Combination non-targeted and sGRP78-targeted nanoparticle drug delivery outperforms either component to treat metastatic ovarian cancer,Journal of Controlled Release

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Combination non-targeted and sGRP78-targeted nanoparticle drug delivery outperforms either component to treat metastatic ovarian cancer
Journal of Controlled Release ( IF 10.5 ) Pub Date : 2024-09-19 , DOI: 10.1016/j.jconrel.2024.09.014
Jenna N Sjoerdsma ₁ , Emily Bromley ₁ , Jaeho Shin ₁ , Tyvette Hilliard ₂ , Yueying Liu ₂ , Caitlin Horgan ₃ , Gyoyeon Hwang ₁ , Michael Bektas ₂ , David Omstead ₄ , Tanyel Kiziltepe ₁ , M Sharon Stack ₂ , Basar Bilgicer ₅

Affiliation

Department of Chemical & Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA; Berthiaume Institute for Precision Health, University of Notre Dame, Notre Dame, IN 46556, USA.
Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA; Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA; Berthiaume Institute for Precision Health, University of Notre Dame, Notre Dame, IN 46556, USA; Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA.
Department of Chemical & Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA.
Department of Chemical & Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA; Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA; Berthiaume Institute for Precision Health, University of Notre Dame, Notre Dame, IN 46556, USA; Department of Chemistry & Biochemistry, University of Notre Dame, Notre Dame, IN 46556, USA; Center for Rare & Neglected Diseases, University of Notre Dame, Notre Dame, IN 46556, USA.

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.

中文翻译：

非靶向和 sGRP78 靶向纳米颗粒药物递送的组合在治疗转移性卵巢癌方面优于任何成分

转移性卵巢癌（MOC）具有高度致命性，部分原因是标准护理化疗对转移性肿瘤和非粘附癌细胞的疗效有限。在这里，我们证明了 GRP78 靶向（TNPGRP78pep）和非靶向（NP）纳米颗粒的联合疗法在同基因小鼠模型中将新型 DM1 前药递送到 MOC 的有效性。细胞表面-GRP78 在 MOC 中过表达，使 GRP78 成为将纳米颗粒选择性递送到 MOC 的最佳靶标。与未治疗的对照相比，NP + TNPGRP78pep 联合治疗将肿瘤负荷降低了 15 倍。治疗组 T 细胞和巨噬细胞水平升高也表明抗肿瘤免疫系统参与。NP 和 TNPGRP78pep 成分通过两种提出的作用机制协同发挥作用。TNPGRP78pep 靶向腹膜腔中的非粘附癌细胞，阻止新实体瘤的形成，而 NP 被动靶向现有的实体瘤部位，向肿瘤微环境提供药物的持续释放。

更新日期：2024-09-19

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