Abstract: Polymer drug conjugates (PDCs) represent a targeted modification of conventional chemotherapeutics, transforming small-molecule drugs like doxorubicin (dox) into macromolecular structures with significantly altered biological properties. By incorporating a biocompatible polymer backbone, a cleavable linker, and an active cytotoxic payload, PDCs achieve prolonged systemic persistence, advantageous biodistribution, and tumor-specific release. This architecture facilitates more reliable exploitation of the enhanced permeability and retention (EPR) effect, thereby encouraging preferential intratumoral accumulation while reducing off-target exposure. The regulated and microenvironment-sensitive release of dox provides a logical approach to mitigate cardiotoxicity, a significant limitation of anthracycline treatment. PDCs can partially bypass efflux-mediated multidrug resistance by using endocytic uptake pathways rather than transporter-dependent mechanisms. Prototypical systems such as HPMA-dox and PEG-dox offer persuasive translational evidence that macromolecular conjugation can enhance the therapeutic index of dox. PDCs collectively demonstrate how advanced molecular engineering might rejuvenate traditional chemotherapeutics for contemporary oncology.
Kumari et al. (Tue,) studied this question.