Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT 84112, USA.
J Control Release. 2012 Mar 28;158(3):451-60. doi: 10.1016/j.jconrel.2011.12.008. Epub 2011 Dec 20.
As an effort to overcome limits of adenovirus (Ad) as a systemic delivery vector for cancer therapy, we developed a novel system using oncolytic Ad plasmid DNA with two bioreducible polymers: arginine-grafted bioreducible poly(disulfide amine)polymer (ABP) and PEG5k-conjugated ABP (ABP5k) in expectation of oncolytic effect caused by progeny viral production followed by replication. The linearized Ad DNAs for active viral replication polyplexed with each polymer were able to replicate only in human cancer cells and produce progeny viruses. The non-immunogenic polymers delivering the DNAs markedly elicited to evade the innate and adaptive immune response. The biodistribution ratio of the polyplexes administered systemically was approximately 99% decreased in liver when compared with naked Ad. Moreover, tumor-to-liver ratio of the Ad DNA delivered by ABP or ABP5k was significantly elevated at 229- or 419-fold greater than that of naked Ad, respectively. The ABP5k improved the chance of the DNA to localize within tumor versus liver with 1.8-fold increased ratio. In conclusion, the innovative and simple system for delivering oncolytic Ad plasmid DNA with the bioreducible polymers, skipping time-consuming steps such as generation and characterization of oncolytic Ad vectors, can be utilized as an alternative approach for cancer therapy.
为了克服腺病毒（Ad）作为癌症治疗全身递送载体的局限性，我们开发了一种使用溶瘤性 Ad 质粒 DNA 与两种生物可还原聚合物的新型系统：精氨酸接枝生物可还原聚（二硫代氨基）聚合物（ABP）和聚乙二醇 5k 接枝 ABP（ABP5k），期望通过随后的复制产生的子代病毒产生溶瘤作用。线性化用于有效病毒复制的 Ad DNA 与每种聚合物形成的多聚物仅能在人类癌细胞中复制并产生子代病毒。递呈 DNA 的非免疫原性聚合物可显著引发逃避先天和适应性免疫反应。与裸 Ad 相比，全身给药的多聚物的生物分布比约降低了 99%。此外，用 ABP 或 ABP5k 递送的 Ad DNA 的肿瘤与肝脏的比值分别比裸 Ad 高 229 倍和 419 倍。ABP5k 提高了 DNA 在肿瘤中与肝脏内定位的机会，比值增加了 1.8 倍。总之，这种具有生物可还原聚合物的新型、简单的递送溶瘤性 Ad 质粒 DNA 的系统，可以绕过生成和表征溶瘤性 Ad 载体等耗时步骤，可作为癌症治疗的替代方法。
