapeutic target for human solid tumors. Proc Natl Acad Sci U S A. 2012 Apr 24;109(17):6662-6667. http://www.pnas.org/content/early/2012/03/20/1121623109

3. Oldenborg PL. CD47: A Cell Surface Glycoprotein Which Regulates Multiple Functions of Hematopoietic Cells in Health and Disease. ISRN Hematology Volume 2013 (2013), Article ID 614619, 19 pages.  http://www.hindawi.com/isrn/hematology/2013/614619/

4. G. Campbell, P. S. Freemont, W. Foulkes, and J. Trowsdale, “An ovarian tumor marker with homology to vaccinia virus contains an IgV- like region and multiple transmembrane domains,”Cancer Research, vol. 52, no. 19, pp. 5416–5420, 1992. http://cancerres.aacrjournals.org/content/52/19/5416.long

5. L. G. Poels, D. Peters, Y. van Megen et al., “Monoclonal antibody against human ovarian tumor-associated antigens,” Journal of the National Cancer Institute, vol. 76, no. 5, pp. 781–791, 1986. http://www.ncbi.nlm.nih.gov/pubmed/3517452

6. CD47. Wikipedia. http://en.wikipedia.org/wiki/CD47

7. Sick E, Boukhari A, Deramaudt T, Rondé P, Bucher B, André P, Gies JP, Takeda K (February 2011). “Activation of CD47 receptors causes proliferation of human astrocytoma but not normal astrocytes via an Akt-dependent pathway”. Glia 59 (2): 308–319. http://www.ncbi.nlm.nih.gov/pubmed/21125662

8. Kaur S, Soto-Pantoja DR, Stein EV, Liu C, Elkahloun AG, Pendrak ML, Nicolae A, Singh SP, Nie Z, Levens D, Isenberg JS, Roberts DD.  “Thrombospondin-1 Signaling through CD47 Inhibits Self-renewal by Regulating c-Myc and Other Stem Cell Transcription Factors”Sci Rep 2013: 3: 1673. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3628113/

9. Shahan TA, Fawzi A, Bellon G, Monboisse JC, Kefalides NA. “Regulation of tumor cell chemotaxis by type IV collagen is mediated by a Ca(2+)-dependent mechanism requiring CD47 and the integrin alpha(V)beta(3)”. J. Biol. Chem 2000. 275 (7): 4796–4802. http://www.jbc.org/content/275/7/4796

10. Isenberg JS, Ridnour LA, Dimitry J, Frazier WA, Wink DA, Roberts DD. “CD47 is necessary for inhibition of nitric oxide-stimulated vascular cell responses by thrombospondin-1”. J. Biol. Chem  2006. 281 (36): 26069–26080.  http://www.jbc.org/content/281/36/26069

11. Smadja DM, d’Audigier C, Bièche I, Evrard S, Mauge L, Dias JV, Labreuche J, Laurendeau I, Marsac B, Dizier B, Wagner-Ballon O, Boisson-Vidal C, Morandi V, Duong-Van-Huyen JP, Bruneval P, Dignat-George F, Emmerich J, Gaussem P. “Thrombospondin-1 is a plasmatic marker of peripheral arterial disease that modulates endothelial progenitor cell angiogenic properties”. Arterioscler. Thromb. Vasc. Biol  2011. 31 (3): 551–559. http://atvb.ahajournals.org/content/31/3/551

12. G. D. Grossfeld, D. A. Ginsberg, J. P. Stein et al., “Thrombospondin-1 expression in bladder cancer: association with p53 alterations, tumor angiogenesis, and tumor progression,” Journal of the National Cancer Institute 1997 vol. 89, no. 3, pp. 219–227. http://www.scopus.com/record/display.url?eid=2-s2.0-18744423089&origin=inward&txGid=9C86356DDB0B6816ACCBF90F9CA44E92.WlW7NKKC52nnQNxjqAQrlA%3a2

13. Chao MP, Weissman IL, Majeti R. “The CD47-SIRPα pathway in cancer immune evasion and potential therapeutic implications”Curr. Opin. Immunol 2012. 24 (2): 225–32. http://www.sciencedirect.com/science/article/pii/S095279151200012Xhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3319521/

