Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland.
Molecules. 2020 Dec 24;26(1):47. doi: 10.3390/molecules26010047.
Anthracyclines belong to the anticancer drugs that are widely used in chemotherapy. However, due to their systemic toxicity they also exert dangerous side effects associated mainly with cardiovascular risks. The pathway that is currently often developed is their chemical and physical modification via formation of conjugated or complexed prodrug systems with a variety of nanocarriers that can selectively release the active species in cancer cells. In this study, six new nanoconjugates were synthesized with the use of polyhedral oligosilsesquioxanes [POSS(OH)] as nanocarriers of the anticancer drugs anthracyclines-doxorubicin (DOX) and daunorubicin (DAU). These prodrug conjugates are also equipped with poly(ethylene glycol) (PEG) moieties of different structure and molecular weight. Water-soluble POSS, succinic anhydride modified (SAMDOX and SAMDAU) with carboxylic function, and PEGs (PEG1, PEG2 and PEGB3) were used for the synthesis. New nanoconjugates were formed via ester bonds and their structure was confirmed by NMR spectroscopy (H-NMR, C-NMR, H-C HSQC, DOSY and H-H COSY), FTIR and DLS. Drug release rate was evaluated using UV-Vis spectroscopy at pH of 5.5. Release profiles of anthracyclines from conjugates - point to a range of 10 to 75% (after 42 h). Additionally, model NMR tests as well as diffusion ordered spectroscopy (DOSY) confirmed formation of the relevant prodrugs. The POSS-anthracycline conjugates exhibited prolonged active drug release time that can lead to the possibility of lowering administered doses and thus giving them high potential in chemotherapy. Drug release from conjugate after 42 h was approx. 10%, 33% for conjugate , 47% for conjugate , , and 75% for conjugate .
蒽环类抗生素属于广泛应用于化疗的抗癌药物。然而，由于其全身毒性，它们也会产生与心血管风险相关的危险副作用。目前经常开发的途径是通过与各种纳米载体形成共轭或络合前药系统来对其进行化学和物理修饰，这些纳米载体可以选择性地将活性物质释放到癌细胞中。在这项研究中，使用多面体低聚倍半硅氧烷[POSS(OH)]作为抗癌药物蒽环类药物阿霉素（DOX）和柔红霉素（DAU）的纳米载体，合成了六种新的纳米缀合物。这些前药缀合物还配备了不同结构和分子量的聚（乙二醇）（PEG）部分。使用水溶性 POSS、带有羧酸官能团的琥珀酸酐修饰物（SAMDOX 和 SAMDAU）和 PEG1、PEG2 和 PEGB3 合成了可溶于水的 POSS，通过酯键形成新的纳米缀合物，并通过核磁共振波谱（H-NMR、C-NMR、H-C HSQC、DOSY 和 H-H COSY）、傅里叶变换红外光谱（FTIR）和动态光散射（DLS）确认其结构。通过在 pH 值为 5.5 时使用紫外-可见光谱评估药物释放率。阿霉素从缀合物中的释放率-在 42 小时后达到 10%至 75%的范围。此外，模型 NMR 测试和扩散有序光谱（DOSY）证实了相关前药的形成。POSS-蒽环类抗生素缀合物表现出延长的活性药物释放时间，这可能导致降低给药剂量的可能性，从而使它们在化疗中有很高的潜力。缀合物在 42 小时后的药物释放率约为 10%，缀合物的药物释放率为 33%，缀合物的药物释放率为 47%，缀合物的药物释放率为 、和 ，缀合物的药物释放率为 75%。
