Long acting carmustine loaded natural extracellular matrix hydrogel for inhibition of glioblastoma recurrence after tumor resection

doi:10.1007/s11705-021-2067-5

Front. Chem. Sci. Eng.

2022, Vol. 16

Issue (4) : 536-545 https://doi.org/10.1007/s11705-021-2067-5

RESEARCH ARTICLE

Long acting carmustine loaded natural extracellular matrix hydrogel for inhibition of glioblastoma recurrence after tumor resection

Sunhui Chen¹, Qiujun Qiu¹, Dongdong Wang², Dejun She², Bo Yin², Meihong Chai³, Huining He³(

), Dong Nyoung Heo⁴, Jianxin Wang¹(

)

¹. Department of Pharmaceutics, School of Pharmacy, Fudan University & Key Laboratory of Smart Drug Delivery, Ministry of Education, Shanghai 201203, China
². Department of Radiology, Huashan Hospital, Fudan University, Shanghai 200040, China
³. Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics, School of Pharmacy, Tianjin Medical University, Tianjin 300070, China
⁴. Department of Dental Materials, School of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea

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Abstract

Many scientific efforts have been made to penetrate the blood-brain barrier and target glioblastoma cells, but the outcomes have been limited. More attention should be given to local inhibition of recurrence after glioblastoma resection to meet real medical needs. A biodegradable wafer containing the chemotherapeutics carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU) was the only local drug delivery system approved for clinical glioblastoma treatment, but with a prolonged survival time of only two months and frequent side effects. In this study, to improve the sustained release and prolonged therapeutic effect of drugs for inhibiting tumor recurrence after tumor resection, both free BCNU and BCNU- poly (lactic-co-glycolic acid) (the ratio of lactic acid groups to glycolic acid groups is 75/25) nanoparticles were simultaneously loaded into natural extracellular matrix hydrogel from pigskin to prepare BCNU gels. The hydrogel was injected into the resection cavity of a glioblastoma tumor immediately after tumor removal in a fully characterized resection rat model. Free drugs were released instantly to kill the residual tumor cells, while drugs in nanoparticles were continuously released to achieve a continuous and effective inhibition of the residual tumor cells for 30 days. These combined actions effectively restricted tumor growth in rats. Thus, this strategy of local drug implantation and delivery may provide a reliable method to inhibit the recurrence of glioblastoma after tumor resection in vivo.

Keywords BCNU glioblastoma recurrence tumor resection nanoparticles hydrogel

Corresponding Author(s): Huining He,Jianxin Wang

Online First Date: 13 July 2021 Issue Date: 21 March 2022

Cite this article:

Sunhui Chen,Qiujun Qiu,Dongdong Wang, et al. Long acting carmustine loaded natural extracellular matrix hydrogel for inhibition of glioblastoma recurrence after tumor resection[J]. Front. Chem. Sci. Eng., 2022, 16(4): 536-545.

URL:

https://academic.hep.com.cn/fcse/EN/10.1007/s11705-021-2067-5
https://academic.hep.com.cn/fcse/EN/Y2022/V16/I4/536

Tab.1 Optimization of BCNU-NPs

Fig.1 Characterization of BCNU-NPs: (a) size distribution and (b) morphology of NPs by TEM; (c) size and (d) zeta potential of different PLGAs (PLGA_75/25 or PLGA_50/50) NPs estimated over time (n = 3) to characterize their stability.

Fig.2 In vitro characteristics of free BCNU, BCNU-NPs and BCNU-gels and MTT assay: (a) drug release behavior in PBS with 0.5% tween-80 (pH 7.4); (b) 200 × and (c) 20000 × magnifications of BCNU-gels; (d) and (e) hemolysis behavior of ECM hydrogel tested compared to the negative and positive control groups; (f) in vitro cytotoxicity study of free BCNU and BCNU-NPs.

Fig.3 Establishment of recurrence model after brain tumor resection (refer to the reporting study [2]): (a) timeline for the entire procedure; (b) IVIS and (c) MRI of animals before, after, and 7 days after tumor resection with no additional drug treatment, respectively.

Fig.4 Anti-tumor recurrence efficacy of different groups after tumor resection: (a) injection behavior and the resected tumor part; (b) body weight loss and (c) survival times (n = 6) for different treatment groups.

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