Design of Oncolytic Adenovirus Conjugated with Novel Polymer for Cancer Treatment

描述（由申请人提供）：该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），该病毒可以系统地用于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Ad的免疫反应、血液循环时间短和肿瘤靶向性差等障碍。众所周知，溶瘤性Ad可以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。随着含治疗性转基因盒的溶瘤性Ad基因组在癌细胞中进行复制，治疗性基因的扩增和Ad复制介导的溶瘤作用可以最大限度地提高肿瘤杀伤效果。表达c-Met特异性shrna的溶瘤性Ad （RdB/shMet）将通过病毒溶瘤和sirna介导的c-Met长时间沉默来产生和表征其附加治疗效果。生物可还原聚合物，精氨酸半胱胺双丙烯酰胺己基（ABP）将聚乙二醇化并与肿瘤靶向肽（ABP- peg - peptide）偶联。然后将RdB/shMet溶瘤性Ad表面与ABP-PEG-Peptide偶联，通过使溶瘤性Ad逃避免疫细胞和抗体的捕获来改善全身递送。在对abp - peg肽结合的溶瘤性Ad进行物理表征后，将评估肿瘤归巢肽依赖的细胞进入和肿瘤特异性杀伤效果。smart的治疗效果和安全性

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.