Prodrug Strategies in Anticancer Chemotherapy

Abstract

The majority of clinically approved anticancer drugs are characterized by a narrow therapeutic window that results mainly from a high systemic toxicity of the drugs in combination with an evident lack of tumor selectivity. Besides the development of suitable galenic formulations such as liposomes or micelles, several promising prodrug approaches have been followed in the last decades with the aim of improving chemotherapy. In this review we elucidate the two main concepts that underlie the design of most anticancer prodrugs: drug targeting and controlled release of the drug at the tumor site. Consequently, active and passive targeting using tumor-specific ligands or macromolecular carriers are discussed as well as release strategies that are based on tumor-specific characteristics such as low pH or the expression of tumor-associated enzymes. Furthermore, other strategies such as ADEPT (antibody-directed enzyme prodrug therapy) and the design of self-eliminating structures are introduced. Chemical realization of prodrug approaches is illustrated by drug candidates that have or may have clinical importance.

Crystal structure of N,N-diethyl-5-bromo-3,4-dihydro-2,4-dioxopyrimidine-1(2H)-carboxamide, C9H12BrN3O3

“…The 5-halouracils and their derivatives have demostrated antitumor and antiviral properties [1][2][3][4]. For example, 5-uorouracil is known as one of the anticancer agents used clinically for the treatment of stomach, colorectal, and neck cancers [5,6].…”

Fluorescent Dyes Used in Polymer Carriers as Imaging Agents in Anticancer Therapy

“…Moreover, with improved optical sensors that can excite fluorophores deep in a tumor mass under low light intensities but with the higher fluorescence quantum yields detection [68] the problems associated with tissue autofluorescence and tissue absorption/scattering of light [69] might be neglected. Another advantage of ligand-targeted therapies is the ability to design a cognate imaging agent with the same targeting ligand [70,71]. Furthermore, ligand (2-[3-(1,3-dicarboxypropyl)ureido]pentanedioic acid) (DUPA) can selectively bind to a cell surface glycoprotein and it is known as prostate-specific membrane antigen [72,73].…”

Prodrug Applications for Targeted Cancer Therapy

“…The details of these advances have been documented in several recent reviews (2)(3)(4)(5)(6). Here, our aim is to present a unified view of the prodrug concept in targeted cancer therapy.…”