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A Stable Irinotecan Liposome with Enhanced Antitumor Activity in a Range of Tumor Models

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Abstract

Purpose

This study aimed to prepare a stable irinotecan liposome (CPT-11 liposome) and evaluate its antitumor efficacy in a range of tumor models.

Methods

CPT-11 liposome was prepared with a Z-average particle size of 110 ~ 120 nm and high entrapment efficiency (> 95%) and had a good stability within 18 months. Then the antitumor efficacy was studied in human colon (Ls-174t), gastric (NCI-N87), pancreatic (BxPC-3) and small cell lung (NCI-H526) cancer xenograft models. The toxicity of high-dose CPT-11 liposome was also evaluated in Beagle dogs.

Results

The results showed that the anti-tumor effects of CPT-11 liposome were markedly superior (at least 10 times higher) to those of the CPT-11 injection group in all four xenograft models. The tissue distribution test in the Ls-174t model further demonstrated that the CPT-11 liposome could alter the plasma and tissue distribution of CPT-11, increase the exposure level of its active metabolite SN-38 in tumor, and ultimately improve antitumor efficiency. Meanwhile, CPT-11 liposome showed a much less toxicity than CPT-11 injection in beagle dogs.

Conclusions

Overall, the CPT-11 liposome may be developed as a new clinical alternative for the cancer patients.

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Data availability

The data required to reproduce these findings cannot be shared at this time as the data also forms part of an ongoing study.

References

  1. Rothenberg ML. Irinotecan (cpt-11): recent developments and future directions–colorectal cancer and beyond. Oncologist. 2001;6:66–80.

    Article  CAS  PubMed  Google Scholar 

  2. Munoz A, Salud A, Alonso V, Escudero P, Sanz J, Martín C, Rivera F, Yubero A, García-Girón C, López-Vivanco G. Final analysis of irinotecan (cpt-11) and capecitabine (x) as first-line treatment of locally advanced (la) or metastatic colorectal cancer (mcrc). J Clin Oncol. 2004;22:3610–3610.

    Article  Google Scholar 

  3. Hattori Y, Shi L, Ding W, Koga K, Kawano K, Hakoshima M, Maitani Y. Novel irinotecan-loaded liposome using phytic acid with high therapeutic efficacy for colon tumors. J Control Release. 2009;136:30–7.

    Article  CAS  PubMed  Google Scholar 

  4. Tsuburaya A, Sugimoto N, Imamura H, Nishikawa K, Imamoto H, Tsujinaka T, Esaki T, Horita Y, Kimura Y, Fujiya T. Molecular biomarker study in a randomised phase iii trial of irinotecan plus s-1 versus s-1 for advanced gastric cancer (gc0301/top-002). Clin Oncol. 2016;28:e45–51.

    Article  CAS  Google Scholar 

  5. Spigel DR, Greco FA, Rubin MS, Shipley D, Thompson DS, Lubiner ET, Eakle JF, Quinn R, Burris HA, Hainsworth JD. Phase ii study of maintenance sunitinib following irinotecan and carboplatin as first-line treatment for patients with extensive-stage small-cell lung cancer. Lung Cancer. 2012;77:359–64.

    Article  PubMed  Google Scholar 

  6. Murata Y, Hirose T, Yamaoka T, Shirai T, Okuda K, Sugiyama T, Kusumoto S, Nakashima M, Ohmori T, Adachi M. Phase ii trial of the combination of carboplatin and irinotecan in elderly patients with small-cell lung cancer. Eur J Cancer. 2011;47:1336–42.

    Article  CAS  PubMed  Google Scholar 

  7. Nakamura Y, Soda H, Oka M, Kinoshita A, Fukuda M, Fukuda M, Takatani H, Nagashima S, Soejima Y, Kasai T. Randomized phase ii trial of irinotecan with paclitaxel or gemcitabine for non-small cell lung cancer: association of ugt1a1* 6 and ugt1a1* 27 with severe neutropenia. J Thorac Oncol. 2011;6:121–7.

