Department of Biomedical Engineering, Worcester Polytechnic Institute, 60 Prescott Street, Worcester, MA 01605, USA.
J Mater Chem B. 2019 Apr 7;7(13):2151-2161. doi: 10.1039/c8tb03020k. Epub 2019 Feb 26.
Drug delivery systems capable of local sustained release of small molecule therapeutics remain a critical need in many fields, including oncology. Here, a system to create tunable hydrogels capable of modulating the loading and release of cationic small molecule therapeutics was developed. Chondroitin sulfate (CS) is a sulfated glycosaminoglycan that has many promising properties, including biocompatibility, biodegradation and chemically modifiable groups for both covalent and non-covalent bonding. CS was covalently modified with photocrosslinkable methacryloyl groups (CSMA) to develop an injectable hydrogel fabrication. Utilizing anionic groups, cationic drugs can be adsorbed and released from the hydrogels. This study demonstrates the synthesis of CSMA with a varying degree of substitution (DS) to generate hydrogels with varying swelling properties, maximum injection force, and drug release kinetics. The DS of the synthesized CSMA ranged from 0.05 ± 0.02 (2 h reaction) to 0.28 ± 0.02 (24 h reaction) with a DS of 1 representing 100% modification. The altered DS resulted in changes in hydrogel properties with the swelling of 20% CSMA hydrogels ranging from 42 (2 h reaction) to 13 (24 h reaction) and injection forces ranging from 18 N (2 h reaction) to 94 N (24 h reaction). The release of sunitinib, an oncology therapeutic that inhibits intracellular signaling by targeting multiple receptor tyrosine kinases, ranged from 18 μg per day (2 h reaction) to 9 μg per day (24 h reaction). While decreasing the DS increased the hydrogel swelling and rate of therapeutic release, it also limited the hydrogel fabrication range to only those containing 10% or higher CSMA. Blended polymer systems with poly(vinyl alcohol)-methacrylate (PVAMA) were fabricated to stabilize the resulting hydrogels via attenuating the swelling properties. Release profiles previously unattainable with the pure CSMA hydrogels were achieved with the blended hydrogel formulations. Overall, these studies identify a method to formulate tunable CSMA and blended CSMA/PVAMA hydrogels capable of sustained release of cationic therapeutics over six weeks with applications in oncology therapeutics.
在许多领域，包括肿瘤学领域，仍然需要能够局部持续释放小分子治疗药物的药物输送系统。在这里，开发了一种创建可调谐水凝胶的系统，该系统能够调节阳离子小分子治疗药物的负载和释放。硫酸软骨素 (CS) 是一种硫酸化糖胺聚糖，具有许多有前途的特性，包括生物相容性、可生物降解性以及用于共价和非共价键合的可化学修饰基团。CS 通过光交联的甲基丙烯酰基进行共价修饰（CSMA）以开发可注射水凝胶制造。利用阴离子基团，可以将阳离子药物吸附并从水凝胶中释放出来。本研究展示了具有不同取代度（DS）的 CSMA 的合成，以生成具有不同溶胀特性、最大注射力和药物释放动力学的水凝胶。合成 CSMA 的 DS 范围为 0.05 ± 0.02（2 小时反应）至 0.28 ± 0.02（24 小时反应），其中 DS 为 1 代表 100%修饰。改变 DS 导致水凝胶性质发生变化，20% CSMA 水凝胶的溶胀范围为 42（2 小时反应）至 13（24 小时反应），注射力范围为 18 N（2 小时反应）至 94 N（24 小时反应）。舒尼替尼是一种通过靶向多种受体酪氨酸激酶来抑制细胞内信号传导的肿瘤治疗药物，其释放量为每天 18 μg（2 小时反应）至每天 9 μg（24 小时反应）。虽然降低 DS 会增加水凝胶的溶胀和治疗药物释放的速度，但它也将水凝胶的制造范围限制在仅包含 10%或更高 CSMA 的范围内。通过制造与聚（乙烯醇）-甲基丙烯酰胺（PVAMA）的混合聚合物系统来稳定所得水凝胶，以减轻其溶胀性质。通过混合水凝胶配方实现了以前无法用纯 CSMA 水凝胶获得的释放曲线。总体而言，这些研究确定了一种配方可调谐 CSMA 和混合 CSMA/PVAMA 水凝胶的方法，该水凝胶能够在六周内持续释放阳离子治疗药物，可应用于肿瘤治疗药物。
