Neves Ana Raquel, Albuquerque Tânia, Faria Rúben, Paul Milan, Biswas Swati, Sousa Ângela, Costa Diana
CICS-UBI-Health Sciences Research Centre, University of Beira Interior, Avenida Infante, D. Henrique, 6200-506 Covilhã, Portugal.
Nanomedicine Research Laboratory, Department of Pharmacy, Birla Institute of Technology & Science-Pilani, Hyderabad Campus, Jawahar Nagar, Medchal, Hyderabad, Telangana 500078, India.
Pharmaceutics. 2021 Aug 13;13(8):1256. doi: 10.3390/pharmaceutics13081256.
Cancer gene therapy, mediated by non-viral systems, remains a major research focus. To contribute to this field, in this work we reported on the development of dendrimer drug/gene ternary complexes. This innovative approach explored the great capacity of both polyamidoamine (PAMAM)-paclitaxel (PTX) conjugate and polyethylenimine (PEI) polymers to complex a p53-encoding plasmid DNA (pDNA), highlighting the utility of considering two compacting agents. The pDNA complexation capacity has been investigated as function of the nitrogen to phosphate groups ratio (N/P), which revealed to be a tailoring parameter. The physicochemical properties of the conceived ternary complexes were revealed and were found to be promising for cellular transfection. Furthermore, the formulated co-delivery systems demonstrated to be biocompatible. The ternary systems were able of cellular internalization and payload intracellular release. Confocal microscopy studies showed the co-localization of stained pDNA with the nucleus of cancer cells, after transfection mediated by these carriers. From this achievement, p53 gene expression occurred with the production of protein. Moreover, the activation of caspase-3 indicated apoptosis of cancer cells. This work represents a great progress on the design of dendrimer drug/gene co-delivery systems towards a more efficient cancer therapy. In this way, it instigates further in vitro studies concerning the evaluation of their therapeutic potential, expectedly supported by the synergistic effect, in tumoral cells.
由非病毒系统介导的癌症基因治疗仍然是一个主要的研究重点。为了推动该领域的发展，在这项工作中，我们报道了树枝状聚合物药物/基因三元复合物的研发情况。这种创新方法探索了聚酰胺胺（PAMAM）-紫杉醇（PTX）共轭物和聚乙烯亚胺（PEI）聚合物与编码p53的质粒DNA（pDNA）形成复合物的强大能力，突出了考虑两种压缩剂的实用性。已研究了pDNA的络合能力与氮磷基团比（N/P）的关系，结果表明N/P是一个可调节参数。所构想的三元复合物的物理化学性质得以揭示，并且发现其在细胞转染方面很有前景。此外，所制备的共递送系统显示出生物相容性。三元系统能够实现细胞内化和有效载荷的细胞内释放。共聚焦显微镜研究表明，在这些载体介导的转染后，染色的pDNA与癌细胞核共定位。基于这一成果，p53基因表达伴随着蛋白质的产生而发生。此外，caspase-3的激活表明癌细胞发生了凋亡。这项工作在树枝状聚合物药物/基因共递送系统的设计方面取得了巨大进展，朝着更有效的癌症治疗方向迈进。通过这种方式，它激发了进一步的体外研究，以评估其在肿瘤细胞中的治疗潜力，预计将得到协同效应的支持。
