靶向纳米药物破坏肿瘤细胞外基质屏障以提高药物输送和癌症治疗效果,Molecular Pharmaceutics

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靶向纳米药物破坏肿瘤细胞外基质屏障以提高药物输送和癌症治疗效果
Molecular Pharmaceutics ( IF 4.5 ) Pub Date : 2023-04-12 , DOI: 10.1021/acs.molpharmaceut.2c00947
Minglong Chen ₁ , Bin Chen ₁ , Xiaoguang Ge ₁ , Qingjie Ma _{1,

2} , Shi Gao _{1,

2}

Affiliation

大多数癌症患者对化疗反应不佳的主要原因之一是药物不能以最佳剂量在肿瘤中积累，最终导致无法阻止癌细胞生长。为了提高药物递送效率，我们通过在表面上用肿瘤靶向肽 c(RGDyK) 和透明质酸酶 (HAase) 修饰氧化铁纳米颗粒 (IONP)，设计了一种高效的肿瘤靶向和基质破坏纳米载体。_{产生的纳米复合物 c(RGDyK)-HAase-IONP 通过结合整合素 α v} β ₃靶向肿瘤并通过在肿瘤细胞外基质（ECM）中高表达的透明质酸（HA）的降解深入肿瘤。体外携带 DOX 的 c(RGDyK)-HAase-IONP 具有良好的生物稳定性和优选的低 pH 药物释放曲线。与不含 HAase 的非靶向 IONP 相比，c(RGDyK)-HAase-IONP 在 MC38 荷瘤小鼠模型中静脉注射后显示出更好的肿瘤靶向效果（高 2.5 倍），这是通过全身荧光成像确定的。5 次全身治疗后，c(RGDyK)-HAase-IONP/DOX（5 mg/kg 等效剂量的 DOX）显着抑制 MC38 肿瘤生长（相对于未治疗组为 22.1 ± 7.4 倍）。与对照组相比，在 c(RGDyK)-HAase-IONP/DOX 处理的肿瘤中检测到肿瘤细胞凋亡增加和增殖减少。总体而言，高效靶向纳米载体 c(RGDyK)-HAase-IONP 通过靶向降解肿瘤 ECM 中致密的 HA 屏障，展示了提高药物递送和肿瘤治疗效果的巨大潜力。我们确定这种肿瘤基质降解纳米系统能够减少肿瘤复发和耐药性，并最终改善临床肿瘤治疗反应。

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Targeted Nanodrugs to Destroy the Tumor Extracellular Matrix Barrier for Improving Drug Delivery and Cancer Therapeutic Efficacy

One of the main reasons why most cancer patients do not respond well to chemotherapy is that drugs cannot accumulate in tumors at an optimal dose, eventually resulting in failure to prevent cancer cell growth. To improve drug delivery efficiency, we engineered a highly efficient tumor-targeted and stroma-breaking nanocarrier by the modification of iron oxide nanoparticles (IONPs) with a tumor-targeting peptide c(RGDyK) and a hyaluronidase (HAase) on the surface. The yielding nanocomplex, c(RGDyK)-HAase-IONP, targeted the tumor by binding integrin α_vβ₃ and went deeply into the tumors by the degradation of hyaluronic acid (HA), which was highly expressed in the tumor extracellular matrix (ECM). Good biostability and a low pH preferred drug release profile were characterized for c(RGDyK)-HAase-IONP carrying DOX in vitro. c(RGDyK)-HAase-IONP showed an improved tumor-targeting (2.5 times higher) effect after intravenous injection in the MC38 tumor-bearing mice model, as determined by whole-body fluorescence imaging compared to the non-targeted IONPs without HAase. After 5 systemic treatments, c(RGDyK)-HAase-IONP/DOX (5 mg/kg of equivalent dose of DOX) significantly inhibited MC38 tumor growth (22.1 ± 7.4 times relative to the non-treated group). Elevated apoptosis and reduced proliferation in the tumor cell were detected in the c(RGDyK)-HAase-IONP/DOX treated tumors compared to the control groups. Overall, the highly efficient targeted nanocarrier c(RGDyK)-HAase-IONP demonstrated tremendous potency for improving drug delivery and tumor therapy efficacy by targeted degradation of the dense HA barrier in the tumor ECM. We determined that such a tumor stroma–degrading nanosystem was capable of reducing tumor recurrence and drug resistance and could ultimately improve clinical tumor treatment responses.

更新日期：2023-04-12

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