Drug Delivery Research Laboratory, Department of Pharmaceutical Sciences, Dr. HS Gour Viswavidyalaya, Sagar (MP), 470003, India.
Mol Pharm. 2012 Jan 1;9(1):176-86. doi: 10.1021/mp200439z. Epub 2011 Nov 28.
The present investigation reports the development of nanoengineered estrogen receptor (ER) targeted pH-sensitive liposome for the site-specific intracellular delivery of doxorubicin (DOX) for breast cancer therapy. Estrone, a bioligand, was anchored on the surface of pH-sensitive liposome for drug targeting to ERs. The estrone-anchored pH-sensitive liposomes (ES-pH-sensitive-SL) showed fusogenic potential at acidic pH (5.5). In vitro cytotoxicity studies carried out on ER-positive MCF-7 breast carcinoma cells revealed that ES-pH-sensitive-SL formulation was more cytotoxic than non-pH-sensitive targeted liposomes (ES-SL). The flow cytometry analysis confirmed significant enhanced uptake (p < 0.05) of ES-pH-sensitive-SL by MCF-7 cells. Intracellular delivery and nuclear localization of the DOX was confirmed by fluorescence microscopy. The mechanism for higher cytotoxicity shown by estrone-anchored pH-sensitive liposomal-DOX was elucidated using reactive oxygen species (ROS) determination. The in vivo biodistribution studies and antitumor activities of formulations were evaluated on tumor bearing female Balb/c mice followed by intravenous administration. The ES-pH-sensitive-SL efficiently suppressed the breast tumor growth in comparison to both ES-SL and free DOX. Serum enzyme activities such as LDH and CPK levels were assayed for the evaluation of DOX induced cardiotoxicity. The ES-pH-sensitive-SL accelerated the intracellular trafficking of encapsulated DOX, thus increasing the therapeutic efficacy. The findings support that estrone-anchored pH-sensitive liposomes could be one of the promising nanocarriers for the targeted intracellular delivery of anticancer agents to breast cancer with reduced systemic side effects.
本研究报告了一种纳米工程雌激素受体（ER）靶向 pH 敏感脂质体的开发，用于阿霉素（DOX）的靶向细胞内递送至乳腺癌治疗。雌酮，一种生物配体，被锚定在 pH 敏感脂质体的表面以实现对 ER 的药物靶向。雌酮锚定的 pH 敏感脂质体（ES-pH 敏感-SL）在酸性 pH（5.5）下表现出融合潜能。在 ER 阳性 MCF-7 乳腺癌细胞上进行的体外细胞毒性研究表明，ES-pH 敏感-SL 制剂比非 pH 敏感靶向脂质体（ES-SL）更具细胞毒性。流式细胞术分析证实 ES-pH 敏感-SL 被 MCF-7 细胞显著增强摄取（p <0.05）。通过荧光显微镜证实了 DOX 的细胞内递送至细胞核的定位。使用活性氧（ROS）测定阐明了雌酮锚定的 pH 敏感脂质体-DOX 表现出更高细胞毒性的机制。通过静脉给药，在荷瘤雌性 Balb/c 小鼠上评估了制剂的体内分布研究和抗肿瘤活性。与 ES-SL 和游离 DOX 相比，ES-pH 敏感-SL 有效地抑制了乳腺癌肿瘤的生长。评估 DOX 诱导的心脏毒性时，测定了血清酶活性，如 LDH 和 CPK 水平。ES-pH 敏感-SL 加速了包封的 DOX 的细胞内转运，从而提高了治疗效果。这些发现支持雌酮锚定的 pH 敏感脂质体可以成为靶向细胞内递送至乳腺癌的有前途的纳米载体之一，可降低全身副作用。
