Host immune response to anti-cancer camptothecin conjugated cyclodextrin-based polymers

Creators: Chen, Yi-Fan; Wang, Yen-Hsin; Lei, Cing-Syuan; Changou, Chun A.; Davis, Mark E.; Yen, Yun

Abstract

Introduction: Efficacy and safety are critical concerns when designing drug carriers. Nanoparticles are a particular type of carrier that has gained recent attention in cancer therapeutics. Methods: In this study, we assess the safety profile of IT-101, a nanoparticle formed by self-assembly of camptothecin (CPT) conjugated cyclodextrin-based polymers. IT-101 delivers CPT to target cancer cells in animal models of numerous human cancers and in humans. Previous data from preclinical and clinical trials indicate that IT-101 has no notable immunological side effects. However, there have been no published studies focused on evaluating the effects of IT-101 on host immune systems. Results: In this work, we demonstrate that IT-101 diminished initial host immune response following first injection of the nanopharmaceutical and induced NK cell activation and T cell proliferation upon further IT-101 exposure. Additionally, IT-101 could attenuate tumor growth more efficiently than CPT treatment only. Conclusions: Drugs administration in whole-body circulation may lead to poorly bioavailable in central nervous system and often has toxic effects on peripheral tissues. Conjugated with cyclodextrin-based polymers not only reduce adverse effects but also modulate the immune responses to elevate drug efficacy. These immune responses may potentially facilitate actions of immune blockage, such as PD1/PDL1 in cancer treatment.

Additional Information

© 2019 The Author(s). This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Received 04 September 2019; Accepted 10 October 2019; Published 23 October 2019. Availability of data and materials: All data and materials supporting the conclusion of this study have been included with the article and the additional information. Acknowledgements: Not applicable. Implications: Nanoparticles have the potential advantage of targeting specific cell types within organs, while the immune responses related to nanoparticles have become safety issues of importance. The potentially facilitated effects for immune therapy are also a critical investigated part of nanoparticles. This work was financially supported by the "TMU Research Center of Cancer Translational Medicine" from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE) in Taiwan. This work was supported by a Health and welfare surcharge of tobacco products grant (CECR grant: MOHW107-TDU-B-212-114014, MOHW108-TDU-B-212-124026 and MOHW108-TDU-B-212-124020 to Y.Y.). This work was also supported by Ministry of Science and Technology (grant number MOST-108-2321-B-038-003 to Y.Y. and MOST-105–2320-B-038-022-MY3 to Y.F.C.). This work was also supported by Taipei Medical University (grant number DP2-108–21121-01-O-04-04 to Y.F.C.). Author Contributions: Y.F.C. designed the experiments, analyzed and interpreted the results, and wrote the manuscript. Both Y.H.W and C.S.L performed the most experiments in this study. C.A.C. performed the analysis of brain tumor mouse model. M.E.D. designed the experiments and checked the final manuscript. Y.Y. designed the experiments, analyzed the sequencing data, and checked the final manuscript. All authors have read and approved the final version of this manuscript. Ethics approval and consent to participate: Animal experiments are approved by the Institutional Animal Care and User Committee of National Defense Medical Center. There is no human subject participation. Consent for publication: Not applicable. This study does not include any individual person's data in any form. The authors declare that they have no competing interests.

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