Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University, Utrecht, The Netherlands.
Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands.
Biomaterials. 2015 Aug;61:33-40. doi: 10.1016/j.biomaterials.2015.04.043. Epub 2015 May 17.
This study investigated the feasibility of the use of polymeric microparticles for sustained and local delivery of immunomodulatory antibodies in immunotherapy of cancer. Local delivery of potent immunomodulatory antibodies avoids unwanted systemic side effects while retaining their anti-tumor effects. Microparticles based on poly(lactic-co-hydroxymethyl-glycolic acid) (pLHMGA) and loaded with two distinct types of immunomodulatory antibodies (CTLA-4 antibody blocking inhibitory receptors on T cells or CD40 agonistic antibody stimulating dendritic cells) were prepared by double emulsion solvent evaporation technique. The obtained particles had a diameter of 12-15 μm to avoid engulfment by phagocytes and were slightly porous as shown by SEM analysis. The loading efficiency of the antibodies in the microparticles was >85%. The in vitro release profile of antiCD40 and antiCTLA-4 from microparticles showed a burst release of about 20% followed by a sustained release of the content up to 80% of the loading in around 30 days. The therapeutic efficacy of the microparticulate formulations was studied in colon carcinoma tumor model (MC-38). Mice bearing subcutaneous MC-38 tumors were treated with the same dose of immunomodulatory antibodies formulated either in incomplete Freund's adjuvant (IFA) or in microparticles. The antibody-loaded microparticles showed comparable therapeutic efficacy to the IFA formulation with no local adverse effects. The biodegradable microparticles were fully resorbed in vivo and no remnants of inflammatory depots as observed with IFA were present in the cured mice. Moreover the microparticles exhibited lower antibody serum levels in comparison with IFA formulations which lowers the probability of systemic adverse effects. In conclusion, pLHMGA microparticles are excellent delivery systems in providing long-lasting and non-toxic antibody therapy for immunotherapy of cancer.
本研究探讨了将免疫调节抗体的聚合物微球用于癌症免疫治疗的持续和局部递药的可行性。局部递药避免了免疫调节抗体的全身性副作用，同时保留了其抗肿瘤效果。基于聚（乳酸-共-羟基乙酸）（pLHMGA）的微球并加载两种不同类型的免疫调节抗体（CTLA-4 抗体阻断 T 细胞上的抑制性受体或 CD40 激动性抗体刺激树突细胞），通过双乳液溶剂蒸发技术制备。所获得的粒子直径为 12-15μm，以避免被吞噬细胞吞噬，并且如 SEM 分析所示，稍微多孔。抗体在微球中的载药效率>85%。从微球中抗 CD40 和抗 CTLA-4 的体外释放曲线显示，大约 20%的突释后，持续释放约 80%的载药量，持续约 30 天。微球制剂的治疗效果在结肠癌细胞肿瘤模型（MC-38）中进行了研究。皮下携带 MC-38 肿瘤的小鼠用相同剂量的免疫调节抗体进行治疗，这些抗体分别以不完全弗氏佐剂（IFA）或微球制剂的形式给药。载药微球与 IFA 制剂具有相当的治疗效果，没有局部不良反应。可生物降解的微球在体内完全被吸收，在治愈的小鼠中没有观察到 IFA 存在的炎症沉积残留物。此外，与 IFA 制剂相比，微球制剂的抗体血清水平较低，从而降低了全身性不良反应的可能性。总之，pLHMGA 微球是一种优异的给药系统，可为癌症免疫治疗提供长效、无毒的抗体治疗。
