Hasibuzzaman M M, He Rui, Khan Ishrat Nourin, Sabharwal Rasna, Salem Aliasger K, Simons-Burnett Andrean Llewela
Interdisciplinary Graduate Program in Human Toxicology University of Iowa Iowa City IA USA.
Department of Pathology University of Iowa Iowa City IA USA.
Bioeng Transl Med. 2022 Dec 7;8(3):e10465. doi: 10.1002/btm2.10465. eCollection 2023 May.
Interleukin-1 alpha (IL-1α) is a pro-inflammatory cytokine that can activate immune effector cells and trigger anti-tumor immune responses. However, dose-limiting toxicities including cytokine storm and hypotension has limited its use in the clinic as a cancer therapy. We propose that polymeric microparticle (MP)-based delivery of IL-1α will suppress the acute pro-inflammatory side effects by allowing for slow and controlled release of IL-1α systemically, while simultaneously triggering an anti-tumor immune response.
Polyanhydride copolymers composed of 1,6-bis-(p-carboxyphenoxy)-hexane:sebacic 20:80 (CPH:SA 20:80) was utilized to fabricate MPs. Recombinant IL-1α (rIL-1α) was encapsulated into CPH:SA 20:80 MPs (IL-1α-MPs) and the MPs were characterized by size, charge, loading efficiency, and in-vitro release and activity of IL-1α. IL-1α-MPs were injected intraperitonially into head and neck squamous cell carcinoma (HNSCC)-bearing C57Bl/6 mice and monitored for changes in weight, tumor growth, circulating cytokines/chemokines, hepatic and kidney enzymes, blood pressure, heart rate, and tumor-infiltrating immune cells.
CPH:SA IL-1α-MPs demonstrated sustained release kinetics of IL-1α (100% protein released over 8-10 days) accompanied by minimal weight loss and systemic inflammation compared to rIL-1α-treated mice. Blood pressure measured by radiotelemetry in conscious mice demonstrates that rIL-1α-induced hypotension was prevented in IL-1α-MP-treated mice. Liver and kidney enzymes were within normal range for all control and cytokine-treated mice. Both rIL-1α and IL-1α-MP-treated mice showed similar delays in tumor growth and similar increases in tumor-infiltrating CD3+ T cells, macrophages, and dendritic cells.
CPH:SA-based IL-1α-MPs generated a slow and sustained systemic release of IL-1α resulting in reduced weight loss, systemic inflammation, and hypotension accompanied by an adequate anti-tumor immune response in HNSCC-tumor bearing mice. Therefore, MPs based on CPH:SA formulations may be promising as delivery vehicles for IL-1α to achieve safe, effective, and durable antitumor responses for HNSCC patients.
白细胞介素-1α（IL-1α）是一种促炎细胞因子，可激活免疫效应细胞并触发抗肿瘤免疫反应。然而，包括细胞因子风暴和低血压在内的剂量限制性毒性限制了其在临床上作为癌症治疗药物的应用。我们提出，基于聚合物微粒（MP）递送IL-1α将通过使IL-1α在全身缓慢且可控地释放来抑制急性促炎副作用，同时触发抗肿瘤免疫反应。
利用由1,6-双-（对羧基苯氧基）-己烷：癸二酸20:80（CPH:SA 20:80）组成的聚酸酐共聚物制备微粒。将重组IL-1α（rIL-1α）封装到CPH:SA 20:80微粒（IL-1α-MPs）中，并对微粒进行大小、电荷、负载效率以及IL-1α的体外释放和活性表征。将IL-1α-MPs经腹腔注射到荷有头颈部鳞状细胞癌（HNSCC）的C57Bl/6小鼠体内，并监测体重、肿瘤生长、循环细胞因子/趋化因子、肝酶和肾酶、血压、心率以及肿瘤浸润免疫细胞的变化。
与rIL-1α治疗的小鼠相比，CPH:SA IL-1α-MPs表现出IL-1α的持续释放动力学（在8 - 10天内100%的蛋白释放），同时体重减轻和全身炎症最小。通过无线电遥测法在清醒小鼠中测量的血压表明，IL-1α-MP治疗的小鼠预防了rIL-1α诱导的低血压。所有对照和细胞因子治疗小鼠的肝酶和肾酶均在正常范围内。rIL-1α和IL-1α-MP治疗的小鼠在肿瘤生长延迟和肿瘤浸润CD3 + T细胞、巨噬细胞和树突状细胞增加方面表现相似。
基于CPH:SA的IL-1α-MPs在荷HNSCC肿瘤的小鼠中产生了IL-1α的缓慢且持续的全身释放，导致体重减轻、全身炎症和低血压减轻，同时伴有足够的抗肿瘤免疫反应。因此，基于CPH:SA制剂的微粒作为IL-1α的递送载体，有望为HNSCC患者实现安全、有效和持久的抗肿瘤反应。
