文獻：Targeted delivery and triggered release of liposomal doxorubicin enhances cytotoxicity against human B lymphoma cells

作者：TIshida a 1, M.J Kirchmeier a 2, E.H Moase a, S Zalipsky b, T.M Allen 

文獻鏈接：https://www.sciencedirect.com/science/article/pii/S0005273601004096

摘要：

Dioleoylphosphatidylethanolamine (DOPE)-containing liposomes that demonstrated pH-dependent release of their contents were stabilized in the bilayer form through the addition of a cleavable lipid derivative of polyethylene glycol (PEG) in which the PEG was attached to a lipid anchor via a disulfide linkage (mPEG-S-S-DSPE). Liposomes stabilized with either a non-cleavable PEG (mPEG-DSPE) or mPEG-S-S-DSPE retained an encapsulated dye at pH 5.5, but treatment at pH 5.5 of liposomes stabilized with mPEG-S-S-DSPE with either dithiothreitol or cell-free extracts caused contents release due to cleavage of the PEG chains and concomitant destabilization of the DOPE liposomes. While formulations loaded with doxorubicin (DXR) were stable in culture media, DXR was rapidly released in human plasma. pH-Sensitive liposomes, targeted to the CD19 epitope on B-lymphoma cells, showed enhanced DXR delivery into the nuclei of the target cells and increased cytotoxicity compared to non-pH-sensitive liposomes. Pharmacokinetic studies suggested that mPEG-S-S-DSPE was rapidly cleaved in circulation. In a murine model of B-cell lymphoma, the therapeutic efficacy of an anti-CD19-targeted pH-sensitive formulation was superior to that of a stable long-circulating formulation of targeted liposomes despite the more rapid drug release and clearance of the pH-sensitive formulation. These results suggest that targeted pH-sensitive formulations of drugs may be able to increase the therapeutic efficacy of entrapped drugs.

通過添加聚乙二醇（PEG）的可切割脂質(zhì)衍生物，其中PEG通過二硫鍵（mPEG-S-S-DSPE）連接到脂質(zhì)錨定物上，含二油酰磷脂酰乙醇胺（DOPE）的脂質(zhì)體以雙層形式穩(wěn)定其內(nèi)容物的pH依賴性釋放。

用不可切割的PEG（mPEG-DSPE）或mPEG-S-S-DSPE穩(wěn)定的脂質(zhì)體在pH 5.5時保留了包封的染料，但用二硫蘇糖醇或無細胞提取物在pH 5.5下處理用mPEG-S-S-S-DSPE固定的脂質(zhì)體，由于PEG鏈的切割和DOPE脂質(zhì)體的伴隨失穩(wěn)，導(dǎo)致內(nèi)容物釋放。

雖然載有阿霉素（DXR）的制劑在培養(yǎng)基中是穩(wěn)定的，但DXR在人血漿中迅速釋放。pH敏感脂質(zhì)體靶向B淋巴瘤細胞上的CD19表位，與非pH敏感脂質(zhì)體制備的脂質(zhì)體相比，顯示出增強的DXR向靶細胞核的遞送，并增加了細胞毒性。

藥代動力學(xué)研究表明，mPEG-S-S-DSPE在循環(huán)中迅速裂解。在B細胞淋巴瘤的小鼠模型中，盡管抗CD19靶向pH敏感制劑的藥物釋放和清除速度更快，但其治療效果優(yōu)于穩(wěn)定的靶向脂質(zhì)體長循環(huán)制劑。

這些結(jié)果表明，靶向pH敏感的藥物制劑可能能夠提高包埋藥物的治療效果。

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DSPE-PEG-Mannose,DSPE-PEG-Man

DSPE-PEG-Methyltetrazine

DSPE-PEG-MTX

DSPE-PEG-nano gold

DSPE-PEG-NB

DSPE-PEG-NBD

DSPE-PEG-NPC

DSPE-PEG-NTA-NI

DSPE-PEG-PCL

DSPE-PEG-PDP

DSPE-PEG-PEI

DSPE-PEG-PLA

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