AAPS PharmSciTech

, Volume 19, Issue 8, pp 3829–3838 | Cite as

Intratumoral Injection Administration of Irinotecan-Loaded Microspheres: In Vitro and In Vivo Evaluation

  • Shengjun Zhu
  • Mingjin DouEmail author
  • Guihua HuangEmail author
Research Article


To reduce the toxic and side effects of intravenous chemotherapeutic drugs on the tumor-patients, the aims of this study were to design and study intratumor-administrated irinotecan-loaded PLGA microspheres (CPT-11-PLGA-MS) in vitro and in vivo according to the structure characteristics of CPT-11. PLGA microspheres containing irinotecan were prepared by emulsion solvent evaporation method and evaluated in terms of their morphology, particle size analysis, in vitro drug release, drug retention and leakage studies in vivo, and pharmacodynamics studies. The CPT-11-PLGA-MS were spherical with mean size of 9.29 ± 0.02 μm, and average encapsulation efficiency were measured of 77.97 ± 1.26% along with the average drug loading of 7.08 ± 0.11%. DSC results indicated that the drug existed in the phase of uncrystallization in the microspheres. The formulation of CPT-11-PLGA-MS could prolong the in vitro drug release to 16 days following Weibull equation. In CPT-11-PLGA-MS after intratumor injection administration was significantly improved. The results demonstrated that the slow-sustained release of CPT-11-PLGA-MS in tumor tissue after intratumor injection of microspheres can reduce the drug leakage to the circulation system, maintain the drug retention, and improve the therapeutic effect, which could become a promising drug delivery system for CPT-11 and could maintain the most effective concentration at the target site to maximum limit.


irinotecan intratumor-administration microspheres 7-ethyl-10-hydroxycamptothecin lactone ring structure 



The authors would like to express thanks to the School of Pharmaceutical Science, Shandong University for providing the required infrastructure to carry out the study.

Compliance with Ethical Standards

Conflict of Interest

The work described has not been submitted elsewhere for publication in whole or in part, and all the authors listed have approved the manuscript that is enclosed. The authors declare that they have no conflict of interest. The authors alone are responsible for the content and writing of this article.