    Article  PubMed  Google Scholar 

  8. Matsumoto K, Katsumata N, Shibata T, Satoh T, Saitou M, Yunokawa M, Takano T, Nakamura K, Kamura T, Konishi I. Phase ii trial of oral etoposide plus intravenous irinotecan in patients with platinum-resistant and taxane-pretreated ovarian cancer (jcog0503). Gynecol Oncol. 2015;136:218–23.

    Article  CAS  PubMed  Google Scholar 

  9. Crozier JA, Advani PP, LaPlant B, Hobday T, Jaslowski AJ, Moreno-Aspitia A, Perez EA. N0436 (alliance): a phase ii trial of irinotecan with cetuximab in patients with metastatic breast cancer previously exposed to anthracycline and/or taxane-containing therapy. Clin Breast Cancer. 2016;16:23–30.

    Article  CAS  PubMed  Google Scholar 

  10. Ohno R, Okada K, Masaoka T, Kuramoto A, Arima T, Yoshida Y, Ariyoshi H, Ichimaru M, Sakai Y, Oguro M. An early phase ii study of cpt-11: a new derivative of camptothecin, for the treatment of leukemia and lymphoma. J Clin Oncol. 1990;8:1907–12.

    Article  CAS  PubMed  Google Scholar 

  11. Bleiberg H, Cvitkovic E. Characterisation and clinical management of cpt-11 (irinotecan)-induced adverse events: the european perspective. Eur J Cancer. 1996;32:S18–23.

    Article  Google Scholar 

  12. Rivory LP. Irinotecan (cpt-11): a brief overview. Clin Exp Pharmacol Physiol. 1996;23:1000–4.

    Article  CAS  PubMed  Google Scholar 

  13. Fassberg J, Stella VJ. A kinetic and mechanistic study of the hydrolysis of camptothecin and some analogues. J Pharm Sci. 1992;81:676–84.

    Article  CAS  PubMed  Google Scholar 

  14. Lokiec F, Canal P, Gay C, Chatelut E, Armand J-P, Roché H, Bugat R, Gonçalvès E, Mathieu-Boué A. Pharmacokinetics of irinotecan and its metabolites in human blood, bile, and urine. Cancer Chemother Pharmacol. 1995;36:79–82.

    Article  CAS  PubMed  Google Scholar 

  15. Hong K, Drummond DC, Kirpotin D. Liposomes useful for drug delivery. US14879302; 2015.

  16. Pattni BS, Chupin VV, Torchilin VP. New developments in liposomal drug delivery. Chem Rev. 2015;115:10938–66.

    Article  CAS  PubMed  Google Scholar 

  17. Wei H, Song J, Li H, Li Y, Zhu S, Zhou X, Zhang X, Yang L. Active loading liposomal irinotecan hydrochloride: Preparation, in vitro and in vivo evaluation. Asian J Pharm Sci. 2013;8:303–11.

    Article  Google Scholar 

  18. Cersosimo RJ. Irinotecan: a new antineoplastic agent for the management of colorectal cancer. Ann Pharmacother. 1998;32:1324–33.

    Article  CAS  PubMed  Google Scholar 

  19. Bulbake U, Doppalapudi S, Kommineni N, Khan W. Liposomal formulations in clinical use: an updated review. Pharmaceutics. 2017;9:12.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Yang F, Jin C, Jiang Y, Li J, Di Y, Ni Q, Fu D. Liposome based delivery systems in pancreatic cancer treatment: from bench to bedside. Cancer Treat Rev. 2011;37:633–42.

    Article  CAS  PubMed  Google Scholar 

  21. Drummond DC, Noble CO, Guo Z, Hong K, Park JW, Kirpotin DB. Development of a highly active nanoliposomal irinotecan using a novel intraliposomal stabilization strategy. Can Res. 2006;66:3271–7.

    Article  CAS  Google Scholar 

  22. Justo OR, Moraes AM. Kanamycin incorporation in lipid vesicles prepared by ethanol injection designed for tuberculosis treatment. J Pharm Pharmacol. 2005;57:23–30.

    Article  CAS  PubMed  Google Scholar 

  23. Yoshino K, Nakamura K, Terajima Y, Kurita A, Matsuzaki T, Yamashita K, Isozaki M, Kasukawa H. Comparative studies of irinotecan-loaded polyethylene glycol-modified liposomes prepared using different peg-modification methods. Biochimica et Biophysica Acta (BBA)-Biomembranes. 2012;1818:2901–7.

