Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel.
Integrin-assisted drug delivery of nano-scaled polymer therapeutics bearing paclitaxel.
复制标题
DOI：
10.1016/j.biomaterials.2011.01.073
复制
发表时间：
2011-05
期刊：
影响因子：
14
通讯作者：
Satchi-Fainaro, Ronit
中科院分区：
文献类型：
--
作者：
Eldar-Boock, Anat;Miller, Keren;Sanchis, Joaquin;Lupu, Ruth;Vicent, Maria J.;Satchi-Fainaro, Ronit
Angiogenesis plays a prominent role in cancer progression. Anti-angiogenic therapy therefore, either alone or in combination with conventional cytotoxic therapy, offers a promising therapy approach. Paclitaxel (PTX) is a wide-used potential cytotoxic drug that also exhibits anti-angiogenic effects at low doses. However, its use, at its full potential, is limited by severe side effects. Here we designed and synthesized a targeted conjugate of PTX，一种聚合物和靶向整合素的部分，导致多谷氨酸（PGA）-PTX-E- [C（RGDFK）2] Nano缩放的纳米尺度con轭共轭，可通过将PTX转换为较大的启用，而驱动型号则易于启动。 。在肿瘤内皮和上皮细胞上过表达的αVβ3整合素的其他活性靶向尤其有价值。表达β3的内皮细胞和几种癌症我们还表明，pga-ptx-e（RGDFK）2]封闭了毛细血管内皮生长因子的内皮细胞迁移到毛细管的毛细管状内皮样细胞中的毛细血管均具有增强型的毛刺，并抑制了内皮细胞的依赖。与游离PTX治疗的小鼠相比。
Angiogenesis plays a prominent role in cancer progression. Anti-angiogenic therapy therefore, either alone or in combination with conventional cytotoxic therapy, offers a promising therapeutic approach. Paclitaxel (PTX) is a widely-used potent cytotoxic drug that also exhibits anti-angiogenic effects at low doses. However, its use, at its full potential, is limited by severe side effects. Here we designed and synthesized a targeted conjugate of PTX, a polymer and an integrin-targeted moiety resulting in a polyglutamic acid (PGA)-PTX-E-[c(RGDfK)2] nano-scaled conjugate. Polymer conjugation converted PTX to a macromolecule, which passively targets the tumor tissue exploiting the enhanced permeability and retention effect, while extravasating via the leaky tumor neovasculature. The cyclic RGD peptidomimetic enhanced the effects previously seen for PGA-PTX alone, utilizing the additional active targeting to the αvβ3 integrin overexpressed on tumor endothelial and epithelial cells. This strategy is particularly valuable when tumors are well-vascularized, but they present poor vascular permeability. We show that PGA is enzymatically-degradable leading to PTX release under lysosomal acidic pH. PGA-PTX-E-[c(RGDfK)2] inhibited the growth of proliferating αvβ3-expressing endothelial cells and several cancer cells. We also showed that PGA-PTX-E-[c(RGDfK)2] blocked endothelial cells migration towards vascular endothelial growth factor; blocked capillary-like tube formation; and inhibited endothelial cells attachment to fibrinogen. Orthotopic studies in mice demonstrated preferential tumor accumulation of the RGD-bearing conjugate, leading to enhanced antitumor efficacy and a marked decrease in toxicity as compared with free PTX-treated mice.
登录
查看更多内容
在非小细胞肺癌的二线治疗中，比较了紫杉醇poliglumex vs多西他赛的第三阶段试验。
影响因子：
8.8
作者：
Paz-Ares, L.;Ross, H.;O'Brien, M.;Riviere, A.;Gatzemeier, U.;Von Pawel, J.;Kaukel, E.;Freitag, L.;Digel, W.;Bischoff, H.;Garcia-Campelo, R.;Iannotti, N.;Reiterer, P.;Bover, I.;Prendiville, J.;Eisenfeld, A. J.;Oldham, F. B.;Bandstra, B.;Singer, J. W.;Bonomi, P.
通讯作者：
Bonomi, P.
影响因子：
10.8
作者：
Mitra, A;Mulholland, J;Line, BR
通讯作者：
Line, BR
影响因子：
6.4
作者：
Monferran, Sylvie;Skuli, Nicolas;Toulas, Christine
通讯作者：
Toulas, Christine
影响因子：
2
作者：
Decock, J.;Obermajer, N.;Kos, J.
通讯作者：
Kos, J.
影响因子：
4.5
作者：
DUNCAN, R;FERRUTI, P;BIGNOTTI, F
通讯作者：
BIGNOTTI, F