SMARTc Unit, Pharmacokinetics Laboratory, CRCM UMR U1068 CNRS UMR 7258 Aix Marseille Université, Marseille, France.
CRCM CNRS UMR 7258 Aix Marseille Université, Marseille, France.
Int J Nanomedicine. 2018 Jun 18;13:3451-3465. doi: 10.2147/IJN.S162454. eCollection 2018.
Trastuzumab plus docetaxel is a mainstay to treat HER2-positive breast cancers. However, developing nanoparticles could help to improve the efficacy/toxicity balance of this doublet by improving drug trafficking and delivery to tumors. This project aimed to develop an immunoliposome in breast cancer, combining docetaxel encapsulated in a stealth liposome engrafted with trastuzumab, and comparing its performances on human breast cancer cell lines with standard combination of docetaxel plus trastuzumab.
Several strategies to engraft trastuzumab to pegylated liposomes were tested. Immunoliposomes made of natural (antibody nanoconjugate-1 [ANC-1]) and synthetic lipids (ANC-2) were synthesized using standard thin film method and compared in size, morphology, docetaxel encapsulation, trastuzumab engraftment rates and stability. Antiproliferative activity was tested on human breast cancer models ranging from almost negative (MDA-MB-231), positive (MDA-MB-453) to overexpressing (SKBR3) HER2. Finally, cell uptake of ANC-1 was studied by electronic microscopy.
ANC-1 showed a greater docetaxel encapsulation rate (73%±6% vs 53%±4%) and longer stability (up to 1 week) as compared with ANC-2. Both ANC presented particle size ≤150 nm and showed similar or higher in vitro antiproliferative activities than standard treatment, ANC-1 performing better than ANC-2. The IC for docetaxel combined to free trastuzumab were 8.7±4, 2±0.7 and 6±2 nM with MDA-MB-231, MDA-MB-453 and SKBR3, respectively. The IC for ANC-1 were 2.5±1, 1.8±0.6 and 3.4±0.8 nM and for ANC-2 were 1.8±0.3 nM, 2.8±0.8 nM and 6.8±1.8 nM with MDA-MB-231, MDA-MB-453 and SKBR3, respectively. Cellular uptake appeared to depend on HER2 expression, the higher the expression, the higher the uptake.
In vitro results suggest that higher antiproliferative efficacy and efficient drug delivery can be achieved in breast cancer models using nanoparticles.
曲妥珠单抗联合多西他赛是治疗人表皮生长因子受体 2（HER2）阳性乳腺癌的主要方法。然而，通过改善药物向肿瘤的输送，开发纳米颗粒可以帮助提高该双联药物的疗效/毒性平衡。本项目旨在开发一种用于乳腺癌的免疫脂质体，将包封在隐形脂质体中的多西他赛与曲妥珠单抗结合，并将其在人乳腺癌细胞系中的性能与标准的多西他赛联合曲妥珠单抗进行比较。
测试了几种将曲妥珠单抗连接到聚乙二醇化脂质体的策略。使用标准的薄膜法合成了由天然（抗体纳米缀合物-1 [ANC-1]）和合成脂质组成的免疫脂质体，并比较了它们的大小、形态、多西他赛包封率、曲妥珠单抗接枝率和稳定性。在人乳腺癌模型（从几乎阴性（MDA-MB-231）、阳性（MDA-MB-453）到过表达（SKBR3）HER2）中测试了抗增殖活性。最后，通过电子显微镜研究了 ANC-1 的细胞摄取。
与 ANC-2 相比，ANC-1 显示出更高的多西他赛包封率（73%±6%比 53%±4%）和更长的稳定性（长达 1 周）。两种 ANC 的粒径均≤150nm，体外抗增殖活性与标准治疗相似或更高，ANC-1 的效果优于 ANC-2。游离曲妥珠单抗与多西他赛联合的 IC50 分别为 MDA-MB-231 8.7±4、2±0.7 和 6±2 nM，MDA-MB-453 为 2±0.7 和 6±2 nM，SKBR3 为 6±2 nM。ANC-1 的 IC50 分别为 2.5±1、1.8±0.6 和 3.4±0.8 nM，ANC-2 的 IC50 分别为 1.8±0.3 nM、2.8±0.8 nM 和 6.8±1.8 nM。细胞摄取似乎依赖于 HER2 的表达，表达水平越高，摄取量越高。
体外结果表明，使用纳米颗粒可以在乳腺癌模型中实现更高的抗增殖疗效和有效的药物输送。
