Full-active pharmaceutical ingredient nanosensitizer for augmented photoimmunotherapy by synergistic mitochondria targeting and immunogenic death inducing

Abstract

The precise and effective activation of the immune response is crucial in promising therapy curing cancer. Photoimmunotherapy (PIT) is an emerging strategy for precise regulation and highly spatiotemporal selectivity. However, this approach faces a significant challenge due to the off-target effect and the immunosuppressive microenvironment. To address this challenge, a nanoscale full-active pharmaceutical ingredient (API) photo-immune stimulator was developed. This formulation overcomes the limitations of PIT by strengthening the ability to penetrate tumors deeply and inducing precise and potent mitochondria-targeted dual-mode photodynamic therapy and photothermal therapy. Along with inhibiting overexpressed Hsp90, this nanosensitizer in turn improves the immunosuppressive microenvironment. Ultimately, this mitochondria-targeted PIT demonstrated potent antitumor efficacy, achieving a remarkable inhibition rate of ≥95% for both established primary tumors and distant abscopal tumors. In conclusion, this novel self-delivery full-API nanosystem enhances the efficacy of phototherapy and reprograms the immunosuppressive microenvironment, thereby holding great promise in the development of precise and effective immunotherapy.

Keywords

full-API nanosystem / heat shock protein / immunogenic cell death / mitochondria targeting / photoimmunotherapy

References

[1] Crunkhorn S. Strengthening the sting of immunotherapy. Nat Rev Drug Discov. 2020; 19(10): 669.

[2] Hiam-Galvez KJ, Allen BM, Spitzer MH. Systemic immunity in cancer. Nat Rev Cancer. 2021; 21(6): 345-359.

[3] Li X, Wenes M, Romero P, Huang SCC, Fendt SM, Ho PC. Navigating metabolic pathways to enhance antitumour immunity and immunotherapy. Nat Rev Clin Oncol. 2019; 16(7): 425-441.

[4] Schudel A, Francis DM, Thomas SN. Material design for lymph node drug delivery. Nat Rev Mater. 2019; 4(6): 415-428.

[5] Li X, Wang H, Chen Y, et al. Novel emerging nano-assisted anti-cancer strategies based on the STING pathway. Acta Mater Medica. 2023; 2(3): 323-341.

[6] Mitchell MJ, Billingsley MM, Haley RM, Wechsler ME, Peppas NA, Langer R. Engineering precision nanoparticles for drug delivery. Nat Rev Drug Discov. 2021; 20(2): 101-124.

[7] Jiang W, Wang Y, Wargo JA, Lang FF, Kim BYS. Considerations for designing preclinical cancer immune nanomedicine studies. Nat Nanotechnol. 2021; 16(1): 6-15.

[8] Zhao LP, Zheng RR, Huang JQ, et al. Self-delivery photo-immune stimulators for photodynamic sensitized tumor immunotherapy. ACS Nano. 2020; 14(12): 17100-17113.

[9] Wang D, Liu J, Wang C, et al. Microbial synthesis of Prussian blue for potentiating checkpoint blockade immunotherapy. Nat Commun. 2023; 14(1): 1-16.

[10] Li J, Duran MA, Dhanota N, et al. Metastasis and immune evasion from extracellular cgamp hydrolysis. Cancer Discov. 2021; 11(5): 1212-1227.

[11] Gan S, Tong X, Zhang Y, Wu J, Hu Y, Yuan A. Covalent organic framework-supported molecularly dispersed near-infrared dyes boost immunogenic phototherapy against tumors. Adv Funct Mater. 2019; 29(46): 1-14.

[12] Yan S, Zeng X, Tang Y, Liu BF, Wang Y, Liu X. Activating antitumor immunity and antimetastatic effect through polydopamine-encapsulated core–shell upconversion nanoparticles. Adv Mater. 2019; 31(46): 1-8.

[13] Guan W, Secondary CA, Author C. Oxygen Tank for synergistic hypoxia relief to enhance mitochondria targeted photodynamic therapy. Biomater Res. 2022: 1-17. Published online.

[14] Yang Z, Wang J, Liu S, et al. Defeating relapsed and refractory malignancies through a nano-enabled mitochondria-mediated respiratory inhibition and damage pathway. Biomaterials. 2020; 229: 119580.

[15] Su X, Cao Y, Liu Y, et al. Localized disruption of redox homeostasis boosting ferroptosis of tumor by hydrogel delivery system. Mater Today Bio. 2021; 12(October):100154.

[16] Yang Z, Wang J, Liu S, et al. Tumor-targeting W18O49 nanoparticles for dual-modality imaging and guided heat-shock-response-inhibited photothermal therapy in gastric cancer. Part Syst Charact. 2019; 36(7): 1-12.