14. Majeti R, Chao MP, Alizadeh AA, Pang WW, Jaiswal S, Gibbs KD, Jr, van Rooijen N, Weissman IL. Cd47 is an adverse prognostic factor and therapeutic antibody target on human acute myeloid leukemia stem cells. Cell. 2009;138(2):286–299. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2726837/

15. Chao MP, Alizadeh AA, Tang C, Jan M, Weissman-Tsukamoto R, Zhao F, Park CY, Weissman IL, Majeti R. Therapeutic antibody targeting of cd47 eliminates human acute lymphoblastic leukemia.Cancer Res. 2011;71 (4):1374–1384. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3041855/

16. Chao MP, Alizadeh AA, Tang C, Myklebust JH, Varghese B, Gill S, Jan M, Cha AC, Chan CK, Tan BT, Park CY, et al. Anti-cd47 antibody synergizes with rituximab to promote phagocytosis and eradicate non-hodgkin lymphoma. Cell. 2010;142(5):699–713. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2943345/

17. Chao MP, Tang C, Pachynski RK, Chin R, Majeti R, Weissman IL. Extranodal dissemination of non-hodgkin lymphoma requires cd47 and is inhibited by anti-cd47 antibody therapy. Blood.2011;118(18):4890–4901. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3208297/

18. Zhao XW, van Beek EM, Schornagel K, Van der Maaden H, Van Houdt M, Otten MA, Finetti P, Van Egmond M, Matozaki T, Kraal G, Birnbaum D, et al. Cd47-signal regulatory protein-alpha (sirpalpha) interactions form a barrier for antibody-mediated tumor cell destruction. Proc Natl Acad Sci U S A.2011;108(45):18342–18347. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215076/

19. Obeid M, Tesniere A, Ghiringhelli F, Fimia GM, Apetoh L, Perfettini JL, Castedo M, Mignot G, Panaretakis T, Casares N, Metivier D, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007;13(1):54–61. http://www.ncbi.nlm.nih.gov/pubmed/17187072

Other related articles on this Open Access Online Scientific Journal include the following:

I. By: Larry Bernstein MD. Treatment for Metastatic HER2 Breast Cancer https://pharmaceuticalintelligence.com/2013/03/03/treatment-for-metastatic-her2-breast-cancer/

II. By: Tilda Barliya PhD. Colon Cancer.  https://pharmaceuticalintelligence.com/2013/04/30/colon-cancer/

III. By: Ritu Saxena PhD. In focus: Triple Negative Breast Cancer. https://pharmaceuticalintelligence.com/2013/01/29/in-focus-triple-negative-breast-cancer/

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Author: Tilda Barliya PhD

Pancreatic cancer has been previously addressed here in our blog (I-IX) but a recent diagnosis of a colleague urged me to go back to the basics and search for more answers and updates hoping it would offer some peace.

Pancreatic cancer is the 4th leading cause of death in the united states with only 3% rate for 5-year survival rate (1). Due to lack of symptoms and limitation in diagnostic methods, patients are mostly diagnosed at mush advanced stages. When reach these stages, patients start to show symptoms of weight loss, abdominal pain, jaundice, by than, the cancer has already spread.

Several treatment options are available in which surgical resection (for the 15%-20% that are eligible for it) increase the 5-year survival rate by up to 20% , and that’s mainly because the cancer comes back about 85 percent of the time (1,2). These statistics are very hard to comprehend, especially with the progress been made in other types of cancer.

So Why pancreatic cancer is so deadly?

Pancreatic cancer biology and genetics

Pancreatic cancer biology and genetics. Nabeel Bardeesy & Ronald A. DePinho. Nature Reviews Cancer 2002: 2, 897-909

The pancreas is a highly vascularized 6 inch dual-function gland that plays a major role in the body. It secretes digestive enzymes and hormones (i.e; insulin, glucagon, somatostatin and pancreatic polypeptide) which assist in the digestion of fats and the absorption of nutrients. These enzymes help further digest carbohydrates, proteins and lipids in the chyme.

