Royal Military College of Canada

Materials Science & Engineering

Protease-Mediated Drug-Delivery

By: Dr. James Wojtyk

The current generation of chemotherapeutic agents show relative reactivity towards neoplastic tissue, but have little or no selectivity. The principal aim of this research is the development of a novel drug-delivery system for existing chemotherapeutic agents that will greatly enhance tumour selectivity and minimize normal tissue toxicity. Our system exploits highly specific enzymes that are over-expressed at the tumour-invading front to accumulate an active chemotherapeutic agent at the tumour site ( US patent No. 5,618,790) . This innovative strategy enables one to enhance the efficiency of delivery of known chemotherapeutic agents while reducing both systemic side effects and the dose of agent administered to the patient.

In order to increase the therapeutic index of these agents, we are synthesizing a series of tri-component pro-drugs that will selectively accumulate in an active form at the tumour site. Our synthetic pro-drugs consist of:

a chemotherapeutic agent( )
a solubilizing compound()
a polypeptide chain ( )

The peptide chain serves as a linker between the drug and the solubilizer but it is designed to be a substrate for the over-expressed enzymes that are located on the tumour periphery.

When the pro-drug reaches the target site, proteolytic enzymes ( ) selectively cleave the peptide, rendering the chemotherapeutic agent insoluble at the tumour site. This deposition leads to accumulation and highly localized cytotoxicity, thereby minimizing damage to healthy tissues.

		Insoluble		Excreted
			+

Novel tri-component drugs that contain either conventional chemotherapeutic agents or photochemotherapeutic agents as the active component are being synthesized and tested through the use of in vitro and in vivo models. Currently, the enzyme specificity of the pro-drug is being optimised through organic syntheses and computational studies. First generation pro-drugs also have a fluorescent chemotherapeutic agent, e.g . porphyrin, that facilitates the spectrophotometric monitoring and quantification of enzyme kinetics and the drug distribution in tissue culture and animal models.