用于腹膜转移瘤治疗的免疫植入件药效学评价及其在大鼠和兔子体内的安全性评价

Safety evaluation of biopolymer immune implants in rats and rabbits as well as therapeutic effects on gastric cancer peritoneal metastasis carcinoma

司星辉 ¹吉国锋 ²马胜 ¹刘丽萍 ³朱真逸 ³张瑜 ¹汤朝晖 ⁴宋万通 ⁴陈学思⁴

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作者信息

1. Key Laboratory of Polymer Ecomaterials,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022,China;Jilin Biomedical Polymers Engineering Laboratory,Changchun 130022,China
2. Key Laboratory of Polymer Ecomaterials,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022,China;Xuanwu Hospital,Capital Medical University,Beijing 100010,China
3. Key Laboratory of Polymer Ecomaterials,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022,China;University of Science and Technology of China,Hefei 230026,China
4. Key Laboratory of Polymer Ecomaterials,Changchun Institute of Applied Chemistry,Chinese Academy of Sciences,Changchun 130022,China;Jilin Biomedical Polymers Engineering Laboratory,Changchun 130022,China;University of Science and Technology of China,Hefei 230026,China
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摘要

瘤作为一种极具侵袭性的恶性肿瘤,具有极高的转移性,临床平均生存期不超过9个月.现有的治疗方法,包括手术切除和局部热灌注化疗,往往只能短暂抑制肿瘤生长,对患者生存期的改善有限.在之前的工作中,我们报道了一种基于亚胺与醛基的免疫植入件,持续释放负载的化疗-免疫治疗药物,有效刺激全身性抗肿瘤免疫反应,实现了肿瘤的高效治疗.在此,我们优化了四臂PEG的末端基团(肼基、羟胺基和胺基),以实现在大动物体内更稳定和更长的药物释放.基于肟键的免疫植入件在临床前评估中表现出优异的机械强度、延长的降解时间和持续的药物释放.在大鼠和兔子中的安全评价显示了出色的生物相容性.植入件负载了化疗药物奥沙利铂和免疫刺激剂雷西莫特,在胃癌腹膜转移瘤中显示出高效的治疗效果,肿瘤抑制率超过96％.这些结果充分支持了免疫植入件在腹膜转移瘤治疗中的临床转化潜力.

Abstract

Peritoneal metastasis carcinoma(PMC),as an extremely aggressive malignant tumor with high metastatic potential,typically exhibits an average clinical survival period of less than 9 months.Unfortunately,the existing treatment modalities,including surgical resection and localized hy-perthermic intraperitoneal chemotherapy(HIPEC),often only provide temporary suppression of tumor growth,offering limited improvement in overall patient survival.We pre-viously reported a biopolymer immune implant which could sustainably release the loaded chemo-immunotherapeutic agents for effectively stimulating systemic antitumor immune responses.Herein,we optimized the terminal groups(hy-drazide,hydroxylamine,and amine)of the 4-arm PEG to achieve more stable and longer drug release especially in large animals.The selected implant based on oxime bonds demon-strated superior performance in terms of mechanical strength,prolonged degradation time and sustained drug release in preclinical evaluations,which is crucial for the immune acti-vation of immunotherapeutic drugs.Safety evaluations in rats and rabbits demonstrated excellent biocompatibility.The implants,loaded with a combination of chemotherapy ox-aliplatin(OxP)and immunostimulant resiquimod(R848),showed significant therapeutic efficacy in a gastric cancer PMC model,achieving a tumor inhibition rate exceeding 96％.Furthermore,the immunological responses post-treatment revealed increased infiltration of CD4+and CD8+T cells,ac-tivation of dendritic cells within the tumor.The results sup-port the clinical translation potential of these implants for PMC therapy,offering a potential breakthrough in the chal-lenging landscape of cancer treatment.

关键词

peritoneal metastatic carcinoma/immunotherapy/implants/gastric cancer

Key words

peritoneal metastatic carcinoma/immunotherapy/implants/gastric cancer

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基金项目

National Natural Science Foundation of China(22105199)

National Natural Science Foundation of China(82203885)

National Natural Science Foundation of China(51833010)

National Natural Science Foundation of China(22222509)

National Natural Science Foundation of China(22375198)

National Natural Science Foundation of China(52103194)

National Natural Science Foundation of China(52273310)

National Natural Science Foundation of China(52025035)

Bureau of International Cooperation Chinese Academy of Sciences(121522KYSB20200029)

Jilin Provincial International Cooperation Key Laboratory of Biomedical Polymers(20210504001GH)

Jilin Province Science and Technology Development Plan(20220402037GH)

China Postdoctoral Science Foundation(BX20220337)

Changchun Science and Technology Development Plan(21ZY09)

Youth Innovation Promotion Association of Chinese Academy of Sciences(2020232)

出版年

2024

中国科学:材料科学(英文)

CSTPCD

ISSN：

段落导航