Delivery of aPD-L1 antibody to i.p. tumors via direct penetration by i.p. route: beyond EPR effect.
Delivery of aPD-L1 antibody to i.p. tumors via direct penetration by i.p. route: beyond EPR effect.
复制标题
将 aPD-L1 抗体腹膜内递送
DOI：
10.1016/j.jconrel.2022.10.032
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发表时间：
2022
影响因子：
10.8
通讯作者：
H. Hatakeyama,
中科院分区：
文献类型：
--
作者：
M. Yamamoto;T. Kurino;R. Matsuda;H. S. Jones;Y. Nakamura;T. Kanamori;A. B. Tsuji;A. Sugyo;R. Tsuda;Y. Matsumoto;Y. Sakurai;H. Suzuki;M. Sano;K. Osada;T. Uehara;Y. Ishii;H. Akita;Y. Arano;A. Hisaka;H. Hatakeyama,
腹膜扩散的化疗效果很差，因为从血液到腹膜内的药物转移有限(I.P.)静脉注射后隔室(静脉注射)行政管理。IP地址。化疗被研究用来改善对肿瘤的药物输送；然而，其有效性仍存在争议。由于抗癌药物分子量小，通过腹膜血管迅速排泄，维持了I.P.像预期那样高度集中是一项挑战。在这项研究中，我们检查了IP。给药是利用腹膜播散性癌模型治疗腹膜播散性肿瘤的一种有效途径。在IP之后。给药后，腹腔注射抗PD-L1抗体的量。与静脉注射后相比，肿瘤增加了大约8倍。行政管理。瘤内分布分析表明，抗PD-L1抗体直接从腹腔输送。肿瘤组织间隙至肿瘤组织表面，腹腔注射后，肿瘤组织内有较深的穿透性。给药；相比之下，静脉注射后。给药后，抗PD-L1抗体通过增强通透性和滞留(EPR)效应仅分布在肿瘤组织的血管周围。腹膜腔内注射PD-L1抗体可提高腹膜腔内注射PD-L1抗体的疗效。给药后与静脉注射后比较。行政管理。这是第一项清楚地证明独立于EPR的ICIS交付给I.P.的研究。Ip后通过直接穿透将ICI大量输送到肿瘤组织的肿瘤。行政管理。
Chemotherapy for peritoneal dissemination is poorly effective owing to limited drug transfer from the blood to the intraperitoneal (i.p.) compartment after intravenous (i.v.) administration. i.p. chemotherapy has been investigated to improve drug delivery to tumors; however, the efficacy continues to be debated. As anticancer drugs have low molecular weight and are rapidly excreted through the peritoneal blood vessels, maintaining the i.p. concentration as high as expected is a challenge. In this study, we examined whether i.p. administration is an efficient route of administration of high-molecular-weight immune checkpoint inhibitors (ICIs) for the treatment of peritoneal dissemination using a model of peritoneal disseminated carcinoma. After i.p. administration, the amount of anti-PD-L1 antibody transferred into i.p. tumors increased by approximately eight folds compared to that after i.v. administration. Intratumoral distribution analysis revealed that anti-PD-L1 antibodies were delivered directly from the i.p. space to the surface of tumor tissue, and that they deeply penetrated the tumor tissues after i.p. administration; in contrast, after i.v. administration, anti-PD-L1 antibodies were only distributed around blood vessels in tumor tissues via the enhanced permeability and retention (EPR) effect. Owing to the enhanced delivery, the therapeutic efficacy of anti-PD-L1 antibody in the peritoneal dissemination models was also improved after i.p. administration compared to that after i.v. administration. This is the first study to clearly demonstrate an EPR-independent delivery of ICIs to i.p. tumors by which ICIs were delivered in a massive amount to the tumor tissue via direct penetration after i.p. administration.