CNRS, UMR 8612, Physico-Chimie, Pharmacotechnie, Biopharmacie, Laboratoire Pharmacologie Cellulaire et Moléculaire des Anticancéreux, Faculté de Pharmacie, 5 rue J.B. Clément, Châtenay-Malabry, F-92296, France.
Pharm Res. 2010 Feb;27(2):327-39. doi: 10.1007/s11095-009-0023-z. Epub 2009 Dec 23.
To determine the better liposomal formulation incorporating the active metabolite of tamoxifen, 4-hydroxy-tamoxifen (4HT) and the biological impact of 4HT-pH-gradient liposomes on response to in vivo treatment.
Several pegylated liposomes were formulated by varying the composition of lipids, increasing external pH from 7.4 to 9.0 and doubling the lipid concentration. Dipalmitoylphosphatidylcholine / cholesterol / distearoylphosphoethanolamine poly(ethylene)glycol liposomes (DL-9 liposomes) were chosen for their physico-chemical properties. Toxicity and release kinetics were assessed in breast cancer MCF-7 as well as in multiple myeloma (MM) cells. In vivo antitumor activity and bio-distribution were measured in the RPMI8226 MM model.
Compared to conventional non-pH-gradient liposomes, 4HT-DL-9 liposomes resulted in concentration of up to 1 mM 4HT, greater stability, relative toxicity and slow 4HT release. Intravenous injections of 4HT-DL-9 liposomes at 4 mg/kg/week blocked MM tumor growth. Ki67 and CD34 labeling decreased in treated tumors, concomitantly with increase of activated caspase-3 supporting a cell proliferation arrest, a decrease of tumor vasculature and the induction of tumor cell death.
This antitumor effect was assumed to be the result of a modified biodistribution of 4HT once trapped in DL-9 liposomes. Such 4HT-containing pH-gradient Stealth nanocarriers could be helpful for MM treatment.
确定更好的包含他莫昔芬活性代谢物 4-羟基他莫昔芬（4HT）的脂质体配方，以及 4HT-pH 梯度脂质体对体内治疗反应的生物学影响。
通过改变脂质组成、将外部 pH 值从 7.4 增加到 9.0 以及将脂质浓度增加一倍，制备了几种聚乙二醇化脂质体。选择二棕榈酰磷脂酰胆碱/胆固醇/二硬脂酰基磷脂酰乙醇胺聚乙二醇（DL-9）脂质体，因为它们具有物理化学特性。在乳腺癌 MCF-7 细胞和多发性骨髓瘤（MM）细胞中评估了毒性和释放动力学。在 RPMI8226 MM 模型中测量了体内抗肿瘤活性和生物分布。
与常规非 pH 梯度脂质体相比，4HT-DL-9 脂质体导致 4HT 浓度高达 1 mM，稳定性更高，相对毒性和缓慢的 4HT 释放。每周静脉注射 4HT-DL-9 脂质体 4mg/kg 可阻止 MM 肿瘤生长。Ki67 和 CD34 标记在治疗的肿瘤中减少，同时激活的 caspase-3 增加，支持细胞增殖停滞、肿瘤血管减少和肿瘤细胞死亡的诱导。
这种抗肿瘤作用被认为是 4HT 一旦被困在 DL-9 脂质体中导致的生物分布改变的结果。这种含有 4HT 的 pH 梯度隐形纳米载体可能有助于 MM 的治疗。
