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AAPS PharmSciTech

, 20:133 | Cite as

Preparation and Evaluation of Irinotecan Poly(Lactic-co-Glycolic Acid) Nanoparticles for Enhanced Anti-tumor Therapy

  • Xuehua Yang
  • Ying Yang
  • Qingwen Jia
  • Yanyun Hao
  • Jingjing Liu
  • Guihua HuangEmail author
Research Article
  • 121 Downloads

Abstract

Irinotecan (IRT), the pro-drug of SN-38, has exhibited potent cytotoxicity against various tumors. In order to enhance the anti-tumor effect of IRT, we prepared IRT-loaded PLGA nanoparticles (IRT-PLGA-NPs) by emulsion-solvent evaporation method. Firstly, IRT-PLGA-NPs were characterized through drug loading (DL), entrapment efficiency (EE), particle size, zeta potential, transmission electron microscopy (TEM), and differential scanning calorimetry (DSC). We next studied the in vitro release characteristics of IRT-PLGA-NPs. Finally, the pharmacokinetics and pharmacodynamics profiles of IRT-PLGA-NPs were investigated. The results revealed that IRT-PLGA-NPs were spherical with an average size of (169.97 ± 6.29) nm and its EE and DL were (52.22 ± 2.41)% and (4.75 ± 0.22)%, respectively. IRT-PLGA-NPs could continuously release drug for 14 days in vitro. In pharmacokinetics studies, for pro-drug IRT, the t1/2β of IRT-PLGA-NPs was extended from 0.483 to 3.327 h compared with irinotecan solution (IRT-Sol), and for its active metabolite SN-38, the t1/2β was extended from 1.889 to 4.811 h, which indicated that IRT-PLGA-NPs could prolong the retention times of both IRT and SN-38. The pharmacodynamics results revealed that the tumor doubling time, growth inhibition rate, and specific growth rate of IRT-PLGA-NPs were 2.13-, 1.30-, and 0.47-fold those of IRT-Sol, respectively, which demonstrated that IRT-PLGA-NPs could significantly inhibit the growth of tumor. In summary, IRT-PLGA-NPs, which exhibited excellent therapeutic effect against tumors, might be used as a potential carrier for tumor treatment in clinic.

Key Words

irinotecan PLGA nanoparticles pharmacokinetics pharmacodynamics 

Notes

Acknowledgments

The authors would like to extend sincere gratitude to Guihua Huang for her instructive advice and useful suggestions on this paper. The authors also thank their teammates in the same laboratory for their selfless assistance.

