Enhanced Anti-Cancer Effect of Folate-Conjugated Olaparib Nanoparticles Combined with Radiotherapy in Cervical Carcinoma

Abstract

Dong Li,1,* Chuanfei Hu,1,* Juan Yang,1 Yin Liao,1 Yue Chen,2,3 Shao Zhi Fu,1 Jing Bo Wu1,3 1Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, People’s Republic of China; 2Department of Nuclear Medicine, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, People’s Republic of China; 3Nuclear Medicine and Molecular Imaging Key Laboratory of Sichuan Province, The Affiliated Hospital of Southwest Medical University, Luzhou 646000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jing Bo WuDepartment of Oncology, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou 646000, People’s Republic of ChinaEmail [email protected] Zhi FuDepartment of Oncology, The Affiliated Hospital of Southwest Medical University, No. 25, Taiping Street, Luzhou 646000, People’s Republic of ChinaTel [phone]Fax [phone]Email [email protected]: Radiotherapy (RT), one of the main treatments for cervical cancer, has tremendous potential for improvement in the efficacy. Poly (ADP-ribose) polymerase (PARP) is a key enzyme in the repair of DNA strand breaks (DSB). Olaparib (Ola) is a PARP inhibitor that is involved in preventing the release of PARP from RT-induced damaged DNA to potentiate the effect of RT. Although the basic mechanism of Ola’s radiosensitization is well known, the radiosensitization mechanism of its nanomedicine is still unclear. In addition, the lack of tumor tissue targeting is a major obstacle for the clinical success of Ola.Materials and Methods: In this study, we developed folate-conjugated active targeting olaparib nanoparticles (ATO) and investigated the anti-tumor effect of ATO combined with radiotherapy (RT) in nude mice using cervical cancer xenograft models. We used folate (FA)-conjugated poly (ϵ-caprolactone)-poly (ethyleneglycol)-poly (e-caprolactone) (PCEC) copolymer to prepare ATO via emulsification/solvent diffusion. Further, we evaluated ATO particle size, potential, encapsulation efficiency, and in vitro release characteristics, and evaluated the shape of ATO via transmission electron microscopy (TEM). We then performed MTT and cell uptake assays to detect cytotoxicity and targeting uptake in vitro. We investigated the anti-tumor properties of ATO in vivo by apoptosis test, 18 F-FDG PET/CT, and immunohistochemical analysis. Finally, the xenografted tumor in nude mice was subjected to RT and/or ATO treatment.Results: The results confirmed that ATO in combination with RT significantly inhibited tumor growth and prolonged survival time of tumor-bearing mice. This may be related to the inhibition of tumor proliferation and DNA damage repair and induction of cell apoptosis in vivo.Conclusion: The ATO developed in this study may represent a novel formulation for olaparib delivery and have promising potential for treating tumors with an over-expression of folate receptors.Keywords: olaparib, cervical cancer, folate, anti-cancer effect, active targeting

Keywords

• olaparib
• cervical cancer
• folate
• anti-cancer effect
• active targeting