Research and Professional Activity
Peptide multi-drug conjugates for targeted anticancer therapy
Current cancer chemotherapeutics are impeded by two important factors – the lack of target cell specificity and the propensity to induce the development of resistance. One promising approach to overcoming these problems is Targeted Drug Delivery (TDD), whereby a carrier with a specific affinity to cancer cells is linked to an anticancer drug. While this strategy is being extensively investigated, the literature describes a very limited range of conjugation methods, mainly using mono-functional linkers for the coupling of drugs to carriers like enzymes, antibodies, peptides and biodegradable polymers (ref. 33). The linkage of many different drugs to a target specific carrier may improve the therapeutic efficacy of TDDs, but this has yet to be achieved.
Prof. Gellerman developed a novel approach for conjugation of chemotherapeutic drugs with tumor targeting carriers, such as peptides, proteins and antibodies, based on a multi-nuclei amino acid platform for TDD. Currently, he is working with small cyclic peptide carriers that are specific ligands to overexpressed receptors in membranes of various cancer cells. His technology aims to provide a solution to the problematic phenomena where the majority of drug combinations used for the treatment of cancer today are cytotoxic (cell-killing) and non-selective (ref. 45, 50). These anticancer drugs are potentially 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. 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 attachments and controlled release capabilities may represent a significantly improved architecture for drug multilinking – multi-released properties in TDD. A major challenge of his research is to design new drug delivery vehicles that will make drug combinations (cocktails) more selective for cancer cells, and thus have lesser side effects (ref. 43, 44). In this approach, the arm of the platform carries an anticancer agent linked though a functional group, providing a controlled chemo- and bio-release profile. Versatility of this approach enables high throughput production (ref. 48) of these drug-loaded platforms and determination of the favorable drug combination/mode of linkage for subsequent conjugation to the potential carrier and targeted cancer therapy. Prof. Gellerman has demonstrated that this technology can switch off/on drug cytotoxicity against specific cancer cells (ref. 34, 36).