  1. 1.
    Hanioka N, Ozawa S, Jinno H, Tanaka-Kagawa T, Nishimura T, Ando M, et al. Interaction of irinotecan (CPT-11) and its active metabolite 7-ethyl-10-hydroxycamptothecin (SN-38) with human cytochrome P450 enzymes[J]. Drug Metab Dispos Biol Fate Chem. 2002;30(4):391–6.CrossRefPubMedGoogle Scholar
  2. 2.
    Wang X, Rao Z, Qin H, Zhang G, Ma Y, Jin Y, et al. Effect of hesperidins on the pharmacokinetics of CPT-11 and its active metabolite SN-38 by regulating hepatic Mrp2 in rats. Biopharm Drug Dispos. 2016;37(7):421–32.CrossRefPubMedGoogle Scholar
  3. 3.
    Lavelle F, Bissery MC, André S, et al. Preclinical evaluation of CPT-11 and its active metabolite SN-38. Semin Oncol. 1996;23(3):11–20.PubMedGoogle Scholar
  4. 4.
    Pommier Y. Topoisomerase I inhibitors: camptothecins and beyond. [J]. Nat Rev Cancer. 2006;6(10):789.CrossRefGoogle Scholar
  5. 5.
    Husain I, Mohler JL, Seigler HF, Besterman JM. Elevation of topoisomerase I messenger RNA, protein, and catalytic activity in human tumors: demonstration of tumor-type specificity and implications for cancer chemotherapy. Cancer Res. 1994;54(2):539–46.PubMedGoogle Scholar
  6. 6.
    Yang X, Hu Z, Sui YC, et al. Simultaneous determination of the lactone and carboxylate forms of irinotecan (CPT-11) and its active metabolite SN-38 by high-performance liquid chromatography: application to plasma pharmacokinetic studies in the rat. J Chromatogr B Analyt Technol Biomed Life Sci. 2005;821(2):221–8.CrossRefPubMedGoogle Scholar
  7. 7.
    Park DJ, Won JH, Cho AR, Yun HJ, Heo JH, Hwhang TH, et al. Determination of irinotecan and its metabolite SN-38 in rabbit plasma and tumors using a validated method of tandem mass spectrometry coupled with liquid chromatography. J Chromatogr B. 2014;962:147–52.CrossRefGoogle Scholar
  8. 8.
    Zhang W, Dutschman GE, Li X, Ye M, Cheng YC. Quantitation of irinotecan and its two major metabolites using a liquid chromatography–electrospray ionization tandem mass spectrometric. J Chromatogr B. 2009;877(27):3038–44.CrossRefGoogle Scholar
  9. 9.
    Jmm L, Lee M H, Garon E, et al. Phase I trial of intratumoral injection of CCL21 gene modified dendritic cells in lung cancer elicits tumor-specific immune responses and CD8+ T cell infiltration Clinical Cancer Research An Official Journal of the American Association for Cancer Research, 2017.Google Scholar
  10. 10.
    Mehta HJ, Begnaud A, Penley AM, Wynne J, Malhotra P, Fernandez-Bussy S, et al. Treatment of isolated mediastinal and hilar recurrence of lung cancer with bronchoscopic endobronchial ultrasound guided intratumoral injection of chemotherapy with cisplatin. Lung Cancer. 2015;90(3):542–7.CrossRefPubMedGoogle Scholar
  11. 11.
    Liu Q S, Zhang S Y, Mei Q L, et al. Percutaneous intratumoral injection of lipiodol emulsion of vinorelbine for rabbits with VX2 tumor:an experimental study Journal of Interventional Radiology, 2016.Google Scholar
  12. 12.
    Danhier F, Ansorena E, Silva JM, Coco R, le Breton A, Préat V. PLGA-based nanoparticles: an overview of biomedical applications. J Control Release. 2012;161(2):505–22.CrossRefPubMedGoogle Scholar
  13. 13.
    Kwon GS, You HB, Cremers H, et al. Release of macromolecules from albumin-heparin microspheres. Int J Pharm. 2017;79(2–3):191–8.Google Scholar
  14. 14.
    Nishino S, Kitamura Y, Kishida A, Yoshizawa H. Preparation and interfacial properties of a novel biodegradable polymer surfactant: poly(ethylene oxide monooleate-block-DL-lactide). Macromol Biosci. 2005;5(11):1066–73.CrossRefPubMedGoogle Scholar
  15. 15.
    Nishino S, Yoshizawa H, Kitamura Y. Preparation of polylactide microspheres with surface morphology control. J Chem Ind Eng. 2002;53:202–3.Google Scholar
  16. 16.
    Nishino S, Kishida A, Yoshizawa H. Morphology control of polylactide microspheres enclosing irinotecan hydrochloride with polylactide based polymer surfactant for reduction of initial burst. Int J Pharm. 2007;330(1–2):32–6.CrossRefPubMedGoogle Scholar
  17. 17.
    Machida Y, Onishi H, Morikawa A. Antitumour characteristics of irinotecan-containing microspheres of poly-d,l-lactic acid or poly(d,l-lactic acid-co-glycolic acid) copolymers. S.t.p.pharma Pratiques. 1998;8(3):175–81.Google Scholar
  18. 18.
    Cavender JL, Murdoch WJ. Morphological studies of the microcirculatory system of periovulatory ovine follicles. Biol Reprod. 1988;39(4):989.CrossRefPubMedGoogle Scholar
  19. 19.
    Machida Y, Onishi H, Kurita A, Hata H., Morikawa A., Machida Y. Pharmacokinetics of prolonged-release CPT-11-loaded microspheres in rats.[J]. J Control Release, 2000, 66(3):159–175.CrossRefPubMedGoogle Scholar
  20. 20.
    Tian L, Gao J, Yang Z, et al. Tamibarotene-Loaded PLGA Microspheres for Intratumoral Injection Administration: Preparation and Evaluation. AAPS PharmSciTech, 2017:1–9.Google Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  1. 1.School of Medicine and Life SciencesUniversity of Jinan-Shandong Academy of Medical SciencesJinanChina
  2. 2.Affiliated Hospital of Shandong Academy of Medical SciencesJinanPeople’s Republic of China
  3. 3.School of Pharmaceutical SciencesShandong UniversityJinanPeople’s Republic of China

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