Theranostics 2018; 8(18):5088-5105. doi:10.7150/thno.26225

Research Paper

Hypoxia-responsive lipid-poly-(hypoxic radiosensitized polyprodrug) nanoparticles for glioma chemo- and radiotherapy

Lei Hua1,2,3*, Zhen Wang1*, Liang Zhao1*, Honglin Mao1, Guanghui Wang4, Kairuo Zhang2, Xuejiao Liu1, Dongmei Wu5, Yuanlin Zheng5, Jun Lu5✉, Rutong Yu1,2,3✉, Hongmei Liu1,2,3✉

1. Institute of Nervous System Diseases, Xuzhou Medical University, Xuzhou, 221002, PR China;
2. Department of Neurosurgery, Brain Hospital, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, PR China;
3. Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, 221002, PR China;
4. Department of Gynaecology and Obstetrics, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221002, PR China;
5. Key Laboratory for Biotechnology on Medicinal Plants of Jiangsu Province, School of Life Science, Jiangsu Normal University, Xuzhou, 221116, PR China.
*These authors contributed equally to this work.

Abstract

Treatment of malignant glioma is a challenge facing cancer therapy. In addition to surgery, and chemotherapy, radiotherapy (RT) is one of the most effective modalities of glioma treatment. However, there are two crucial challenges for RT facing malignant glioma therapy: first, gliomas are known to be resistant to radiation due to their intratumoral hypoxia; second, radiosensitizers may exhibit a lack of target specificity, which may cause a lower concentration of radiosensitizers in tumors and toxic side effects in normal tissues. Thus, novel angiopep-2-lipid-poly-(metronidazoles)n (ALP-(MIs)n) hypoxic radiosensitizer-polyprodrug nanoparticles (NPs) were designed to enhance the radiosensitizing effect on gliomas.

Methods: In this study, different degrees and biodegradabilites of hypoxic radiosensitizer MIs-based polyprodrug (P-(MIs)n) were synthesized as a hydrophobic core. P-(MIs)n were mixed with DSPE-PEG2000, angiopep-2-DSPE-PEG2000 and lecithin to self-assemble ALP-(MIs)n through a single-step nanoprecipitation method. The ALP-(MIs)n encapsulate doxorubicin (DOX) (ALP-(MIs)n/DOX) and provoke the release of DOX under hypoxic conditions for glioma chemo- and radiotherapy. In vivo glioma targeting was tested in an orthotopic glioma using live animal fluorescence/bioluminescence imaging. The effect on sensitization to RT of ALP-(MIs)n and the combination of chemotherapy and RT of ALP-(MIs)n/DOX for glioma treatment were also investigated both in vitro and in vivo.

Results: ALP-(MIs)n/DOX effectively accumulated in gliomas and could reach the hypoxic glioma site after systemic in vivo administration. These ALP-(MIs)n showed a significant radiosensitizing effect on gliomas and realized combination chemotherapy and RT for glioma treatment both in vitro and in vivo.

Conclusions: In summary, we constructed a lipid-poly-(hypoxic radiosensitized polyprodrug) nanoparticles for enhancing the RT sensitivity of gliomas and achieving the combination of radiation and chemotherapy for gliomas.

Keywords: glioma, radiosensitized polyprodrug, chemo- and radiotherapy, hypoxia-responsive, blood-brain barrier

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How to cite this article:
Hua L, Wang Z, Zhao L, Mao H, Wang G, Zhang K, Liu X, Wu D, Zheng Y, Lu J, Yu R, Liu H. Hypoxia-responsive lipid-poly-(hypoxic radiosensitized polyprodrug) nanoparticles for glioma chemo- and radiotherapy. Theranostics 2018; 8(18):5088-5105. doi:10.7150/thno.26225. Available from http://www.thno.org/v08p5088.htm