pH-sensitive oncolytic adenovirus hybrid targeting acidic tumor microenvironment and angiogenesis.
pH-sensitive oncolytic adenovirus hybrid targeting acidic tumor microenvironment and angiogenesis.
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DOI：
10.1016/j.jconrel.2015.01.005
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发表时间：
2015-05-10
影响因子：
10.8
通讯作者：
Yun, Chae-Ok
中科院分区：
文献类型：
--
作者：
Choi, Joung-Woo;Jung, Soo-Jung;Kasala, Dayananda;Hwang, June Kyu;Hu, Jun;Bae, You Han;Yun, Chae-Ok
关键词：
尽管溶瘤腺病毒（Ads）是癌症基因治疗的有吸引力的选择，但裸Ad的静脉内施用仍然遇到不利的宿主反应、非特异性相互作用和靶向癌细胞的异质性。为了克服这些障碍并实现对肿瘤微环境的特异性靶向，用pH敏感的嵌段共聚物甲氧基聚（乙二醇）-b-聚（l-组氨酸-co-l-苯丙氨酸）（PEGbPHF）包被Ad。评估了所产生的纳米复合物Ad/PEGbPHF的物理化学性质。在pH6.4时，表达GFP的Ad/PEGbPHF在科萨基和腺病毒受体（CAR）阳性和阴性细胞中均诱导比裸Ad显著更高的GFP表达。为了评估Ad/PEGbPHF复合物平台的治疗功效，使用表达靶向VEGF启动子的转录阻遏物（KOX）的溶瘤Ad来形成复合物。在pH 6.4下，与在pH 7.4下的裸KOX或KOX/PEGbPHF相比，KOX/PEGbPHF显著抑制VEGF基因表达、癌细胞迁移、血管发芽和癌细胞杀伤作用，表明KOX/PEGbPHF可以克服在肿瘤组织中经常观察到的CAR缺乏。全身给予肿瘤异种移植模型的KOX/PEGbPHF的抗肿瘤活性显著高于裸KOX的抗肿瘤活性。此外，KOX/PEGbPHF显示出较低的肝毒性，并且不诱导针对Ad的天然免疫应答。总之，这些结果表明，pH敏感性聚合物包被的Ad复合物在暴露于缺氧肿瘤微环境时显著增加净正电荷，允许被动靶向肿瘤组织。与裸KOX相比，由于其改善的肿瘤选择性、增加的治疗功效和较低的毒性，其可提供用于全身治疗的上级潜力。
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 pH 6.4, 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 pH 6.4, 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 pH 7.4, 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.
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DOI：
10.1016/j.jconrel.2012.04.014
发表时间：
2012-12-10
期刊：
Journal of controlled release : official journal of the Controlled Release Society
影响因子：
--
作者：
Denison TA;Bae YH
通讯作者：
Bae YH
影响因子：
5.1
作者：
Baker, A;Saltik, M;Cotten, M
通讯作者：
Cotten, M
影响因子：
3.7
作者：
GREEN, M;DAESCH, GE
通讯作者：
DAESCH, GE
影响因子：
4.7
作者：
Chang, Kai-Ling;Higuchi, Yuriko;Hashida, Mitsuru
通讯作者：
Hashida, Mitsuru
影响因子：
15.9
作者：
Heise, C;Kirn, DH
通讯作者：
Kirn, DH