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MT1‐MMP‐Activated Liposomes to Improve Tumor Blood Perfusion and Drug Delivery for Enhanced Pancreatic Cancer Therapy
Advanced Science ( IF 14.3 ) Pub Date : 2020-07-10 , DOI: 10.1002/advs.201902746 Yan Wei 1 , Sha Song 2 , Nianxiu Duan 2 , Feng Wang 3 , Yuxi Wang 1 , Yiwei Yang 1 , Chengyuan Peng 4 , Junjun Li 1 , Di Nie 1 , Xinxin Zhang 1 , Shiyan Guo 1 , Chunliu Zhu 1 , Miaorong Yu 1 , Yong Gan 1
Advanced Science ( IF 14.3 ) Pub Date : 2020-07-10 , DOI: 10.1002/advs.201902746 Yan Wei 1 , Sha Song 2 , Nianxiu Duan 2 , Feng Wang 3 , Yuxi Wang 1 , Yiwei Yang 1 , Chengyuan Peng 4 , Junjun Li 1 , Di Nie 1 , Xinxin Zhang 1 , Shiyan Guo 1 , Chunliu Zhu 1 , Miaorong Yu 1 , Yong Gan 1
Affiliation
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Promoting tumor angiogenesis effectively and specifically to resolve tumor‐associated hypoperfusion holds promise for improving pancreatic cancer therapy. Herein, a doxorubicin (DOX) loaded smart liposome, MC‐T‐DOX, is constructed, that carries appropriately low‐density cilengitide, an αvβ3 integrin‐specific Arg‐Gly‐Asp (RGD)‐mimetic cyclic peptide, via a membrane type 1‐matrix metalloproteinase (MT1‐MMP) cleavable peptide. After being administered systemically in a hypoperfused pancreatic cancer mouse model at a low dose of cilengitide, the proangiogenic activity of MC‐T‐DOX is specifically “turned on” in tumor vessels through cleavage by MT1‐MMP on tumor endothelial cells to release cilengitide. This locally released cilengitide increases tumor blood perfusion, thereby improving the accumulation and distribution of MC‐T‐DOX in the tumor site. The loaded‐DOX then displays enhanced penetration and increased cellular uptake upon heat‐triggered release from MC‐T‐DOX in the tumor interstitium, contributing to the improved tumor therapy efficacy. Therefore, the strategy of combining the modulation of tumor vascular promotion with smart nanodrug delivery represents a promising approach to improving drug delivery and therapeutic efficacy in a wide range of hypoperfused tumors.
中文翻译：
MT1-MMP 激活脂质体改善肿瘤血液灌注和药物输送以增强胰腺癌治疗
有效地促进肿瘤血管生成以解决肿瘤相关的低灌注问题有望改善胰腺癌的治疗。在此，构建了一种负载阿霉素（DOX）的智能脂质体MC-T-DOX，其携带适当的低密度西仑吉肽，一种α v β 3整合素特异性Arg-Gly-Asp（RGD）模拟环肽，通过1 型膜基质金属蛋白酶 (MT1-MMP) 可裂解肽。在低灌注胰腺癌小鼠模型中全身给药低剂量西仑吉肽后，MC-T-DOX 的促血管生成活性通过肿瘤内皮细胞上的 MT1-MMP 裂解而在肿瘤血管中特异性“开启”，从而释放西仑吉肽。这种局部释放的西仑吉肽增加了肿瘤的血液灌注，从而改善了 MC-T-DOX 在肿瘤部位的积累和分布。然后，负载的 DOX 在肿瘤间质中热触发 MC-T-DOX 释放时表现出增强的渗透性和增加的细胞摄取，有助于提高肿瘤治疗效果。因此，将肿瘤血管促进调节与智能纳米药物递送相结合的策略代表了一种改善多种低灌注肿瘤的药物递送和治疗效果的有前途的方法。
更新日期：2020-09-10
中文翻译：
MT1-MMP 激活脂质体改善肿瘤血液灌注和药物输送以增强胰腺癌治疗
有效地促进肿瘤血管生成以解决肿瘤相关的低灌注问题有望改善胰腺癌的治疗。在此，构建了一种负载阿霉素（DOX）的智能脂质体MC-T-DOX，其携带适当的低密度西仑吉肽，一种α v β 3整合素特异性Arg-Gly-Asp（RGD）模拟环肽，通过1 型膜基质金属蛋白酶 (MT1-MMP) 可裂解肽。在低灌注胰腺癌小鼠模型中全身给药低剂量西仑吉肽后，MC-T-DOX 的促血管生成活性通过肿瘤内皮细胞上的 MT1-MMP 裂解而在肿瘤血管中特异性“开启”，从而释放西仑吉肽。这种局部释放的西仑吉肽增加了肿瘤的血液灌注，从而改善了 MC-T-DOX 在肿瘤部位的积累和分布。然后，负载的 DOX 在肿瘤间质中热触发 MC-T-DOX 释放时表现出增强的渗透性和增加的细胞摄取，有助于提高肿瘤治疗效果。因此，将肿瘤血管促进调节与智能纳米药物递送相结合的策略代表了一种改善多种低灌注肿瘤的药物递送和治疗效果的有前途的方法。
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