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Giving old cancer drugs new opportunities

Newly developed technologies to fight the dread disease utilize older standbys to solve problems
Dr. Mark Eidelman of Rambam Hospital in Haifa, operating on a patient in Loja, Ecuador in June 2012 (photo credit: Rambam Health Care Campus)
Dr. Mark Eidelman of Rambam Hospital in Haifa, operating on a patient in Loja, Ecuador in June 2012 (photo credit: Rambam Health Care Campus)

Cancer has a tremendous influence on social life. The American Cancer Society clams that over 1 million new cases of cancer are diagnosed in the U.S. annually. A third of Americans will develop cancer at some time in their lifetime (over 85 million people). More than half a million in the U.S. will die from the cancer and its complications, making it the second leading cause of death in the U.S and define cancer as a crucial public health problem especially since these numbers are expected to increase.

Current cancer chemotherapeutics are limited by two important characteristics — the lack of target cell specificity and the propensity to induce development of resistance. One promising approach to overcome these problems is to use Targeted Drug Delivery (TDD), whereby a carrier that has a specific affinity to cancer cells is linked to an anticancer drug.

While this strategy is being investigated extensively, the literature describes very limited range of conjugation methods using mainly mono-functional linkers for the coupling of drugs to carriers like enzymes, antibodies, peptides, and biodegradable polymers. The linkage of several and different drugs to a target specific carrier might improve the therapeutic efficacy of TDDs, but this has yet to be achieved. Moreover, the possibility of engineering deviations in time release of different drug moieties from such a multi-conjugate suggests that employing a platform with multiple attachment and controlled release capabilities may represent a significantly improved architecture for drug multi-linking —  multi-released properties in TDD.

TDD also aims to provide a solution to the problematic phenomena where the majority of drugs used for the treatment of cancer today are cytotoxic (cell-killing) and non-selective drugs. These drugs have the potential to be very harmful to the body unless they are very specific to cancer cells — something difficult to achieve because the modifications that change a healthy cell into a cancerous one can be subtle.

Indeed, many ‘effective’ drugs have failed in advanced clinical trials due to their high toxicity. A major challenge is to design new drug delivery platforms that will make drugs more selective for cancer cells, and thus have lesser side effects.

In collaboration with Prof. Michael Firer (also from Ariel University), I have developed a novel approach for conjugation of chemotherapeutic drugs with tumor targeting carriers based on multi-nuclei platform.

In this approach, the arm of the platform carries an anticancer agent linked though functional group, providing controlled chemo- and bio-release profile.

The versatility of this approach enables quick production of these drug-loaded platforms and determination of the favorable drug combination or mode of linkage for subsequent conjugation to the potential carrier and targeted cancer therapy.

Additionally, we have demonstrated that this technology can switch off/on drug cytotoxicity against specific cancer cells

Biologically degradable platforms loaded with various drugs for conjugation to the carrier were successfully synthesized using simple, fast and convenient synthetic methodology. Each arm of the platform carries an anticancer agent linked though same or different functional group, providing differential release profiles for each drug and also enabling switch off/switch on” regulation of drug cytotoxicity by conjugation to a cell targeting peptide carrier.

Another merit of such conjugation method can be the improvement of old drugs that suffer from low efficacy and high toxicity, or “revival” of drug candidates that failed in clinical trials. By conjugation to the carrier, inefficient bio-agents can gain better pharmacological properties. The results presented in this article potentiate the implementation of these platforms in targeted drug delivery of chemotherapeutic “cocktails” and diagnostic agents in general.

About the Author
Dr. Gary Gellerman is an associate Professor at Ariel University. Dr. Gellerman serves both as the Chairman of the Department of Biological Chemistry and as the elected dean for the faculty of Natural Sciences.
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