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.
J Control Release. 2015 Apr 10;203:16-22. doi: 10.1016/j.jconrel.2015.02.006. Epub 2015 Feb 7.
The aim of the current study was to develop a cancer vaccine formulation for treatment of human papillomavirus (HPV)-induced malignancies. Synthetic long peptides (SLPs) derived from HPV16 E6 and E7 oncoproteins have been used for therapeutic vaccination in clinical trials with promising results. In preclinical and clinical studies adjuvants based on mineral oils (such as incomplete Freund's adjuvant (IFA) and Montanide) are used to create a sustained release depot at the injection site. While the depot effect of mineral oils is important for induction of robust immune responses, their administration is accompanied with severe adverse and long lasting side effects. In order to develop an alternative for IFA family of adjuvants, polymeric nanoparticles (NPs) based on hydrophilic polyester (poly(d,l lactic-co-hydroxymethyl glycolic acid) (pLHMGA)) were prepared. These NPs were loaded with a synthetic long peptide (SLP) derived from HPV16 E7 oncoprotein and a toll like receptor 3 (TLR3) ligand (poly IC) by double emulsion solvent evaporation technique. The therapeutic efficacy of the nanoparticulate formulations was compared to that of HPV SLP+poly IC formulated in IFA. Encapsulation of HPV SLP antigen in NPs substantially enhanced the population of HPV-specific CD8+ T cells when combined with poly IC either co-encapsulated with the antigen or in its soluble form. The therapeutic efficacy of NPs containing poly IC in tumor eradication was equivalent to that of the IFA formulation. Importantly, administration of pLHMGA nanoparticles was not associated with adverse effects and therefore these biodegradable nanoparticles are excellent substitutes for IFA in cancer vaccines.
本研究旨在开发一种用于治疗人乳头瘤病毒（HPV）诱导恶性肿瘤的癌症疫苗制剂。源自 HPV16 E6 和 E7 癌蛋白的合成长肽（SLP）已在临床试验中用于治疗性疫苗接种，并取得了有希望的结果。在临床前和临床研究中，基于矿物油（如不完全弗氏佐剂（IFA）和 Montanide）的佐剂用于在注射部位形成持续释放的储存库。虽然矿物油的储存效应对于诱导强大的免疫反应很重要，但它们的给药伴随着严重的、持久的副作用。为了开发替代 IFA 家族佐剂的方法，制备了基于亲水性聚酯（聚（DL 丙交酯-co-羟甲基乙交酯）（pLHMGA））的聚合物纳米颗粒（NPs）。通过双乳液溶剂蒸发技术，将这些 NPs 负载源自 HPV16 E7 癌蛋白的合成长肽（SLP）和 Toll 样受体 3（TLR3）配体（poly IC）。与在 IFA 中配制的 HPV SLP+poly IC 相比，纳米颗粒制剂的治疗效果进行了比较。当与 poly IC 联合使用时，将 HPV SLP 抗原包封在 NPs 中可大大增加 HPV 特异性 CD8+T 细胞的数量，无论是与抗原共包封还是以其可溶性形式存在。含有 poly IC 的 NPs 的治疗效果在肿瘤消除方面与 IFA 制剂相当。重要的是，pLHMGA 纳米粒子的给药与不良反应无关，因此这些可生物降解的纳米粒子是癌症疫苗中 IFA 的理想替代品。
