Journal Home > Volume 16 , Issue 5
Nano Research 2023, 16(5): 7187-7198 https://doi.org/10.1007/s12274-022-5340-0
Research Article | Issue | Published: 10 January 2023

RNA sequencing-based optimization of biological lipid droplets for sonodynamic therapy to reverse tumor hypoxia and elicit robust immune response

Show Author's Information Zhan Shi1,2,§,  Xue Wang1,2,§,  Jiali Luo1,2,  Yiqing Zeng1,2,  Qing Wen1,2,  Yurong Hong1,2,  Tao Zhang1,2( ),  Pintong Huang1,2,3( )
Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
Research Center of Ultrasound in Medicine and Biomedical Engineering, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China
Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou 310009, China

§ Zhan Shi and Xue Wang contributed equally to this work.

Keywords:
immunotherapy, hypoxia, pancreatic cancer, lipid droplet, mitochondria-targeted sonodynamic therapy
Topics:
NanobiotechnologyTumors
Cite this article:
Shi Z, Wang X, Luo J, et al. RNA sequencing-based optimization of biological lipid droplets for sonodynamic therapy to reverse tumor hypoxia and elicit robust immune response. Nano Research, 2023, 16(5): 7187-7198. https://doi.org/10.1007/s12274-022-5340-0
Download citation
EndNote(RIS)
BibTeX

8217

Views

106

Downloads

Citations

5

Crossref

4

WoS

4

Scopus

0

CSCD

Abstract Full text Electronic supplementary material About this article

Mitochondria-targeted sonodynamic therapy (SDT) is a promising strategy to inhibit tumor growth and activate the anti-tumor immune responses. Identifying the mechanisms underlying mitochondria-targeted SDT, further optimizing its efficacy, and developing novel sonosensitizer carriers with good biocompatibility pose major challenges to the clinical practice of SDT. In this study, we investigated the mechanisms of mitochondria-targeted SDT and demonstrated that it suppressed the mitochondrial electron transport chain (ETC) in pancreatic cancer cells through RNA-sequencing analysis. Based on these findings, we constructed the functional lipid droplets (LDs) (CPI-613/IR780@LDs), which combined mitochondria-targeted SDT with the tricarboxylic acid (TCA) cycle inhibitor CPI-613. CPI-613/IR780@LDs synergistically inhibited the TCA cycle and the ETC of mitochondrial aerobic respiration to reduce oxygen consumption and increase reactive oxygen species (ROS) generation at the tumor site, thus enhancing the efficacy of SDT in hypoxic pancreatic cancer. Moreover, the combination of mitochondria-targeted SDT and anti-PD-1 antibody exhibited excellent tumor inhibition and activated anti-tumor immune responses by increasing tumor-infiltrating CD8+ T cells and reducing regulatory T cells, synergistically arresting the growth of both primary and metastatic pancreatic tumors. Meanwhile, lipid droplets are cell-derived biological carriers with natural mitochondrial targeting ability and can achieve efficient hydrophobic drug loading through active phagocytosis. Therefore, the functional lipid droplet-based SDT combined with anti-PD-1 antibody holds great potential in the clinical treatment of hypoxic pancreatic cancer.


menu
Abstract
Full text
Outline
Electronic supplementary material
About this article

RNA sequencing-based optimization of biological lipid droplets for sonodynamic therapy to reverse tumor hypoxia and elicit robust immune response

Show Author's information Zhan Shi1,2,§, Xue Wang1,2,§, Jiali Luo1,2, Yiqing Zeng1,2, Qing Wen1,2, Yurong Hong1,2, Tao Zhang1,2( ), Pintong Huang1,2,3( )
Department of Ultrasound in Medicine, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou 310009, China
Research Center of Ultrasound in Medicine and Biomedical Engineering, The Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou 310009, China
Research Center for Life Science and Human Health, Binjiang Institute of Zhejiang University, Hangzhou 310009, China

§ Zhan Shi and Xue Wang contributed equally to this work.

