MT1-MMP-Activated Liposomes to Improve Tumor Blood Perfusion and Drug Delivery for Enhanced Pancreatic Cancer Therapy.
MT1-MMP-Activated Liposomes to Improve Tumor Blood Perfusion and Drug Delivery for Enhanced Pancreatic Cancer Therapy.
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DOI：
10.1002/advs.201902746
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发表时间：
2020-09
期刊：
影响因子：
--
通讯作者：
Gan Y
中科院分区：
文献类型：
--
作者：
Wei Y;Song S;Duan N;Wang F;Wang Y;Yang Y;Peng C;Li J;Nie D;Zhang X;Guo S;Zhu C;Yu M;Gan Y
有效地促进肿瘤血管生成，特异性地解决肿瘤相关的低灌注，有望改善胰腺癌治疗。本文中，构建了负载多柔比星（DOX）的智能脂质体，MC-T-DOX，其通过膜型1-基质金属蛋白酶（MT 1-MMP）可切割肽携带适当低密度的西仑吉肽，一种αvβ3整合素特异性Arg-Gly-Asp（RGD）模拟环肽。在低灌注胰腺癌小鼠模型中以低剂量西仑吉肽全身给药后，MC-T-DOX的促血管生成活性在肿瘤血管中通过MT 1-MMP切割肿瘤内皮细胞释放西仑吉肽而特异性“开启”。这种局部释放的西仑吉肽增加肿瘤血液灌注，从而改善MC-T-DOX在肿瘤部位的积累和分布。然后，负载的DOX在肿瘤组织中从MC-T-DOX热触发释放时显示出增强的渗透和增加的细胞摄取，有助于改善肿瘤治疗功效。因此，将肿瘤血管促进的调节与智能纳米药物递送相结合的策略代表了在广泛的低灌注肿瘤中改善药物递送和治疗功效的有前途的方法。将低密度膜1型基质金属蛋白酶（MT 1-MMP）激活的西仑吉肽（MC）修饰到负载多柔比星（DOX）的热敏脂质体上，产生MC-T-DOX。MC-T-DOX被肿瘤内皮细胞上的MT 1-MMP激活以释放西仑吉肽，西仑吉肽然后改善肿瘤血液灌注，从而增强MC-T-DOX的肿瘤内递送。随后，在氚中，热触发的DOX从MC-T-DOX释放促进其生物利用度，从而发挥改善的抗肿瘤功效。
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. Low‐density membrane type 1‐matrix metalloproteinase (MT1‐MMP)‐activated cilengitide (MC) is modified onto thermosensitive liposomes loaded with doxorubicin (DOX), yielding MC‐T‐DOX. MC‐T‐DOX is activated by MT1‐MMP on tumor endothelial cells to release cilengitide, which then improves tumor blood perfusion, thereby enhancing intratumoral delivery of MC‐T‐DOX. Subsequently, in the interstitium, heat‐triggered DOX release from MC‐T‐DOX facilitates its bioavailability, thereby exerting improved antitumor efficacy.
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影响因子：
50.3
作者：
Özdemir BC;Pentcheva-Hoang T;Carstens JL;Zheng X;Wu CC;Simpson TR;Laklai H;Sugimoto H;Kahlert C;Novitskiy SV;De Jesus-Acosta A;Sharma P;Heidari P;Mahmood U;Chin L;Moses HL;Weaver VM;Maitra A;Allison JP;LeBleu VS;Kalluri R
通讯作者：
Kalluri R
影响因子：
64.5
作者：
BROOKS, PC;MONTGOMERY, AMP;CHERESH, DA
通讯作者：
CHERESH, DA
影响因子：
56.9
作者：
BROOKS, PC;CLARK, RAF;CHERESH, DA
通讯作者：
CHERESH, DA
影响因子：
24.5
作者：
Jacobetz MA;Chan DS;Neesse A;Bapiro TE;Cook N;Frese KK;Feig C;Nakagawa T;Caldwell ME;Zecchini HI;Lolkema MP;Jiang P;Kultti A;Thompson CB;Maneval DC;Jodrell DI;Frost GI;Shepard HM;Skepper JN;Tuveson DA
通讯作者：
Tuveson DA
影响因子：
2.8
作者：
Mas-Moruno C;Rechenmacher F;Kessler H
通讯作者：
Kessler H