Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.
Eur J Pharm Sci. 2018 Jan 1;111:293-302. doi: 10.1016/j.ejps.2017.09.041. Epub 2017 Sep 28.
To achieve tumor-selective drug delivery, various nanocarriers have been explored using either passive or active targeting strategies. Despite the great number of studies published annually in the field, only nanocarriers using approved excipients reach the clinical stage. In our study, two classic nanoscale formulations, nanoemulsion (NE) and liposome (Lipo) were selected for the encapsulation of lycobetaine (LBT). To improve the lipid solubility of LBT, oleic acid (OA) was used to complex (LBT-OA) with lycobetaine (LBT). Besides, PEGylated lecithin was used to enhance the circulation time. The release behaviors of LBT from non-PEGylated and PEGylated NE and Lipo were compared. PEGylated LBT-OA loaded Lipo (LBT-OA-PEG-Lipo) exhibited a sustained release rate pattern, and in vivo pharmacokinetic profiles showed the extended circulation compared nanoemlusions. Besides, LBT-OA-PEG-Lipo showed an enhanced anti-tumor effect in the mice xenograft lung carcinoma model. Moreover, a multi-target peptide nRGD was co-administered as a therapeutic adjuvant with LBT-OA loaded formulations, which demonstrated improved tumor penetration and enhanced extravasation of formulations. Also, co-administration of nRGD significantly improved the in vivo antitumor efficacy of different formulations, likely due to the depletion of tumor-associated macrophages (TAMs). Thus, LBT-OA-PEG-Lipo+nRGD may represent a promising strategy for cancer chemotherapy against lung carcinoma.
为了实现肿瘤选择性药物递送，已经探索了各种使用被动或主动靶向策略的纳米载体。尽管每年在该领域发表的研究数量众多，但只有使用已批准的赋形剂的纳米载体才能进入临床阶段。在我们的研究中，选择了两种经典的纳米制剂，即纳米乳剂（NE）和脂质体（Lipo）来包封甜菜碱（LBT）。为了提高 LBT 的脂溶性，使用油酸（OA）与甜菜碱（LBT）复合（LBT-OA）。此外，还使用了聚乙二醇化卵磷脂来延长循环时间。比较了非聚乙二醇化和聚乙二醇化 NE 和 Lipo 中 LBT 的释放行为。载有 PEGylated LBT-OA 的脂质体（LBT-OA-PEG-Lipo）表现出持续释放率的模式，体内药代动力学研究表明与纳米乳剂相比具有延长的循环时间。此外，LBT-OA-PEG-Lipo 在荷瘤肺癌小鼠模型中显示出增强的抗肿瘤作用。此外，还将多靶肽 nRGD 与 LBT-OA 负载的制剂一起作为治疗佐剂联合给药，这表明制剂的肿瘤穿透性增强和外渗增强。此外，nRGD 的联合给药显著提高了不同制剂的体内抗肿瘤疗效，可能是由于肿瘤相关巨噬细胞（TAMs）的耗竭。因此，LBT-OA-PEG-Lipo+nRGD 可能代表一种有前途的针对肺癌的癌症化疗策略。
