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Triple negative breast cancer (TNBC) is highly malignant and prone to recurrence and metastasis. Patients with TNBC usually have poor prognosis. Hence, it is urgent to develop new comprehensive treatments for TNBC. The combination of heat shock protein (HSP) inhibitor and the photothermal agent can reduce the temperature required to kill tumor cells, thus achieving mild-temperature photothermal therapy (PTT). Compared with traditional PTT, mild-temperature PTT not only decreases tumor thermoresistance introduced by the overexpression of HSP, but also reduces the damage to normal tissues. Meanwhile, Azo initiator 2,2-azobis[2-(2-imidazolin-2-yl) propane]-dihydroch-loride (AIPH) can be thermally decomposed to generate oxygen-independent free radicals. Herein, a new therapeutic multifunctional nanoplatform (M-17AAG-AIPH) by loading heat shock protein 90 (HSP90) inhibitor (17AAG) and AIPH incorporated into mesoporous polydopamine (MPDA) was successfully constructed for mild-temperature PTT combined with oxygen-independent cytotoxic free radicals against TNBC. Under 808 nm laser irradiation, the mild-temperature PTT arising from the combined effects of 17AAG and MPDA induced a rapid release and decomposition of AIPH, promoting the apoptosis of cancer cells in hypoxic microenvironments. Both in vitro and in vivo results showed that the designed nanoplatform can significantly inhibit tumor growth and provided an efficient new therapeutic strategy for TNBC. There is still an urgent need for new strategies for the treatment of triple negative breast cancer (TNBC). In this work, we successfully constructed a new therapeutic multifunctional nanoplatform (M-17AAG-AIPH) by co-carrying heat shock protein 90 (HSP90) inhibitor (17AAG) and AIPH on mesoporous polydopamine (MPDA). MPDA owned good biocompatibility and outstanding photothermal-conversion ability. The loading of 17AAG can reduce the heat resistance of tumor cells via specifically inhibiting the activity of HSP90, so as to achieve mild-temperature PTT. Meanwhile, 17AAG and MPDA mediated mild-temperature PTT promoted the decomposition of AIPH into oxygen-independent cytotoxic free radicals. Both in vitro and in vivo results showed that M-17AAG-AIPH can significantly inhibit tumor growth and provided an efficient new therapeutic strategy for TNBC. [Display omitted] [ABSTRACT FROM AUTHOR]

Photodynamic therapy (PDT) is an effective noninvasive therapeutic strategy that can convert oxygen to highly cytotoxic singlet oxygen (1O 2) through the co-localization of excitation light and photosensitizers. However, compromised by the hypoxic tumor microenvironment, the therapeutic efficacy of PDT is reduced seriously. Herein, to overcome tumor-associated hypoxia, and further achieve tumor-targeted synergistic chemotherapy/PDT/photothermal therapy (PTT), we have constructed a biodegradable oxygen-producing nanoplatform (named Ini@PM-HP), which was composed of the porous metal-organic framework (PCN-224(Mn)), the poly (ADP-ribose) polymerase (PARP) inhibitor (Iniparib), and the polydopamine-modified hyaluronic acid (HA-PDA). Since HA can specifically bind to the overexpressed HA receptors (cluster determinant 44, CD44) on tumor cell, Ini@PM-HP prefers to accumulate at the tumor site once injected intravenously. Then iniparib can be released in tumor environment (TME), thereby dysfunctioning DNA damage repair and promoting cell apoptosis. At the same time, the chelating of Mn and tetrakis(4-carboxyphenyl) porphyrin (Mn-TCPP) can generate O 2 in situ by reacting with endogenous H 2 O 2 , relieving the hypoxic TME and achieving enhanced PDT. Moreover, owing to the high photothermal conversion efficiency of PDA, PTT can be driven by the 808 nm laser irradiation. As systematically demonstrated in vitro and in vivo , this nanotherapeutic approach enables the combined therapy with great inhibition on tumor. Overall, the as-prepared nanoplatform provide a promising strategy to overcome tumor-associated hypoxia, and shows great potential for combination tumor therapy. A delicately designed biodegradable oxygen-producing nanoplatform Ini@PM-HP is constructed to achieve combination therapy of solid tumors. Taking advantage of the active-targeting, PTT, enhanced PDT and PARPi, this nanotherapeutic approach successfully enables the combined chemo/photothermal/photodynamic therapy with great inhibition of solid tumors. [Display omitted] [ABSTRACT FROM AUTHOR]