Abstract

Mitochondria-targeted sonodynamic therapy (SDT) is a promising strategy to inhibit tumor growth and activate the anti-tumor immune responses. Identifying the mechanisms underlying mitochondria-targeted SDT, further optimizing its efficacy, and developing novel sonosensitizer carriers with good biocompatibility pose major challenges to the clinical practice of SDT. In this study, we investigated the mechanisms of mitochondria-targeted SDT and demonstrated that it suppressed the mitochondrial electron transport chain (ETC) in pancreatic cancer cells through RNA-sequencing analysis. Based on these findings, we constructed the functional lipid droplets (LDs) (CPI-613/IR780@LDs), which combined mitochondria-targeted SDT with the tricarboxylic acid (TCA) cycle inhibitor CPI-613. CPI-613/IR780@LDs synergistically inhibited the TCA cycle and the ETC of mitochondrial aerobic respiration to reduce oxygen consumption and increase reactive oxygen species (ROS) generation at the tumor site, thus enhancing the efficacy of SDT in hypoxic pancreatic cancer. Moreover, the combination of mitochondria-targeted SDT and anti-PD-1 antibody exhibited excellent tumor inhibition and activated anti-tumor immune responses by increasing tumor-infiltrating CD8+ T cells and reducing regulatory T cells, synergistically arresting the growth of both primary and metastatic pancreatic tumors. Meanwhile, lipid droplets are cell-derived biological carriers with natural mitochondrial targeting ability and can achieve efficient hydrophobic drug loading through active phagocytosis. Therefore, the functional lipid droplet-based SDT combined with anti-PD-1 antibody holds great potential in the clinical treatment of hypoxic pancreatic cancer.

Keywords: immunotherapy, hypoxia, pancreatic cancer, lipid droplet, mitochondria-targeted sonodynamic therapy

References(38)

[1]

Park, W.; Chawla, A.; O’Reilly, E. M. Pancreatic cancer: A review. JAMA 2021, 326, 851–862.
DOI Google Scholar
[2]

The Lancet Gastroenterology & Hepatology. Pancreatic cancer: A state of emergency? Lancet Gastroenterol. Hepatol. 2021, 6, 81.
DOI Google Scholar
[3]

Son, S. B.; Kim, J. H.; Wang, X. W.; Zhang, C. L.; Yoon, S. A.; Shin, J.; Sharma, A.; Lee, M. H.; Cheng, L.; Wu, J. S. et al. Multifunctional sonosensitizers in sonodynamic cancer therapy. Chem. Soc. Rev. 2020, 49, 3244–3261.
DOI Google Scholar
[4]

Canavese, G.; Ancona, A.; Racca, L.; Canta, M.; Dumontel, B.; Barbaresco, F.; Limongi, T.; Cauda, V. Nanoparticle-assisted ultrasound: A special focus on sonodynamic therapy against cancer. Chem. Eng. J. 2018, 340, 155–172.
DOI Google Scholar
[5]

Kim, H. M.; Cho, B. R. Small-molecule two-photon probes for bioimaging applications. Chem. Rev. 2015, 115, 5014–5055.
DOI Google Scholar
[6]

Zhang, Q. Y.; Bao, C. X.; Cai, X. J.; Jin, L. W.; Sun, L. L.; Lang, Y. H.; Li, L. B. Sonodynamic therapy-assisted immunotherapy: A novel modality for cancer treatment. Cancer Sci. 2018, 109, 1330–1345.
DOI Google Scholar
[7]

Inui, T.; Makita, K.; Miura, H.; Matsuda, A.; Kuchiike, D.; Kubo, K.; Mette, M.; Uto, Y.; Nishikata, T.; Hori, H. et al. Case report: A breast cancer patient treated with GcMAF, sonodynamic therapy and hormone therapy. Anticancer Res. 2014, 34, 4589–4593.
Google Scholar
[8]

Shi, X. E.; Zhang, X.; Zhang, X. L.; Guo, H. Z.; Wang, S. The integration of reactive oxygen species generation and prodrug activation for cancer therapy. BIO Integr. 2022, 3, 32–40.
DOI Google Scholar
[9]

Zuo, S.; Zhang, Y.; Wang, Z.; Wang, J. Mitochondria-targeted mesoporous titanium dioxide nanoplatform for synergistic nitric oxide gas-sonodynamic therapy of breast cancer. Int. J. Nanomedicine. 2022, 17, 989–1002.
DOI Google Scholar
[10]

Fulda, S.; Galluzzi, L.; Kroemer, G. Targeting mitochondria for cancer therapy. Nat. Rev. Drug Discov. 2010, 9, 447–464.
DOI Google Scholar
[11]

Vasan, K.; Werner, M.; Chandel, N. S. Mitochondrial metabolism as a target for cancer therapy. Cell Metab. 2020, 32, 341–352.
DOI Google Scholar
[12]