[17] Pick E, Kluger Y, Giltnane JM, et al. High HSP90 expression is associated with decreased survival in breast cancer. Cancer Res. 2007; 67(7): 2932-2937.

[18] Huston A, Leleu X, Jia X, et al. Targeting Akt and heat shock protein 90 produces synergistic multiple myeloma cell cytotoxicity in the bone marrow microenvironment. Clin Cancer Res. 2008; 14(3): 865-874.

[19] Aswad A, Liu T. Targeting Heat Shock Protein 90 for Anti-Cancer Drug Development. 1st ed., Elsevier Inc.; 2021. Vol.

[20] Zhang A, Zhang Q, Alfranca G, et al. GSH-triggered sequential catalysis for tumor imaging and eradication based on star-like Au/Pt enzyme carrier system. Nano Res. 2020; 13(1): 160-172.

[21] Hu C, Yang J, Qi Z, et al. Heat shock proteins: biological functions, pathological roles, and therapeutic opportunities. MedComm. 2022; 3(3): 1-39.

[22] Kamal A, Thao L, Sensintaffar J, et al. A high-affinity conformation of Hsp90 confers tumour selectivity on Hsp90 inhibitors. Nature. 2003; 425(6956): 407-410.

[23] Dimopoulos MA, Mitsiades CS, Anderson KC, Richardson PG. Tanespimycin as antitumor therapy. Clin Lymphoma, Myeloma Leuk. 2011; 11(1): 17-22.

[24] Talaei S, Mellatyar H, Asadi A, Akbarzadeh A, Sheervalilou R, Zarghami N. Spotlight on 17-AAG as an Hsp90 inhibitor for molecular targeted cancer treatment. Chem Biol Drug Des. 2019; 93(5): 760-786.

[25] Liu Y, Qiu N, Shen L, et al. Nanocarrier-mediated immunogenic chemotherapy for triple negative breast cancer. J Control Release. 2020; 323: 431-441.

[26] Hicks GEJ, Li S, Obhi NK, Jarrett-Wilkins CN, Seferos DS. Programmable assembly of π-conjugated polymers. Adv Mater. 2021; 33(46): 1-21.

[27] Li SL, Xiao T, Lin C, Wang L. Advanced supramolecular polymers constructed by orthogonal self-assembly. Chem Soc Rev. 2012; 41(18): 5950-5968.

[28] Zhao LP, Zheng RR, Chen HQ, et al. Self-delivery nanomedicine for O2-economized photodynamic tumor therapy. Nano Lett. 2020; 20(3): 2062-2071.

[29] Zhao L, Zheng R, Liu L, et al. Self-delivery oxidative stress amplifier for chemotherapy sensitized immunotherapy. Biomaterials. 2021; 275(May):120970.

[30] Chen C, Tong Y, Zheng Y, et al. Cytosolic delivery of thiolated Mn-cGAMP nanovaccine to enhance the antitumor immune responses. Small. 2021; 17(19): e2102241.

[31] Li X, Wang H, Li Z, et al. Oxygen tank for synergistic hypoxia relief to enhance mitochondria-targeted photodynamic therapy. Biomater Res. 2022; 26(1): 1-17.

[32] Jeong EM, Yoon JH, Lim J, et al. Real-time monitoring of glutathione in living cells reveals that high glutathione levels are required to maintain stem cell function. Stem Cell Reports. 2018; 10(2): 600-614.

[33] Gan S, Tong X, Zhang Y, Wu J, Hu Y, Yuan A. Covalent organic framework-supported molecularly dispersed near-infrared dyes boost immunogenic phototherapy against tumors. Adv Funct Mater. 2019; 29(46): 1902757.

[34] Wang H, Guo Y, Gan S, et al. Photosynthetic microorganisms-based biophotothermal therapy with enhanced immune response. Small. 2021; 17(18): e2007734.

[35] Yang Z, Wang J, Liu S, et al. Tumor-targeting W18O49 nanoparticles for dual-modality imaging and guided heat-shock-response-inhibited photothermal therapy in gastric cancer. Part Part Syst Charact. 2019; 36(7): 1900124.

[36] Yang Y, Zhu W, Dong Z, et al. 1D coordination polymer nanofibers for low-temperature photothermal therapy. Adv Mater. 2017; 29(40): 1703588.

[37] Mo JH, Choi IJ, Jeong WJ, Jeon EH, Ahn SH. HIF-1α and HSP90: target molecules selected from a tumorigenic papillary thyroid carcinoma cell line. Cancer Sci. 2012; 103(3): 464-471.

[38] Yan JW, Zhu JY, Zhou KX, et al. Neutral merocyanine dyes: for in vivo NIR fluorescence imaging of amyloid-β plaques. Chem Commun. 2017; 53(71): 9910-9913.

