Therapeutic Overcoming of Cancer Stem Cell-Featured Chemo-Resistant Ovarian Cancer via Photodynamic Therapy and Cascadic Chemotherapy Combined Hyaluronan Nanoparticles

AMI: Acta Biomaterialia Pub Date : 1900-01-01 DOI:10.2139/ssrn.3873675

Junghan Lee, Enkhzaya Davaa, Yixin Jiang, Jung Joo Kim, M. H. Kim, H. An, Jinho Kim, Steve K. Cho, Su-Geun Yang

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Abstract

In this study, we designed combination cancer therapeutic hyaluronan nanoparticles (NIR-responsive ROS-generating pheophorbide A and ROS-cleavable thioketal-linked SN38; PheoA-SN38-HC NPs). And the combined therapeutic effects of PheoA-SN38-HC NPs were investigated against HEY-T30 human ovarian cancer (OC) model which highly co-expresses cancer stem cell (CSC) markers and exhibits strong chemo-resistance. Clinical Proteomic Tumor Analysis Consortium (CPTAC) data showed that the expression of CSC markers (CD44, ALDH1A1, and CD117) rather than folic acid receptor is highly associated with poor clinical outcomes in OC patients. Western assay, migration and colony forming assay proved chemo-resistant HEY-T30 cells overexpress CSC markers and much more invasive than other cancer cells. Synthesized NPs were ~250 nm and spherical by DLS and TEM analysis. FACS and microscopic analysis revealed the active targeting property of PheoA-SN38-HC NPs in CD44+ HEY-T30 cells. Moreover, synergistic effects of the combination therapy of photodynamic ROS generation and ROS-triggered SN38 release were clearly demonstrated with in vitro HEY-T30 cells and an in vivo xenograft mouse model. In particular, the paracrine cytotoxic effect of SN38 released by ROS-trigger suggested that combination design could compensate for the clinical limitation of photodynamic therapy.

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通过光动力疗法和级联化疗联合透明质酸纳米颗粒治疗癌症干细胞特征的化疗抗性卵巢癌

在这项研究中，我们设计了联合抗癌透明质酸纳米粒子(NIR-responsive ROS-generating pheophide A和ros -可切割的硫酮连接SN38;PheoA-SN38-HC NPs)。并研究了PheoA-SN38-HC NPs联合治疗高度共表达肿瘤干细胞(CSC)标记物并表现出较强化疗耐药的HEY-T30人卵巢癌(OC)模型的疗效。临床蛋白质组学肿瘤分析协会(CPTAC)的数据显示，CSC标志物(CD44、ALDH1A1和CD117)而不是叶酸受体的表达与OC患者的不良临床结果高度相关。Western实验、迁移和集落形成实验证明hy - t30耐药细胞过表达CSC标记物，比其他癌细胞更具侵袭性。经DLS和TEM分析，合成的纳米粒子为~250 nm，呈球形。FACS和显微镜分析显示PheoA-SN38-HC NPs在CD44+ HEY-T30细胞中的活性靶向性。此外，在体外hy - t30细胞和体内异种移植小鼠模型中，光动力ROS生成和ROS触发的SN38释放的联合治疗的协同效应被清楚地证明。特别是ROS-trigger释放的SN38的旁分泌细胞毒作用提示联合设计可以弥补光动力治疗的临床局限性。

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AMI: Acta Biomaterialia

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