Abstract
The inevitable challenge in conventional chemotherapy is to deliver the anticancer drugs to the dense population of tumors cells while minimizing the drug-associated side effects on the normal cells. Cancer cells' preference for glycolysis for energy production is well recognized. Intuitively, taking advantage of such cancer-associated metabolism would be a promising strategy for anticancer drug delivery with minimal side effects. In this investigation, we have designed a binary prodrug PDOX as a sequential drug delivery regimens to realize the combination therapy for cancer. As cancer cells exhibit abrupt metabolism with elevated pyruvate dehydrogenase kinase (PDK) activity, dichloroacetic acid (DCA, a well-known PDK inhibitor) was used in combination with anticancer drug doxorubicin (DOX). The designed molecular prodrug was activated selectively by cancer-associated esterase to deliver DCA and DOX, respectively, and induced synergetic effects. Hence, sequential targeted delivery of molecular prodrug PDOX offers a promising approach to overcome the offside drug toxicity, pharmacokinetics, and biodistribution of individuals and provide an alternative option for cancer treatment.
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