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

• Published in: PloS one 2019-11, Vol.14 (11), p.e0225774-e0225774
• Main Authors: Tayyar, Yaman, Shiels, Ryan, Bulmer, Andrew C, Lam, Alfred K, Clarke, Daniel, Idris, Adi, McMillan, Nigel A
• Format: Article
• Language: English
• Subjects: Acids; Administration, Intravaginal; Administration, Topical; Animals; Antibiotics; Aurora kinase; Aurora Kinase A - antagonists & inhibitors; Azepines - administration & dosage; Azepines - pharmacology; Biology and Life Sciences; Cancer; Cancer cells; Cancer therapies; Cervical cancer; Chromatography; Delivery (Childbirth); Drug delivery; Drug delivery systems; Drug development; Drug therapy; Engineering and Technology; Enzyme inhibitors; Female; Health aspects; High performance liquid chromatography; HIV; House mouse; Human immunodeficiency virus; Human papilloma viruses; Human papillomavirus; Humans; Inhibitors; Kinases; Liquid chromatography; Mass spectrometry; Medicine and Health Sciences; Mice; Novels; Papillomavirus infections; Penicillin G; Physical Sciences; Protein Kinase Inhibitors - pharmacology; Pyrimidines - administration & dosage; Pyrimidines - pharmacology; Research and Analysis Methods; Scientific imaging; Side effects; Silicones; Tumor Cells, Cultured; Uterine Cervical Neoplasms - drug therapy; Vaccination; Vaccines; Vagina; Viruses; Xenograft Model Antitumor Assays
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0225774

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.