Compliance with Ethical Standards

Conflict of Interest

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

References

  1. 1.
    Van Cutsem E, Kohne CH, Láng I, et al. Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol. 2011;29(15):2011–9.CrossRefGoogle Scholar
  2. 2.
    Lara PN Jr, Natale R, Crowley J, Lenz HJ, Redman MW, Carleton JE, et al. Phase III trial of irinotecan/cisplatin compared with etoposide/cisplatin in extensive-stage small-cell lung cancer: clinical and pharmacogenomic results from SWOG S0124. J Clin Oncol. 2009;27(15):2530–5.CrossRefGoogle Scholar
  3. 3.
    Musa F, Pothuri B, Blank SV, Ling HT, Speyer JL, Curtin J, et al. Phase II study of irinotecan in combination with bevacizumab in recurrent ovarian cancer. Gynecol Oncol. 2017;144(2):279–84.CrossRefGoogle Scholar
  4. 4.
    Hennebelle I, Terret C, Chatelut E, Bugat R, Canal P, Guichard S. Characterization of CPT-11 converting carboxylesterase activity in colon tumor and normal tissues: comparison with p-nitro-phenylacetate converting carboxylesterase activity. Anti-Cancer Drugs. 2000;11(6):465–70.CrossRefGoogle Scholar
  5. 5.
    Slatter JG, Schaaf LJ, Sams JP, Feenstra KL, Johnson MG, Bombardt PA, et al. Pharmacokinetics, metabolism, and excretion of irinotecan (CPT-11) following iv infusion of [14C] CPT-11 in cancer patients. Drug Metab Dispos. 2000;28(4):423–33.PubMedGoogle Scholar
  6. 6.
    Sapra P, Zhao H, Mehlig M, Malaby J, Kraft P, Longley C, et al. Novel delivery of SN38 markedly inhibits tumor growth in xenografts, including a camptothecin-11–refractory model. Clin Cancer Res. 2008;14(6):1888–96.CrossRefGoogle Scholar
  7. 7.
    Sepehri N, Rouhani H, Tavassolian F, Montazeri H, Khoshayand MR, Ghahremani MH, et al. SN38 polymeric nanoparticles: in vitro cytotoxicity and in vivo antitumor efficacy in xenograft balb/c model with breast cancer versus irinotecan. Int J Pharm. 2014;471(1–2):485–97.CrossRefGoogle Scholar
  8. 8.
    Mert O, Esendağlı G, Doğan AL, Demir AS. Injectable biodegradable polymeric system for preserving the active form and delayed-release of camptothecin anticancer drugs. RSC Adv. 2012;2(1):176–85.CrossRefGoogle Scholar
  9. 9.
    Onishi H, Machida Y, Machida Y. Antitumor properties of irinotecan-containing nanoparticles prepared using poly (DL-lactic acid) and poly (ethylene glycol)-block-poly (propylene glycol)-block-poly (ethylene glycol). Biol Pharm Bull. 2003;26(1):116–9.CrossRefGoogle Scholar
  10. 10.
    Leonard SC, Lee H, Gaddy DF, Klinz SG, Paz N, Kalra AV, et al. Extended topoisomerase 1 inhibition through liposomal irinotecan results in improved efficacy over topotecan and irinotecan in models of small-cell lung cancer. Anti-Cancer Drugs. 2017;28(10):1086–96.CrossRefGoogle Scholar
  11. 11.
    Emami J, Maghzi P, Hasanzadeh F, Sadeghi H, Mirian M, Rostami M. PLGA-PEG-RA-based polymeric micelles for tumor targeted delivery of irinotecan. Pharm Dev Technol. 2018;23(1):41–54.CrossRefGoogle Scholar
  12. 12.
    Bala V, Rao S, Boyd BJ, Prestidge CA. Prodrug and nanomedicine approaches for the delivery of the camptothecin analogue SN38. J Control Release. 2013;172(1):48–61.CrossRefGoogle Scholar
  13. 13.
    Garcia-Carbonero R, Supko JG. Current perspectives on the clinical experience, pharmacology, and continued development of the camptothecins. Clin Cancer Res. 2002;8(3):641–61.PubMedGoogle Scholar
  14. 14.
    Ci T, Chen L, Yu L, et al. Tumor regression achieved by encapsulating a moderately soluble drug into a polymeric thermogel. Sci Rep. 2014;4:5473.CrossRefGoogle Scholar
  15. 15.
    Reis CP, Neufeld RJ, Ribeiro AJ, et al. Nanoencapsulation I. Methods for preparation of drug-loaded polymeric nanoparticles. Nanomedicine. 2006;2(1):8–21.CrossRefGoogle Scholar
  16. 16.
    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.CrossRefGoogle Scholar
  17. 17.
    Sharma S, Parmar A, Kori S, Sandhir R. PLGA-based nanoparticles: a new paradigm in biomedical applications. TrAC Trends Anal Chem. 2016;80:30–40.CrossRefGoogle Scholar
  18. 18.
    Guo M, Rong WT, Hou J, Wang DF, Lu Y, Wang Y, et al. Mechanisms of chitosan-coated poly (lactic-co-glycolic acid) nanoparticles for improving oral absorption of 7-ethyl-10-hydroxycamptothecin. Nanotechnology. 2013;24(24):245101.CrossRefGoogle Scholar
  19. 19.
    Sahoo SK, Panyam J, Prabha S, Labhasetwar V. Residual polyvinyl alcohol associated with poly (D, L-lactide-co-glycolide) nanoparticles affects their physical properties and cellular uptake. J Control Release. 2002;82(1):105–14.CrossRefGoogle Scholar
  20. 20.
    Tian L, Gao J, Yang Z, Zhang Z, Huang G. Tamibarotene-loaded PLGA microspheres for intratumoral injection administration: preparation and evaluation. AAPS PharmSciTech. 2018;19(1):275–83.CrossRefGoogle Scholar
  21. 21.
    Liu D, Gao J, Zhang C, et al. HPLC determination of irinotecan and its active metabolite SN-38 in rat plasma. Chin J Pharm Anal. 2011;31(4):625–8.Google Scholar
  22. 22.
    Yang Y, Gao J, Ma X, Huang G. Inclusion complex of tamibarotene with hydroxypropyl-β-cyclodextrin: preparation, characterization, in-vitro and in-vivo evaluation. Asian J Pharm Sci. 2017;12(2):187–92.CrossRefGoogle Scholar
  23. 23.
    Acharya S, Sahoo SK. PLGA nanoparticles containing various anticancer agents and tumour delivery by EPR effect. Adv Drug Deliv Rev. 2011;63(3):170–83.CrossRefGoogle Scholar
  24. 24.
    Kunii R, Onishi H, Ueki K, Koyama KI, Machida Y. Particle characteristics and biodistribution of camptothecin-loaded PLA/(PEG-PPG-PEG) nanoparticles. Drug Deliv. 2008;15(1):3–10.CrossRefGoogle Scholar
  25. 25.
    Ueki K, Onishi H, Sasatsu M, Machida Y. Preparation of carboxy-PEG-PLA nanoparticles loaded with camptothecin and their body distribution in solid tumor–bearing mice. Drug Dev Res. 2009;70(7):512–9.CrossRefGoogle Scholar
  26. 26.
    Kunii R, Onishi H, Machida Y. Preparation and antitumor characteristics of PLA/(PEG-PPG-PEG) nanoparticles loaded with camptothecin. Eur J Pharm Biopharm. 2007;67(1):9–17.CrossRefGoogle Scholar
  27. 27.
    Çirpanli Y, Bilensoy E, Doğan AL, et al. Comparative evaluation of polymeric and amphiphilic cyclodextrin nanoparticles for effective camptothecin delivery. Eur J Pharm Biopharm. 2009;73(1):82–9.CrossRefGoogle Scholar
  28. 28.
    Tian L, Liu J, Jia Q, Ying Y, Yang Z, Huang G. Preparation and evaluation of artemether liposomes for enhanced anti-tumor therapy. AAPS PharmSciTech. 2018;19(2):512–21.CrossRefGoogle Scholar
  29. 29.
    Koizumi F, Kitagawa M, Negishi T, Onda T, Matsumoto SI, Hamaguchi T, et al. Novel SN-38-incorporating polymeric micelles, NK012, eradicate vascular endothelial growth factor-secreting bulky tumors. Cancer Res. 2006;66(20):10048–56.CrossRefGoogle Scholar
  30. 30.
    Cirpanli Y, Bilensoy E, Dogan AL, Calis S. Development of polymeric and cyclodextrin nanoparticles for camptothecin delivery. J Control Release. 2010;148(1):e21–3.CrossRefGoogle Scholar
  31. 31.
    Sawyer AJ, Saucier-Sawyer JK, Booth CJ, Liu J, Patel T, Piepmeier JM, et al. Convection-enhanced delivery of camptothecin-loaded polymer nanoparticles for treatment of intracranial tumors. Drug Deliv Transl Res. 2011;1(1):34–42.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2019

Authors and Affiliations

  • Xuehua Yang
    • 1
  • Ying Yang
    • 1
  • Qingwen Jia
    • 2
  • Yanyun Hao
    • 1
  • Jingjing Liu
    • 1
  • Guihua Huang
    • 1
    Email author
  1. 1.The School of Pharmaceutical ScienceShandong UniversityJi’nanChina
  2. 2.Shandong Academy of Pharmaceutical SciencesJi’nanChina

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