Abstract
Purpose
Our goal was to increase the targetability of our nanoparticles to specific targets to increase their penetration into the tumor and to enhance immunotherapy with ketoconazole (KTZ), BMS-202, and indocyanine green (ICG)-induced photothermal therapy (PTT) for anticancer effects.
Methods
We prepared liposomes through a thin film formation process in which hydrophobic drugs BMS-202 and KTZ were embedded in a lipid bilayer, and ICG was embedded inside the liposomes as a hydrophilic drug. In the process, the cell membranes of specific target cancer cells were fused to increase penetration and targeting. The resulting nanoparticles were evaluated in vitro and in vivo to confirm their anticancer effects.
Results
Numerous experiments have demonstrated the properties of BMS-202/ICG/KTZ-loaded hybrid liposomes. The results of the in vitro/in vivo experiments confirmed successful enhancement of the targeting ability of the nanoparticles prepared by fusing with the cell membranes of specific cancer cells to increase their targetability and penetration. In addition, although the drug alone did not show significant cytotoxicity to 4T1 cancer cells by MTT assay, liposomes containing both KTZ and BMS-202 showed a significant effect on secondary tumor suppression in animal experiments compared to liposomes containing only a single drug, confirming the effectiveness of the enhanced immunotherapy.
Conclusion
Our study showed that exosome inhibition and immune checkpoint blockade act synergistically in cancer immunotherapy.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Chen G, Huang AC, Zhang W, Zhang G, Wu M, Xu W, Yu Z, Yang J, Wang B, Sun H, Xia H, Man Q, Zhong W, Antelo LF, Wu B, Xiong X, Liu X, Guan L, Li T, Liu S, Yang R, Lu Y, Dong L, McGettigan S, Somasundaram R, Radhakrishnan R, Mills G, Lu Y, Kim J, Chen YH, Dong H, Zhao Y, Karakousis GC, Mitchell TC, Schuchter LM, Herlyn M, Wherry EJ, Xu X, Guo W (2018) Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560:382–386. https://doi.org/10.1038/s41586-018-0392
Datta A, Kim H, McGee L, Johnson AE, Talwar S, Marugan J, Southall N, Hu X, Lal M, Mondal D, Ferrer M, Abdel-Mageed AB (2018) High-throughput screening identified selective inhibitors of exosome biogenesis and secretion: a drug repurposing strategy for advanced cancer. Sci Rep 8:8161. https://doi.org/10.1038/s41598-018-26411-7
Dobosz P, Dzieciątkowski T (2019) The Intriguing history of Cancer Immunotherapy. Front Immunol 10:2965. https://doi.org/10.3389/fimmu.2019.02965
Elmowafy E, Soliman ME (2023) Polysaccharide-based platforms for nasal delivery: design, features, and perspectives. J Pharm Investig 53:571–599. https://doi.org/10.1007/s40005-023-00626-x
Emens LA, Ascierto PA, Darcy PK, Demaria S, Eggermont AMM, Redmond WL, Seliger B, Marincola FM (2017) Cancer immunotherapy: opportunities and challenges in the rapidly evolving clinical landscape. Eur J Cancer 81:116–129. https://doi.org/10.1016/j.ejca.2017.01.035
Farkona S, Diamandis EP, Blasutig IM (2016) Cancer immunotherapy: the beginning of the end of cancer? BMC Med 14:73. https://doi.org/10.1186/s12916-016-0623-5
Greenberg JW, Kim H, Moustafa AA, Datta A, Barata PC, Boulares AH, Abdel-Mageed AB, Krane LS (2021) Repurposing ketoconazole as an exosome directed adjunct to sunitinib in treating renal cell carcinoma. Sci Rep 11:10200. https://doi.org/10.1038/s41598-021-89655-w
Le XT, Lee J, Nguyen NT, Lee WT, Lee ES, Oh KT, Choi H-G, Shin BS, Youn YS (2022) Combined phototherapy with metabolic reprogramming-targeted albumin nanoparticles for treating Breast cancer. Biomater Sci 10:7117–7132. https://doi.org/10.1039/d2bm01281b
Lee E, Lee ES (2023) Tumor extracellular vesicles carrying antitumor (KLAKLAK)2 peptide and tumor-specific antigens for improved Tumor therapy. J Pharm Investig 53:505–516. https://doi.org/10.1007/s40005-023-00617-y
Lee WT, Lee J, Kim H, Nguyen NT, Lee ES, Oh KT, Choi H-G, Youn YS (2021) Photoreactive-proton-generating hyaluronidase/albumin nanoparticles-loaded PEG-hydrogel enhances antitumor efficacy and disruption of the hyaluronic acid extracellular matrix in AsPC-1 tumors. Mater Today Bio 12:100164. https://doi.org/10.1016/j.mtbio.2021.100164
Lee WT, Yoon J, Kim SS, Kim H, Nguyen NT, Le XT, Lee ES, Oh KT, Choi H-G, Youn YS (2022) Combined Antitumor Therapy using in situ Injectable Hydrogels formulated with Albumin nanoparticles containing Indocyanine Green, Chlorin e6, and Perfluorocarbon in hypoxic tumors. Pharmaceutics 14:148. https://doi.org/10.3390/pharmaceutics14010148
