Herein we describe biodegradable nanovectors comprised of block copolymers of poly(ethylene glycol) and poly(trimethylene carbonate) (PEG–PTMC) that change their morphology and surface charge when exposed to tumor environment conditions. Well-defined, drug-loaded nanovectors were prepared via direct hydration using liquid oligo(ethylene glycol) as a dispersant. Systematic introduction of basic imidazole-functional TMC derivatives, through modular polymerization, resulted in polymers that self-assembled in multilamellar nanoparticles (at neutral pH) and that were loaded with hydrophobic drugs. The resultant multilamellar nanovectors demonstrated a significant size reduction and charge reversal at pH ≈ 6.5, which yielded cationic nanovectors that were tailored for tumor penetration. Invitro studies using 3D heterospheroids demonstrate that this platform has excellent potential to promote enhanced tumor penetration under physiological conditions.
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