Acid-sensitive PEGylated paclitaxel prodrug nanoparticles for cancer therapy: Effect of PEG length on antitumor efficacy

Paclitaxel is one of the most widely used anticancer agents, but strong side effects and low bioavailability limit its clinical efficacy. The use of tumor microenvironment-responsive prodrugs is promising to solve these problems, and a smart linkage is crucial to achieve the efficient release of paclitaxel from such prodrugs in tumor. Herein, an acid-responsive acetone-based acyclic ketal linkage is used to construct paclitaxel prodrugs with different length of poly(ethylene glycol) (PEG). The PEGylated acetone-based acyclic-ketal-linked prodrugs of paclitaxel (PKPs) self-assembled into nanoparticles that were stable in normal physiological environment but released paclitaxel rapidly in mildly acidic environment in tumor. The length of PEG had considerable impact on size and critical micelle concentration of PKP nanoparticles, thereby affecting prodrug hydrolysis kinetics, pharmacokinetics, biodistribution, and antitumor activity for PKP nanoparticles. In an A2780 xenograft mouse model, PKP nanoparticles displayed improved pharmacokinetics and superior antitumor efficacy against Taxol. Our results demonstrate that acyclic-ketal-based prodrugs are useful for the development of acid-responsive anticancer nanomedicines.