Viral genome DNA/lipoplexes elicit in situ oncolytic viral replication and potent antitumor efficacy via systemic delivery
Viral genome DNA/lipoplexes elicit in situ oncolytic viral replication and potent antitumor efficacy via systemic delivery
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DOI：
10.1016/j.jconrel.2011.06.014
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发表时间：
2011-10-30
影响因子：
10.8
通讯作者：
Yun, Chae-Ok
中科院分区：
文献类型：
--
作者：
Kwon, Oh-Joon;Kang, Eunah;Yun, Chae-Ok
修饰病毒基因组以表达强效和癌症选择性治疗基因，增强了腺病毒（Ads）在癌症分子治疗中的作用。然而，Ad在体内全身递送的有效性受到中和抗体、血液循环时间短和高水平的非特异性肝脏摄取导致肝毒性的限制。因此，我们在原位肺癌模型中研究了肿瘤坏死因子相关凋亡诱导配体表达的溶瘤性Ad基因组DNA （pmT-d19/stTR）通过脂质包膜的全身递送作为癌症病毒治疗的替代方法。阳离子脂质体（DOTAP/DOPE）与pmT-d19/stTR络合生成pmT-d19/stTR + DOTAP/DOPE，在最佳DNA脂质比（1:6）下，平均直径为143.3 +/- 5.7 nm。全身给药pmT-d19/stTR + DOTAP/DOPE在体内引起了非常有效的抗肿瘤反应，与磷酸盐缓冲盐水、裸Ad (mT-d19/stTR)-或pmT-d19/stTR处理组相比，肿瘤体积分别减少了94.5%、90.5%和92.4%。此外，与mT-d19/stTR治疗组相比，pmT-d19/stTR + DOTAP/ dope治疗组小鼠的先天免疫反应和ad特异性中和抗体显著降低。定量pcr和免疫组织化学分析表明，病毒的复制优先发生在肿瘤组织中。此外，pmT-d19/stTR + DOTAP/ dope处理小鼠的病毒基因组肿瘤与肝脏的比率显著升高，分别比mT-d19/stTR-和pmT-d19/stTR处理小鼠高934倍和27倍。这些结果表明，溶瘤病毒基因组DNA与脂质体的全身递送是一种强大的替代裸Ad，克服了传统Ad有限的临床适用性，并能够有效治疗弥散性转移性肿瘤。(C) 2011 Elsevier B.V.版权所有
Modifying the viral genome to express potent and cancer-selective therapeutic genes has enhanced the role of adenoviruses (Ads) in cancer molecular therapeutics. However, the efficacy of Ad systemic delivery in vivo is limited by neutralizing antibodies, short blood circulation time, and high levels of nonspecific liver uptake resulting in hepatotoxicity. We therefore investigated the systemic delivery of tumor necrosis factor-related apoptosis-inducing ligand-expressing oncolytic Ad genome DNA (pmT-d19/stTR) via lipid envelopment as an alternative approach for cancer virotherapy in an orthotopic lung cancer model. Cationic liposomes (DOTAP/DOPE) were complexed with pmT-d19/stTR to generate pmT-d19/stTR + DOTAP/DOPE with the average diameter of which was 143.3 +/- 5.7 nm at the optimal DNA: lipid ratio (1:6). Systemic administration of pmT-d19/stTR + DOTAP/DOPE elicited highly effective antitumor responses in vivo, with tumor volumes decreasing 94.5%, 90.5%, and 92.4% compared to phosphate buffered saline-, naked Ad (mT-d19/stTR)-, or pmT-d19/stTR-treated groups, respectively. Additionally, innate immune responses and Ad-specific neutralizing antibodies were significantly decreased in pmT-d19/stTR + DOTAP/DOPE-treated mice compared to those in the mT-d19/stTR-treated group. The biodistribution profile analyzed by quantitative-PCR and immunohistochemical analysis demonstrated that viral replication occurred preferentially in tumor tissues. Moreover, the viral genome tumor-to-liver ratio was significantly elevated in pmT-d19/stTR + DOTAP/DOPE-treated mice, which was 934- and 27-fold greater than the mT-d19/stTR- and pmT-d19/stTR-treated mice, respectively. These results demonstrate that systemic delivery of oncolytic viral genome DNA with liposomes is a powerful alternative to naked Ad, overcoming the limited clinical applicability of conventional Ads and enabling effective treatment of disseminated metastatic tumors. (C) 2011 Elsevier B.V. All rights reserved.