用透明质酸基纳米水凝胶阻断透明质酸酶活性：开发通用注射制剂
Halting hyaluronidase activity with hyaluronan-based nanohydrogels: development of versatile injectable formulations
摘要：
羟丙甲纤维素（HA）是用于粘度补充和化妆品应用的最常用的生物聚合物之一。然而，目前可注射的基于HA的制剂存在相关的限制：I）未修饰的HA被内源性透明质酸酶（HAase）快速降解，导致短暂的持久性质; II）交联的HA，尽管显示出对HAase的增强的稳定性，但通常含有有毒的化学交联剂。因此，在本文中，我们提出了生物相容性自组装透明质酸-胆固醇纳米水凝胶（HA-CH NH），其能够结合HAase并在体外抑制酶活性，比目前市售的基于HA的交联制剂（例如JonexaTM）更有效。HA-CH NH通过混合机制抑制HA酶，其中NH以比HA高7倍的亲和力常数与HA酶结合。类似的NH，基于结冷胶-胆固醇，证明没有结合到HAase，也没有抑制酶活性，表明这种效果可能是由于HA-CH特异性结合到酶的活性位点。因此，HA-CH NH被工程化到可注射的杂合HA混合物或物理水凝胶中，能够停止HA的酶促降解。
英文摘要：
Hyaluronan (HA) is among the most used biopolymers for viscosupplementation and cosmetic applications. However, the current injectable HA-based formulations present relevant limitations: I) unmodified HA is quickly degraded by endogenous hyaluronidases (HAase), resulting in short lasting properties; II) cross-linked HA, although shows enhanced stability against HAase, often contains toxic chemical cross-linkers. As such, herein, we present biocompatible self-assembled hyaluronan-cholesterol nanohydrogels (HA-CH NHs) able to bind to HAase and inhibit the enzyme activity in vitro, more efficiently than currently marketed HA-based cross-linked formulations (e.g. JonexaTM). HA-CH NHs inhibit HAase through a mixed mechanism, by which NHs bind to HAase with an affinity constant 7-fold higher than that of HA. Similar NHs, based on gellan-cholesterol, evidenced no binding to HAase, neither inhibition of the enzyme activity, suggesting this effect might be due to the specific binding of HA-CH to the active site of the enzyme. Therefore, HA-CH NHs were engineered into injectable hybrid HA mixtures or physical hydrogels, able to halt the enzymatic degradation of HA.
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