Choi Joung-Woo, Jung Soo-Jung, Kasala Dayananda, Hwang June Kyu, Hu Jun, Bae You Han, Yun Chae-Ok
Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsinmi-ro, Seongdong-gu, Seoul, Republic of Korea.
Department of Pharmaceutics and Pharmaceutical Chemistry, The University of Utah, 30S 2000 E, Room 2972, Salt Lake City, UT 84112, USA.
J Control Release. 2015 May 10;205:134-43. doi: 10.1016/j.jconrel.2015.01.005. Epub 2015 Jan 7.
Although oncolytic adenoviruses (Ads) are an attractive option for cancer gene therapy, the intravenous administration of naked Ad still encounters unfavorable host responses, non-specific interactions, and heterogeneity in targeted cancer cells. To overcome these obstacles and achieve specific targeting of the tumor microenvironment, Ad was coated with the pH-sensitive block copolymer, methoxy poly(ethylene glycol)-b-poly(l-histidine-co-l-phenylalanine) (PEGbPHF). The physicochemical properties of the generated nanocomplex, Ad/PEGbPHF, were assessed. At pH6.4, GFP-expressing Ad/PEGbPHF induced significantly higher GFP expression than naked Ad in both coxsackie and adenovirus receptor (CAR)-positive and -negative cells. To assess the therapeutic efficacy of the Ad/PEGbPHF complex platform, an oncolytic Ad expressing VEGF promoter-targeting transcriptional repressor (KOX) was used to form complexes. At pH6.4, KOX/PEGbPHF significantly suppressed VEGF gene expression, cancer cell migration, vessel sprouting, and cancer cell killing effect compared to naked KOX or KOX/PEGbPHF at pH7.4, demonstrating that KOX/PEGbPHF can overcome the lack of CAR that is frequently observed in tumor tissues. The antitumor activity of KOX/PEGbPHF systemically administered to a tumor xenograft model was significantly higher than that of naked KOX. Furthermore, KOX/PEGbPHF showed lower hepatic toxicity and did not induce an innate immune response against Ad. Altogether, these results demonstrate that pH-sensitive polymer-coated Ad complex significantly increases net positive charge upon exposure to hypoxic tumor microenvironment, allowing passive targeting to the tumor tissue. It may offer superior potential for systemic therapy, due to its improved tumor selectivity, increased therapeutic efficacy, and lower toxicity compared to naked KOX.
尽管溶瘤腺病毒是癌症基因治疗的一个有吸引力的选择，但裸腺病毒的静脉注射仍会遇到不利的宿主反应、非特异性相互作用以及靶向癌细胞的异质性问题。为了克服这些障碍并实现对肿瘤微环境的特异性靶向，腺病毒被包裹上了pH敏感的嵌段共聚物，即甲氧基聚（乙二醇）-b-聚（l-组氨酸-co-l-苯丙氨酸）（PEGbPHF）。对生成的纳米复合物Ad/PEGbPHF的物理化学性质进行了评估。在pH6.4时，表达绿色荧光蛋白（GFP）的Ad/PEGbPHF在柯萨奇病毒和腺病毒受体（CAR）阳性及阴性细胞中诱导的GFP表达均显著高于裸腺病毒。为了评估Ad/PEGbPHF复合平台的治疗效果，使用了一种表达靶向VEGF启动子的转录抑制因子（KOX）的溶瘤腺病毒来形成复合物。在pH6.4时，与裸KOX或pH7.4的KOX/PEGbPHF相比，KOX/PEGbPHF显著抑制了VEGF基因表达、癌细胞迁移、血管生成以及癌细胞杀伤作用，表明KOX/PEGbPHF可以克服肿瘤组织中常见的CAR缺乏问题。将KOX/PEGbPHF系统给药至肿瘤异种移植模型的抗肿瘤活性显著高于裸KOX。此外，KOX/PEGbPHF显示出较低的肝毒性，并且不会诱导针对腺病毒的先天免疫反应。总之，这些结果表明，pH敏感聚合物包裹的腺病毒复合物在暴露于缺氧肿瘤微环境时会显著增加净正电荷，从而实现对肿瘤组织的被动靶向。与裸KOX相比，它可能因其改善的肿瘤选择性、增强的治疗效果和更低的毒性而在全身治疗方面具有更大的潜力。
