Development of an intravaginal ring for the topical delivery of Aurora kinase A inhibitor, MLN8237


Autoři: Yaman Tayyar aff001;  Ryan Shiels aff001;  Andrew C. Bulmer aff001;  Alfred K. Lam aff002;  Daniel Clarke aff001;  Adi Idris aff001;  Nigel A. McMillan aff001
Působiště autorů: School of Medical Science, Griffith University, Southport, Australia aff001;  Menzies Health Institute Queensland, Griffith University, Southport, Australia aff002
Vyšlo v časopise: PLoS ONE 14(11)
Kategorie: Research Article
doi: 10.1371/journal.pone.0225774

Souhrn

Human papilloma virus (HPV) is the main culprit in cervical cancers. Although the HPV vaccine is now available, the slow and gradual process for HPV cancers to form means little will change, even for vaccinated individuals. This warrants the development of new therapeutic strategies in both the newly diagnosed and recurrent patients. We have previously shown that Alisertib (MLN8237), an Aurora A kinase inhibitor, potently and selectively kills HPV-positive cervical cancer cells. However, Alisertib is known for its unfavorable side effects when administered systemically. A targeted delivery approach is therefore warranted. The topical delivery of drugs to the cervix for the treatment of cervical cancer is an underexplored area of research that has the potential to significantly improve therapeutic outcome. Here, we design a novel topical drug delivery system for localized delivery in the vaginal tract using intravaginal silicone rings loaded with Alisertib. We assessed the suitability of the drug for the application and delivery method and develop a high-performance liquid chromatography method, then show that the vaginal rings were effective at releasing Alisertib over an extended period of time. Furthermore, we showed that Alisertib-loaded vaginal rings did not induce overt inflammation in the mouse vaginal tract. Our work has major translational implications for the future development of vaginal ring devices for the topical treatment of cervical cancer.

Klíčová slova:

Cancer treatment – Cervical cancer – Drug delivery – High performance liquid chromatography – Human papillomavirus – Inflammation – Medical implants – Silicones


Zdroje

1. Forman D, de Martel C, Lacey CJ, Soerjomataram I, Lortet-Tieulent J, Bruni L, et al. Global burden of human papillomavirus and related diseases. Vaccine. 2012;30 Suppl 5:F12–23.

2. zur Hausen H. Papillomavirus infections—a major cause of human cancers. Biochim Biophys Acta. 1996;1288(2):F55–78. doi: 10.1016/0304-419x(96)00020-0 8876633

3. Cancer of the Cervix Uteri (Invasive), 5-Year Relative and Period Survival by Race, Diagnosis Year, Age and Stage at Diagnosis [Internet]. The National Cancer Institute. 2016 [cited 24 October 2016]. http://seer.cancer.gov/csr/1975_2013/browse_csr.php?sectionSEL=5&pageSEL=sect_05_table.08.html#b.

4. Gabrielli B, Bokhari F, Ranall MV, Oo ZY, Stevenson AJ, Wang W, et al. Aurora A Is Critical for Survival in HPV-Transformed Cervical Cancer. Mol Cancer Ther. 2015;14(12):2753–61. doi: 10.1158/1535-7163.MCT-15-0506 26516156

5. Martin D, Fallaha S, Proctor M, Stevenson A, Perrin L, McMillan N, et al. Inhibition of Aurora A and Aurora B Is Required for the Sensitivity of HPV-Driven Cervical Cancers to Aurora Kinase Inhibitors. Mol Cancer Ther. 2017;16(9):1934–41. doi: 10.1158/1535-7163.MCT-17-0159 28522591

6. Pecorelli S, Odicino F. Cervical cancer staging. Cancer J. 2003;9(5):390–4. doi: 10.1097/00130404-200309000-00009 14690314

7. Seiden MV. Chapter 97. Gynecologic Malignancies. In: Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson JL, Loscalzo J, editors. Harrison's Principles of Internal Medicine, 18e. New York, NY: The McGraw-Hill Companies; 2012.

8. Malcolm RK, Edwards KL, Kiser P, Romano J, Smith TJ. Advances in microbicide vaginal rings. Antiviral Res. 2010;88 Suppl 1:S30–9.

9. Malcolm K, Woolfson D, Russell J, Andrews C. In vitro release of nonoxynol-9 from silicone matrix intravaginal rings. J Control Release. 2003;91(3):355–64. doi: 10.1016/s0168-3659(03)00260-8 12932713

10. Stafford MK, Ward H, Flanagan A, Rosenstein IJ, Taylor-Robinson D, Smith JR, et al. Safety study of nonoxynol-9 as a vaginal microbicide: Evidence of adverse effects. Journal of Acquired Immune Deficiency Syndromes and Human Retrovirology. 1998;17(4):327–31. doi: 10.1097/00042560-199804010-00006 9525433

11. Van Damme L, Ramjee G, Alary M, Vuylsteke B, Chandeying V, Rees H, et al. Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial. Lancet. 2002;360(9338):971–7. doi: 10.1016/s0140-6736(02)11079-8 12383665

12. Malcolm RK, Woolfson AD, Toner CF, Morrow RJ, McCullagh SD. Long-term, controlled release of the HIV microbicide TMC120 from silicone elastomer vaginal rings. J Antimicrob Chemother. 2005;56(5):954–6. doi: 10.1093/jac/dki326 16155060

13. Woolfson AD, Malcolm RK, Morrow RJ, Toner CF, McCullagh SD. Intravaginal ring delivery of the reverse transcriptase inhibitor TMC 120 as an HIV microbicide. Int J Pharm. 2006;325(1–2):82–9. doi: 10.1016/j.ijpharm.2006.06.026 16884869

14. Bell SE, Dennis AC, Fido LA, Malcolm RK, Sirimuthu NM, Toner CF, et al. Characterization of silicone elastomer vaginal rings containing HIV microbicide TMC120 by Raman spectroscopy. J Pharm Pharmacol. 2007;59(2):203–7. doi: 10.1211/jpp.59.2.0007 17270074

15. Fetherston SM, Boyd P, McCoy CF, McBride MC, Edwards KL, Ampofo S, et al. A silicone elastomer vaginal ring for HIV prevention containing two microbicides with different mechanisms of action. Eur J Pharm Sci. 2013;48(3):406–15. doi: 10.1016/j.ejps.2012.12.002 23266465

16. Morrow RJ, Woolfson AD, Donnelly L, Curran R, Andrews G, Katinger D, et al. Sustained release of proteins from a modified vaginal ring device. Eur J Pharm Biopharm. 2011;77(1):3–10. doi: 10.1016/j.ejpb.2010.10.010 21055465

17. Dang TTN. Polymeric matrix devices for controlled delivery of agents to prevent bacterial and viral infection: The University of Queensland, School of Pharmacy; 2014.

18. Yugawa T, Nishino K, Ohno S, Nakahara T, Fujita M, Goshima N, et al. Noncanonical NOTCH signaling limits self-renewal of human epithelial and induced pluripotent stem cells through ROCK activation. Mol Cell Biol. 2013;33(22):4434–47. doi: 10.1128/MCB.00577-13 24019071

19. Owen DH, Katz DF. A vaginal fluid simulant. Contraception. 1999;59(2):91–5. doi: 10.1016/s0010-7824(99)00010-4 10361623

20. Malcolm RK, Boyd PJ, McCoy CF, Murphy DJ. Microbicide vaginal rings: Technological challenges and clinical development. Adv Drug Deliv Rev. 2016;103:33–56. doi: 10.1016/j.addr.2016.01.015 26829289

21. Wyatt TL, Whaley KJ, Cone RA, Saltzman WM. Antigen-releasing polymer rings and microspheres stimulate mucosal immunity in the vagina. J Control Release. 1998;50(1–3):93–102. doi: 10.1016/s0168-3659(97)00114-4 9685876

22. Radomsky ML, Whaley KJ, Cone RA, Saltzman WM. Controlled vaginal delivery of antibodies in the mouse. Biol Reprod. 1992;47(1):133–40. doi: 10.1095/biolreprod47.1.133 1637941

23. Tayyar Y, Jubair L, Fallaha S, McMillan NAJ. Critical risk-benefit assessment of the novel anti-cancer aurora a kinase inhibitor alisertib (MLN8237): A comprehensive review of the clinical data. Crit Rev Oncol Hematol. 2017;119:59–65. doi: 10.1016/j.critrevonc.2017.09.006 29065986


Článek vyšel v časopise

PLOS One


2019 Číslo 11