Nethi Susheel Kumar, Li Xiaolei, Bhatnagar Shubhmita, Prabha Swayam
Fels Cancer Institute for Personalized Medicine, Lewis-Katz School of Medicine, Temple University, Philadelphia, PA 19140, USA.
School of Pharmacy, Temple University, Philadelphia, PA 19140, USA.
Pharmaceutics. 2023 Jun 15;15(6):1742. doi: 10.3390/pharmaceutics15061742.
Mesenchymal stem cells (MSCs) have been studied for their potential in facilitating tumor-targeted delivery of chemotherapeutics due to their tumor-homing characteristics. We hypothesized that targeting effectiveness of MSCs can be further enhanced by incorporating tumor-targeting ligands on MSC surfaces that will allow for enhanced arrest and binding within the tumor tissue. We utilized a unique strategy of modifying MSCs with synthetic antigen receptors (SARs), targeting specific antigens overexpressed on cancer cells. MSCs were surface-functionalized by first incorporating recombinant protein G (PG) on the surface, followed by binding of the targeting antibody to the PG handle. We functionalized MSCs with antibodies targeting a tyrosine kinase transmembrane receptor protein, epidermal growth factor receptor (EGFR), overexpressed in non-small-cell lung cancer (NSCLC). The efficacy of MSCs functionalized with anti-EGFR antibodies (cetuximab and D8) was determined in murine models of NSCLC. Cetuximab-functionalized MSCs demonstrated improved binding to EGFR protein and to EGFR overexpressing A549 lung adenocarcinoma cells. Further, cetuximab-functionalized MSCs loaded with paclitaxel nanoparticles were efficient in slowing orthotopic A549 tumor growth and improving the overall survival relative to that of other controls. Biodistribution studies revealed a six-fold higher retention of EGFR-targeted MSCs than non-targeted MSCs. Based on these results, we conclude that targeting ligand functionalization could be used to enhance the concentration of therapeutic MSC constructs at the tumor tissue and to achieve improved antitumor response.
间充质干细胞（MSCs）因其肿瘤归巢特性，在促进化疗药物的肿瘤靶向递送方面的潜力已得到研究。我们假设，通过在MSC表面掺入肿瘤靶向配体，可以进一步提高MSCs的靶向有效性，这将增强其在肿瘤组织内的滞留和结合。我们采用了一种独特的策略，用合成抗原受体（SARs）修饰MSCs，靶向癌细胞上过度表达的特定抗原。首先在表面掺入重组蛋白G（PG），然后将靶向抗体与PG连接，从而使MSCs表面功能化。我们用靶向一种酪氨酸激酶跨膜受体蛋白——表皮生长因子受体（EGFR）的抗体对MSCs进行功能化，EGFR在非小细胞肺癌（NSCLC）中过度表达。在NSCLC小鼠模型中测定了用抗EGFR抗体（西妥昔单抗和D8）功能化的MSCs的疗效。西妥昔单抗功能化的MSCs显示出与EGFR蛋白以及与过度表达EGFR的A549肺腺癌细胞的结合有所改善。此外，负载紫杉醇纳米颗粒的西妥昔单抗功能化的MSCs在减缓原位A549肿瘤生长和提高总体生存率方面比其他对照组更有效。生物分布研究表明，EGFR靶向的MSCs的滞留量是非靶向MSCs的六倍。基于这些结果，我们得出结论，靶向配体功能化可用于提高治疗性MSC构建体在肿瘤组织中的浓度，并实现更好的抗肿瘤反应。
