Department of Orthopaedics, West Virginia University, West Virginia, Morgantown, USA.
WVU Cancer Institute, West Virginia University, Morgantown, West Virginia, USA.
J Orthop Res. 2023 Jul;41(7):1565-1581. doi: 10.1002/jor.25491. Epub 2022 Dec 12.
Clinical trials exploring bolus intravenous delivery of interleukin-12 (IL-12) for treatment of solid tumors ultimately failed due to lack of clinical response and severe dose-limiting toxicities. The present study was conducted to evaluate whether recombinant murine IL-12 (rmIL-12) could be successfully encapsulated within Poly (D, l-lactide-co-glycolide) (PLGA) nanospheres (rmIL-12ns) for safe and effective systemic delivery at pharmacologic scale. Optimal fabrication of rmIL-12ns occurs with dichloromethane as the organic solvent and emulsion formation via ultrasonication at 50% power (250 W sonicator) for 10 s (50W10s). We then determined whether utilization of synthesis modifiers including fetal bovine serum (FBS), magnesium hydroxide [Mg(OH) ], trehalose, or the surfactants polysorbate 80 and Span 60 alone or in combination could increase the encapsulation efficiency (EE) and/or modify the burst elution profile characteristic of the 50W10s rmIL-12ns formulation. The greatest EEs compared to the unmodified formulation were measured with modifications containing the surfactants polysorbate 80 and Span 60 (surfactant: 28.3 ± 6.10%, p = 0.29 and Surf/FBS: 85.4 ± 2.19%, p = 0.039). The Surf/FBS formulation was further modified for in vivo murine injection by substituting FBS with mouse serum albumin (MSA). The resulting Surf/MSA rmIL-12ns were then characterized before delivery at three doses (0.1, 1, and 10 mg rmIL-12ns) in our established murine model of metastatic osteosarcoma to assess efficacy. Preliminary results suggested no evidence of disease with delivery of the 0.1 mg dose in 75% of mice (3 of 4) versus a nontreated historical control (2 of 34).
探索白细胞介素 12（IL-12）静脉推注治疗实体瘤的临床试验最终因缺乏临床反应和严重的剂量限制毒性而失败。本研究旨在评估重组鼠白细胞介素 12（rmIL-12）是否可以成功封装在聚（D，L-丙交酯-共-乙交酯）（PLGA）纳米球（rmIL-12ns）中，以实现安全有效的全身给药。rmIL-12ns 的最佳制备是使用二氯甲烷作为有机溶剂，并通过超声在 50%功率（250W 超声仪）下形成乳液 10s（50W10s）。然后，我们确定是否可以利用合成修饰剂，包括胎牛血清（FBS）、氢氧化镁[Mg（OH）]、海藻糖或表面活性剂聚山梨酯 80 和司盘 60 单独或联合使用，来提高包封效率（EE）和/或改变 50W10s rmIL-12ns 制剂的突释洗脱特性。与未修饰的制剂相比，添加表面活性剂聚山梨酯 80 和司盘 60 的修饰制剂的 EE 最大（表面活性剂：28.3±6.10%，p=0.29 和 Surf/FBS：85.4±2.19%，p=0.039）。Surf/FBS 制剂进一步用鼠血清白蛋白（MSA）代替 FBS 进行体内小鼠注射的修饰。然后在我们建立的转移性骨肉瘤小鼠模型中，在三个剂量（0.1、1 和 10mg rmIL-12ns）下对得到的 Surf/MSA rmIL-12ns 进行了特征描述，以评估疗效。初步结果表明，与未处理的历史对照（3/34）相比，在 75%的小鼠（4/3）中，以 0.1mg 剂量给药没有疾病证据。
