Drug induced self-assembly of triblock copolymers into polymersomes for the synergistic dual-drug delivery of platinum drugs and paclitaxel

Co-delivery of two drugs in one nanoparticle is increasingly used to overcome, for example, multi-drug resistance in cancer therapy and therefore suitable drug carriers need to be developed. In this work, a well-known polymer based on poly(glutamic acid) (PGA) and poly(ethylene glycol) (PEG), PGA-PEG-PGA, was employed as a reactive scaffold for the attachment of paclitaxel (Ptx) and platinum(IV) prodrugs. While the polymer itself is water-soluble, the chemical conjugation of both drugs induces self-assembly into polymersomes with a high drug loading content of 28 wt% of Ptx and 11 wt% of the platinum drug. These polymersomes were found to be stable against enzymatic degradation, yet allowed the release of the platinum drugs in a reductive environment. Twenty-two percent of platinum was released after 48 hours, suggesting a two-step model where Pt-drugs are released within a few days, while Ptx has a slower, prolonged, release. Using traditional A549 and LNCap cell lines in 2D culture to test cytotoxicity, the free Ptx drug performed better than Ptx delivered in nanoparticles, as expected, due to the slow cleavage of the drug. However, experiments in 3D cell culture models with A549 spheroids revealed that the drug carrier enabled a higher accumulation of Pt-drugs inside the cells, and after 14 days incubation, the drug-loaded carrier performed slightly better than the free drugs over the longer timeframe. Further, Chou-Talalay analysis confirmed the synergistic effect of the combination of platinum drug and Ptx in the nanoparticle system.