Biomimetic Shells Endow Sub-50 nm Nanoparticles with Ultra-high Paclitaxel Payloads for Specific and Robust Chemotherapy.

Poor loading capacity and nonspecific tumor accumulation of current drug delivery system remain the critical challenges that prevent nanomedicine from maximizing therapeutic efficacy in cancer treatment. Herein, poly(ester amide) (PEA) polymers composed of cationic and hydrophobic segments were formulated with paclitaxel/human serum albumin (PTX/HSA) complex, as well as free PTX, to construct a core-shell nanoparticle (NP) platform with the interior simultaneously reserving PTX and PTX/HSA complex, while the exterior absorbing PTX/HSA complex. Following systematic screening, the optimized NPs, namely APP1i@e NPs, exhibited small particle size (43.95 nm), maximal PTX loading (42.23%), excellent dynamic stability (at least 1 week), and acid-triggered release. In vitro results showed that, after being trafficked through caveolae-mediated endocytosis, APP1i@e NPs successfully escaped from endo/lysosomes, then rapidly released cargos in the acidic cytosol, which continued to enhance cytotoxicity by mitochondrial control of apoptosis and suppression of microtubule dynamics. Longer blood circulation and higher tumor accumulation after intravenous injection confirmed that surface PEGylation imparted APP1i@e NPs with the ability to control their pharmacokinetics and biodistribution. Biomimetic shell design with HSA, which enlarged PTX stock and improved biosafety, made APP1i@e NPs more suitable for in vivo application. Furthermore, in vivo safety and efficacy demonstrated that APP1i@e NPs effectively inhibited growth of ovarian xenograft tumors, whereas significantly avoiding toxic issues associated with PTX. APP1i@e NPs with surface PEG coating and biomimetic HSA design, therefore, may provide a remarkable improvement in the therapeutic index of taxanes used in the clinic.