Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84108, USA.
J Control Release. 2011 May 30;152(1):84-9. doi: 10.1016/j.jconrel.2011.01.021. Epub 2011 Feb 2.
This study primarily focused on the anti-metastatic activity of doxorubicin (DOX) loaded in a pH-sensitive mixed polymeric micelle formed from two block polymers: poly(L-lactide) (PLLA) (Mn 3000)-b-poly(ethylene glycol) (PEG) (Mn 2000)-folate and poly(L-histidine) (PHis) (Mn 4700)-b-PEG (Mn 2000). Tumor formation and metastasis in mice were examined using a murine mammary carcinoma cell of 4T1 which is one of the most aggressive metastatic cancer cell lines. The efficacy was evaluated by tumor size, body weight change, survival rate, dorsal skin fold window chamber model, and histological observation of the lung, heart, liver and spleen after treatment with various DOX formulations. When the tumor reached 50-100 mm³ in size, the mice were treated 4 times at a 3-day interval at a dose of 10 mg DOX/kg. The mixed micelle formulation resulted in retarded tumor growth, no weight loss, and no death for 4-5 weeks. In another set of the in vivo test for histological evaluation of the organs, the mice were similarly treated but the formulations were injected one day after 4T1 cell inoculation. The treatment by DOX loaded mixed micelle showed no apparent metastasis till 28 days. However, significant metastasis to the lung and heart was observed on Day 28 when the mice were treated with DOX carried by PBS, PLLA-b-PEG micelle and PHis-b-PEG micelle.
本研究主要关注载多柔比星（DOX）的 pH 敏感混合聚合物胶束的抗转移活性，该胶束由两种嵌段聚合物形成：聚（L-丙交酯）（PLLA）（Mn 3000）-b-聚乙二醇（PEG）（Mn 2000）-叶酸和聚（L-组氨酸）（PHis）（Mn 4700）-b-PEG（Mn 2000）。使用 4T1 鼠乳腺癌细胞作为模型，研究了该胶束在小鼠中的肿瘤形成和转移。4T1 是最具侵袭性的转移性癌细胞系之一。通过肿瘤大小、体重变化、存活率、背部皮肤折叠窗室模型以及治疗后肺、心、肝和脾的组织学观察来评估疗效，用各种 DOX 制剂处理。当肿瘤大小达到 50-100mm³时，每隔 3 天用 10mg DOX/kg 剂量进行 4 次治疗。混合胶束制剂可使肿瘤生长缓慢，体重无下降，4-5 周内无死亡。在另一组用于器官组织学评估的体内试验中，同样进行了治疗，但在接种 4T1 细胞后一天注射制剂。载 DOX 的混合胶束治疗在 28 天内未见明显转移。然而，当用 PBS、PLLA-b-PEG 胶束和 PHis-b-PEG 胶束携带的 DOX 治疗时，在第 28 天观察到明显的肺和心脏转移。
