Hopkins Kelsey, Buno Kevin, Romick Natalie, Freitas Dos Santos Antonio Carlos, Tinsley Samantha, Wakelin Elizabeth, Kennedy Jacqueline, Ladisch Michael, Allen-Petersen Brittany L, Solorio Luis
Weldon School of Biomedical Engineering, Purdue University, West Lafayette, IN 47907, USA.
Department of Agricultural and Biological Engineering, Purdue University, West Lafayette, IN 47907, USA.
PNAS Nexus. 2022 Sep 17;1(4):pgac193. doi: 10.1093/pnasnexus/pgac193. eCollection 2022 Sep.
In pancreatic cancer, excessive hyaluronic acid (HA) in the tumor microenvironment creates a viscous stroma, which reduces systemic drug transport into the tumor and correlates with poor patient prognosis. HA can be degraded through both enzymatic and nonenzymatic methods to improve mass transport properties. Here, we use an in situ forming implant to provide sustained degradation of HA directly at a local, targeted site. We formulated and characterized an implant capable of sustained release of hyaluronidase (HAase) using 15 kDa poly(lactic-co-glycolic) acid and bovine testicular HAase. The implant releases bioactive HAase to degrade the HA through enzymatic hydrolysis at early timepoints. In the first 24 h, 17.9% of the HAase is released, which can reduce the viscosity of a 10 mg/mL HA solution by 94.1% and deplete the HA content within primary human pancreatic tumor samples and ex vivo murine tumors. At later timepoints, as lower quantities of HAase are released (51.4% released in total over 21 d), the degradation of HA is supplemented by the acidic by-products that accumulate as a result of implant degradation. Acidic conditions degrade HA through nonenzymatic methods. This formulation has potential as an intratumoral injection to allow sustained degradation of HA at the pancreatic tumor site.
在胰腺癌中，肿瘤微环境中过量的透明质酸（HA）会形成粘性基质，这会减少全身药物向肿瘤的转运，并与患者预后不良相关。HA可通过酶促和非酶促方法降解，以改善物质传输特性。在此，我们使用原位形成植入物在局部靶向部位直接实现HA的持续降解。我们使用15 kDa聚乳酸-乙醇酸共聚物和牛睾丸透明质酸酶（HAase）制备并表征了一种能够持续释放透明质酸酶的植入物。该植入物在早期通过酶促水解释放生物活性HAase以降解HA。在最初的24小时内，17.9%的HAase被释放出来，这可使10 mg/mL HA溶液的粘度降低94.1%，并消耗原代人胰腺肿瘤样本和离体小鼠肿瘤内的HA含量。在后期，由于释放的HAase量较少（21天内总共释放51.4%），HA的降解由植入物降解积累的酸性副产物补充。酸性条件通过非酶促方法降解HA。这种制剂有潜力作为瘤内注射剂，在胰腺肿瘤部位实现HA的持续降解。
