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TPGS-Based Dual-Targeted Crosslinked Micelles to Reverse Chemoresistance

D-α-Tocopherol polyethylene glycol succinate (TPGS) has been widely applied in drug delivery systems (DDS) to reverse tumor multidrug resistance (MDR) caused by overexpression of P-glycoprotein (P-gp). However its capability of inhibiting overexpression of P-gp is still limited due to poor penetration and premature drug release. Herein, the dual-targeted CMs based on charge reversal cell penetration peptide (cTAT) functionalized TPGS (cTAT-TPGS) and folic acid functionalized polypeptide (Folic acid-PEG-<i>b</i>-poly(Aspartic-Lipoic acid), FA-PPAL) were designed to reverse chemoresistance and improve chemotherapeutic efficacy. TAT was shielded by fatty acids and polypeptide introduced disulfide bonds. The CMs could keep stability with minimal drug leakage in blood circulation, whereas charge of TAT transform positive to improve the penetration and rapid dissociation of CMs to control drug release in low acidic and reductive environment of cancer cells. Furthermore, DOX achieved high accumulation in drug resistant cancer cells and directly released inside nucleus, leading to anti-MDR abilities and effective inhibition of tumor growth. Moreover, the DOX-loaded CMs showed excellent biosafety, especially for the myocardium tissue. Overall, this novel strategy provided an effective platform for drug target delivery and reversal of MDR.