Frattaruolo, L.; Brindisi, M.; Curcio, R.; Marra, F.; Dolce, V.; Cappello, A. R. Targeting the mitochondrial metabolic network: A promising strategy in cancer treatment. Int. J. Mol. Sci. 2020, 21, 6014.
DOI Google Scholar
[13]

Faubert, B.; Solmonson, A.; DeBerardinis, R. J. Metabolic reprogramming and cancer progression. Science 2020, 368, eaaw5473.
DOI Google Scholar
[14]

Cluntun, A. A.; Lukey, M. J.; Cerione, R. A.; Locasale, J. W. Glutamine metabolism in cancer: Understanding the heterogeneity. Trends Cancer 2017, 3, 169–180.
DOI Google Scholar
[15]

DeBerardinis, R. J.; Chandel, N. S. We need to talk about the Warburg effect. Nat. Metab. 2020, 2, 127–129.
DOI Google Scholar
[16]

Kalyanaraman, B.; Cheng, G.; Hardy, M.; Ouari, O.; Lopez, M.; Joseph, J.; Zielonka, J.; Dwinell, M. B. A review of the basics of mitochondrial bioenergetics, metabolism, and related signaling pathways in cancer cells: Therapeutic targeting of tumor mitochondria with lipophilic cationic compounds. Redox Biol. 2018, 14, 316–327.
DOI Google Scholar
[17]

Pustylnikov, S.; Costabile, F.; Beghi, S.; Facciabene, A. Targeting mitochondria in cancer: Current concepts and immunotherapy approaches. Transl. Res. 2018, 202, 35–51.
DOI Google Scholar
[18]

Orang, A. V.; Petersen, J.; McKinnon, R. A.; Michael, M. Z. Micromanaging aerobic respiration and glycolysis in cancer cells. Mol. Metab. 2019, 23, 98–126.
DOI Google Scholar
[19]

Anderson, R. G.; Ghiraldeli, L. P.; Pardee, T. S. Mitochondria in cancer metabolism, an organelle whose time has come? Biochim. Biophys. Acta Rev. Cancer 2018, 1870, 96–102.
DOI Google Scholar
[20]

Nowak, K. M.; Schwartz, M. R.; Breza, V. R.; Price, R. J. Sonodynamic therapy: Rapid progress and new opportunities for non-invasive tumor cell killing with sound. Cancer Lett. 2022, 532, 215592.
DOI Google Scholar
[21]

Liang, S.; Deng, X. R.; Ma, P. A.; Cheng, Z. Y.; Lin, J. Recent advances in nanomaterial-assisted combinational sonodynamic cancer therapy. Adv. Mater. 2020, 32, 2003214.
DOI Google Scholar
[22]

Qu, F.; Wang, P.; Zhang, K.; Shi, Y.; Li, Y. X.; Li, C. R.; Lu, J. H.; Liu, Q. H.; Wang, X. B. Manipulation of mitophagy by “all-in-one” nanosensitizer augments sonodynamic glioma therapy. Autophagy 2020, 16, 1413–1435.
DOI Google Scholar
[23]

Gao, Y.; Tong, H. B.; Li, J. L.; Li, J. C.; Huang, D.; Shi, J. S.; Xia, B. Mitochondria-targeted nanomedicine for enhanced efficacy of cancer therapy. Front. Bioeng. Biotechnol. 2021, 9, 720508.
DOI Google Scholar
[24]

Huang, P.; Qian, X. Q.; Chen, Y.; Yu, L. D.; Lin, H.; Wang, L. Y.; Zhu, Y. F.; Shi, J. L. Metalloporphyrin-encapsulated biodegradable nanosystems for highly efficient magnetic resonance imaging-guided sonodynamic cancer therapy. J. Am. Chem. Soc. 2017, 139, 1275–1284.
DOI Google Scholar
[25]

Chen, J.; Luo, H. L.; Liu, Y.; Zhang, W.; Li, H. X.; Luo, T.; Zhang, K.; Zhao, Y. X.; Liu, J. J. Oxygen-self-produced nanoplatform for relieving hypoxia and breaking resistance to sonodynamic treatment of pancreatic cancer. ACS Nano 2017, 11, 12849–12862.
DOI Google Scholar
[26]

Li, Y. K.; Zhao, Z.; Liu, H.; Fetse, J. P.; Jain, A.; Lin, C. Y.; Cheng, K. Development of a tumor-responsive nanopolyplex targeting pancreatic cancer cells and stroma. ACS Appl. Mater. Interfaces 2019, 11, 45390–45403.
DOI Google Scholar
[27]

