Mmp-9 responsive PEG cleavable nanovesicles for efficient delivery of chemotherapeutics to pancreatic cancer.
Mmp-9 responsive PEG cleavable nanovesicles for efficient delivery of chemotherapeutics to pancreatic cancer.
复制标题
DOI：
10.1021/mp500108p
复制
发表时间：
2014-07-07
影响因子：
4.9
通讯作者：
Mallik S
中科院分区：
文献类型：
--
作者：
Kulkarni PS;Haldar MK;Nahire RR;Katti P;Ambre AH;Muhonen WW;Shabb JB;Padi SK;Singh RK;Borowicz PP;Shrivastava DK;Katti KS;Reindl K;Guo B;Mallik S
正常和肿瘤组织之间的生化参数的显着差异提供了一个机会，化学设计药物载体，响应这些变化，并提供药物在所需的网站。例如，基质金属蛋白酶-9（MMP-9）酶在肿瘤组织的细胞外基质中的过表达可以作为化学调节从载体的药物递送的触发物。在这项研究中，我们已经合成了MMP-9可切割的胶原模拟脂肽，其与POPC、POPE-SS-PEG和胆固醇半琥珀酸酯脂质形成纳米囊泡。当掺入这些纳米囊泡中时，脂肽保留三螺旋构象。PEG基团保护底物脂肽免受MMP-9的水解。然而，在谷胱甘肽水平升高的情况下，PEG基团被还原性去除，使脂肽暴露于MMP-9。由此产生的肽键断裂扰乱囊泡的脂质双层，导致囊封内容物的释放。这些聚乙二醇化纳米囊泡能够以50%的效率包封抗癌药物吉西他滨。它们在生理条件下和人血清中稳定。在二维和三维“肿瘤样”球体培养物中使用胰腺导管癌细胞（PANC-1和MIAPaCa-2）证明了有效的药物释放。在无胸腺雌性裸鼠的异种移植模型中静脉内施用吉西他滨包封的纳米囊泡后观察到肿瘤生长减少。
Significant differences in biochemical parameters between normal and tumor tissues offer an opportunity to chemically design drug carriers which respond to these changes and deliver the drugs at the desired site. For example, overexpression of the matrix metalloproteinase-9 (MMP-9) enzyme in the extracellular matrix of tumor tissues can act as a trigger to chemically modulate the drug delivery from the carriers. In this study, we have synthesized an MMP-9-cleavable, collagen mimetic lipopeptide which forms nanosized vesicles with the POPC, POPE-SS-PEG, and cholesteryl-hemisuccinate lipids. The lipopeptide retains the triple-helical conformation when incorporated into these nanovesicles. The PEG groups shield the substrate lipopeptides from hydrolysis by MMP-9. However, in the presence of elevated glutathione levels, the PEG groups are reductively removed, exposing the lipopeptides to MMP-9. The resultant peptide-bond cleavage disturbs the vesicles’ lipid bilayer, leading to the release of encapsulated contents. These PEGylated nanovesicles are capable of encapsulating the anticancer drug gemcitabine with 50% efficiency. They were stable in physiological conditions and in human serum. Effective drug release was demonstrated using the pancreatic ductal carcinoma cells (PANC-1 and MIAPaCa-2) in two-dimensional and three-dimensional “tumor-like” spheroid cultures. A reduction in tumor growth was observed after intravenous administration of the gemcitabine-encapsulated nanovesicles in the xenograft model of athymic, female nude mice.
登录
查看更多内容
快速生成体外多细胞球体，用于研究单克隆抗体治疗。
影响因子：
3.9
作者：
Phung YT;Barbone D;Broaddus VC;Ho M
通讯作者：
Ho M
影响因子：
3.8
作者：
Longati P;Jia X;Eimer J;Wagman A;Witt MR;Rehnmark S;Verbeke C;Toftgård R;Löhr M;Heuchel RL
通讯作者：
Heuchel RL
影响因子：
15
作者：
Elegbede AI;Banerjee J;Hanson AJ;Tobwala S;Ganguli B;Wang R;Lu X;Srivastava DK;Mallik S
通讯作者：
Mallik S
影响因子：
10.8
作者：
Choi, Mi-Ran;Stanton-Maxey, Katie J.;Clare, Susan E.
通讯作者：
Clare, Susan E.
纳米颗粒上生物可还原纳米壳的刺激触发生长和去除
影响因子：
4.6
作者：
Han, Li-Fen;Chen, Qian-Bao;You, Ye-Zi
通讯作者：
You, Ye-Zi