Hepatoma targeting peptide conjugated bio-reducible polymer complexed with oncolytic adenovirus for cancer gene therapy.
Hepatoma targeting peptide conjugated bio-reducible polymer complexed with oncolytic adenovirus for cancer gene therapy.
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DOI：
10.1016/j.jconrel.2015.09.068
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发表时间：
2015-12-28
期刊：
影响因子：
--
通讯作者：
Kim S
中科院分区：
文献类型：
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作者：
Choi JW;Kim HA;Nam K;Na Y;Yun CO;Kim S
尽管腺病毒（Ad）载体在肿瘤基因治疗中具有内体逃逸能力强、核进入机制高效、转导能力强、治疗效果好等诸多优势，但肿瘤特异性靶向和抗病毒免疫应答仍是临床面临的关键挑战。为了克服这些障碍，实现肿瘤特异性靶向，我们将聚乙二醇化的ABP与肝癌具有高亲和力和选择性的HCBP1肽偶联，构建了靶向肿瘤的生物可还原聚合物——精氨酸移植生物可还原聚合物(ABP)-PEG-HCBP1。与裸ad /GFP或ad /GFP- abp相比，abp - peg - hcbp1表达的ad (ad /GFP)-ABP-PEG-HCBP1表现出肝癌特异性摄取和转导。竞争分析表明，Ad/ gfp - abp - peg -HCBP1介导的转导被HCBP1肽特异性抑制，而不是柯萨奇和腺病毒受体特异性抗体。此外，ABP-PEG-HCBP1可以保护Ad对血清的生物活性，并显著降低Ad的先天和适应性免疫反应。表达shMet的溶瘤性Ad （oAd; RdB/shMet）与ABP-PEG-HCBP1复合物有效地将oAd传递到肝癌细胞中。与oAd/ABP复合物相比，oAd/ABP- peg - hcbp1显示出更强的癌细胞杀伤效果。此外，用oAd/shMet-ABP-PEG-HCBP1复合物处理的Huh7和HT1080癌细胞在肝癌中显著降低Met和VEGF的表达，而在非肝癌中没有。总之，这些结果表明，hcbp1缀合的生物可还原聚合物可用于安全有效地递送溶瘤性Ad治疗肝癌。
Despite adenovirus (Ad) vector’s numerous advantages for cancer gene therapy, such as high ability of endosomal escape, efficient nuclear entry mechanism, and high transduction, and therapeutic efficacy, tumor specific targeting and antiviral immune response still remain as a critical challenge in clinical setting. To overcome these obstacles and achieve cancer-specific targeting, we constructed tumor targeting bioreducible polymer, an arginine grafted bio-reducible polymer (ABP)-PEG-HCBP1, by conjugating PEGylated ABP with HCBP1 peptides which has high affinity and selectivity towards hepatoma. The ABP-PEG-HCBP1-conjugated replication incompetent GFP-expressing ad, (Ad/GFP)-ABP-PEG-HCBP1, showed a hepatoma cancer specific uptake and transduction compared to either naked Ad/GFP or Ad/GFP-ABP. Competition assays demonstrated that Ad/GFP-ABP-PEG-HCBP1-mediated transduction was specifically inhibited by HCBP1 peptide rather than coxsackie and adenovirus receptor specific antibody. In addition, ABP-PEG-HCBP1 can protect biological activity of Ad against serum, and considerably reduced both innate and adaptive immune response against Ad. shMet-expressing oncolytic Ad (oAd; RdB/shMet) complexed with ABP-PEG-HCBP1 delivered oAd efficiently into hepatoma cancer cells. The oAd/ABP-PEG-HCBP1 demonstrated enhanced cancer cell killing efficacy in comparison to oAd/ABP complex. Furthermore, Huh7 and HT1080 cancer cells treated with oAd/shMet-ABP-PEG-HCBP1 complex had significantly decreased Met and VEGF expression in hepatoma cancer, but not in non-hepatoma cancer. In sum, these results suggest that HCBP1-conjugated bioreducible polymer could be used to deliver oncolytic Ad safely and efficiently to treat hepatoma.