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

Abstract

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.

7-(2-Anilinopyrimidin-4-yl)-1-benzazepin-2-ones Designed by a “Cut and Glue” Strategy Are Dual Aurora A/VEGF-R Kinase Inhibitors

“…However, in a randomized phase III trial in patients with relapsed and refractory peripheral T-cell lymphoma (PTCL), alisertib has not been significantly superior over the comparator drug regimens (pralatrexate, romidepsin or gemcitabine, respectively) [ 18 ]. Recently it has been shown that alisertib selectively kills HPV-positive cervical cancer cells, and for a targeted application an intravaginal alisertib-loaded ring was constructed [ 19 ]. Based on this, a developing research area on Aurora kinases as therapeutic targets and new inhibitor chemotypes are of interest.…”