Conglomerated Imiquimod and Metronidazole Incorporated Biodegradable Nanofibrous Mats for Potential Therapy of Cervical Cancer

Yi-Pin Chen,1,2 Chiao-Fan Chiu,3,4 Chien-Neng Wang,1 Chu-Chi Lin,1 Chia-Rui Shen,5– 7 Yi-Chen Yao,8 Yi-Hua Kuo,8 Shih-Jung Liu8,9 1Department of Obstetrics and Gynecology, Keelung Chang Gung Memorial Hospital, Keelung, 20401, Taiwan; 2School of Traditional Chinese Medicine, College of Medicine, Chang Gung University, Taoyuan, Taiwan; 3Department of Pediatrics, Linkou Medical Center, Chang Gung Memorial Hospital, Taoyuan, 333, Taiwan; 4Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University, Taoyuan, 33302, Taiwan; 5Department of Medical Biotechnology and Laboratory Science, Chang Gung University, Taoyuan, 33302, Taiwan; 6Department of Ophthalmology, Lin-Kou Chang Gung Memorial Hospital, Taoyuan, Taiwan; 7R&D Center of Biochemical Engineering Technology, Department of Chemical Engineering, Ming Chi University of Technology, New Taipei, Taiwan; 8Department of Mechanical Engineering, Chang Gung University, Taoyuan, 33302, Taiwan; 9Bone and Joint Research Center, Department of Orthopedic Surgery, Chang Gung Memorial Hospital-Linkou, Taoyuan, 33305, TaiwanCorrespondence: Shih-Jung Liu, Department of Mechanical Engineering, Chang Gung University, 259, Wen-Hwa 1st Road, Kwei-Shan, Tao-Yuan, 33302, Taiwan, Tel +886-3-2118166, Fax +886-3-2118558, Email [email protected]: In clinical practice, imiquimod is used to treat Human Papillomavirus (HPV)-related lesions, such as condyloma and Cervical Intraepithelial Neoplasia (CIN). Metronidazole is the most commonly prescribed antibiotic for bacterial vaginosis. The study developed biodegradable imiquimod- and metronidazole-loaded nanofibrous mats and assessed their effectiveness for the topical treatment of cervical cancer, a type of HPV-related lesion.Methods: Nanofibers of two distinct poly[(d,l)-lactide-co-glycolide] (PLGA)-to-drug ratios (6:1 and 4:1) were manufactured through the electrospinning technology. The in vitro release behavior of imiquimod and metronidazole was evaluated via an elution method, while the in vivo discharge behavior was evaluated on a mice model. Additionally, a model of cervical cancer was established using C57BL/6J mice, and it was utilized to evaluate the efficacy of drug-eluting nanofibers through in vivo testing. Mice afflicted with cervical cancer were separated into three distinct groups for the study: The mice in Group A served as the control and received no treatment. Group B received treatment with pure PLGA nanofibers (no drugs loaded), whereas Group C received treatment with nanofibers loaded with imiquimod and metronidazole. Post implantation, the variations in tumor sizes of rats receiving the implantation of drug-eluting nanofibers were monitored.Results: The experimental data show that drug-eluting nanofibers could discharge in vitro high concentrations of imiquimod and metronidazole for exceeding 30 days. In vivo, each membrane consistently released elevated concentrations of imiquimod/metronidazole at the intended site in mice over a four-week period, with minimal systemic drug concentration detected in the bloodstream. The mice treated with drug-loaded nanofibers displayed noticeably reduced tumor volumes compared to both the control group and the group treated with pristine nanofibers. Histological examination revealed the absence of any discernible tissue inflammation.Conclusion: Biodegradable nanofibers with a sustainable release of imiquimod and metronidazole demonstrated their effectiveness and lasting impact of treating mice with cervical cancer.Keywords: cervical cancer, degradable nanofibers, imiquimod, metronidazole, extended drug release