iRGD peptide conjugation potentiates intraperitoneal tumor delivery of paclitaxel with polymersomes.
iRGD peptide conjugation potentiates intraperitoneal tumor delivery of paclitaxel with polymersomes.
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DOI：
10.1016/j.biomaterials.2016.07.023
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发表时间：
2016-10
期刊：
影响因子：
14
通讯作者：
Teesalu T
中科院分区：
文献类型：
--
作者：
Simón-Gracia L;Hunt H;Scodeller P;Gaitzsch J;Kotamraju VR;Sugahara KN;Tammik O;Ruoslahti E;Battaglia G;Teesalu T
聚合物囊泡是可用于有效载荷的细胞质递送的多功能纳米级囊泡。最近，我们证明了pH敏感的聚合物囊泡对腹膜内肿瘤病变表现出内在的选择性。肿瘤归巢肽iRGD具有隐蔽的C-末端规则（CendR）基序，其负责神经纤毛蛋白-1（NRP-1）结合并触发肽的外渗和肿瘤穿透。iRGD功能化增加了许多肿瘤模型中全身性载药纳米颗粒的肿瘤选择性和治疗功效。在这里，我们研究了腹膜内施用紫杉醇负载的iRGD-聚合物囊泡是否在腹膜癌病的治疗中显示出改善的功效。首先，我们证明了用RPARPAR（原型CendR肽）或iRGD功能化的pH敏感性聚合物囊泡在表达NRP-1的细胞中内化，并且内化的聚合物囊泡在胞质溶胶内释放其货物。负载有紫杉醇的CendR靶向聚合物囊泡对NRP-1阳性细胞比对NRP-1阴性细胞更具细胞毒性。在携带胃（MKN-45 P）或结肠（CT 26）来源的腹膜肿瘤的小鼠中，腹膜内给药的RPARPAR和iRGD-聚合物囊泡显示出比非靶向聚合物囊泡更高的肿瘤选择性蓄积和渗透。最后，与原始紫杉醇-聚合物囊泡或Abraxane相比，负载紫杉醇的iRGD-聚合物囊泡在腹膜肿瘤生长抑制和抑制局部扩散方面显示出改善的功效。我们的研究表明，iRGD功能化提高了紫杉醇-聚合物囊泡用于腹膜内治疗腹膜癌转移的疗效。
Polymersomes are versatile nanoscale vesicles that can be used for cytoplasmic delivery of payloads. Recently, we demonstrated that pH-sensitive polymersomes exhibit an intrinsic selectivity towards intraperitoneal tumor lesions. A tumor homing peptide, iRGD, harbors a cryptic C-end Rule (CendR) motif that is responsible for neuropilin-1 (NRP-1) binding and for triggering extravasation and tumor penetration of the peptide. iRGD functionalization increases tumor selectivity and therapeutic efficacy of systemic drug-loaded nanoparticles in many tumor models. Here we studied whether intraperitoneally administered paclitaxel-loaded iRGD-polymersomes show improved efficacy in the treatment of peritoneal carcinomatosis. First, we demonstrated that the pH-sensitive polymersomes functionalized with RPARPAR (a prototypic CendR peptide) or iRGD internalize in the cells that express NRP-1, and that internalized polymersomes release their cargo inside the cytosol. CendR-targeted polymersomes loaded with paclitaxel were more cytotoxic on NRP-1-positive cells than on NRP-1-negative cells. In mice bearing peritoneal tumors of gastric (MKN-45P) or colon (CT26) origin, intraperitoneally administered RPARPAR and iRGD-polymersomes showed higher tumor-selective accumulation and penetration than untargeted polymersomes. Finally, iRGD-polymersomes loaded with paclitaxel showed improved efficacy in peritoneal tumor growth inhibition and in suppression of local dissemination compared to the pristine paclitaxel-polymersomes or Abraxane. Our study demonstrates that iRGD-functionalization improves efficacy of paclitaxel-polymersomes for intraperitoneal treatment of peritoneal carcinomatosis.
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影响因子：
4.6
作者：
Meng J;Guo F;Xu H;Liang W;Wang C;Yang XD
通讯作者：
Yang XD
影响因子：
4.6
作者：
Chierico L;Joseph AS;Lewis AL;Battaglia G
通讯作者：
Battaglia G
影响因子：
8.8
作者：
Akashi, Y.;Oda, T.;Ohara, Y.;Miyamoto, R.;Kurokawa, T.;Hashimoto, S.;Enomoto, T.;Yamada, K.;Satake, M.;Ohkohchi, N.
通讯作者：
Ohkohchi, N.
影响因子：
17.1
作者：
LoPresti, Caterina;Massignani, Marzia;Battaglia, Giuseppe
通讯作者：
Battaglia, Giuseppe
影响因子：
15
作者：
Battaglia, G;Ryan, AJ
通讯作者：
Ryan, AJ