Rethinking nanoparticulate polymer–drug conjugates for cancer theranostics

Abstract Polymer–drug conjugates (PDCs) fabricated as nanoparticles have hogged the limelight in cancer theranostics in the past decade. Many researchers have devoted to developing novel and efficient polymeric drug delivery system since the first generation of poly( N ‐[2‐hydroxypropyl]methacrylamide) copolymer–drug conjugates. However, none of them has been approved for chemotherapy in clinic. An ideal PDC nanoparticle for cancer theranostics should possess several properties, including prolonged circulation in blood, sufficient accumulation and internalization in tumors, and efficient drug release in target sites. To achieve these goals, it is important to rationally design the nanoparticulate PDCs based on circulation, accumulation, penetration, internalization, and drug release (CAPIR) cascade. Specifically, CAPIR cascades are divided into five steps: (1) circulation in the vascular compartment without burst release, (2) accumulation in tumors via enhanced permeability and retention effect, (3) subsequent penetration into the deep regions of tumors, (4) internalization into tumor cells, and (5) release of drugs as free molecules to exert their pharmacological effects. In this review, we focus on the development and novel approaches of nanoparticulate PDCs based on CAPIR cascade, and provide an outlook on future clinical application. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease