AAPS PharmSciTech

, Volume 19, Issue 7, pp 3141–3151 | Cite as

Evaluation of Anti-Tumor Efficacy of Vorinostat Encapsulated Self-Assembled Polymeric Micelles in Solid Tumors

  • Sri Vishnu Kiran Rompicharla
  • Prakruti Trivedi
  • Preeti Kumari
  • Omkara Swami Muddineti
  • Sowmya Theegalapalli
  • Balaram Ghosh
  • Swati BiswasEmail author
Research Article


Vorinostat (VOR), a potent HDAC inhibitor, suffers from low solubility and poor absorption, which hinders its successful application in therapy, especially in the treatment of solid tumors. In this study, an effort to improve the physicochemical characteristics of VOR was made by encapsulating it in PEG-PLGA copolymeric micelles. VOR-loaded PEG-PLGA micelles (VOR-PEG-PLGA) were produced by thin-film hydration and physicochemically characterized. The PEG-PLGA micelles had an average size of 124.06 ± 2.6 nm, polydispersity index of 0.27 ± 0.1, and entrapment efficiency of 90 ± 2.1%. Micelles were characterized by TEM, DSC, and drug release studies. The drug release occurred in a sustained manner up to 72 h from PEG-PLGA micelles. In the in vitro cell-based studies using human breast cancer (MDA MB 231) and murine melanoma (B16F10) cell lines, VOR-PEG-PLGA micelles exhibited superior cellular internalization, enhanced cytotoxic activity, and greater apoptosis compared to free drug. Percent cell killing of 54.9% for VOR-PEG-PLGA-treated cells was observed after 24 h compared to 36% for free VOR in MDA MB 231 cell line. Further, significant tumor suppression was witnessed in B16F10 tumor-bearing mice treated with VOR-PEG-PLGA micelles with a 1.78-fold reduction in tumor volume compared to free VOR-treated animals. Overall, the VOR-PEG-PLGA micelles improved the biopharmaceutical properties of VOR, which resulted in enhanced anti-tumor efficacy. Therefore, the newly developed nano-formulation of VOR could be considered as an effective treatment option in solid tumors.


polymeric micelles vorinostat drug delivery anticancer in vivo efficacy 



The authors acknowledge Evonik India Pvt. Ltd., Mumbai, India for the gift sample of Resomer RG504H. The authors also thank the Department of Biotechnology (Bio-CARe scheme, BT/Bio-CARe/07/10003/2013-2014) for funding.

Compliance with Ethical Standards

Conflict of Interest

Authors declare no conflict of interest.

Animal Studies

All institutional and national guidelines for the care and use of laboratory animals were followed.


  1. 1.
    Siegel RL, Miller KD, Jemal A. Cancer statistics, 2017. CA Cancer J Clin. 2017;67(1):7–30.CrossRefGoogle Scholar
  2. 2.
    Rahib L, Smith BD, Aizenberg R, Rosenzweig AB, Fleshman JM, Matrisian LM. Projecting cancer incidence and deaths to 2030: the unexpected burden of thyroid, liver, and pancreas cancers in the United States. Cancer Res. 2014;74(11):2913–21.CrossRefGoogle Scholar
  3. 3.
    Bhise K, Kashaw SK, Sau S, Iyer AK. Nanostructured lipid carriers employing polyphenols as promising anticancer agents: quality by design (QbD) approach. Int J Pharm. 2017;526(1–2):506–15.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Yang X, Li Z, Wang N, Li L, Song L, He T, et al. Curcumin-encapsulated polymeric micelles suppress the development of colon cancer in vitro and in vivo. Sci Rep. 2015;5:10322.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    Smith BC, Denu JM. Chemical mechanisms of histone lysine and arginine modifications. Biochim Biophys Acta. 2009;1789(1):45–57.CrossRefGoogle Scholar
  6. 6.
    Khan O, La Thangue NB. HDAC inhibitors in cancer biology: emerging mechanisms and clinical applications. Immunol Cell Biol. 2011;90:85.CrossRefGoogle Scholar
  7. 7.
    Witt O, Deubzer HE, Milde T, Oehme I. HDAC family: what are the cancer relevant targets? Cancer Lett. 2009;277(1):8–21.CrossRefGoogle Scholar
  8. 8.
    Kumar P, Wasim L, Chopra M, Chhikara A. Co-delivery of vorinostat and etoposide via disulfide cross-linked biodegradable polymeric Nanogels: synthesis, characterization, biodegradation, and anticancer activity. AAPS PharmSciTech. 2018;19(2):634–47.CrossRefGoogle Scholar
  9. 9.
    Richon VM, Garcia-Vargas J, Hardwick JS. Development of vorinostat: current applications and future perspectives for cancer therapy. Cancer Lett. 2009;280(2):201–10.CrossRefGoogle Scholar
  10. 10.
    Pan C-H, Chang Y-F, Lee M-S, Wen BC, Ko J-C, Liang S-K, et al. Vorinostat enhances the cisplatin-mediated anticancer effects in small cell lung cancer cells. BMC Cancer. 2016;16:857.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Siegel D, Hussein M, Belani C, Robert F, Galanis E, Richon VM, et al. Vorinostat in solid and hematologic malignancies. J Hematol Oncol. 2009;2(1):31.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Mottamal M, Zheng S, Huang T, Wang G. Histone deacetylase inhibitors in clinical studies as templates for new anticancer agents. Molecules. 2015;20(3):3898–941.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Katoch O, Dwarakanath B, Agrawala PK. HDAC inhibitors: applications in oncology and beyond. HOAJ Biology. 2013;2(1).CrossRefGoogle Scholar
  14. 14.
    Marks PA. Histone deacetylase inhibitors: a chemical genetics approach to understanding cellular functions. Biochim Biophys Acta. 2010;1799:717–25.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Bubna AK. Vorinostat—an overview. Indian J Dermatol. 2015;60(4):419.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Richon VM. Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor. Br J Cancer. 2006;95(Suppl 1):S2–6.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Mohamed EA, Zhao Y, Meshali MM, Remsberg CM, Borg TM, Foda AM, et al. Vorinostat with sustained exposure and high solubility in poly (ethylene glycol)-b-poly (dl-lactic acid) micelle nanocarriers: characterization and effects on pharmacokinetics in rat serum and urine. J Pharm Sci. 2012;101(10):3787–98.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Mohamed EA, Abu Hashim II, Yusif RM, Suddek GM, Shaaban AAA, Badria FAE. Enhanced in vitro cytotoxicity and anti-tumor activity of vorinostat-loaded pluronic micelles with prolonged release and reduced hepatic and renal toxicities. Eur J Pharm Sci. 2017;96(Supplement C):232–42.CrossRefGoogle Scholar
  19. 19.
    Tran TH, Choi JY, Ramasamy T, Truong DH, Nguyen CN, Choi H-G, et al. Hyaluronic acid-coated solid lipid nanoparticles for targeted delivery of vorinostat to CD44 overexpressing cancer cells. Carbohydr Polym. 2014;114:407–15.CrossRefGoogle Scholar
  20. 20.
    Tran TH, Chu DT, Truong DH, Tak JW, Jeong J-H, Hoang VL, Yong CS, Kim JO. Development of lipid nanoparticles for a histone deacetylases inhibitor as a promising anticancer therapeutic. Drug Deliv. 2014;1–9.Google Scholar
  21. 21.
    Han L, Wang T, Wu J, Yin X, Fang H, Zhang N. A facile route to form self-carried redox-responsive vorinostat nanodrug for effective solid tumor therapy. Int J Nanomedicine. 2016;11:6003–22.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Cho HK, Cheong IW, Lee JM, Kim JH. Polymeric nanoparticles, micelles and polymersomes from amphiphilic block copolymer. Korean J Chem Eng. 2010;27(3):731–40.CrossRefGoogle Scholar
  23. 23.
    Shin DH, Tam YT, Kwon GS. Polymeric micelle nanocarriers in cancer research. Front Chem Sci Eng. 2016;10(3):348–59.CrossRefGoogle Scholar
  24. 24.
    Xiong X-B, Falamarzian A, Garg SM, Lavasanifar A. Engineering of amphiphilic block copolymers for polymeric micellar drug and gene delivery. J Control Release. 2011;155(2):248–61.CrossRefGoogle Scholar
  25. 25.
    Thipparaboina R, Chavan RB, Kumar D, Modugula S, Shastri NR. Micellar carriers for the delivery of multiple therapeutic agents. Colloids Surf B Biointerfaces. 2015;135(Supplement C):291–308.CrossRefGoogle Scholar
  26. 26.
    Jhaveri AM, Torchilin VP. Multifunctional polymeric micelles for delivery of drugs and siRNA. Front Pharmacol. 2014;5(77).Google Scholar
  27. 27.
    Torchilin V. Tumor delivery of macromolecular drugs based on the EPR effect. Adv Drug Deliv Rev. 2011;63(3):131–5.CrossRefGoogle Scholar
  28. 28.
    Matsumura Y. Preclinical and clinical studies of NK012, an SN-38-incorporating polymeric micelles, which is designed based on EPR effect. Adv Drug Deliv Rev. 2011;63(3):184–92.CrossRefGoogle Scholar
  29. 29.
    Sunoqrot S, Bugno J, Lantvit D, Burdette JE, Hong S. Prolonged blood circulation and enhanced tumor accumulation of folate-targeted dendrimer–polymer hybrid nanoparticles. J Control Release. 2014;191:115–22.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Zhang Y, Huang Y, Li S. Polymeric micelles: nanocarriers for cancer-targeted drug delivery. AAPS PharmSciTech. 2014;15(4):862–71.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Hu X, Yang FF, Liu CY, Ehrhardt C, Liao YH. In vitro uptake and transport studies of PEG-PLGA polymeric micelles in respiratory epithelial cells. Eur J Pharm Biopharm. 2017;114:29–37.CrossRefGoogle Scholar
  32. 32.
    Zhang K, Tang X, Zhang J, Lu W, Lin X, Zhang Y, et al. PEG–PLGA copolymers: their structure and structure-influenced drug delivery applications. J Controlled Release. 2014;183(Supplement C):77–86.CrossRefGoogle Scholar
  33. 33.
    Bi Y, Liu L, Lu Y, Sun T, Shen C, Chen X, et al. T7 peptide-functionalized PEG-PLGA micelles loaded with carmustine for targeting therapy of glioma. ACS Appl Mater Interfaces. 2016;8(41):27465–73.CrossRefGoogle Scholar
  34. 34.
    Dinarvand R, Sepehri N, Manoochehri S, Rouhani H, Atyabi F. Polylactide-co-glycolide nanoparticles for controlled delivery of anticancer agents. Int J Nanomedicine. 2011;6:877–95.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Yoo HS, Park TG. Biodegradable polymeric micelles composed of doxorubicin conjugated PLGA–PEG block copolymer. J Control Release. 2001;70(1):63–70.CrossRefGoogle Scholar
  36. 36.
    Wang H, Zhao Y, Wu Y. Hu Y-l, nan K, Nie G, et al. enhanced anti-tumor efficacy by co-delivery of doxorubicin and paclitaxel with amphiphilic methoxy PEG-PLGA copolymer nanoparticles. Biomaterials. 2011;32(32):8281–90.CrossRefGoogle Scholar
  37. 37.
    Rompicharla SVK, Trivedi P, Kumari P, Ghanta P, Ghosh B, Biswas S. Polymeric micelles of suberoylanilide hydroxamic acid to enhance the anticancer potential in vitro and in vivo. Nanomedicine. 2017;12(1):43–58.CrossRefGoogle Scholar
