Redox-responsive paclitaxel-pentadecanoic acid conjugate encapsulated human serum albumin nanoparticles for cancer therapy.

Human serum albumin (HSA) is an important nanocarrier of hydrophobic drugs due to its biocompatibility, bioresorbability, non-immunogenicity and intrinsic targetability. However, HSA/drug nanocomplexes have to experience complicated manufacturing process including multiple high-pressure homogenization and removing organic solvent under reduced pressure condition. Besides, the clinical application of these HSA/drug nanocomplexes is often limited because of their unsatisfactory stability and restricted dose. To overcome these issues, a redox-responsive paclitaxel-pentadecanoic acid prodrug conjugate embedded human serum albumin nanoparticles (NPs) was developed as a model in this report. First, PTX was activated and conjugated with 11-mercaptoundecanoic acid through a disulfide bond. The resultant disulfide bond bridged paclitaxel-pentadecanoic acid conjugate (PTX-SS-C10-COOH) was characterized by NMR and MS. After that, PTX-SS-C10-COOH dissolved in ethanol was mixed with HSA in water followed by lyophilization to generate HSA/PTX-SS-C10-COOH nanoparticles (HPTX NPs). Dynamic light scattering (DLS) and transmission electron microscopy (TEM) characterization indicated that the HPTX NPs have spherical structure with an average diameter of approximately 120 nm. The formation of HSA/PTX-SS-C10-COOH NPs was confirmed by fluorescence quenching technology, ascribed to electrostatic and hydrophobic interactions. The HPTX NPs displayed a highdrug loading of 29.78 % and an entrapment efficiency of 94.16 %. Their reduced responsiveness was validated by glutathione (GSH)-triggered fast release of PTX. The pharmacokinetics, antitumor efficacy and systemic toxicity of HPTX NPs were thoroughly evaluated. The results showed that the HPTX NPs had longer retention, more effective tumor growth inhibition and lower toxicity compared with commercialized Taxol®. Importantly, the HPTX NPs could be administered at much high dose to achieve a significant tumor growth inhibition compared with Abraxane®. Together, the redox-responsive HPTX NPs with high drug loading is a promising strategy to deliver PTX for cancer chemotherapy.