Abstract
Currently, architecting a rational and efficient nanoplatform combing with multi-therapeutic modalities is highly obligatory for advanced cancer treatment. In order to remedy the self-limiting hypoxic dilemma of photodynamic therapy (PDT), herein, a facile photosensitizer (i.e., chlorin e6, Ce6) and bioreductive prodrug (i.e., tirapazamine, TPZ)-coloaded hyaluronic acid (HA) nanomicelles (denoted as TPZ@HA-Ce6) was developed for the cascading mode of photo-bioreductive cancer therapy. Taking the typical advantage of Ce6 coupled HA conjugate, TPZ was easily and successfully accommodated into the hydrophobic core of HA-Ce6 nanomicelles, yielding TPZ@HA-Ce6. It showed good dispersibility and stability with the hydrodynamic size of ca. 170 nm. It targeted the CD44 overexpressed cancer cells by receptor-mediated endocytosis way and killed them effectively with singlet oxygen and the subsequent TPZ radicals resulting from the oxygen depletion of PDT. The later was further verified by the hypoxia probe in vivo. Using murine mammary carcinoma 4T1 model, TPZ@HA-Ce6 nanomicelles exhibited cascading and synergistic anticancer effect of PDT and TPZ bioreductive therapy compared with each monotherapy. This work suggests the promising prospect of the hybrid hyaluronic nanomicelles for highly efficient cancer combination treatment.
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