[39] Huang Z, Wang Y, Yao D, Wu J, Hu Y, Yuan A. Nanoscale coordination polymers induce immunogenic cell death by amplifying radiation therapy mediated oxidative stress. Nat Commun. 2021; 12(1): 1-18.

[40] Wang W, Cheng Y, Yu P, et al. Perfluorocarbon regulates the intratumoural environment to enhance hypoxia-based agent efficacy. Nat Commun. 2019; 10(1): 1-11.

[41] Wang H, Liu H, Guo Y, et al. Photosynthetic microorganisms coupled photodynamic therapy for enhanced antitumor immune effect. Bioact Mater. 2022; 12(August): 97-106.

[42] Wang Y, Chen J, Duan R, et al. High-Z sensitized radiotherapy synergizes with the intervention of the pentose phosphate pathway for in situ tumor vaccination. Adv Mater. 2022:2109726. Published online.

[43] Gajewski TF, Schreiber H, Fu YX. Innate and adaptive immune cells in the tumor microenvironment. Nat Immunol. 2013; 14(10): 1014-1022.

[44] Sanmamed MF, Nie X, Desai SS, et al. A burned-out CD8 + T-cell subset expands in the tumor microenvironment and curbs cancer immunotherapy. Cancer Discov. 2021; 11(7): 1700-1715.

[45] Li X, Ai S, Lu X, Liu S, Guan W. Nanotechnology-based strategies for gastric cancer imaging and treatment. RSC Adv. 2021; 11(56): 35392-35407.

[46] Li X, Chen Y, Dong Y, Ma Z, Zheng W, Lin Y. Prediction of immune infiltration and prognosis for patients with gastric cancer based on the immune-related genes signature. Heliyon. 2023; 9(12): e22433.

[47] Pustylnikov S, Costabile F, Beghi S, Facciabene A. Targeting mitochondria in cancer: current concepts and immunotherapy approaches. Transl Res. 2018; 202: 35-51.

[48] Zhou Z, Zhang B, Zai W, et al. Perfluorocarbon nanoparticle-mediated platelet inhibition promotes intratumoral infiltration of T cells and boosts immunotherapy. Proc Natl Acad Sci U S A. 2019; 116(24): 11972-11977.

[49] Wang W, Xu H, Ye Q, et al. Systemic immune responses to irradiated tumours via the transport of antigens to the tumour periphery by injected flagellate bacteria. Nat Biomed Eng. 2022; 6(1): 44-53.

[50] Wang H, Liu H, Guo Y, et al. Photosynthetic microorganisms coupled photodynamic therapy for enhanced antitumor immune effect. Bioact Mater. 2022; 12(October): 97-106.

[51] Qin J, Gong N, Liao Z, et al. Recent progress in mitochondria-targeting-based nanotechnology for cancer treatment. Nanoscale. 2021; 13(15): 7108-7118.

[52] Guo X, Yang N, Ji W, et al. Mito-Bomb: targeting mitochondria for cancer therapy. Adv Mater. 2021; 33(43): e2007778.

[53] Roushandeh AM, Kuwahara Y, Roudkenar MH. Mitochondrial transplantation as a potential and novel master key for treatment of various incurable diseases. Cytotechnology. 2019; 71(2): 647-663.

[54] Catherine B, Guido K. Mitochondria–the death signal integrators. Science (80-). 2000; 289(5482): 1150-1151.

[55] Cabral H, Li J, Miyata K, Kataoka K. Controlling the biodistribution and clearance of nanomedicines. Nat Rev Bioeng. 2024; 2(3): 214-232.

[56] Ouyang P, Yang W, Sun J, et al. Endocrine toxicity of immune checkpoint inhibitors: a network meta-analysis of the current evidence. Acta Mater Medica. 2024; 3(1): 1-19.

[57] Li X, Wang H, Li Z, et al. Oxygen switches: refueling for cancer radiotherapy. Front Oncol. 2022; 12: 1-10.

[58] Zhou Z, Zhang B, Zai W, et al. Perfluorocarbon nanoparticle-mediated platelet inhibition promotes intratumoral infiltration of T cells and boosts immunotherapy. Proc Natl Acad Sci U S A. 2019; 116(24): 11972-11977.

[59] Wang H, Mu J, Chen Y, et al. Hybrid ginseng-derived extracellular vesicles-like particles with autologous tumor cell membrane for personalized vaccination to inhibit tumor recurrence and metastasis. Adv Sci. 2024; 2308235: 1-17.

RIGHTS & PERMISSIONS

2024 The Author(s). MedComm published by Sichuan International Medical Exchange & Promotion Association (SCIMEA) and John Wiley & Sons Australia, Ltd.