Mesenchymal Stem Cells As Guideposts for Nanoparticle-Mediated Targeted Drug Delivery in Ovarian Cancer
Mesenchymal Stem Cells As Guideposts for Nanoparticle-Mediated Targeted Drug Delivery in Ovarian Cancer
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DOI：
10.3390/cancers12040965
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发表时间：
2020-04-01
期刊：
影响因子：
5.2
通讯作者：
Prabha, Swayam
中科院分区：
文献类型：
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作者：
Layek, Buddhadev;Shetty, Mihir;Prabha, Swayam
纳米载体已被广泛用于各种实体肿瘤及其转移的系统靶向。然而，目前的药物输送系统普遍存在对肿瘤细胞缺乏选择性的问题。在这里，我们开发了一种新的两步靶向策略，依赖于在肿瘤组织中选择性地积累靶向合成受体(即叠氮部分)，然后递送与这些受体具有高结合亲和力的载药纳米粒。以间充质干细胞(MSCs)为载体，以二苄基环辛炔(DBCO)为靶向配体，进行肿瘤特异性叠氮化物的蓄积。在卵巢癌的原位转移和患者来源的异种移植(PDX)肿瘤模型中进行了生物分布和抗肿瘤疗效研究。我们的研究表明，在接受叠氮标记的MSCs(MSC-Az)的小鼠中，纳米颗粒在肿瘤中的保留浓度明显更高。此外，我们观察到，与对照组相比，接受MSC-Az和加载紫杉醇的DBCO功能化纳米粒的小鼠肿瘤生长显著减少(p<；0.05)并提高了存活率。这些研究证明了两步靶向策略的可行性，以有效地输送用于治疗实体瘤的集中化疗。
Nanocarriers have been extensively utilized for the systemic targeting of various solid tumors and their metastases. However, current drug delivery systems, in general, suffer from a lack of selectivity for tumor cells. Here, we develop a novel two-step targeting strategy that relies on the selective accumulation of targetable synthetic receptors (i.e., azide moieties) in tumor tissues, followed by delivery of drug-loaded nanoparticles having a high binding affinity for these receptors. Mesenchymal stem cells (MSCs) were used as vehicles for the tumor-specific accumulation of azide moieties, while dibenzyl cyclooctyne (DBCO) was used as the targeting ligand. Biodistribution and antitumor efficacy studies were performed in both orthotopic metastatic and patient-derived xenograft (PDX) tumor models of ovarian cancer. Our studies show that nanoparticles are retained in tumors at a significantly higher concentration in mice that received azide-labeled MSCs (MSC-Az). Furthermore, we observed significantly reduced tumor growth (p < 0.05) and improved survival in mice receiving MSC-Az along with paclitaxel-loaded DBCO-functionalized nanoparticles compared to controls. These studies demonstrate the feasibility of a two-step targeting strategy for efficient delivery of concentrated chemotherapy for treating solid tumors.