Haddadzadegan Soheil, Saleh Ahmad, Veider Florina, Knoll Patrick, Laffleur Flavia, Kali Gergely, Bernkop-Schnürch Andreas
ThioMatrix Forschungs- und Beratungs GmbH, Trientlgasse 65, Innsbruck, 6020, Austria.
Center for Sustainable Materials (SusMat), School of Materials Science and Engineering, Nanyang Technological University, Singapore, 639798, Singapore.
Drug Deliv Transl Res. 2025 Mar 20. doi: 10.1007/s13346-025-01832-w.
This study evaluates the in vivo mucoadhesive properties of thiolated cyclodextrins (CDs) with varying S-protection using polyethylene glycol (PEG) of different chain lengths. Free thiol groups of thiolated β-CDs (CD-SH) were S-protected with 1 kDa and 2 kDa PEG bearing a terminal thiol group, leading to third-generation of thiolated CDs (CD-SS-PEG). The structure of these thiolated CDs was confirmed and characterized by FT-IR, 1 H NMR, and colorimetric assays. Thiolated and S-protected CDs were evaluated regarding viscosity, cellular uptake and, in vitro and in vivo mucoadhesion. The viscosity of CD-SH, CD-SS-PEG 1 kDa, and CD-SS-PEG 2 kDa mixtures with mucus increased 9-, 7-, and 5.5-fold, respectively, compared to unmodified CD within 3 h. Cellular uptake on Caco-2 cells was 1.75 times higher for highly thiolated CDs than for unmodified CD. In vitro residence time on porcine intestine was prolonged 7-, 8.4-, and 7.9-fold for CD-SH, CD-SS-PEG 1 kDa, and CD-SS-PEG 2 kDa, respectively. In vivo results indicated CD-SS-PEG 1 kDa had the highest potential. Our comprehensive in vitro, ex vivo, and in vivo ffindings demonstrate that CD-SS-PEG 1 kDa is a highly promising candidate for mucoadhesive drug delivery systems.
本研究使用不同链长的聚乙二醇（PEG）评估了具有不同S-保护基的硫醇化环糊精（CDs）的体内粘膜粘附特性。硫醇化β-环糊精（CD-SH）的游离硫醇基团用带有末端硫醇基团的1 kDa和2 kDa PEG进行S-保护，从而得到第三代硫醇化环糊精（CD-SS-PEG）。通过傅里叶变换红外光谱（FT-IR）、核磁共振氢谱（1H NMR）和比色法对这些硫醇化环糊精的结构进行了确认和表征。对硫醇化和S-保护的环糊精进行了粘度、细胞摄取以及体外和体内粘膜粘附方面的评估。与未修饰的环糊精相比，CD-SH、1 kDa的CD-SS-PEG和2 kDa的CD-SS-PEG与粘液的混合物在3小时内的粘度分别增加了9倍、7倍和5.5倍。高度硫醇化的环糊精在Caco-2细胞上的摄取量比未修饰的环糊精高1.75倍。CD-SH、1 kDa的CD-SS-PEG和2 kDa的CD-SS-PEG在猪肠道上的体外停留时间分别延长了7倍、8.4倍和7.9倍。体内结果表明1 kDa的CD-SS-PEG具有最高的潜力。我们全面的体外、离体和体内研究结果表明，1 kDa的CD-SS-PEG是粘膜粘附药物递送系统极具前景的候选物。
