Prodrug Applications for Targeted Cancer Therapy

Abstract

Abstract. Prodrugs are widely used in the targeted delivery of cytotoxic compounds to cancer cells. To date, targeted prodrugs for cancer therapy have achieved great diversity in terms of target selection, activation chemistry, as well as size and physicochemical nature of the prodrug. Macromolecular prodrugs such as antibody-drug conjugates, targeted polymer-drug conjugates and other conjugates that self-assemble to form liposomal and micellar nanoparticles currently represent a major trend in prodrug development for cancer therapy. In this review, we explore a unified view of cancer-targeted prodrugs and highlight several examples from recombinant technology that exemplify the prodrug concept but are not identified as such. Recombinant "prodrugs" such as engineered anthrax toxin show promise in biological specificity through the conditionally targeting of multiple cellular markers. Conditional targeting is achieved by structural complementation, the spontaneous assembly of engineered inactive subunits or fragments to reconstitute functional activity. These complementing systems can be readily adapted to achieve conditionally bispecific targeting of enzymes that are used to activate low-molecular weight prodrugs. By leveraging strengths from medicinal chemistry, polymer science, and recombinant technology, prodrugs are poised to remain a core component of highly focused and tailored strategies aimed at conditionally attacking complex molecular phenotypes in clinically relevant cancer.

HSP90 Inhibitor–SN-38 Conjugate Strategy for Targeted Delivery of Topoisomerase I Inhibitor to Tumors

“…Thus, targeted delivery of cytocidal amounts of toxic agents to tumor cells remains an ongoing challenge for cancer therapy. To address this concern, a variety of site-selective drug delivery strategies have been designed to deliver chemotherapeutics more directly to tumors (2), including coupling anticancer drugs to monoclonal antibodies, peptides, and synthetic polymers (3)(4)(5)(6)(7). In particular, significant translational progress has been made in the field of antibody-drug conjugates (ADC; ref.…”

Enzyme‐MOF Nanoreactor Activates Nontoxic Paracetamol for Cancer Therapy

“…To date, enzymes overexpressed in tumor cells have been used to activate prodrugs. 10 , 12 Nevertheless, because these targeting enzymes may also be present in normal cells, albeit at lower levels, many of these prodrug therapies retained poor selectivity and demonstrated minimal success. 13 , 14 To circumvent this problem, an alternative strategy involves delivering exogenous “activating” enzymes into cancer cells.…”

Self-assembling prodrugs

“…In doing so, the prodrug offers improved bioavailability through enhanced absorption from the gastrointestinal (GI) tract into systemic circulation or via topical application. Other routes to improve ADMET properties include the addition of ionisable groups to increase solubility, 4 the masking of metabolically labile groups to prevent their premature breakdown, 5 the conjugation of peptidic epitopes for the active targeting of specific cell surface receptors, 6–8 and the site-sensitive activation of the prodrug for selective release. 9, 10 …”