在治疗转移性卵巢癌方面，非靶向和 sGRP78 靶向纳米粒子联合给药的效果优于其中任何一种成分。

IF 10.5 1区医学 Q1 CHEMISTRY, MULTIDISCIPLINARY

Journal of Controlled Release Pub Date : 2024-09-11 DOI:10.1016/j.jconrel.2024.09.014

Jenna N Sjoerdsma,Emily Bromley,Jaeho Shin,Tyvette Hilliard,Yueying Liu,Caitlin Horgan,Gyoyeon Hwang,Michael Bektas,David Omstead,Tanyel Kiziltepe,M Sharon Stack,Basar Bilgicer

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引用次数: 0

摘要

转移性卵巢癌（MOC）非常致命，部分原因是标准化疗对转移性肿瘤和非粘附性癌细胞的疗效有限。在这里，我们展示了一种GRP78靶向（TNPGRP78pep）和非靶向（NP）纳米颗粒的组合疗法，这种疗法能在合成小鼠模型中有效地将新型DM1-药物递送至MOC。细胞表面-GRP78在MOC中过度表达，使GRP78成为选择性向MOC递送纳米颗粒的最佳靶点。与未经处理的对照组相比，NP + TNPGRP78pep 组合治疗可将肿瘤负荷降低 15 倍。治疗组中T细胞和巨噬细胞水平的增加也表明抗肿瘤免疫系统的参与。NP 和 TNPGRP78pep 成分通过两种拟议的作用机制发挥协同作用。TNPGRP78pep 靶向腹腔中的非粘附癌细胞，防止形成新的实体瘤，而 NP 则被动地靶向现有的实体瘤部位，向肿瘤微环境持续释放药物。

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Combination non-targeted and sGRP78-targeted nanoparticle drug delivery outperforms either component to treat metastatic ovarian cancer.

Metastatic ovarian cancer (MOC) is highly deadly, due in part to the limited efficacy of standard-of-care chemotherapies to metastatic tumors and non-adherent cancer cells. Here, we demonstrated the effectiveness of a combination therapy of GRP78-targeted (TNPGRP78pep) and non-targeted (NP) nanoparticles to deliver a novel DM1-prodrug to MOC in a syngeneic mouse model. Cell surface-GRP78 is overexpressed in MOC, making GRP78 an optimal target for selective delivery of nanoparticles to MOC. The NP + TNPGRP78pep combination treatment reduced tumor burden by 15-fold, compared to untreated control. Increased T cell and macrophage levels in treated groups also suggested antitumor immune system involvement. The NP and TNPGRP78pep components functioned synergistically through two proposed mechanisms of action. The TNPGRP78pep targeted non-adherent cancer cells in the peritoneal cavity, preventing the formation of new solid tumors, while the NP passively targeted existing solid tumor sites, providing a sustained release of the drug to the tumor microenvironment.

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来源期刊

Journal of Controlled Release 医学-化学综合

CiteScore

18.50

自引率

5.60%

发文量

700

审稿时长

39 days

期刊介绍： The Journal of Controlled Release (JCR) proudly serves as the Official Journal of the Controlled Release Society and the Japan Society of Drug Delivery System. Dedicated to the broad field of delivery science and technology, JCR publishes high-quality research articles covering drug delivery systems and all facets of formulations. This includes the physicochemical and biological properties of drugs, design and characterization of dosage forms, release mechanisms, in vivo testing, and formulation research and development across pharmaceutical, diagnostic, agricultural, environmental, cosmetic, and food industries. Priority is given to manuscripts that contribute to the fundamental understanding of principles or demonstrate the advantages of novel technologies in terms of safety and efficacy over current clinical standards. JCR strives to be a leading platform for advancements in delivery science and technology.