Combination Therapy of OvCA with Oligonucleotides and Photodynamic Therapy

OvCA 与寡核苷酸和光动力疗法的联合治疗

• 批准号: 9187917
• 负责人: Xin Ming
• 金额: $ 28.37万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9187917
• 关键词: 3-Dimensional; ABCB1 gene; Address; Affect; Albumins; Animal Model; Apoptosis; Apoptotic; BCL2 gene; Cancer Model; Cancer Patient; Carrier Proteins; Cause of Death; Cell Culture Techniques; Cessation of life; Clinical; Combination Drug Therapy; Combined Modality Therapy; Complement; Custom; Diagnosis; Disseminated Malignant Neoplasm; Drug resistance; Endosomes; Family member; Genes; Goals; Grant; Hypoxia; Lasers; Ligands; Light; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Medicine; Membrane; Methods; MicroRNAs; Micrometastasis; Modality; Modeling; Neoplasm Metastasis; Nuclear; Oligonucleotides; Oncogenes; PUVA Photochemotherapy; Paclitaxel; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Photosensitization; Physicians; Procedures; RNA Splicing; Recurrence; Refractory; Residual state; Resistance; Singlet Oxygen; Site; Small Interfering RNA; System; Testing; Therapeutic; Toxic effect; Treatment Failure; Woman; Xenograft Model; Xenograft procedure; base; cancer cell; cancer therapy; cell killing; chemotherapy; cytotoxicity; design; efficacy study; fluorescence imaging; in vivo; irradiation; killings; nanoparticle; overexpression; permissiveness; public health relevance; receptor; resistance mechanism; response; synergism; targeted delivery; therapy resistant; tumor; tumor microenvironment

 DESCRIPTION (provided by applicant): Drug resistance causes treatment failure and death in more than 90% of patients with metastatic cancer. Ovarian cancer (OvCa) is a leading cause of death from cancer in women with a projected 14,270 deaths in US in 2014, and is generally diagnosed in advanced stages when the tumor has metastasized and numerous micrometastases with intrinsic or acquired resistance have formed. We aim to synchronize delivery of therapeutic oligonucleotides (ONs) and photodynamic therapy (PDT) agents to OvCa using nanoparticles (NPs), and thus to provide a combination therapy to overcome drug resistance in OvCa. ONs and PDT can provide mechanistically distinct therapies for resistant OvCa but both have limitations when used as monotherapy. ONs are capable of targeting any specific gene that causes drug resistance; however, their therapeutic activity had been constrained by the poor access to their intracellular sites of action because of non-productive endosomal trapping. PDT is a clinically approved anticancer procedure; however, it suffers from sub-lethal cancer cell killing due to its own resistance mechanisms and a short duration of action. We hypothesize that NP-based co-delivery enables complementation of these two modalities, leading to synergism at two levels. Firstly, when delivered together to endosomes in OvCa cells, laser-activated PDT triggers endosomal escape of ONs to their intracellular action sites. Thereafter, the functional delivery of the ONs can target specific genes and overcome drug resistance in multiple modes. Thus, when apoptosis-promoting Bcl-x splice-switching oligonucleotide (SSO) is used, it can guide PDT to an apoptotic pathway. When MDR1 siRNA is used, it can resensitize OvCa to paclitaxel, the first line chemotherapy drug to OvCa. We have prepared ultra-small OvCa-targeted NPs carrying ONs and the PDT drug Ce6. Preliminary studies indicated that laser activation of Ce6 enables functional delivery of the ONs and causes cytotoxicity to OvCa cells. In this proposal, 4 specific aims are designed to test our hypothesis and realize the goal: 1. Elucidate cellular mechanisms for synergism of ONs and PDT and then optimize the NPs for greater synergistic action. 2. Evaluate therapeutic activity of the NPs in 3-D OvCa models that recapitulate some key features of in vivo microenvironment. 3. Test photochemical delivery of Bcl-x SSO in vivo. 4. Test photochemical delivery of MDR1 siRNA. Studies proposed in this grant will thus provide distinct approaches to address the two underlying causes of drug resistance in OvCa: increased intrinsic survival ability and reduced intracellular drug concentration of OvCa cells.

 描述（由适用提供）：耐药性导致90％以上转移性癌症患者的治疗失败和死亡。卵巢癌（OVCA）是2014年美国预计14,270人死亡的癌症死亡的主要原因，当肿瘤发生转移且大量具有内在耐药性或获得性耐药性的微晶酶时，通常在高级阶段被诊断出。我们的目标是使用纳米颗粒（NPS）同步治疗性寡核苷酸（ONS）和光动力疗法（PDT）剂（PDT）剂，从而提供联合治疗以克服OVCA中的耐药性。 ONS和PDT可以为抗性OVCA提供机械不同的疗法，但用作单一疗法时都有局限性。 ONS能够靶向引起耐药性的任何特定基因。但是，由于非生产性内体捕获，由于不良进入其细胞内作用部位的机会限制了它们的治疗活性。 PDT是临床认可的抗癌手术；然而，由于其自​​身的抗药性机制和短时间的作用，它遭受了亚致死性癌细胞的杀伤。我们假设基于NP的共交付能够完成这两种模式，从而导致两个级别的协同作用。首先，当一起递送到OVCA细胞中的内体时，激光激活的PDT触发了ONS的内体逃逸到其细胞内作用位点。此后，ONS的功能递送可以靶向特定基因，并以多种模式克服耐药性。当使用促进凋亡的Bcl-X剪接开关寡核苷酸（SSO）时，它可以引导PDT到凋亡途径。当使用MDR1 siRNA时，它会使OVCA对紫杉醇的OVCA（ovca的第一线化学疗法药物）恢复活力。我们已经准备了携带ONS和PDT药物CE6的超小型OVCA靶向NP。初步研究表明，CE6的激光激活使ONS的功能递送并导致细胞毒性向OVCA细胞。在该提案中，设计了4个特定目标旨在检验我们的假设并实现目标：1。阐明了ONS和PDT协同作用的细胞机制，然后优化NP，以实现更大的协同作用。 2。评估NPS在3-D中的治疗活性 概括体内微环境的一些关键特征的OVCA模型。 3。在体内测试BCL-X SSO的光化学递送。 4。测试MDR1 siRNA的光化学输送。因此，该赠款中提出的研究将提供不同的方法来解决OVCA中耐药性的两个潜在原因：内在的生存能力提高和OVCA细胞的细胞内药物浓度降低。