  38. 38.
    Kashi TSJ, Eskandarion S, Esfandyari-Manesh M, Marashi SMA, Samadi N, Fatemi SM, et al. Improved drug loading and antibacterial activity of minocycline-loaded PLGA nanoparticles prepared by solid/oil/water ion pairing method. Int J Nanomedicine. 2012;7:221–34.PubMedPubMedCentralGoogle Scholar
  39. 39.
    Guo Y, He W, Yang S, Zhao D, Li Z, Luan Y. Co-delivery of docetaxel and verapamil by reduction-sensitive PEG-PLGA-SS-DTX conjugate micelles to reverse the multi-drug resistance of breast cancer. Colloids Surf B Biointerfaces. 2017;151(Supplement C):119–27.CrossRefGoogle Scholar
  40. 40.
    Tran TH, Ramasamy T, Truong DH, Shin BS, Choi H-G, Yong CS, et al. Development of vorinostat-loaded solid lipid nanoparticles to enhance pharmacokinetics and efficacy against multidrug-resistant cancer cells. Pharm Res. 2014;31(8):1978–88.CrossRefGoogle Scholar
  41. 41.
    Hrzenjak A, Moinfar F, Kremser M-L, Strohmeier B, Petru E, Zatloukal K, et al. Histone deacetylase inhibitor vorinostat suppresses the growth of uterine sarcomas in vitro and in vivo. Mol Cancer. 2010;9(1):1–11.CrossRefGoogle Scholar
  42. 42.
    Dorati R, Colonna C, Serra M, Genta I, Modena T, Pavanetto F, et al. γ-Irradiation of PEGd, lPLA and PEG-PLGA multiblock copolymers: I. Effect of irradiation doses. AAPS PharmSciTech. 2008;9(2):718–25.CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Li H, Tong Y, Bai L, Ye L, Zhong L, Duan X, et al. Lactoferrin functionalized PEG-PLGA nanoparticles of shikonin for brain targeting therapy of glioma. Int J Biol Macromol. 2017.Google Scholar
  44. 44.
    Koopaei MN, Maghazei MS, Mostafavi SH, Jamalifar H, Samadi N, Amini M, et al. Enhanced antibacterial activity of roxithromycin loaded pegylated poly lactide-co-glycolide nanoparticles. DARU Journal of Pharmaceutical Sciences. 2012;20(1):92.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Babu A, Templeton AK, Munshi A, Ramesh R. Nanodrug delivery systems: a promising technology for detection, diagnosis, and treatment of cancer. AAPS PharmSciTech. 2014;15(3):709–21.CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Kumari P, Swami MO, Nadipalli SK, Myneni S, Ghosh B, Biswas S. Curcumin delivery by poly (lactide)-based co-polymeric micelles: an in vitro anticancer study. Pharm Res. 2016;33(4):826–41.CrossRefGoogle Scholar
  47. 47.
    Batrakova E, Bronich T, Vetro J, Kabanov VA. Polymer micelles as drug carriers. 2006;57–93.Google Scholar
  48. 48.
    Shi C, Zhang Z, Wang F, Ji X, Zhao Z, Luan Y. Docetaxel-loaded PEO-PPO-PCL/TPGS mixed micelles for overcoming multidrug resistance and enhancing antitumor efficacy. J Mater Chem B. 2015;3(20):4259–71.CrossRefGoogle Scholar
  49. 49.
    Mohanty C, Acharya S, Mohanty AK, Dilnawaz F, Sahoo SK. Curcumin-encapsulated MePEG/PCL diblock copolymeric micelles: a novel controlled delivery vehicle for cancer therapy. Nanomedicine. 2010;5(3):433–49.CrossRefGoogle Scholar
  50. 50.
    Mulik RS, Monkkonen J, Juvonen RO, Mahadik KR, Paradkar AR. Transferrin mediated solid lipid nanoparticles containing curcumin: enhanced in vitro anticancer activity by induction of apoptosis. Int J Pharm. 2010;398(1–2):190–203.CrossRefGoogle Scholar
  51. 51.
    Uehara N, Kanematsu S, Miki H, Yoshizawa K, Tsubura A. Requirement of p38 MAPK for a cell-death pathway triggered by vorinostat in MDA-MB-231 human breast cancer cells. Cancer Lett. 2012;315(2):112–21.CrossRefGoogle Scholar

Copyright information

© American Association of Pharmaceutical Scientists 2018

Authors and Affiliations

  • Sri Vishnu Kiran Rompicharla
    • 1
  • Prakruti Trivedi
    • 1
  • Preeti Kumari
    • 1
  • Omkara Swami Muddineti
    • 1
  • Sowmya Theegalapalli
    • 1
  • Balaram Ghosh
    • 1
  • Swati Biswas
    • 1
    Email author
  1. 1.Birla Institute of Technology and Science Pilani, Hyderabad CampusHyderabadIndia

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