It is postulated that a tumor starts to overcome  the functionally of the pancreas;  causing reduction of important hormones (insulin) and enzymes (digestive enzymes) production thus impacting the overall ability of the body to absorb nutrients and get energy coins thus affecting  the overall performance of the body. Several studies were conducted to evaluate the connection between dietary factors and induction of pancreatic cancer, however no direct correlation was observed (11, 12)

More so, the pancreas is located at the junction of several organs; liver, gall bladder and intestines,  thus enabling metastatic cells to harbor multiple vital organ. Most patients die for liver failure due to liver metastases.

These factors; late- diagnosis, reduction in overall body function and failure of vital organs (such as the liver due to metastasis), cause the aggressive and fast death of these panvreatic patients.

A growing number of studies have identified common mutational profiles in simultaneous lesions, providing supportive evidence of the relationship between pancreatic intraepithelial neoplasia (PanINs) and the pathogenesis of pancreatic adenocarcinoma. Nabeel Bardeesy and Ronald A. DePinho summarized this data in Figure and table inserted herein. Intriguingly, there seems to be an ordered series of mutational events in association with specific neoplastic stages (1,4).

Pancreatic cancer biology and genetics. Nabeel Bardeesy & Ronald A. DePinho. Nature Reviews Cancer 2002, 2: 897-909.

The combination of these multiple mutations render pancreatic cancer cells resistant to current chemo and radiotherapy. More so, known pancreatic cancer antigens have generated relatively weak immune responses due to these combined mutagenesis (5, 16). These crucial somatic genetic mutations can generate pancreatic cancer proteins that are essentially altered self proteins

Therefore, in order to design a good  immunotherapeutic approach one must incorporate at least one agent against a pancreatic cancer target as well as one or more agents that will modify both local and systemic mechanisms of pancreatic-cancer-induced.

Another important element that needs to be taken into consideration are the immunological checkpoints. These checkpoints serve two  purposes:

  1. To help generate and maintain self-tolerance, by eliminating T cells that are specific for self-antigens.
  2. To restrain the amplitude of normal T-cell responses so that they do not ‘overshoot’ in their natural response to foreign pathogens

The prototypical immunological checkpoint is mediated by the cytotoxic-T-lymphocyte-associated protein 4 (CTLA4) counter regulatory receptor that is expressed by T cells when they become activated (6).  CTLA4 binds two B7 FAMILY members on the surface APCs — B7.1 (also known as CD80) and B7.2 (also known as CD86): with roughly 20-fold higher affinity than the T-cell surface protein CD28 binds these molecules. CD28 is a co-stimulatory receptor that is constitutively expressed on naive T cells. Because of its higher affinity, CTLA4 out-competes CD28 for B7.1/B7.2 binding, resulting in the downmodulation of T-cell responses (7). Monoclonal antibodies that downregulate B7-H1 and B7-H4 are currently in clinical development. This is just one example of the potential use of targeted therapy for use in clinical trials.

Dan Laheru* and Elizabeth M. Jaffee have summarized the immunotherapy clinical trials  back in 2005:

Immunotherapy for pancreatic cancer |[mdash]| science driving clinical progress

Herein you can read about the latest summary of the NCI portfolio on Pancreatic cancer and research highlights : http://www.cancer.gov/researchandfunding/reports/pancreatic-research-progress.pdf

Here’s their recommendation for future plans for clinical trials:

  • Perform well-designed Phase II studies to help define strategies likely to succeed in a Phase III setting.
  • Adopt consistent entry and evaluation criteria for Phase II trials.
  • Conduct high-priority Phase III trials as intergroup trials and include scientifically appropriate biorepositories.
  • Conduct trials on rational combinations of targeted agents and develop predictive biomarkers to assist in patient selection.
  • Explore use of immune therapies, particularly among those with earlier stage disease.
  • Share trial outcomes, including those of trials with negative results.