    Article  CAS  PubMed  Google Scholar 

  24. Majzoub RN, Chan C-L, Ewert KK, Silva BF, Liang KS, Jacovetty EL, Carragher B, Potter CS, Safinya CR. Uptake and transfection efficiency of pegylated cationic liposome–DNA complexes with and without rgd-tagging. Biomaterials. 2014;35:4996–5005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Stewart PL. Cryo-electron microscopy and cryo-electron tomography of nanoparticles. Wiley Interdiscip Rev Nanomed Nanobiotechnol. 2017;9: e1417.

    Article  Google Scholar 

  26. Biloti DN, Santana MHA, Pessine FBT. Lipid membrane with low proton permeability. Biochimica et Biophysica Acta (BBA)-Biomembranes. 2003;1611:1–4.

    Article  CAS  PubMed  Google Scholar 

  27. Díaz RS, Monreal J. Unusual low proton permeability of liposomes prepared from the endogenous myelin lipids. J Neurochem. 1994;62:2022–9.

    Article  PubMed  Google Scholar 

  28. Chou T-H, Chen S-C, Chu I-M. Effect of composition on the stability of liposomal irinotecan prepared by a ph gradient method. J Biosci Bioeng. 2003;95:405–8.

    Article  CAS  PubMed  Google Scholar 

  29. Hobbs SK, Monsky WL, Yuan F, Roberts WG, Griffith L, Torchilin VP, Jain RK. Regulation of transport pathways in tumor vessels: role of tumor type and microenvironment. Proc Natl Acad Sci. 1998;95:4607–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Nagayasu A, Uchiyama K, Kiwada H. The size of liposomes: a factor which affects their targeting efficiency to tumors and therapeutic activity of liposomal antitumor drugs. Adv Drug Deliv Rev. 1999;40:75–87.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Qingping Han from Sichuan Kelun Pharmaceutical Research Institute Co. Ltd., Tom Huang and Eric Rong from KLUS PHARMA INCKLUS PHARMA INC for their valuable advice. We would like to thank the Sichuan Institute for Food and Drug Control for the internal pH determination and Shanghai Institute of Materia Medica, Chinese Academy of Sciences and the Shanghai Center for Drug Metabolism and Pharmacokinetics Research for the antitumor efficiency and Pharmacokinetic and pharmacodynamics study.

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Author notes

  1. Zhengxing Su and Li Li contributed equally to this work.

Authors and Affiliations

  1. Sichuan Kelun Pharmaceutical Research Institute Co. Ltd., Chengdu, 611130, China

    Zhengxing Su, Fei Hao, Jinlong Zhao, Ming Li & Dong Zhao

  2. Hunan Kelun Pharmaceutical Institute Co. Ltd., Yueyang, 414199, China

    Zhengxing Su & Jinlong Zhao

  3. Department of Pharmacy, Chengdu Women’s and Children’s Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, 611731, China

    Li Li

  4. Sichuan Kelun-Biotech Biopharmaceutical Co., Ltd., Chengdu, 611130, China

    Xi Zhao

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  1. Zhengxing Su
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Contributions

Conceptualization, Zhengxing Su, Li Li, Dong Zhao; Investigation, Zhengxing Su, Li Li, Fei Hao, Jinlong Zhao, Ming Li, Xi Zhao; Resources, Dong Zhao; original manuscript, Fei Hao; Review & editing, Zhengxing Su, Li Li; Supervision, Dong Zhao; Project administration, Ming Li, Xi Zhao; All the authors have acknowledged the manuscript and agreed to the published version of the manuscript.

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Correspondence to Dong Zhao.

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Su, Z., Li, L., Hao, F. et al. A Stable Irinotecan Liposome with Enhanced Antitumor Activity in a Range of Tumor Models. Pharm Res 40, 3043–3058 (2023). https://doi.org/10.1007/s11095-023-03622-w

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  • DOI: https://doi.org/10.1007/s11095-023-03622-w

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