Design of Oncolytic Adenovirus Conjugated with Novel Polymer for Cancer Treatment

描述（由申请人提供）：本项目的总体目标是用设计的聚合物构建智能溶瘤腺病毒（Ad），其可以全身给药以治疗原发性和转移性癌症。我们已经证明，这种有效的Ad全身递送克服了与Ad的免疫反应、短的血液循环时间和差的肿瘤靶向相关的障碍。众所周知，溶瘤Ad选择性地在肿瘤细胞中复制并杀死肿瘤细胞，同时保留正常细胞。当包括治疗性转基因盒的溶瘤Ad基因组在癌细胞中复制时，可以通过扩增治疗性基因以及Ad复制介导的溶瘤来最大化癌症杀伤效果的水平。将产生表达c-Met特异性shRNA的溶瘤Ad（RdB/shMet），并通过病毒溶瘤和c-Met的持久siRNA介导的沉默来表征附加治疗功效。生物可还原聚合物精氨酸化胱胺双丙烯酰胺己基（ABP）将被聚乙二醇化并与肿瘤靶向肽（ABP-PEG-肽）缀合。然后将RdB/shMet溶瘤Ad的表面与ABP-PEG-肽缀合，以通过使溶瘤Ad能够逃避免疫细胞和抗体的捕获来改善全身递送。在ABP-PEG-肽缀合的溶瘤Ad的物理表征之后，将评价肿瘤归巢肽依赖性细胞进入和肿瘤特异性杀伤功效。smart的疗效和安全性特征 溶瘤Ad纳米复合物将在代表临床相关肿瘤模型的原位肿瘤模型中评估。将评估针对Ad的免疫应答、肝毒性、血液清除率特征和身体分布特征。聚合物屏蔽和肿瘤靶向溶瘤Ad纳米复合物可能具有协同治疗作用，这是由于其Ad复制系统和聚合物全身递送的特征。ABP-PEG-肽缀合的溶瘤Ad可以逃避中和抗Ad Ab，并减少肝脏蓄积和与血液组分的相互作用，这导致静脉内注射后延长的血液循环时间。此外，癌症特异性靶向可以通过EPR介导的被动靶向以及肿瘤特异性肽介导的主动靶向来显著改善。更重要的是，溶瘤Ad在肿瘤选择性感染后，可以持续复制并感染邻近的肿瘤细胞，最终提高治疗价值。此外，对肿瘤细胞的有限选择性降低了正常细胞的毒性，使得可以治疗肿瘤细胞。 原发性和转移性病灶。

DESCRIPTION (provided by applicant): The overall goal of this project is to construct smart oncolytic adenovirus (Ad) with designed polymer which can be administered systemically to treat primary and metastatic cancer. We have demonstrated that this efficient systemic delivery of Ad overcome the obstacles associated with immune reaction, short blood circulation time and poor tumor targeting of Ad. Oncolytic Ad has been well-known to selectively replicate in and kill tumor cells, while sparing normal cells. As oncolytic Ad genome including therapeutic transgene cassette replicates in cancer cells, the level of cancer- killing effect can be maximized by amplification of therapeutic gene as well as Ad replication-mediated oncolysis. c-Met-specific shRNA-expressing oncolytic Ad (RdB/shMet) will be generated and characterized for additive therapeutic efficacy through viral oncolysis and long lasting siRNA-mediated silencing of c- Met. Bioreducible polymer, arginated cystamine bisacrylamide hexyl (ABP) will be pegylated and conjugated with tumor-targeting peptides (ABP-PEG-Peptide). Surface of RdB/shMet oncolytic Ad will then be conjugated with ABP-PEG-Peptide to improve systemic delivery by enabling oncolytic Ads to evade capture by immune cells and antibodies. After physical characterization of ABP-PEG-Peptide-conjugated oncolytic Ad, tumor- homing peptide-dependent cell entry and tumor-specific killing efficacy will be evaluated. Therapeutic efficacy and safety profile of smart oncolytic Ad nanocomplex will be assessed in orthotopic tumor models which represent a clinically relevant tumor model. Immune response against Ad, liver toxicity, blood clearance profile, and body distribution profile will be assessed. Polymer-shielded and tumor-targeted oncolytic Ad nanocomplex may have a synergistic therapeutic effect due to features of its replicating system of Ad and systemic delivery of polymers. ABP-PEG-Peptide- conjugated oncolytic Ad may evade neutralizing anti-Ad Abs and decreases both liver accumulation and interaction with blood components, which results in extended blood circulation time after intravenous injection. In addition, cancer-specific targeting can be significantly improved by EPR-mediated passive targeting as well as tumor-specific peptide-mediated active targeting. More importantly, oncolytic Ad can keep continuously replicating and infecting neighboring tumor cells after tumor-selective infection, ultimately enhancing therapeutic value. Further, the restricted selectivity to tumor cells reduces toxicity of normal cells, making it possible to treat primary and metastatic lesions via systemic delivery.