Department of Bioengineering, College of Engineering, Hanyang University, 222 Wangsimni-ro, Seongdong-gu, Seoul, 04763, Republic of Korea.
Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, Salt Lake City, UT, 84112, USA.
Biomaterials. 2017 Nov;145:207-222. doi: 10.1016/j.biomaterials.2017.08.035. Epub 2017 Aug 23.
Combination treatment consisting of oncolytic adenovirus (Ad) and paclitaxel (PTX) is a promising strategy to achieve synergistic antitumor effect. However, a co-administration approach is subject to inherent limitations due to the poor solubility of PTX and chemoresistance of tumor cells. In order to overcome these limitations, an oncolytic Ad expressing a p53 variant (oAd-vp53) that is resistant to p53 inactivation in the tumor microenvironment was complexed with PEGylated and PTX-conjugated polymeric micelle (APP). This approach generated an oAd-vp53/APP complex (176.4 nm in diameter) that could concurrently deliver both oncolytic Ad and the nanoparticulate drug APP to tumors. APP-complexed replication-incompetent Ad (dAd/APP) exhibited 12-fold higher transduction efficiency than naked dAd in coxsackie adenovirus receptor (CAR)-negative cancer cells. This increased efficiency was attributed to more efficient cellular internalization mediated by charge interactions between APP and anionic cell membranes. Furthermore, oAd-vp53/APP elicited synergistically higher cancer cell killing than naked oAd-vp53, APP, or oAd-vp53 in combination with PTX (oAd-vp53 + PTX); this synergistic effect was shown to be due to superior induction of apoptosis and viral replication. Importantly, oAd-vp53/APP induced more potent and synergistic antitumor effect through both local and systemic administration by enhancing replication of oncolytic Ad and induction of apoptosis in tumor tissue. Further, the APP coating on the surface of Ad markedly attenuated the host immune response against Ad and decreased hepatic sequestration, resulting in minimal hepatotoxicity and a good safety profile. These attributes enabled oAd-vp53/APP to elicit potent antitumor effect over multiple treatment cycles. Altogether, we demonstrate that concurrent delivery of oncolytic Ad and APP as a single nanocomplex is a promising strategy for achieving synergistic antitumor effect.
联合治疗由溶瘤腺病毒（Ad）和紫杉醇（PTX）组成，是实现协同抗肿瘤效果的有前途的策略。然而，由于 PTX 的溶解度差和肿瘤细胞的化疗耐药性，联合给药方法受到固有限制。为了克服这些限制，表达对肿瘤微环境中 p53 失活具有抗性的 p53 变体（oAd-vp53）的溶瘤 Ad 与聚乙二醇化和 PTX 缀合的聚合物胶束（APP）复合。这种方法生成了能够同时将溶瘤 Ad 和纳米颗粒药物 APP 递送到肿瘤的 oAd-vp53/APP 复合物（直径 176.4nm）。APP 复合的复制缺陷型 Ad（dAd/APP）在 Coxsackie 腺病毒受体（CAR）阴性癌细胞中的转导效率比裸 dAd 高 12 倍。这种效率的提高归因于 APP 与阴离子细胞膜之间的电荷相互作用介导的更有效的细胞内化。此外，oAd-vp53/APP 比裸 oAd-vp53、APP 或 oAd-vp53 与 PTX 联合（oAd-vp53+PTX）引起更高的协同癌细胞杀伤作用；这种协同作用被证明是由于凋亡和病毒复制的诱导更高。重要的是，oAd-vp53/APP 通过增强溶瘤 Ad 的复制和诱导肿瘤组织中的凋亡，通过局部和全身给药引起更有效和协同的抗肿瘤作用。此外，Ad 表面的 APP 涂层显着减弱了宿主对 Ad 的免疫反应，并减少了肝内蓄积，导致最小的肝毒性和良好的安全性。这些特性使 oAd-vp53/APP 能够在多个治疗周期中产生强大的抗肿瘤作用。总之，我们证明了作为单一纳米复合物同时递送电溶瘤 Ad 和 APP 是实现协同抗肿瘤效果的有前途的策略。
