Centre of Molecular and Macromolecular Studies, Polish Academy of Sciences, Sienkiewicza 112, 90-363 Lodz, Poland.
Department of General Biophysics, Faculty of Biology and Environmental Protection, University of Lodz, 141/143 Pomorska Street, 90-236 Lodz, Poland.
Biomacromolecules. 2022 Oct 10;23(10):4203-4219. doi: 10.1021/acs.biomac.2c00691. Epub 2022 Sep 7.
Injectable, self-healing hydrogels with enhanced solubilization of hydrophobic drugs are urgently needed for antimicrobial intravaginal therapies. Here, we report the first hydrogel systems constructed of dynamic boronic esters cross-linking unimolecular micelles, which are a reservoir of antifungal hydrophobic drug molecules. The selective hydrophobization of hyperbranched polyglycidol with phenyl units in the core via ester or urethane bonds enabled the solubilization of clotrimazole, a water-insoluble drug of broad antifungal properties. The encapsulation efficiency of clotrimazole increases with the degree of the HbPGL core modification; however, the encapsulation is more favorable in the case of urethane derivatives. In addition, the rate of clotrimazole release was lower from HbPGL hydrophobized via urethane bonds than with ester linkages. In this work, we also revealed that the hydrophobization degree of HbPGL significantly influences the rheological properties of its hydrogels with poly(acrylamide--2-acrylamidephenylboronic acid). The elastic strength of networks () and the thermal stability of hydrogels increased along with the degree of HbPGL core hydrophobization. The degradation of the hydrogel constructed of the neat HbPGL was observed at approx. 40 °C, whereas the hydrogels constructed on HbPGL, where the monohydroxyl units were modified above 30 mol %, were stable above 50 °C. Moreover, the flow and self-healing ability of hydrogels were gradually decreased due to the reduced dynamics of macromolecules in the network as an effect of increased hydrophobicity. The changes in the rheological properties of hydrogels resulted from the engagement of phenyl units into the intermolecular hydrophobic interactions, which besides boronic esters constituted additional cross-links. This study demonstrates that the HbPGL core hydrophobized with phenyl units at 30 mol % degrees via urethane linkages is optimal in respect of the drug encapsulation efficiency and rheological properties including both self-healable and injectable behavior. This work is important because of a proper selection of a building component for the construction of a therapeutic hydrogel platform dedicated to the intravaginal delivery of hydrophobic drugs.
具有增强疏水性药物增溶能力的可注射自修复水凝胶是抗菌阴道内治疗的迫切需要。在这里，我们报告了第一个由动态硼酸酯交联单分子胶体制成的水凝胶体系，该体系是抗真菌疏水性药物分子的储库。通过酯键或氨酯键将超支化聚缩水甘油以苯基单元在核心中选择性疏水化，使克霉唑（一种具有广泛抗真菌性质的水溶性差药物）能够溶解。克霉唑的包封效率随 HbPGL 核修饰程度的增加而增加；然而，在氨酯衍生物的情况下，包封更有利。此外，通过氨酯键疏水化的 HbPGL 比通过酯键释放克霉唑的速度更低。在这项工作中，我们还揭示了 HbPGL 的疏水化程度显著影响其与聚丙烯酰胺-2-丙烯酰胺基苯硼酸共聚的水凝胶的流变性能。网络的弹性强度（）和水凝胶的热稳定性随着 HbPGL 核疏水化程度的增加而增加。在约 40°C 观察到由纯 HbPGL 构建的水凝胶的降解，而在 HbPGL 构建的水凝胶中，当单羟基单元修饰超过 30mol%时，在高于 50°C 时是稳定的。此外，由于网络中大分子的动态性降低，水凝胶的流动和自修复能力逐渐降低，这是由于疏水性增加的结果。水凝胶流变性能的变化是由于苯基单元参与了分子间的疏水相互作用，除了硼酸酯外，还构成了额外的交联。这项研究表明，通过氨酯键将苯基单元以 30mol%的程度疏水化的 HbPGL 在药物包封效率和流变性能方面是最优的，包括自修复和可注射行为。由于选择合适的构建组件来构建专门用于阴道内递送疏水性药物的治疗性水凝胶平台，因此这项工作非常重要。
