Key Laboratory of Drug Targeting and Novel Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
Key Laboratory of Drug Targeting and Novel Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, PR China.
Acta Biomater. 2016 Jan;30:94-105. doi: 10.1016/j.actbio.2015.11.005. Epub 2015 Nov 4.
Adenoviral vectors have attracted substantial interest for systemic tumor gene therapy, but further work is needed to reduce their immunogenicity and alter their biodistribution before they can be used in the clinic. Here we describe a bio-inspired, cleavable PEGylated β-cyclodextrin-polyethyleneimine conjugate (CDPCP) that spontaneously coats adenovirus in solution. This cleavable PEG coating reduces the innate and adaptive immunogenicity of adenovirus particles, as well as improves their biodistribution away from the liver and into the tumor. Insertion of a matrix metalloproteinase substrate sequence into the conjugate allows PEG cleavage at the tumor site, simultaneously reducing liver biodistribution and increasing transgene expression in tumors, thereby avoiding the "PEG dilemma". Cationic β-cyclodextrin-PEI not only provides electrostatic attraction to promote envelope attachment to the viral capsid, but it also improves vector internalization and transduction after PEG cleavage. These results suggest that CDPCP may help expand the use of adenoviral vectors in cancer gene therapy.
The synthesized β-cyclodextrin-PEI-MMP-cleavable-PEG polymer (CDPCP), held great potential for gene therapy when applied for adenovirus coating. The β-cyclodextrin-PEI provided a powerful electrostatic attraction to attach the whole polymer onto the viral capsid, while the MMPs-cleavable PEG reduced innate and adaptive immunogenicity and improved the biodistribution of adenovirus vectors due to the tumor-specific enzyme triggered PEG cleavage. More importantly, an ingenious cooperation between the two components could solve the PEG dilemma. The CDPCP/Ad complexes exhibited a comprehensive and valued profile to be a candidate vector for future tumor gene therapy, we believe the current investigation on this kind of biomaterial may be of particular interest to the readership of Acta biomaterialia.
腺病毒载体因其在全身肿瘤基因治疗中的应用而受到广泛关注，但在临床应用之前，还需要进一步降低其免疫原性和改变其生物分布。在这里，我们描述了一种受生物启发的、可切割的聚乙二醇化 β-环糊精-聚乙烯亚胺缀合物（CDPCP），它可在溶液中自发包裹腺病毒。这种可切割的 PEG 涂层降低了腺病毒颗粒的固有和适应性免疫原性，并改善了其生物分布，使其远离肝脏进入肿瘤。在缀合物中插入基质金属蛋白酶底物序列允许在肿瘤部位进行 PEG 切割，同时减少肝脏生物分布，并增加肿瘤中的转基因表达，从而避免“PEG 困境”。阳离子 β-环糊精-PEI 不仅提供静电吸引力以促进包膜与病毒衣壳的附着，而且还改善了 PEG 切割后的载体内化和转导。这些结果表明，CDPCP 可能有助于扩大腺病毒载体在癌症基因治疗中的应用。
当用于腺病毒包被时，合成的 β-环糊精-PEI-MMP 可切割-PEG 聚合物（CDPCP）在基因治疗方面具有很大的潜力。β-环糊精-PEI 提供了强大的静电吸引力，将整个聚合物附着在病毒衣壳上，而 MMP 可切割的 PEG 通过肿瘤特异性酶触发的 PEG 切割降低了腺病毒载体的固有和适应性免疫原性，并改善了其生物分布。更重要的是，这两个组件之间的巧妙合作可以解决 PEG 困境。CDPCP/Ad 复合物表现出全面而有价值的特性，可作为未来肿瘤基因治疗的候选载体，我们相信对这种生物材料的当前研究可能会引起 Acta biomaterialia 的读者特别关注。
