Biodegradable Polymeric Nanogels vs Polymer-Drug Conjugates: A Superior Drug Delivery Strategy Enabling Potentiated Cancer Treatment

Abstract The advantages of biodegradable polymeric nanogels (PNGs) versus traditional polymer-drug conjugates (PDCs) have been noticed recently, yet have not been thoroughly studied so far. We synthesized three PNGs and three PDCs of paclitaxel, based on the same biocompatible and biodegradable polymers for straightforward comparisons, and evaluated their therapeutic outcomes and in vivo systemic safety. The nanomedicines leveraged different disulfide-containing dual-stimuli-responsive drug linkers, each incorporating a disulfide group and an ester bond separated by carbon chains of varying lengths, to attach PTX molecules to the polymeric framework, enabling stimuli-activated, tumor-specific drug release. The nature of drug linkages and the structural characteristics of PDCs and PNGs markedly influenced the performance of the nanomedicines. The PNGs uniformly exhibited a hydrodynamic diameter of ∼85 nm (PDI: ∼0.22), a zeta potential value of approximately −28 mV, a dry-state diameter of ∼65 nm, and a drug loading of ∼12% (wt %). Notably, the PNGs demonstrated more potent antitumor efficacy than the PDCs, as evidenced by their higher in vitro cytotoxicity and superior in vivo therapeutic efficiency, which are attributable to their combined therapeutic advantages, including better dynamic stability, higher consistency in blood serum, enhanced tumor accumulation, and more efficiently controlled intracellular drug release in cancer cells. The nanomaterials exhibited excellent systemic tolerance, inducing negligible toxic effects on major organs, even during long-term administration. This work underscores the advantages of biodegradable nanogel architectures and provides a robust, biosafe, and effective platform for precision cancer nanomedicine featuring controlled drug delivery, boosted therapeutic efficacy, and uncompromised systemic safety.