Enhanced Anti-Cancer Effect of Folate-Conjugated Olaparib Nanoparticles Combined with Radiotherapy in Cervical Carcinoma
| Autor: | Dong, Li, Chuanfei, Hu, Juan, Yang, Yin, Liao, Yue, Chen, Shao Zhi, Fu, Jing Bo, Wu |
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| Rok vydání: | 2020 |
| Předmět: |
active targeting
anti-cancer effect cervical cancer Mice Nude Uterine Cervical Neoplasms Antineoplastic Agents Apoptosis folate Combined Modality Therapy Xenograft Model Antitumor Assays olaparib Piperazines Mice Folic Acid Cell Line Tumor Positron Emission Tomography Computed Tomography Animals Humans Nanoparticles Phthalazines Female Original Research |
| Zdroj: | International Journal of Nanomedicine |
| ISSN: | 1178-2013 |
| Popis: | Background 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. |
| Databáze: | OpenAIRE |
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