| Breast cancer is the most severe disease among women worldwide,in which frequent metastasis and recurrence account for its high mortality.Traditional therapeutic modalities mainly consist of surgery,chemotherapy,radiotherapy,endocrine therapy and targeted therapy.However,these therapies cannot result in satisfactory outcome due to their own limitations,leaving the risks of metastasis and recurrence.Harnessing the immune system to fight against breast cancer is widely acknowledged as an effective strategy to address metastasis and recurrence.It was reported that phototherapy,including photothermal therapy(PTT)and photodynamic therapy(PDT),could trigger immunogenic cell death(ICD)and thereby boost specific antitumor immune response.However,PTT cannot contribute to potent ICD,and owing to the short half-life and low transfer distance of reactive oxygen species(ROS)of ROS,the efficiency of PDT was largely restricted.Therefore,the subsequent PDT-induced immunity cannot result in satisfied antitumor immune response.Chemotherapeutic drug such as doxorubicin(DOX)was also recognized as ICD-inducer,whereas its ICD-inducing efficiency was relatively weak resulting from its fatal multidrug resistant(MDR).Hence,finding another effective strategy to maximize phototherapy and overcome MDR of chemotherapy to boost potent antitumor immunity is in the most urgent demand.Mitochondria are the vital organelles in supplying energy and regulating intrinsic cell apoptosis,which are hypersensitive to excessive ROS and hyperthermia.Additionally,MDR of DOX could be efficiently overcome by directly acting on mitochondria to bypass drug resistance mechanisms.Based on the above considerations,a rationally engineered immunity amplifier via mitochondria-targeted photo-chemotherapeutic nanoparticles was achieved to address metastasis and recurrence of breast cancer.IR780 iodide is a widely investigated phototherapeutic agent due to its advantage of excellent performance both in photothermal and photodynamic therapy.Therefore,IR780 was modified by conjugating with triphenylphosphonium cation(TPP)to obtain mitochondria-targeted TPP-IR780(T780).Furthermore,the newly synthesized T780 was co-assembled with DOX via ?-? and hydrophobic interaction along with bovine serum albumin(BSA)as biomimetic corona(BSA@T780/DOX NPs).This multifunctional nanoplatform could achieve the maximal photo-chemotherapy,trigger potent ICD and boost specific antitumor immune response to fight against metastasis and recurrence of breast cancer via mitochondria-targeted drug delivery.1.Construction and characterization of BSA@T780/DOX NPsMitochondria-targeted T780 was firstly synthesized and further co-assembled with DOX to form T780/DOX NPs.The co-existence of UV-Vis absorbance peaks of T780 and DOX proved the successful assembling.BSA was selected as biomimetic corona to shelter the toxicity in circulation to form BSA@T780/DOX NPs,and TEM image demonstrated the successful BSA coating on the surface of T780/DOX NPs.Besides,in vitro temperature-increasing and singlet oxygen detection results showed the excellent properties of BSA@T780/DOX NPs both in PTT and PDT.The release behavior of DOX indicated that little leakage of DOX happened before nanoparticles arriving at mitochondria.2.In vitro cellular antitumor evaluation of BSA@T780/DOX NPsMouse breast cancer 4T1 cells were applied to investigate the in vitro cellular antitumor evaluation of BSA@T780/DOX NPs.Laser scanning confocal microscopy(LSCM)showed nearly all T780 and DOX localized preferably in mitochondria.The MDR reversal capability of BSA@T780/DOX NPs was studied on MCF-7 cells and DOX-resistant MCF-7/ADR cells.The results showed that BSA@T780/DOX NPs performed enhanced chemotherapeutic effects compared with free DOX and the mixture of DOX and T780.The exposure of calreticulin and up-regulation of HSP70 proved the ICD induced by BSA@T780/DOX NPs.What's more,the high-efficient ICD could stimulate higher T cell proliferation ratio,indicating BSA@T780/DOX NPs could trigger immune response in vitro.3.In vivo photo-chemotherapeutic and immunotherapeutic evaluation of BSA@T780/DOX NPsAntitumor effects of BSA@T780/DOX NPs were evaluated on female Balb/c mice.In vivo biodistribution and unilateral antitumor effects showed that BSA@T780/DOX NPs preferentially accumulated in tumor sites and efficiently inhibited the growth of tumors.Moreover,elevated cleaved caspase 3 verified the mitochondria mediated intrinsic apoptosis induced by BSA@T780/DOX NPs.The increase of helper T cells and cytotoxic T cells and the decrease of regulatory T cells in spleen demonstrated the activation of antitumor immune response.Moreover,their changes in distant tumor indicated the abscopal effects of the amplified immunity of BSA@T780/DOX NPs against pre-existing metastatic tumors.Furthermore,BSA@T780/DOX NPs were superior in preventing metastasis and postsurgical recurrence.In summary,mitochondria-targeted coassembled nanoparticles were proposed to amplify simultaneous photo-chemotherapy for triggering high-efficient immune response against breast cancer.The BSA@T780/DOX NPs demonstrated excellent immunotherapy efficacy on ablation of unilateral tumor,inhibition of bilateral tumors and prevention of lung metastasis and postsurgical recurrence,providing broad potential for mitochondria-targeted photo-chemotherapy triggered immunotherapy against breast cancer. |
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