A 2D Nanoradiosensitizer Enhances Radiotherapy and Delivers STING Agonists to Potentiate Cancer Immunotherapy

Overview

Journal Adv Mater

Date 2022 Aug 11

PMID 35952624

Authors

Taokun Luo

Geoffrey T Nash

Xiaomin Jiang

Xuanyu Feng

Jianming Mao

Jianqiao Liu

Aditya Juloori

Alexander T Pearson

Wenbin Lin

Affiliations

Soon will be listed here.

Abstract

Despite potent preclinical antitumor activity, activation of stimulator of interferon genes (STING) has shown modest therapeutic effects in clinical studies. Many STING agonists, including 2',3'-cyclic guanosine monophosphate-adenosine monophosphate (cGAMP), show poor pharmacokinetic properties for sustaining STING activation in tumors and achieving optimal antitumor efficacy. Improved delivery of STING agonists and their effective combination with other treatments are needed to enhance their therapeutic effects. Herein, a 2D nanoplatform, cGAMP/MOL, is reported via conjugating cGAMP to a nanoscale metal-organic layer (MOL) for simultaneous STING activation and radiosensitization. The MOL not only exhibits strong radiosensitization effects for enhanced cancer killing and induction of immunogenic cell death, but also retains cGAMP in tumors for sustained STING activation. Compared to free cGAMP, cGAMP/MOL elicits stronger STING activation and regresses local tumors upon X-ray irradiation. Further combination with an immune checkpoint inhibitor bridges innate and adaptive immune systems by activating the tumor microenvironment to elicit systemic antitumor responses.

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References

Kang J, Demaria S, Formenti S . Current clinical trials testing the combination of immunotherapy with radiotherapy. J Immunother Cancer. 2016; 4:51. PMC: 5028964. DOI: 10.1186/s40425-016-0156-7. View

Qian J, Schoenfeld J . Radiotherapy and Immunotherapy for Head and Neck Cancer: Current Evidence and Challenges. Front Oncol. 2021; 10:608772. PMC: 7886974. DOI: 10.3389/fonc.2020.608772. View

Hafner M, Niepel M, Chung M, Sorger P . Growth rate inhibition metrics correct for confounders in measuring sensitivity to cancer drugs. Nat Methods. 2016; 13(6):521-7. PMC: 4887336. DOI: 10.1038/nmeth.3853. View

Carozza J, Bohnert V, Nguyen K, Skariah G, Shaw K, Brown J . Extracellular cGAMP is a cancer cell-produced immunotransmitter involved in radiation-induced anti-cancer immunity. Nat Cancer. 2021; 1(2):184-196. PMC: 7990037. DOI: 10.1038/s43018-020-0028-4. View

Bowen J, LEVINSON C . Phosphate concentration and transport in Ehrlich ascites tumor cells: effect of sodium. J Cell Physiol. 1982; 110(2):149-54. DOI: 10.1002/jcp.1041100207. View

Ghosh P, Han G, De M, Kim C, Rotello V . Gold nanoparticles in delivery applications. Adv Drug Deliv Rev. 2008; 60(11):1307-1315. DOI: 10.1016/j.addr.2008.03.016. View

Goretti Penido M, Alon U . Phosphate homeostasis and its role in bone health. Pediatr Nephrol. 2012; 27(11):2039-2048. PMC: 3461213. DOI: 10.1007/s00467-012-2175-z. View

Li S, Luo M, Wang Z, Feng Q, Wilhelm J, Wang X . Prolonged activation of innate immune pathways by a polyvalent STING agonist. Nat Biomed Eng. 2021; 5(5):455-466. PMC: 8126516. DOI: 10.1038/s41551-020-00675-9. View

Xie J, Gong L, Zhu S, Yong Y, Gu Z, Zhao Y . Emerging Strategies of Nanomaterial-Mediated Tumor Radiosensitization. Adv Mater. 2018; 31(3):e1802244. DOI: 10.1002/adma.201802244. View

10.

Obeid M, Tesniere A, Ghiringhelli F, Fimia G, Apetoh L, Perfettini J . Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2006; 13(1):54-61. DOI: 10.1038/nm1523. View

11.

Jiang X, Du B, Yu M, Jia X, Zheng J . Surface-ligand effect on radiosensitization of ultrasmall luminescent gold nanoparticles. J Innov Opt Health Sci. 2017; 9(4):16420031-16420038. PMC: 5639719. DOI: 10.1142/S1793545816420037. View

12.

Byun D, Wolchok J, Rosenberg L, Girotra M . Cancer immunotherapy - immune checkpoint blockade and associated endocrinopathies. Nat Rev Endocrinol. 2017; 13(4):195-207. PMC: 5629093. DOI: 10.1038/nrendo.2016.205. View

13.

Weichselbaum R, Liang H, Deng L, Fu Y . Radiotherapy and immunotherapy: a beneficial liaison?. Nat Rev Clin Oncol. 2017; 14(6):365-379. DOI: 10.1038/nrclinonc.2016.211. View

14.

Moon J, Huang B, Irvine D . Engineering nano- and microparticles to tune immunity. Adv Mater. 2012; 24(28):3724-46. PMC: 3786137. DOI: 10.1002/adma.201200446. View

15.

Reutelingsperger C, van Heerde W . Annexin V, the regulator of phosphatidylserine-catalyzed inflammation and coagulation during apoptosis. Cell Mol Life Sci. 1997; 53(6):527-32. PMC: 11147358. DOI: 10.1007/s000180050067. View

16.

Korangath P, Barnett J, Sharma A, Henderson E, Stewart J, Yu S . Nanoparticle interactions with immune cells dominate tumor retention and induce T cell-mediated tumor suppression in models of breast cancer. Sci Adv. 2020; 6(13):eaay1601. PMC: 7096167. DOI: 10.1126/sciadv.aay1601. View

17.

Nam K, Park S, Reis R, Dravid V, Kim H, Mirkin C . Conductive 2D metal-organic framework for high-performance cathodes in aqueous rechargeable zinc batteries. Nat Commun. 2019; 10(1):4948. PMC: 6821766. DOI: 10.1038/s41467-019-12857-4. View

18.

Bonvalot S, Rutkowski P, Thariat J, Carrere S, Ducassou A, Sunyach M . NBTXR3, a first-in-class radioenhancer hafnium oxide nanoparticle, plus radiotherapy versus radiotherapy alone in patients with locally advanced soft-tissue sarcoma (Act.In.Sarc): a multicentre, phase 2-3, randomised, controlled trial. Lancet Oncol. 2019; 20(8):1148-1159. DOI: 10.1016/S1470-2045(19)30326-2. View

19.

Baker S, Worthley L . The essentials of calcium, magnesium and phosphate metabolism: part I. Physiology. Crit Care Resusc. 2006; 4(4):301-6. View

20.

Ni K, Lan G, Guo N, Culbert A, Luo T, Wu T . Nanoscale metal-organic frameworks for x-ray activated in situ cancer vaccination. Sci Adv. 2020; 6(40). PMC: 7852401. DOI: 10.1126/sciadv.abb5223. View