文獻(xiàn)：Preparation, therapeutic efficacy and intratumoral localization of targeted daunorubicin liposomes conjugating folate-PEG-CHEMS

作者：Subin Xiong a b, Bo Yu b, Jun Wu c, Hong Li b, Robert J. Lee

文獻(xiàn)鏈接：https://www.sciencedirect.com/science/article/abs/pii/S0753332210001915

摘要：

Folate polyethylene glycol-cholesterol hemisuccinate (folate-PEG-CHEMS) is a novel folate ligand firstly synthesized by our group and demonstrated good stability and potential targeting results on KB cells in vitro. The current study further explored endocytosis mechanisms of liposomes via folate receptor on L1210JF cells and assessed targeted therapeutic efficacy of folate-PEG-CHEMS anchored liposomes loading daunorubicin (F-L-DNR) in vivo. Folate-PEG-CHEMS was synthesized by a modified method. The liposome properties, cell cytotoxicity, intracellular and intratumoral localization, and therapeutic efficacy on a murine tumor model bearing L1210JF cells were evaluated. High encapsulation efficiency (95.1% ± 1.5%) and appropriate particle size (76.0 ± 35.5 nm) and zeta potential (?12.83 ± 1.36 mV) were achieved for F-L-DNR. IC50 of F-L-DNR on L1210JF cells was 2–3-folds lower than that of non-targeted liposomal daunorubicin (L-DNR). Anticancer efficacy on L1210JF tumor model indicated that mice survival time of F-L-DNR group at doses of 5 mg/kg and 10 mg/kg was significantly longer than that of L-DNR or free DNR. Confocal fluorescence photographs of F-L-DNR indicated enhanced endocytosis of liposomes via folate receptor on L1210JF cells, prolonged retaining time in tumors and improved drug release in the tumor site at 24 h post intravenous injection of F-L-DNR. In conclusion, folate-PEG-CHEMS is an effective ligand for folate-targeted daunorubicin liposomes to achieve increased drug release in tumor and therapeutic efficacy.

本研究進(jìn)一步探討了脂質(zhì)體通過(guò)葉酸受體在L1210JF細(xì)胞上的內(nèi)吞機(jī)制，并評(píng)估了葉酸-PEG-CHEMS錨定的荷柔紅霉素脂質(zhì)體（F-L-DNR）在體內(nèi)的靶向治療效果。

采用改進(jìn)的方法合成了葉酸-PEG-CHEMS。評(píng)估了脂質(zhì)體特性、細(xì)胞毒性、細(xì)胞內(nèi)和瘤內(nèi)定位以及對(duì)攜帶L1210JF細(xì)胞的小鼠腫瘤模型的治療效果。

F-L-DNR實(shí)現(xiàn)了高包封率（95.1%±1.5%）和適當(dāng)?shù)牧�徑�?6.0±35.5 nm）和ζ電位（-12.83±1.36 mV）。F-L-DNR對(duì)L1210JF細(xì)胞的IC50比非靶向柔紅霉素脂質(zhì)體（L-DNR）低2-3倍。

F-L-DNR組在5mg/kg和10mg/kg劑量下的小鼠存活時(shí)間明顯長(zhǎng)于L-DNR或游離DNR。

F-L-DNR的共聚焦熒光照片表明，靜脈注射F-L-DNR后24小時(shí)，脂質(zhì)體通過(guò)L1210JF細(xì)胞上的葉酸受體增強(qiáng)了內(nèi)吞作用，延長(zhǎng)了在腫瘤中的保留時(shí)間，并改善了腫瘤部位的藥物釋放。

總之，葉酸-PEG-CHEMS是葉酸靶向柔紅霉素脂質(zhì)體的有效配體，可以增加腫瘤中的藥物釋放和治療效果。

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