International Journal of Nanomedicine (Nov 2019)
Enhancing Radiotherapeutic Effect With Nanoparticle-Mediated Radiosensitizer Delivery Guided By Focused Gamma Rays In Lewis Lung Carcinoma-Bearing Mouse Brain Tumor Models
Abstract
Sa-Hoe Lim,1,2 Chun-Hao Li,3 Young-Il Jeong,4 Woo-Youl Jang,1,2 Jin-Myung Choi,2 Shin Jung1,2 1Department of Neurosurgery, Chonnam National University Medical School and Hwasun Hospital, Hwasun, Korea; 2Brain Tumor Research Laboratory, Chonnam National University Research Institute of Medical Sciences, Chonnam National University Hwasun Hospital, Hwasun, Korea; 3Department of Neurosurgery, Affiliated Hospital of Yanbian University, Yanji, Jilin 133000, People’s Republic of China; 4Biomedical Research Institute, Pusan National University Hospital, Pusan 602-739, Republic of KoreaCorrespondence: Shin JungDepartment of Neurosurgery, Chonnam National University Hwasun Hospital, 322, Seoyang-ro, Hwasun-eup, Hwasun-Gun, Jeollanam-do 519-763, Republic of KoreaTel +82-61-379-8588Fax +82-61-379-7181Email [email protected]: Targeting radiosensitizer-incorporated nanoparticles to a tumor could allow for less normal tissue toxicity with more efficient drug release, thus improving the efficacy and safety of radiation treatment. The aim of this study was to improve tumor-specific delivery and bioavailability of a nanoparticle-mediated radiosensitizer in mouse brain tumor models.Methods: A pH-sensitive nanoparticle, chitoPEGAcHIS, was conjugated to recombinant peptide HVGGSSV that could bind to tax-interaction protein 1 (TIP-1) as a radiation-inducible receptor. Then the c-Jun N-terminal kinase (JNK) inhibitor, SP600125 was incorporated into this copolymer to fabricate a HVGGSSV-chitoPEGAcHIS-SP600125 (HVSP-NP) nanoradiosensitizer. In vitro and in vivo radiation treatment were performed using a Gamma Knife unit. The tumor targetability of HVSP-NP was estimated by optical bioluminescence. Synergistic therapeutic effects of radiation treatment and HVSP-NP were investigated in Lewis lung carcinoma (LLC) cell-bearing mouse brain tumor models.Results: The SP600125 JNK inhibitor effectively reduced DNA damage repair to irradiated LLC cells. A pH sensitivity assay indicated that HVSP-NP swelled at acidic pH and increased in diameter, and its release rate gradually increased. Optical bioluminescence assay showed that radiation induced TIP-1 expression in mouse brain tumor and that the nanoradiosensitizer selectively targeted irradiated tumors. Radiation treatment with HVSP-NP induced greater apoptosis and significantly inhibited tumor growth compared to radiation alone.Conclusion: As a novel nanoradiosensitizer, HVSP-NP was found to be able to selectively target irradiated tumors and significantly increase tumor growth delay in LLC-bearing mouse brain tumor models. This research shows that delivering a pH-sensitive nanoradiosensitizer to a brain tumor in which TIP-1 is induced by radiation can result in improved radiosensitizer-release in an acidic microenvironment of tumor tissue and in created synergistic effects in radiation treatment.Keywords: brain neoplasms, radiotherapy, TIP-1 receptor, nanoparticles, radiosensitizer