Cao, Y.; Wu, T. T.; Dai, W. H.; Dong, H. F.; Zhang, X. J. TiO2 nanosheets with the Au nanocrystal-decorated edge for mitochondria-targeting enhanced sonodynamic therapy. Chem. Mater. 2019, 31, 9105–9114.
DOI Google Scholar
[28]

Liang, T. X. Z.; Wen, D.; Zhong, X. T.; Jiang, L. P.; Zhu, J. J.; Gu, Z. Therapeutic potential of adipose tissue. Sci. Bull. 2020, 65, 1702–1704.
DOI Google Scholar
[29]

Liang, T. X. Z.; Wen, D.; Chen, G. J.; Chan, A.; Chen, Z. W.; Li, H. J.; Wang, Z. J.; Han, X.; Jiang, L. P.; Zhu, J. J. et al. Adipocyte-derived anticancer lipid droplets. Adv. Mater. 2021, 33, 2100629.
DOI Google Scholar
[30]

Yang, B. W.; Chen, Y.; Shi, J. L. Reactive oxygen species (ROS)-based nanomedicine. Chem. Rev. 2019, 119, 4881–4985.
DOI Google Scholar
[31]

Wang, L.; Niu, C. C. IR780-based nanomaterials for cancer imaging and therapy. J. Mater. Chem. B 2021, 9, 4079–4097.
DOI Google Scholar
[32]

Bellio, C.; DiGloria, C.; Spriggs, D. R.; Foster, R.; Growdon, W. B.; Rueda, B. R. The metabolic inhibitor CPI-613 negates treatment enrichment of ovarian cancer stem cells. Cancers (Basel) 2019, 11, 1678.
DOI Google Scholar
[33]

Stuart, S. D.; Schauble, A.; Gupta, S.; Kennedy, A. D.; Keppler, B. R.; Bingham, P. M.; Zachar, Z. A strategically designed small molecule attacks alpha-ketoglutarate dehydrogenase in tumor cells through a redox process. Cancer Metab. 2014, 2, 4.
DOI Google Scholar
[34]

Alistar, A.; Morris, B. B.; Desnoyer, R.; Klepin, H. D.; Hosseinzadeh, K.; Clark, C.; Cameron, A.; Leyendecker, J.; D’Agostino, R. Jr.; Topaloglu, U. et al. Safety and tolerability of the first-in-class agent CPI-613 in combination with modified FOLFIRINOX in patients with metastatic pancreatic cancer: A single-centre, open-label, dose-escalation, phase 1 trial. Lancet Oncol 2017, 18, 770–778.
DOI Google Scholar
[35]

Gao, L. X.; Xu, Z. G.; Huang, Z.; Tang, Y.; Yang, D. L.; Huang, J. H.; He, L. L.; Liu, M. R.; Chen, Z. Z.; Teng, Y. CPI-613 rewires lipid metabolism to enhance pancreatic cancer apoptosis via the AMPK-ACC signaling. J. Exp. Clin. Cancer Res. 2020, 39, 73.
DOI Google Scholar
[36]

Lin, Y. X.; Xu, J. X.; Lan, H. Y. Tumor-associated macrophages in tumor metastasis: Biological roles and clinical therapeutic applications. J. Hematol. Oncol. 2019, 12, 76.
DOI Google Scholar
[37]

Ganesh, K.; Massagué, J. Targeting metastatic cancer. Nat. Med. 2021, 27, 34–44.
DOI Google Scholar
[38]

Liu, J.; Xu, M. Z.; Yuan, Z. Immunoscore guided cold tumors to acquire “temperature” through integrating physicochemical and biological methods. BIO Integr. 2020, 1, 6–14.
DOI Google Scholar
File
12274_2022_5340_MOESM1_ESM.pdf (628.6 KB)
12274_2022_5340_MOESM2_ESM.xlsx (84 KB)
12274_2022_5340_MOESM3_ESM.xlsx (46.1 KB)
Publication history
Copyright
Acknowledgements

Publication history

Received: 19 October 2022
Revised: 16 November 2022
Accepted: 17 November 2022
Published: 10 January 2023
Issue date: May 2023

Copyright

© Tsinghua University Press 2022

Acknowledgements

We greatly acknowledge the financial support from the National Natural Science Foundation of China (Nos. 32201138, 82030048, and 82230069) and the Key Research and Development Program of Zhejiang Province (No. 2019C03077).

Return