Nanodelivery of a self-assembling prodrug with exceptionally high drug loading potentiates chemotherapy efficacy

Nanomedicines have achieved several successful clinical applications for cancer therapy over the past decades. To date, numerous nanomedicine formats and design rationales have been proposed to improve pharmaceutical delivery and treatment efficacy. Despite these advances, the achievement of high drug loading and loading efficiencies of drug payloads in nanocarriers remains a technical challenge. In addition, study of the correlation between therapeutic potential and drug loading has been ignored. Here, using a self-assembling dimeric cabazitaxel prodrug, we show that the prodrug can be quantitatively entrapped within clinically approved polymer matrices for intravenous injection and that the drug loading in the nanoparticles (NPs) is tunable. The engineered NPs (NPs1-4) with different drug loading values exhibit dissimilar morphologies, release kinetics, in vitro cytotoxic activity, pharmacokinetic properties, tissue distribution, and in vivo anticancer efficacy and safety profiles. Furthermore, the effect of drug loading on the treatment outcomes was explored through detailed in vitro and in vivo studies. Intriguingly, among the constructed NPs, those comprising poly(ethylene glycol)-block-poly(D,L-lactic acid) (PEG-PLA) copolymers showed substantially prolonged pharmacokinetic properties in the blood circulation, which further promoted their intratumoral delivery and accumulation. Furthermore, the PEG-PLA-composed NPs with high drug loading (~50%) demonstrated favorable efficacy and safety profile in animal models. These data provide convincing evidence that the in vivo performance of a given self-assembling drug is not compromised by high drug loading in nanoplatforms, which may potentially reduce concerns over excipient-associated side effects and immunotoxicities. Overall, our study provides new insight into the rationale for designing more effective and less toxic delivery systems.