Antibody-activated trans-endothelial delivery of mesoporous organosilica nanomedicine augments tumor extravasation and anti-cancer immunotherapy.
Antibody-activated trans-endothelial delivery of mesoporous organosilica nanomedicine augments tumor extravasation and anti-cancer immunotherapy.
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抗体激活介孔有机二氧化硅纳米药物的跨内皮递送增强肿瘤外渗和抗癌免疫治疗
DOI：
10.1016/j.bioactmat.2020.12.023
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发表时间：
2021-07
影响因子：
18.9
通讯作者：
Tu S
中科院分区：
文献类型：
--
作者：
Huang T;Li S;Fang J;Li F;Tu S
肿瘤脉管系统构成了将癌症纳米药物有效递送到肿瘤中的巨大障碍。通过肿瘤血管中的内皮间隙的被动途径的杠杆作用可能解释了纳米药物有限地外渗到肿瘤微环境（TME）中。本文中，开发了携带抗PD-L1抗体（aPD-L1）和吲哚西莫德的免疫治疗剂的安装有膜联蛋白A1抗体的介孔有机二氧化硅纳米平台，以靶向管腔内皮细胞的膜联蛋白A1蛋白并触发由膜小窝介导的纳米药物的主动跨内皮转胞吞。这种策略使得纳米药物能够快速外渗穿过肿瘤内皮，并在肿瘤内皮中相对广泛地积累。aPD-L1和吲哚西莫德以还原响应性方式从aPD/IND@MON-aANN中释放，并协同促进细胞毒性T淋巴细胞的肿瘤内浸润并逆转免疫抑制性TME，从而证明在皮下4 T1乳腺肿瘤中的实质性抗肿瘤功效和延长4 T1肿瘤转移模型存活的显著抗转移能力。此外，aPD/IND@MON-aANN纳米药物还表现出明显优于游离药物的组合疗法，以有效地减弱肿瘤诱导的原位肺癌的进展。总的来说，aPD/IND@MON-aANN纳米平台通过抗体激活的跨内皮途径提高了递送效率，增强了免疫功效，为癌症纳米药物的开发提供了前景。纳米药物通过由缀合的aANXA 1引发的经由小窝的主动转胞吞作用克服肿瘤血管屏障。纳米平台响应性地释放aPD-L1和Indoximod，以协同提高免疫治疗的疗效。纳米药物在小鼠乳腺癌和肺癌中显示出抗肿瘤能力。
Tumor vasculature constitutes a formidable hurdle for the efficient delivery of cancer nanomedicine into tumors. The leverage of passive pathway through inter-endothelial gaps in tumor blood vessels might account for limited extravasation of nanomedicine into tumor microenvironment (TME). Herein, Annexin A1 antibody-installed mesoporous organosilica nanoplatforms carrying immunotherapeutics of anti-PD-L1 antibody (aPD-L1) and Indoximod are developed to target at caveolar Annexin-A1 protein of luminal endothelial cells and to trigger the active trans-endothelial transcytosis of nanomedicine mediated by caveolae. Such strategy enables rapid nanomedicine extravasation across tumor endothelium and relatively extensive accumulation in tumor interstitium. aPD-L1 and Indoximod release from aPD/IND@MON-aANN in a reduction-responsive manner and synergistically facilitate the intratumoral infiltration of cytotoxic T lymphocytes and reverse the immunosuppressive TME, thus demonstrating substantial anti-tumor efficacy in subcutaneous 4T1 breast tumors and remarkable anti-metastatic capacity to extend the survival of 4T1 tumor metastasis model. Moreover, aPD/IND@MON-aANN nanomedicine also exhibits distinct superiority over the combination therapy of free drugs to potently attenuate the progression of urethane-induced orthotopic lung cancers. Collectively, aPD/IND@MON-aANN nanoplatforms with boosted delivery efficiency via antibody-activated trans-endothelial pathway and enhanced immunotherapeutic efficacy provides perspectives for the development of cancer nanomedicines. The nanomedicine overcomes tumor vascular barrier by active transcytosis via caveolae initiated by the conjugated aANXA1. The nanoplatform responsively releases aPD-L1 and Indoximod to synergistically improve the efficacy of immunotherapy. The nanomedicine shows anti-tumor capacity in mice breast cancers and lung cancers.
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影响因子：
9.7
作者：
Miller, YE;Dwyer-Nield, LD;Malkinson, AM
通讯作者：
Malkinson, AM
影响因子：
82.9
作者：
Binnewies M;Roberts EW;Kersten K;Chan V;Fearon DF;Merad M;Coussens LM;Gabrilovich DI;Ostrand-Rosenberg S;Hedrick CC;Vonderheide RH;Pittet MJ;Jain RK;Zou W;Howcroft TK;Woodhouse EC;Weinberg RA;Krummel MF
通讯作者：
Krummel MF
影响因子：
64.8
作者：
Oh, P;Li, Y;Schnitzer, JE
通讯作者：
Schnitzer, JE
影响因子：
14.8
作者：
Kumar, S.;Aaron, J.;Sokolov, K.
通讯作者：
Sokolov, K.
癌症纳米医学：进步，挑战和机遇。
DOI：
10.1038/nrc.2016.108
发表时间：
2017-01
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Shi J;Kantoff PW;Wooster R;Farokhzad OC
通讯作者：
Farokhzad OC