Targeted systemic dendrimer delivery of CSF-1R inhibitor to tumor-associated macrophages improves outcomes in orthotopic glioblastoma.
Targeted systemic dendrimer delivery of CSF-1R inhibitor to tumor-associated macrophages improves outcomes in orthotopic glioblastoma.
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DOI：
10.1002/btm2.10205
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发表时间：
2021-05
影响因子：
7.4
通讯作者：
Kannan RM
中科院分区：
文献类型：
--
作者：
Liaw K;Reddy R;Sharma A;Li J;Chang M;Sharma R;Salazar S;Kannan S;Kannan RM
胶质母细胞瘤是最常见和最具侵袭性的原发脑癌，中位生存期为16-20个 月，5年生存率为5%。免疫治疗的最新进展表明，通过靶向肿瘤相关巨噬细胞(TAMs)的集落刺激因子-1(CSF-1)信号通路来解决肿瘤免疫状况具有改善胶质母细胞瘤治疗的潜力。然而，这种治疗方法在临床上的成功有限，部分原因是缺乏实体肿瘤的特异性细胞靶向和全身毒性。在本研究中，我们提出了一种新型的羟基树枝状分子介导的免疫疗法，将CSF-1R抑制剂BLZ945(D-BLZ)从系统选择性地输送到胶质母细胞瘤脑肿瘤的TAMs中，以局部方式重新极化肿瘤免疫环境。我们发现，BLZ945与树枝状大分子的偶联可以在细胞内和肿瘤内条件下实现持续释放。我们证明，与游离的BLZ945相比，单次全身剂量的针对TAMS的D-BLZ减少了TAMS中亲肿瘤的表达，并促进了细胞毒性T细胞的渗透，导致了更长的生存期和减轻的疾病负担。我们的结果表明，树枝状大分子-药物结合物可以通过选择性地向TAMs传递免疫治疗来促进全身给药对肿瘤免疫反应的特异性、局部性操作，从而在提高治疗效果的同时减少非靶向效应。
Glioblastoma is the most common and aggressive form of primary brain cancer, with median survival of 16–20 months and a 5‐year survival rates of <5%. Recent advances in immunotherapies have shown that addressing the tumor immune profile by targeting the colony‐stimulating factor 1 (CSF‐1) signaling pathway of tumor‐associated macrophages (TAMs) has the potential to improve glioblastoma therapy. However, such therapies have shown limited successes in clinical translation partially due to lack of specific cell targeting in solid tumors and systemic toxicity. In this study, we present a novel hydroxyl dendrimer‐mediated immunotherapy to deliver CSF‐1R inhibitor BLZ945 (D‐BLZ) from systemic administration selectively to TAMs in glioblastoma brain tumors to repolarize the tumor immune environment in a localized manner. We show that conjugation of BLZ945 to dendrimers enables sustained release in intracellular and intratumor conditions. We demonstrate that a single systemic dose of D‐BLZ targeted to TAMs decreases pro‐tumor expression in TAMs and promotes cytotoxic T cell infiltration, resulting in prolonged survival and ameliorated disease burden compared to free BLZ945. Our results demonstrate that dendrimer‐drug conjugates can facilitate specific, localized manipulation of tumor immune responses from systemic administration by delivering immunotherapies selectively to TAMs, thereby improving therapeutic efficacy while reducing off‐target effects.
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DOI：
10.1073/pnas.1720948115
发表时间：
2018-04-24
影响因子：
11.1
作者：
Peranzoni E;Lemoine J;Vimeux L;Feuillet V;Barrin S;Kantari-Mimoun C;Bercovici N;Guérin M;Biton J;Ouakrim H;Régnier F;Lupo A;Alifano M;Damotte D;Donnadieu E
通讯作者：
Donnadieu E
影响因子：
6.4
作者：
Hwang, Thomas J.;Gyawali, Bishal
通讯作者：
Gyawali, Bishal
影响因子：
2.8
作者：
Ma, Zhigang;Lian, Jie;Zhang, Yanqiao
通讯作者：
Zhang, Yanqiao
影响因子：
32.4
作者：
Noy, Roy;Pollard, Jeffrey W.
通讯作者：
Pollard, Jeffrey W.
Langerhans细胞促进上皮DNA损伤和鳞状细胞癌。
DOI：
10.1126/science.1211600
发表时间：
2012-01-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Modi BG;Neustadter J;Binda E;Lewis J;Filler RB;Roberts SJ;Kwong BY;Reddy S;Overton JD;Galan A;Tigelaar R;Cai L;Fu P;Shlomchik M;Kaplan DH;Hayday A;Girardi M
通讯作者：
Girardi M