Preclinical evaluation of injectable sirolimus formulated with polymeric nanoparticle for cancer therapy

Ha Na Woo¹*, Hye Kyung Chung²*, Eun Jin Ju¹, Joohee Jung^1,3, Hye-Won Kang⁴, Sa-Won Lee⁴, Min-Hyo Seo⁴, Jin Seong Lee⁵, Jung Shin Lee^1,6, Heon Joo Park⁷, Si Yeol Song^1,8, Seong-Yun Jeong¹, Eun Kyung Choi^1,2,8
1Institute for Innovative Cancer Research, ²Center for Development and Commercialization of Anti-cancer Therapeutics, Asan Medical Center, Seoul, ³College of Pharmacy, Duksung Women's University, Seoul, ⁴Department of Parenteral Delivery Program, Samyang Pharmaceuticals R&D, Daejeon, ⁵Department of Radiology and Research Institute of Radiology, ⁶Department of Internal Medicine, Asan Medical Center, Seoul, ⁷Department of Microbiology, College of Medicine, Inha University, Inchon, ⁸Department of Radiation Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

*These authors contributed equally to this study

Abstract: Nanoparticles are useful delivery vehicles for promising drug candidates that face obstacles for clinical applicability. Sirolimus, an inhibitor of mammalian target of rapamycin has gained attention for targeted anticancer therapy, but its clinical application has been limited by its poor solubility. This study was designed to enhance the feasibility of sirolimus for human cancer treatment. Polymeric nanoparticle (PNP)–sirolimus was developed as an injectable formulation and has been characterized by transmission electron microscopy and dynamic light scattering. Pharmacokinetic analysis revealed that PNP–sirolimus has prolonged circulation in the blood. In addition, PNP–sirolimus preserved the in vitro killing effect of free sirolimus against cancer cells, and intravenous administration displayed its potent in vivo anticancer efficacy in xenograft tumor mice. In addition, PNP–sirolimus enhanced the radiotherapeutic efficacy of sirolimus both in vitro and in vivo. Clinical application of PNP–sirolimus is a promising strategy for human cancer treatment.

Keywords: sirolimus, polymeric nanoparticle, anticancer, radiotherapy