According to the NCI clinical trial results from two phase III clinical trials, the targeted therapies sunitinib (Sutent®) and everolimus (Afinitor®) increased the length of time patients with pancreatic neuroendocrine tumors (panNET) survived without the disease progressing. And, in the sunitinib trial, patients who received the drug also had better overall survival. The findings were published February 9, 2011, in the New England Journal of Medicine (NEJM). Although neuroadenoma is rare and presents only 2% of all pancreatic cancer, no effective treatment was available, now these results may offer some hope (9).

More so, a four-drug chemotherapy regimen has produced the longest improvement in survival ever seen in a phase III clinical trial of patients with metastatic pancreatic cancer, one of the deadliest types of cancer (10). Patients who received the regimen, called FOLFIRINOX, lived approximately 4 months longer than patients treated with the current standard of caregemcitabine (11.1 months compared with 6.8 months).

In summary:

Remarkable progress has been made in understanding the  genetics and development biology pancreatic cancer have offered new potential targets for therapy. ” The availability of powerful new technologies and continued contributions of investigators in many related disciplines provides a measure of optimism towards future progress in treating this disease (1)”. Latest results of clinical trials may also shade some hope for patients suffering from this horrible disease.

On a personal note, I hope these new opportunities and clinical trials will offer another avenue to my colleague……

REFERENCES

1. Nabeel Bardeesy and Ronald A.DePinho. Pancreatic cancer biology and genetics. Nature Cancer reviews 2002, 2: 897-909. http://www.nature.com/nrc/journal/v2/n12/full/nrc949.html

2. Melinda Wenner. What makes pancreatic cancer so deadly. Scientific American 2008. http://www.scientificamerican.com/article.cfm?id=experts-pancreatic-cancer-gene-upshaw

3. Pancreas. Wikipedia. http://en.wikipedia.org/wiki/Pancreas

4. Jaffee, E. M., Hruban, R. H., Canto, M. & Kern, S.E. Focus on pancreas cancer. Cancer Cell 2, 25–28 (2002). http://www.sciencedirect.com/science/article/pii/S1535610802000934

5.  Dan Laheru* and Elizabeth M. Jaffee. Immunotherapy for pancreatic cancer – science driving clinical progress.  Nature Reviews: Cancer. 2005. 5: 459-467. http://www.nature.com/nrc/journal/v5/n6/full/nrc1630.html

6. Coyle, A. J. & Gutierrez-Ramos, J. C. The expanding B7 superfamily: increasing complexity in co-stimulatory signals regulating T cell function. Nature Immunol 2001. 2, 203–209. http://www.nature.com/ni/journal/v2/n3/full/ni0301_203.html

7.  Walunas, T. L., Bakker, C. Y. & Bluestone, J. A. CTLA-4 ligation blocks CD28-dependent T cell activation. J. Exp. Med 1996. 183, 2541–2550. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2192609/

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2192609/pdf/je18362541.pdf

8. Pancreatic Cancer: A summary of NCI’s portfolio and highlights of recent research progress 2010. http://www.cancer.gov/researchandfunding/reports/pancreatic-research-progress.pdf

9. NCI bulletin: Targeted Therapies May Be Effective Against Rare Pancreatic Cancer. http://www.cancer.gov/clinicaltrials/results/summary/2011/panNET-Therapy0411

10. NCI bulletin: Chemotherapy Regimen Extends Survival in Advanced Pancreatic Cancer Patients http://www.cancer.gov/clinicaltrials/results/summary/2011/pancreatic-chemo0611

11. Nilsen TI, Vatten LJ. A prospective study of lifestyle factors and the risk of pancreatic cancer in NordTrondelag, Norway. Cancer Causes Control 2000;11:645-52. http://www.ncbi.nlm.nih.gov/pubmed/10977109

12. Marshall JR, Freudenheim J. Alcohol. In: Schottenfeld D, Fraumeni JF Jr., eds. Cancer Epidemiology and  Prevention, 3rd ed. New York: Oxford University Press, 2006. P. 243-58. http://www.oxfordscholarship.com/view/10.1093/acprof:oso/9780195149616.001.0001/acprof-9780195149616

13. Alison P. Klein. Identifying people at a high risk of developing pancreatic cancer. Nature Reviews Cancer 2012, 13: 66-74. http://www.nature.com/nrc/journal/v13/n1/full/nrc3420.html

