HPMA polymer-based site-specific delivery of oligonucleotides to hepatic stellate cells.
HPMA polymer-based site-specific delivery of oligonucleotides to hepatic stellate cells.
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DOI：
10.1021/bc800237t
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发表时间：
2009-02
影响因子：
4.7
通讯作者：
Mahato, Ram I.
中科院分区：
文献类型：
--
作者：
Yang, Ningning;Ye, Zhaoyang;Li, Feng;Mahato, Ram I.
目的：研究I型胶原特异性三链形成寡核苷酸(TFO)与N-(2-羟丙基)甲基丙烯酰胺(HPMA)的生物偶联能否将其靶向输送到肝星状细胞(HSC)。将M6P-GFLG-HPMA-GFLG-32P-TFO生物偶联后，用PAGE、HPLC法和GPC法对其进行了表征，并测定了其生物分布。当TFO与木瓜酶孵育时，TFO从结合物上解离出来，并与目标DNA双链形成三链。该结合物可显著抑制HSC-T6细胞1型胶原基因的表达。大鼠尾静脉注射M6P-GFLG-HPMA-GFLG-32P-TFO后，M6P-GFLG-HPMA-GFLG-32P-TFO迅速从循环中清除，并主要蓄积在肝脏。血药浓度-时间曲线呈双相分布，t1/2为12.37min，消除为t1/2为2886.48分钟。正常大鼠和肝纤维化大鼠肝星状细胞在注射M6P-GFLG-HPMA-GFLG-32P-TFO后30min经肝脏灌流分离出大量M6P-GFLG-HPMA-GFLG-32P-TFO。肝纤维化大鼠预先注射M6P-GFLG-HPMA-GFLG-ONP可使肝脏对结合物的摄取率从60%降至13%，提示M6P/TGFII受体介导了HSC对结合物的内吞作用。肝纤维化大鼠近80%的肝脏摄取是由HSC贡献的。综上所述，M6P-HPMA-GFLG结合物显著增加了TFO向HSCs的输送，有可能用于治疗肝纤维化。
The objective was to determine whether bioconjugation of type I collagen specific triplex forming oligonucleotide (TFO) to N-(2-hydroxypropyl) methacrylamide (HPMA) containing tetrapeptide Gly-Phe-Leu-Gly (GFLG) and mannose 6-phosphate (M6P) can provide their targeted delivery to hepatic stellate cells (HSCs). Following bioconjugation, M6P-GFLG-HPMA-GFLG-32P-TFO was characterized by PAGE, HPLC and GPC, and then its biodistribution was determined. TFO was dissociated from the conjugate when incubated with papain and formed triplex with the target DNA duplex. Type 1 collagen gene expression was significantly inhibited when HSC-T6 cells were transfected with this conjugate. Following tail vein injection into rats, M6P-GFLG-HPMA-GFLG-32P-TFO was rapidly cleared from the circulation and accumulated mainly in the liver. The plasma concentration versus time profile was biphasic, with 12.37 min as t1/2 of distribution and 2886.48 min as t1/2 of elimination. A large proportion of the injected M6P-GFLG-HPMA-GFLG-32P-TFO was taken up by the HSCs of both normal and fibrotic rats, which were isolated by liver perfusion at 30 min post injection. Pre-injection of M6P-GFLG-HPMA-GFLG-ONP into fibrotic rats decreased the liver uptake of the conjugates from 60% to 13%, suggesting M6P/TGFII receptor-mediated endocytosis of the conjugates by HSCs. Almost 80% of the total liver uptake in fibrotic rats was contributed by HSCs. In conclusion, conjugation with M6P-HPMA-GFLG significantly increased TFO delivery to the HSCs and could be potentially used for treating liver fibrosis.
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DOI：
10.1073/pnas.88.17.7595
发表时间：
1991-09-01
影响因子：
11.1
作者：
AGRAWAL, S;TEMSAMANI, J;TANG, JY
通讯作者：
TANG, JY
影响因子：
4.7
作者：
Jensen, KD;Kopecková, P;Kopecek, J
通讯作者：
Kopecek, J
影响因子：
14.9
作者：
Nakanishi, M;Weber, KT;Guntaka, RV
通讯作者：
Guntaka, RV
影响因子：
2.9
作者：
Ye, ZY;Cheng, K;Mahato, RI
通讯作者：
Mahato, RI
影响因子：
3.7
作者：
Hagens, Werner I.;Mattos, Adriana;Greupink, Rick;de Jager-Krikken, Alie;Reker-Smit, Catharina;van Loenen-Weemaes, AnneMiek;Gouw, Annette S. H.;Poelstra, Klaas;Beljaars, Leonie
通讯作者：
Beljaars, Leonie