Reduced malignant glioblastoma recurrence post-resection through the anti-CD47 antibody and Temozolomide co-embedded in-situ hydrogel system.
Reduced malignant glioblastoma recurrence post-resection through the anti-CD47 antibody and Temozolomide co-embedded in-situ hydrogel system.
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DOI：
10.1016/j.jconrel.2023.05.046
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发表时间：
2023-06
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通讯作者：
Lu Ye;Wei Lv;Weichong He;Shengnan Li;Zhiyi Min;L. Gong;Qi Zhang;C. Teng;Shanbo Sun;Lingyan Lv;Yi Guo;Hongliang Xin
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作者：
Lu Ye;Wei Lv;Weichong He;Shengnan Li;Zhiyi Min;L. Gong;Qi Zhang;C. Teng;Shanbo Sun;Lingyan Lv;Yi Guo;Hongliang Xin
浸润性胶质瘤的生长使手术切除不完全，残留的肿瘤细胞迅速增殖。残留的胶质瘤细胞通过上调与巨噬细胞信号调节蛋白α结合的抗吞噬分子CD47来逃避巨噬细胞的吞噬作用。具体地说，阻断CD47Sirpα通路是脑胶质瘤切除后治疗的一种潜在策略。此外，抗CD47抗体(α-CD47)与替莫唑胺(替莫唑胺)联合应用不仅能破坏肿瘤细胞的DNA，而且还能诱导内质网应激反应，从而增强肿瘤细胞的前吞噬作用。然而，血脑屏障的阻塞使得系统的联合治疗对于脑胶质瘤切除术后的治疗并不理想。在此，我们设计了一种基于可模塑温敏性羟丙基甲壳素共聚物的温度敏感型水凝胶系统，将α-CD47和α@Gel Forin包裹在术后腔内给药中。通过体外和体内评价，α-CD47和TMZ@Gel通过促进巨噬细胞的吞噬、募集和激活CD8+T细胞和NK细胞而显著抑制脑胶质瘤切除后的复发。
Infiltrative glioma growth makes surgical excision incomplete, and the residual tumor cells proliferate rapidly. Residual glioma cells evade phagocytosis by macrophages through upregulating anti-phagocytosis molecule CD47, which binds to the signal regulatory protein alpha (SIRPα) of macrophages. Specifically, blocking the CD47-SIRPα pathway is a potential strategy for post-resection glioma treatment. In addition, the anti-CD47 antibody (α-CD47) in combination with temozolomide (TMZ) caused an enhanced pro-phagocytic effect due to the TMZ not only destroying DNA but also inducing endoplasmic reticulum stress response of glioma cells. However, the obstruction of the blood-brain barrier makes systemic combination therapy not ideal for post-resection glioma treatment. Herein, we designed a temperature-sensitive hydrogel system based on a moldable thermosensitive hydroxypropyl chitin (HPCH) copolymer to encapsulate both α-CD47 and TMZ as α-CD47&TMZ@Gel forin situpostoperative cavity administration. Through thein vitroandin vivoevaluations, α-CD47&TMZ@Gel significantly inhibited glioma recurrence post-resection through enhancement of pro-phagocytosis of macrophages, recruitment, and activation of CD8+T cells and NK cells.