Abstract
Successful delivery of drugs to the target site is half the battle against tumors as intracellular alkalization pH (pHi) microenvironments severely restricted the efficacy of chemotherapy drugs delivered into tumor cells. Herein, a redox-selective pH-triggered "lysosomal bomb" (DSA/CC-DOX) is developed based on vaterite calcium carbonate and disulfide-cross-linked sodium alginate (DSA) with doxorubicin (DOX) encapsulated. Benefiting from the acid-triggered volume expansion of CaCO3, DSA/CC-DOX NPs can act like a "lysosomal bomb" that rapidly tears the lysosomal membrane with the release of acidic inclusions and the loaded DOX, and then the alkalized pHi in human liver tumor cells (HepG2) can be decreased from 7.61 to 7.09, thus promoting the intracellular accumulation of DOX nearly 3 times more than the free drug. In addition, facilitated by the responsive break of the disulfide bond to GSH, the release of DOX in HepG2 is nearly 8 times that of human normal liver cell (LO2). Notably, DSA/CC-DOX treatment increased the tumor inhibition rate of free drug by 16% and effectively reduced the cardiotoxicity of DOX in the mouse H22 liver cancer model. Overall, acidifying the tumor intracellular environment is a prospective way to improve the antitumor capacity of chemotherapy drug.
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