Prodrugs as drug delivery system in oncology.

Abstract

The use of conventional chemotherapy in the treatment of cancer has been restricted by the lack of cell specificity, which causes toxicity regarding healthy cells resulting in limiting side effects responsible for low therapeutic efficiency. To overcome these drawbacks, the design of prodrugs has evolved and improved by covalently linking the drug through a degradable spacer. The use of these prodrugs as drug delivery systems, which are able to inactivate the drug during its biodistribution to specifically deliver the drug to its target, is an important breakthrough in cancer therapy. This strategy consisting in the covalent binding of a promoiety to daily used therapeutic compounds has been clinically proven in the design of targeted prodrugs leading enhanced therapeutic efficacy and increase of the therapeutic index. This review summarizes and compares several strategies that improve the therapeutic index of chemotherapy (i.e. conventional drugs) by their chemical transformation into prodrugs improving pharmacokinetic profiles and optimizing administration routes in comparison to the initial drug. This review provides an overview of the methods used to control the structure and function of prodrugs and, ultimately, their current and future potential in increasing the therapeutic index of daily used anticancer drugs. First, prodrugs' design and their activation within the tumor microenvironment or within the tumor cell will be exposed. Then, the different strategies used leading to these prodrugs will be presented.