Jerzy Haber Institute of Catalysis and Surface Chemistry Polish Academy of Sciences, 30-239 Krakow, Poland.
Department of Biomaterials and Composites, Faculty of Materials Science and Ceramics, AGH-University of Science and Technology, 30-059 Krakow, Poland.
Int J Mol Sci. 2021 Oct 16;22(20):11167. doi: 10.3390/ijms222011167.
Two generations of positively charged poly(amidoamine) dendrimers (PAMAMs) were selected for study as potential carriers for the anticancer drug 5-fluorouracil (5FU), a drug primarily used in the treatment of colorectal cancer. Analytical techniques, such as UV-Vis spectrophotometry, NMR Spectroscopy and Laser Doppler Velocimetry (LDV), have shown that the most critical factor determining the formation of a PAMAM-5FU complex is the starting components' protonation degree. The tests confirmed the system's ability to attach about 20 5FU molecules per one dendrimer molecule for the G4PAMAM dendrimer and about 25 molecules for the G6PAMAM dendrimer, which gives a system yield of 16% for the fourth generation and 5% for sixth generation dendrimers. Additionally, using the QCM-D method, the adsorption efficiency and the number of drug molecules immobilized in the dendrimer structure were determined. A new aspect in our study was the determination of the change in zeta potential (ζ) induced by the immobilization of 5FU molecules on the dendrimer's outer shell and the importance of this effect in the direct contact of the carrier with cells. Cytotoxicity tests (resazurin reduction and MTS tests) showed no toxicity of dendrimers against mouse fibroblast cells (L929) and a significant decrease in cell viability in the case of four human malignant cell lines: malignant melanoma (A375), glioblastoma (SNB-19), prostate cancer (Du-145) and colon adenocarcinoma (HT-29) during incubation with PAMAM-5FU complexes. The purpose of our work was to investigate the correlation between the physicochemical properties of the carrier and active substance and the system efficiency and optimizing conditions for the formation of an efficient system based on PAMAM dendrimers as nanocarriers for 5-fluorouracil. An additional aspect was to identify potential application properties of the complexes, as demonstrated by cytotoxicity tests.
两代带正电荷的聚酰胺-胺树枝状大分子（PAMAMs）被选为研究对象，作为抗癌药物 5-氟尿嘧啶（5FU）的潜在载体，5FU 主要用于治疗结直肠癌。分析技术，如紫外-可见分光光度法、NMR 光谱和激光多普勒测速（LDV），表明决定 PAMAM-5FU 复合物形成的最关键因素是起始组分的质子化程度。测试证实了该系统能够将大约 20 个 5FU 分子连接到一个树枝状大分子分子上，对于 G4PAMAM 树枝状大分子约为 25 个分子，对于 G6PAMAM 树枝状大分子约为 25 个分子，这使得第四代系统产率为 16%，第六代系统产率为 5%。此外，使用 QCM-D 方法，确定了吸附效率和固定在树枝状大分子结构中的药物分子数量。我们研究的一个新方面是确定 5FU 分子固定在树枝状大分子外壳上引起的动电电势（ζ）的变化，以及该效应在载体与细胞直接接触中的重要性。细胞毒性试验（resazurin 还原和 MTS 试验）表明，树枝状大分子对小鼠成纤维细胞（L929）没有毒性，并且在用 PAMAM-5FU 复合物孵育时，四种人恶性细胞系：恶性黑色素瘤（A375）、神经胶质瘤（SNB-19）、前列腺癌（Du-145）和结肠腺癌（HT-29）的细胞活力显著降低。我们的工作目的是研究载体和活性物质的物理化学性质与系统效率之间的相关性，并优化基于 PAMAM 树枝状大分子作为 5-氟尿嘧啶纳米载体的有效体系的形成条件。另一个方面是通过细胞毒性试验确定复合物的潜在应用特性。
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