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: 9323752
• 负责人: Xin Ming
• 金额: $ 19.4万
• 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/9323752
• 关键词: 3-Dimensional; ABCB1 gene; Address; Affect; Albumins; Animal Model; Animals; Apoptosis; Apoptotic; BCL2 gene; Cancer Model; Cancer Patient; Carrier Proteins; Cause of Death; Cell Culture Techniques; Cells; Cessation of life; Combined Modality Therapy; Diagnosis; Disseminated Malignant Neoplasm; Drug resistance; Endosomes; Extracellular Matrix; Family member; Flow Cytometry; Fluorescence; Gene Family; Genes; Goals; Grant; Health; Heterogeneity; Hypoxia; Integrins; Lasers; Lead; Ligands; Link; Malignant Neoplasms; Malignant neoplasm of ovary; Measures; Mediating; Medicine; Membrane; MicroRNAs; Micrometastasis; Modality; Modeling; Neoplasm Metastasis; Nuclear; Oligonucleotides; Oncogenes; PUVA Photochemotherapy; Paclitaxel; Pathway interactions; Patients; Penetration; Pharmaceutical Preparations; Physicians; Procedures; Process; RNA Splicing; Recurrence; Refractory; Reporter Genes; Residual state; Resistance; Resistance development; Singlet Oxygen; Site; Small Interfering RNA; Staging; System; Testing; Therapeutic; Treatment Failure; Tumor Tissue; Woman; Xenograft Model; Xenograft procedure; anticancer activity; base; cancer cell; cancer therapy; cell killing; chemotherapy; cytotoxicity; design; in vivo; killings; nanoparticle; overexpression; receptor; response; synergism; systemic toxicity; targeted delivery; therapy resistant; tool; treatment response; 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 it 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 therapy 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 a prosurvival autophagic mechanism 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 effects trigger 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 a pro-death 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 integrin-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. Evaluate anticancer activity of the NPs carrying Bcl-x SSO and Ce6 in vivo. 4. Test therapeutic activity of the NPs carrying MDR1 siRNA and Ce6. 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（由申请人提供）：耐药性导致 90% 以上的转移性癌症患者治疗失败和死亡。卵巢癌 (OvCa) 是女性癌症死亡的主要原因，预计 2014 年美国将有 14,270 人死亡。当肿瘤已经转移并且已经形成许多具有内在或获得性耐药性的微转移时，它通常被诊断出来。我们的目标是同步递送治疗性寡核苷酸。使用纳米粒子（NP）对 OvCa 进行光动力治疗（ONs）和光动力治疗（PDT）药物，从而提供克服 OvCa 耐药性的联合疗法，ONs 和 PDT 可以为耐药 OvCa 提供机械上不同的治疗，但两者在用作时都有局限性。单一疗法能够针对引起耐药性的任何特定基因；然而，由于非生产性内体捕获，其治疗活性因其难以进入其细胞内作用位点而受到限制。 PDT 是一种临床批准的抗癌方法；然而，由于促存活的自噬机制和作用持续时间短，它会导致亚致死性的癌细胞杀死，我们发现基于 NP 的共递送能够实现这两种方式的互补，从而导致首先，当一起递送至 OvCa 细胞中的内体时，激光激活的 PDT 效应会触发 ON 的内体逃逸至其细胞内作用位点，随后，ON 的功能性递送。 ONs可以靶向特定基因并以多种方式克服耐药性，因此，当使用促进细胞凋亡的Bcl-x剪接转换寡核苷酸（SSO）时，它可以引导PDT进入促死亡细胞凋亡途径。 ，它可以使 OvCa 对紫杉醇（OvCa 的一线化疗药物）重新敏感。我们制备了携带 ON 的超小整合素靶向纳米粒子和PDT 药物 Ce6。 初步研究表明，激光激活 Ce6 能够实现 ON 的功能性传递并对 OvCa 细胞产生细胞毒性。 在该提案中，设计了 4 个具体目标来检验我们的假设并实现目标： 1. 阐明协同作用的细胞机制。 ON 和 PDT，然后优化 NP 以获得更大的协同作用 2. 在 3-D OvCa 模型中评估 NP 的治疗活性，该模型概括了一些关键。 3. 评估携带 Bcl-x SSO 和 Ce6 的 NP 的体内抗癌活性 4. 测试携带 MDR1 siRNA 和 Ce6 的 NP 的治疗活性 因此，本次资助中提出的研究将提供不同的方法来解决这一问题。 OvCa耐药的两个根本原因是：OvCa细胞内在生存能力增加和细胞内药物浓度降低。