14. John P. Morris, Sam C. Wang & Matthias Hebrok. KRAS, Hedgehog, Wnt and the twisted developmental biology of pancreatic ductal adenocarcinoma.Nature Reviews Cancer 2012. 10:683-695.  http://www.nature.com/nrc/journal/v10/n10/full/nrc2899.html

15. Patrick Goymer. Imaging: Early detection for pancreatic cancer. Nature Reviews Cancer 2008, 8: 408-409. http://www.nature.com/nrc/journal/v8/n6/full/nrc2407.html

16. Koido S, Homma S, Takahara A, Namiki Y, Tsukinaga S, Mitobe J, Odahara S, Yukawa T, Matsudaira H, Nagatsuma K, Uchiyama K, Satoh K, Ito M, Komita H, Arakawa H, Ohkusa T, Gong J, Tajiri H. Current Immunotherapeutic Approaches in Pancreatic Cancer, Clin Dev Immunol. 2011;2011:267539. http://www.hindawi.com/journals/cdi/2011/267539/

Other related articles on this open Access Online Scientific Journal, include the following:

I. Pancreatic cancer genomes: Axon guidance pathway genes – aberrations revealed.

Aviva Lev-Ari, PhD, RN, 10/24/2012

https://pharmaceuticalintelligence.com/2012/10/24/pancreatic-cancer-genomes-axon-guidance-pathway-genes-aberrations-revealed/

II. Biomarker tool development for Early Diagnosis of Pancreatic Cancer: Van Andel Institute and Emory University.

Aviva Lev-Ari PhD,RN, 10/24/2012

https://pharmaceuticalintelligence.com/2012/10/24/biomarker-tool-development-for-early-diagnosis-of-pancreatic-cancer-van-andel-institute-and-emory-university/

III. Personalized Pancreatic Cancer Treatment Option.

Aviva Lev-Ari PhD, RN, 10/16/2012

https://pharmaceuticalintelligence.com/2012/10/16/personalized-pancreatic-cancer-treatment-option/

IV. Battle of Steve Jobs and Ralph Steinman with Pancreatic cancer: How we lost.

Ritu Saxena PhD, 5/21/2012

https://pharmaceuticalintelligence.com/2012/05/21/battle-of-steve-jobs-and-ralph-steinman-with-pancreatic-cancer-how-we-lost/

V.  Early Biomarker for Pancreatic Cancer Identified.

Prabodh Kandala, PhD, 5/17/2012

https://pharmaceuticalintelligence.com/2012/05/17/early-biomarker-for-pancreatic-cancer-identified/

VI. Usp9x: Promising therapeutic target for pancreatic cancer.

Ritu Saxen PhD, 5/14/2012

https://pharmaceuticalintelligence.com/2012/05/14/promising-therapeutic-target-discovered-for-pancreatic-cancer/

VII. Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing.

Stephen J. Williams, PhD, 10/4/2013

https://pharmaceuticalintelligence.com/2013/04/10/issues-in-personalized-medicine-in-cancer-intratumor-heterogeneity-and-branched-evolution-revealed-by-multiregion-sequencing/

VIII. In Focus: Targeting of Cancer Stem Cells.

Ritu Saxena, PhD, 3/27/2013

https://pharmaceuticalintelligence.com/2013/03/27/in-focus-targeting-of-cancer-stem-cells/

IIX. New Ecosystem of Cancer Research: Cross Institutional Team Science.

Aviva Lev-Ari. PhD, RN, 3/24/2013

https://pharmaceuticalintelligence.com/2013/03/24/new-ecosystem-of-cancer-research-cross-institutional-team-science/

IX. In Focus: Identity of Cancer Stem Cells.

Ritu Saxena, PhD, 3/22/2013

https://pharmaceuticalintelligence.com/2013/03/22/in-focus-identity-of-cancer-stem-cells/

 

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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:

  1. enhances drug permeation
  2. controls the release of drug
  3. 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

http://jocpr.com/vol2-iss3-2010/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):76-90http://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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