Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Department of Pharmaceutical Chemistry, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia.
Int J Nanomedicine. 2020 Jul 30;15:5433-5443. doi: 10.2147/IJN.S256898. eCollection 2020.
Human epidermal growth factor receptor2 (Her2) positive breast cancer represents 25% of breast cancer cases. Targeted therapy with Her2 monoclonal antibody, trastuzumab (TZ), represents the first-line treatment for this type of breast cancer. In addition, neratinib, an irreversible inhibitor of the HER-2 receptor tyrosine kinase, has recently been approved as adjuvant therapy to TZ. This study aims to formulate (TZ)-grafted dendrimers loaded with neratinib, allowing a dual treatment alongside reducing the associated resistance as well as targeted therapy.
TZ was conjugated on the surface of dendrimer using hetero-cross linker, MAL-PEG-NHS, and the zeta potential, and in vitro release of neratinib from dendrimers was characterized. Formulated dendrimers were also fluorescently conjugated with fluorescein isothiocyanate to visualize and quantify their SKBR-3 cellular uptake.
The G4 PAMAM dendrimer showed successful encapsulation of neratinib and a sustained release profile. Comparative in vitro studies revealed that these TZ-targeted dendrimers loaded with neratinib were more selective and have higher antiproliferation activity against SKBR-3 cells compared to neratinib alone and neratinib loaded dendrimer.
In the current study, neratinib loaded in plain and trastuzumab-grafted dendrimer were successfully prepared. Enhanced cellular uptake of trastuzumab conjugated dendrimers was shown, together with a higher cytotoxic effect than plain neratinib dendrimers. These findings suggest the potential of TZ-conjugated dendrimers as targeting carrier for cytotoxic drugs, including neratinib.
人表皮生长因子受体 2（Her2）阳性乳腺癌占乳腺癌病例的 25%。针对这种类型的乳腺癌，Her2 单克隆抗体曲妥珠单抗（TZ）的靶向治疗是一线治疗方法。此外，不可逆的 HER-2 受体酪氨酸激酶抑制剂奈拉替尼（neratinib）最近已被批准作为 TZ 的辅助治疗药物。本研究旨在构建负载奈拉替尼的（TZ）接枝树突状聚合物，实现双重治疗，同时降低相关耐药性和靶向治疗。
使用杂交连接剂 MAL-PEG-NHS 将 TZ 接枝到树突状聚合物表面，并对奈拉替尼从树突状聚合物中的体外释放进行表征。还将荧光染料异硫氰酸荧光素与配制的树突状聚合物进行荧光偶联，以可视化和定量评估其 SKBR-3 细胞摄取。
G4 PAMAM 树突状聚合物成功包载了奈拉替尼，并表现出持续释放的特性。体外比较研究表明，与单独使用奈拉替尼和负载奈拉替尼的树突状聚合物相比，这些负载奈拉替尼的 TZ 靶向树突状聚合物对 SKBR-3 细胞具有更高的选择性和更强的抗增殖活性。
在本研究中，成功制备了负载奈拉替尼的普通和曲妥珠单抗接枝树突状聚合物。结果表明，与普通奈拉替尼树突状聚合物相比，曲妥珠单抗接枝树突状聚合物具有更高的细胞摄取率和更强的细胞毒性作用。这些发现表明，TZ 接枝树突状聚合物作为包括奈拉替尼在内的细胞毒性药物的靶向载体具有潜在应用前景。
