Yaman Serkan, Ramachandramoorthy Harish, Iyer Priyanka, Chintapula Uday, Nguyen Tam, Sabnani Manoj, Kotadia Tanviben, Ghaffari Soroush, Pop Laurentiu M, Hannan Raquibul, Weidanz Jon A, Nguyen Kytai T
Department of Bioengineering, University of Texas at Arlington, TX, USA.
Joint Bioengineering Program, University of Texas Southwestern Medical Center, TX, USA.
Bioact Mater. 2024 Jan 11;34:422-435. doi: 10.1016/j.bioactmat.2023.12.027. eCollection 2024 Apr.
Cell membrane-derived nanoparticles (NPs) have recently gained popularity due to their desirable features in drug delivery such as mimicking properties of native cells, impeding systemic clearance, and altering foreign body responses. Besides NP technology, adoptive immunotherapy has emerged due to its promise in cancer specificity and therapeutic efficacy. In this research, we developed a biomimetic drug carrier based on chimeric antigen receptor (CAR) transduced T-cell membranes. For that purpose, anti-HER2 CAR-T cells were engineered via lentiviral transduction of anti-HER2 CAR coding lentiviral plasmids. Anti-HER2 CAR-T cells were characterized by their specific activities against the HER2 antigen and used for cell membrane extraction. Anti-cancer drug Cisplatin-loaded poly (D, l-lactide--glycolic acid) (PLGA) NPs were coated with anti-human epidermal growth factor receptor 2 (HER2)-specific CAR engineered T-cell membranes. Anti-HER2 CAR-T-cell membrane-coated PLGA NPs (CAR-T-MNPs) were characterized and confirmed via fluorescent microscopy and flow cytometry. Membrane-coated NPs showed a sustained drug release over the course of 21 days in physiological conditions. Cisplatin-loaded CAR-T-MNPs also inhibited the growth of multiple HER2+ cancer cells . In addition, uptake studies revealed that CAR-T-MNPs showed an increased uptake by A549 cells. These results were also confirmed via biodistribution and therapeutic studies using a subcutaneous lung cancer model in nude mice. CAR-T-MNPs localized preferentially at tumor areas compared to those of other studied groups and consisted of a significant reduction in tumor growth in tumor-bearing mice. In Conclusion, the new CAR modified cell membrane-coated NP drug-delivery platform has demonstrated its efficacy both and Therefore, CAR engineered membrane-coated NP system could be a promising cell-mimicking drug carrier that could improve therapeutic outcomes of lung cancer treatments.
细胞膜衍生的纳米颗粒（NPs）近来因其在药物递送方面的理想特性而受到关注，这些特性包括模拟天然细胞的性质、阻碍全身清除以及改变异物反应。除了纳米颗粒技术外，过继性免疫疗法因其在癌症特异性和治疗效果方面的前景也应运而生。在本研究中，我们基于嵌合抗原受体（CAR）转导的T细胞膜开发了一种仿生药物载体。为此，通过慢病毒转导抗HER2 CAR编码慢病毒质粒来构建抗HER2 CAR-T细胞。抗HER2 CAR-T细胞通过其对HER2抗原的特异性活性进行表征，并用于细胞膜提取。负载抗癌药物顺铂的聚（D，L-丙交酯-乙交酯）（PLGA）纳米颗粒用抗人表皮生长因子受体2（HER2）特异性CAR工程化的T细胞膜进行包被。通过荧光显微镜和流式细胞术对抗HER2 CAR-T细胞膜包被的PLGA纳米颗粒（CAR-T-MNPs）进行表征和确认。膜包被的纳米颗粒在生理条件下21天内显示出持续的药物释放。负载顺铂的CAR-T-MNPs也抑制了多种HER2+癌细胞的生长。此外，摄取研究表明CAR-T-MNPs在A549细胞中的摄取增加。这些结果也通过使用裸鼠皮下肺癌模型的生物分布和治疗研究得到证实。与其他研究组相比，CAR-T-MNPs优先定位于肿瘤区域，并且荷瘤小鼠的肿瘤生长显著减少。总之，新的CAR修饰的细胞膜包被的NP药物递送平台已证明其有效性。因此，CAR工程化的膜包被NP系统可能是一种有前途的细胞模拟药物载体，可以改善肺癌治疗的疗效。
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