Layer-by-layer assembly of hierarchical nanoarchitectures to enhance the systemic performance of nanoparticle albumin-bound paclitaxel

Although protein-bound paclitaxel (PTX, Abraxane^®) has been established as a standard PTX-based therapy against multiple cancers, its clinical success is limited by unfavorable pharmacokinetics, suboptimal biodistribution, and acute toxicities. In the present study, we aimed to apply the principles of a layer-by-layer (LbL) technique to improve the poor colloidal stability and pharmacokinetic pattern of nanoparticle albumin-bound paclitaxel (nab-PTX). LbL-based nab-PTX was successfully fabricated by the alternate deposition of polyarginine (pARG) and poly(ethylene glycol)-block-poly (L-aspartic acid) (PEG-b-PLD) onto an albumin conjugate. The presence of protective entanglement by polyamino acids prevented the dissociation of nab-PTX and improved its colloidal stability even at a 100-fold dilution. The combined effect of high nanoparticle internalization and controlled release of PTX from LbL-nab-PTX increased its cytotoxicity in MCF-7 and MDA-MB-231 breast cancer cells. LbL-nab-PTX consistently induced apoptosis in approximately 52% and 22% of MCF-7 and MDA-MB-231 cancer cells, respectively. LbL assembly of polypeptides effectively prevented exposure of PTX to the systemic environment and thereby inhibited drug-induced hemolysis. Most importantly, LbL assembly of polypeptides to nab-PTX effectively increased the blood circulation potential of PTX and improved therapeutic efficacy via a significantly higher area under the curve (AUC)_0–∞. We report for the first time the application of LbL functional architectures for improving the systemic performance of nab-PTX with a view toward its clinical translation for cancer therapy.