Dynamic micelles with detachable PEGylation at tumoral extracellular pH for enhanced chemotherapy

Abstract

Although surface PEGylation of nanomedicines can decrease serum protein adsorption in vivo, it also blocks uptake by tumor cells. This dilemma could be overcome by employing detachably PEGylated strategy at tumoral extracellular microenvironment to achieve improved cellular uptake while prolonged circulation times. Herein, the amphiphilic graft copolymers with pH-sensitive ortho ester-linked mPEG in side chains and polyurethanes in backbone, can self-assemble into the free and doxorubicin (DOX)-loaded micelles. The pH-sensitive micelles could undergo several characteristics as follows: (i) PEGylated shells for stability in sodium dodecyl sulfonate (SDS) solution; (ii) DePEGylation via degradation of ortho ester linkages at tumoral extracellular pH (6.5) for gradually dynamic size changes and effective release of DOX; and (iii) enhanced cellular uptake and cytotoxicity via positive DOX. Moreover, the dynamic micelles with detachable PEGylation could quickly penetrate the centers of SH-SY5Y multicellular spheroids (MCs) and strongly inhibit tumor growth in vitro and in vivo, and might be considered as promising and effective drug carriers in tumor therapy.

Keywords

• Micelles
• Ortho ester
• PEGylation
• Size transition
• Antitumor