Li Z, Rana I, Park G, Lee J, Park CE, Nam J (2023) Pattern recognition receptors and their nano-adjuvants for cancer immunotherapy. J Pharm Investig 53:685–706. https://doi.org/10.1007/s40005-023-00633-y
Lin MJ, Svensson-Arvelund J, Lubitz GS, Marabelle A, Melero I, Brown BD, Brody JD (2022) Cancer vaccines: the next immunotherapy frontier. Nat Cancer 3:911–926. https://doi.org/10.1038/s43018-022-00418-6
Liu J, Chen Z, Li Y, Zhao W, Wu J, Zhang Z (2021) PD-1/PD-L1 checkpoint inhibitors in Tumor Immunotherapy. Front Pharmacol 12:731798. https://doi.org/10.3389/fphar.2021.731798
Nguyen T-D, Dang LN, Jang J-H, Park S (2023) Recent advances in Alzheimer’s Disease pathogenesis and therapeutics from an immune perspective. J Pharm Investig 53:667–684. https://doi.org/10.1007/s40005-023-00631-0
Ribas A, Hamid O, Daud A, Hodi FS, Wolchok JD, Kefford R, Joshua AM, Patnaik A, Hwu WJ, Weber JS, Gangadhar TC, Hersey P, Dronca R, Joseph RW, Zarour H, Chmielowski B, Lawrence DP, Algazi A, Rizvi NA, Hoffner B, Mateus C, Gergich K, Lindia JA, Giannotti M, Li XN, Ebbinghaus S, Kang SP, Robert C (2016) Association of Pembrolizumab with Tumor Response and Survival among patients with Advanced Melanoma. JAMA 315:1600–1609. https://doi.org/10.1001/jama.2016.4059
Ro S-Y, Choi H-M, Choi S-H, Lee S-W, Lim S-J (2023) Tricaprin as a membrane permeability regulator: sustained small hydrophilic substance release from liposomes. J Pharm Investig 53:539–548. https://doi.org/10.1007/s40005-023-00621-2
Sun J-Y, Zhang D, Wu S, Xu M, Zhou X, Lu X-J, Ji J (2020) Resistance to PD-1/PD-L1 blockade cancer immunotherapy: mechanisms, predictive factors, and future perspectives. Biomark Res 8:35. https://doi.org/10.1186/s40364-020-00212-5
Thapa RK, Kim JO (2023) Nanomedicine-based commercial formulations: current developments and future prospects. J Pharm Investig 53:19–33. https://doi.org/10.1007/s40005-022-00607-6
Waldman AD, Fritz JM, Lenardo MJ (2020) A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat Rev Immunol 20:651–668. https://doi.org/10.1038/s41577-020-0306-5
Yin Z, Yu M, Ma T, Zhang C, Huang S, Karimzadeh MR, Momtazi-Borojeni AA, Chen S (2022) Mechanisms underlying low-clinical responses to PD-1/PD-L1 blocking antibodies in immunotherapy of cancer: a key role of exosomal PD-L1. J Immunother Cancer 9:e001698. https://doi.org/10.1136/jitc-2020-001698
Zak KM, Grudnik P, Magiera K, Dömling A, Dubin G, Holak TA (2017) Structural Biology of the Immune checkpoint receptor PD-1 and its ligands PD-L1/PD-L2. Structure 25:1163–1174. https://doi.org/10.1016/j.str.2017.06.011
Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, Torrejon DY, Abril-Rodriguez G, Sandoval S, Barthly L, Saco J, Moreno BH, Mezzadra R, Chmielowski B, Ruchalski K, Shintaku IP, Sanchez PJ, Puig-Saus C, Cherry G, Seja E, Kong X, Pang J, Berent-Maoz B, Comin-Anduix B, Graeber TG, Tumeh PC, Schumacher TN, Lo RS, Ribas A (2016) Mutations Associated with Acquired Resistance to PD-1 blockade in Melanoma. N Engl J Med 375:819–829. https://doi.org/10.1056/NEJMoa1604958
Zhang W, Gong C, Chen Z, Li M, Li Y, Gao J (2021) Tumor microenvironment-activated cancer cell membrane-liposome hybrid nanoparticle-mediated synergistic metabolic therapy and chemotherapy for non-small cell Lung cancer. J Nanobiotechnol 19:339. https://doi.org/10.1186/s12951-021-01085-y
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Conflict of interest
All authors (J. Lee, W.T. Lee, X.T. Le, and Y.S. Youn) declare that they have no conflicts of interest.
Human and animal rights
The animal study protocol was approved by the Institutional Animal Care and Use Committee at Sungkyunkwan University (No. SKKU IACUC 2022-07-18-1) and followed standard protocols for animal handling and care.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Junyeong Lee and Woo Tak Lee have contributed equally to this work.
Supplementary Information
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Lee, J., Lee, W.T., Le, X.T. et al. Cancer cell membrane-decorated hybrid liposomes for treating metastatic breast cancer based on enhanced cancer immunotherapy. J. Pharm. Investig. (2024). https://doi.org/10.1007/s40005-023-00661-8
Received:
Accepted:
Published:
DOI: https://doi.org/10.1007/s40005-023-00661-8