Novel multi-stimuli responsive functionalized PEG-based co-delivery nanovehicles toward sustainable treatments of multidrug resistant tumor

Abstract

The efficacy of ongoing anticancer treatment is often compromised by some barriers, such as low drug content, nonspecific release of drug delivery system, and multidrug resistance (MDR) effect of tumors. Herein, in the research a novel functionalized PEG-based polymer cystine–(polyethylene glycol)₂-b-(poly(2-methacryloyloxyethyl ferrocenecarboxylate)₂) (Cys–(PEG₄₅)₂-b-(PMAOEFC)₂) with multi-stimuli sensitive mechanism was constructed, in which doxorubicin (DOX) was chemical bonded through Schiff base structure to provide acid labile DOX prodrug (DOX)₂–Cys–(PEG₄₅)₂-b-(PMAOEFC)₂. Afterwards, paclitaxel (PTX) and its diselenide bond linked PTX dimer were encapsulated into the prodrug through physical loading, to achieve pH and triple redox responsive (DOX)₂–Cys–(PEG₄₅)₂-b-(PMAOEFC)₂^@PTX and (DOX)₂–Cys–(PEG₄₅)₂-b-(PMAOEFC)₂^@PTX dimer with ultrahigh drugs content. The obtained nanovehicles could self-assemble into globular micelles with good stability based on fluorescence spectra and TEM observation. Moreover, there was a remarkable “reassembly–disassembly” behavior caused by phase transition of micelles under the mimic cancerous physiological environment. DOX and PTX could be on-demand released in acid and redox stress mode, respectively. Meanwhile, in vivo anticancer studies revealed the significant tumor inhibition of nanoformulas. This work offered facile strategies to fabricate drug nanaovehicles with tunable drug content and types, it has a profound significance in overcoming MDR effect, which provided more options for sustainable cancer treatment according to the desired drug dosage and the stage of tumor growth.