Promoting antitumor efficacy by suppressing hypoxia via nano self-assembly of two irinotecan-based dual drug conjugates having a HIF-1α inhibitor.

Hypoxia inducible factor (HIF-1α), as a major transcription factor in response to hypoxia, revealed that it could be a promising tumor-specific target for anticancer therapy. In view of clinical application, the formation of a hypoxic microenvironment in tumors can decrease the curative effect of cytotoxic chemotherapeutic drugs. To promote the antitumor efficacy of chemical drugs by suppressing hypoxia, we designed and conjugated a hydrophobic HIF-1α inhibitor (YC-1) to a hydrophilic anticancer drug, irinotecan (Ir), into one molecular entity via dicarboxylate and PEG3 linkages. Benefiting from its amphiphilicity, the resulting conjugate could act as molecular building blocks to self-assemble into nanoparticles (Ir-YC-1 and Ir-PEG3-YC-1 NPs) in water, which improved the solubility of drugs. As expected, the Ir-YC-1 NPs significantly down-regulated the expression of HIF-1α and VEGF proteins, and exhibited 5.7-fold increased antitumor activity compared to Ir when administered to A549 cells under the hypoxic condition. This novel, simple, and effective strategy for overcoming tumor hypoxia and enhancing the antitumor effect of chemical drugs has great potential in cancer therapy.