GSH-activatable Camptothecin Prodrug-loaded Gold Nanostar Coated with Hyaluronic Acid for Targeted Breast Cancer Therapy via Multiple Radiosensitization Strategies

Breast cancer has overtaken lung cancer to rank as the top malignant tumor in terms of incidence. Herein, gold nanostar (denoted as AuNS) is used for loading disulfide-coupled camptothecin-fluorophore prodrugs (denoted as CPT-SS-FL) to form the nanocomposite of AuNS@CPT-SS-FL (denoted as AS), which, in turn, further encapsulated with hyaluronic acid (HA) to give the final nanoplatform of AuNS@CPT-SS-FL@HA (denoted as ASH). ASH effectively carries the prodrug and targets the CD44 receptor on the surface of tumor cells. The endogenously overexpressed glutathione (GSH) in tumor cells breaks the disulfide bond to activate the prodrug and release the radiosensitizer drug camptothecin (CPT) and the fluorescent imaging reagent rhodamine derivative as fluorophore (FL). The released FL can track the precise release position of radiosensitizer camptothecin in tumor cells in real time. While the AuNS has strong X-ray absorption and deposition ability due to the high atomic coefficient of elemental Au (Z = 79). At the same time, AuNS can alleviate the tumor microenvironment (TME) hypoxia through its mild photothermal therapy (PTT). Therefore, through the multiple radiosensitizing effects of GSH depletion, high atomic coefficient of Au, and hypoxia alleviation, accompanied by the radiosensitizer camptothecin, the designed ASH nanoplatform can effectively induce strong immunogenic cell death (ICD) at the tumor site via radiosensitizing therapy combined with PTT. This work provides a new way of constructing a structurally compact and highly functionalized hierarchical system toward efficient breast cancer treatment through ameliorating TME with multiple modalities.