Optimization of SWCNT/siRNA complex formulation for tumor accumulation

用于肿瘤积累的 SWCNT/siRNA 复合物配方的优化

• 批准号: 8393935
• 负责人: Lynn Kirkpatrick
• 金额: $ 29.81万
• 依托单位: ENSYSCE BIOSCIENCES, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-25 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8393935
• 关键词: Adverse effects; Affect; Animal Model; Area; Biodistribution; Biological; Biotechnology; Blood Circulation; Caliber; Cancer Control; Cancer Etiology; Cancer Patient; Carbon; Carbon Nanotubes; Cell Line; Cells; Clinical; Clinical Trials; Complex; Cytoplasm; DNA; Data; Dependence; Development; Diagnosis; Disease; Double-Stranded RNA; Drug Formulations; Drug or chemical Tissue Distribution; Ensure; Genes; Growth; Half-Life; Human; In Vitro; Individual; KRAS2 gene; Lead; Legal patent; Length; Licensing; Malignant Neoplasms; Medical; Membrane; Messenger RNA; MicroRNAs; Modality; Mus; Nanotechnology; Normal tissue morphology; One-Step dentin bonding system; Outcome; Patients; Penetration; Plasma; Preparation; Process; Production; Property; Proteins; RNA; RNA Interference; Research; Rice; Rights; Role; Sampling; Small Interfering RNA; Solutions; Surface; System; Technology; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Transfection; Tube; Tumor Tissue; Universities; Work; base; cancer cell; cancer therapy; cancer type; drug development; drug discovery; effective therapy; experience; improved; in vivo; interest; intravenous administration; killings; mutant; neoplastic cell; new technology; novel; pre-clinical; programs; single walled carbon nanotube; small molecule; tumor; tumor xenograft; uptake

DESCRIPTION (provided by applicant): Ensysce Biosciences Inc. is a biotechnology company located in Houston, TX, exploiting the pionering nanotechnology studies of the late 1996 Nobel Laureate, Dr. Richard Smalley of Rice University. The rights to Dr. Smalley's work on carbon nanotube technology in the area of therapeutics, as well as other critical carbon nanotube patents, have been in-licensed or applied for by Ensysce and the company has initiated a number of research programs to utilize carbon nanotubes to treat cancer including that described herein to deliver short interfering RNAs (siRNA). Ensysce's interest in the single-walled carbon nanotubes (SWCNT) delivery system spans a number of therapeutic modalities including the delivery of RNAis. siRNA, are a type of small segments of double- stranded RNA that are being explored to control cancer growth in a highly specific fashion. However, efficient means are needed to deliver the RNAi into tumor cells. Ensysce's data show that the solubilized SWCNT/siRNA complexes delivered to mice intravenously cause little to no toxicity, accumulate in tumor and produce tumor target-protein knockdown and antitumor activity. Ensysce is now exploring means to optimize the tumor accumulation and produce robust antitumor activity. Ensysce data has also shown that circulating the half-life of SWCNT/siRNA complex affect its biodistribution, although complexes with even short t1/2 were found to produce god antitumor activity in human tumor xengrafts in animal models. This proposal will undertake a comprehensive examination of a number of formulations of SWCNT/siRNA to determine their tumor and tissue distribution following intravenous administration. The preparation with the most promising tumor versus tissue distribution will be further examined for antitumor eficacy using siRNA for KRAS. Mutant KRAS (mut-KRAS) is the prototypical undruggable cancer target. It is found in 25% of patient tumors across many cancer types and an estimated 320,000 individuals who will be diagnosed with mut-KRAS in the US in 2012 most of who will die of their disease. There is no treatment for KRAS and finding effective therapies for KRAS is arguably the single most important unmet medical need in cancer today. Therefore reducing its presence with siRNA delivered by SWCNT provides approach to this deadly problem. Hence, this project will extensively evaluate the biodistribution properties of a number of SWCNT complexes delivered systemically and will provide data on the efficacy of SWCNT/siRNA complexes in tumors. Ultimately, this work will pave the way for the use of a powerful new siRNA delivery system with the potential for inhibiting many different cancer causing targets in a clinical setting for the treatment of cancer. PUBLIC HEALTH RELEVANCE: Novel selective cancer therapies are still needed to improve outcome for patients without unnecessary toxic side effects. Short interfering RNA (siRNA) is one such potential modality as it can block the activity of genes that are essential for the cancer growth but not for normal tissue. However, the major barrier to the development of clinical siRNA therapies is the lack of an effective delivery mechanism to administer it to a patient and carry it into the tumor cell. Ensysce's research has shown that single-walled carbon nanotubes (SWCNT) can complex with siRNA and act as a delivery vehicle to carry siRNA into cancer cells hence providing a selective therapeutic outcome. To ensure delivery of the siRNA to tumors it has been found that the circulation time (half-life) of the complexes is important. This proposal will undertake a comprehensive examination of a number of SWCNT preparations with a range of circulation half-lives to determine the tumor and tissue distribution following intravenous administration. The preparation with the most promising tumor versus tissue distribution will be further examined for antitumor activity in combination with another cancer therapy. These critical studies will move this novel technology one step closer to full pre-clinical development and eventually to a clinical trial study.

描述（由申请人提供）：Ensysce Biosciences Inc.是一家位于德克萨斯州休斯顿的生物技术公司，利用1996年底诺贝尔奖获得者，莱斯大学的理查德斯莫利博士的开创性纳米技术研究。Smalley博士在治疗领域的碳纳米管技术工作的权利，以及其他关键的碳纳米管专利，已经被Ensysce授权或申请，该公司已经启动了一些研究计划，利用碳纳米管治疗癌症，包括本文所述的递送短干扰RNA（siRNA）。Ensysce对单壁碳纳米管（SWCNT）输送系统的兴趣涵盖了许多治疗方式，包括RNAi的输送。siRNA是一种双链RNA的小片段，正在探索以高度特异性的方式控制癌症生长。然而，需要有效的手段将RNAi递送到肿瘤细胞中。Ensysce的数据显示，静脉内递送给小鼠的溶解的SWCNT/siRNA复合物几乎没有毒性，在肿瘤中积累并产生肿瘤靶蛋白敲低和抗肿瘤活性。Ensysce现在正在探索优化肿瘤积累并产生强大抗肿瘤活性的方法。Ensysce数据还表明，循环SWCNT/siRNA复合物的半衰期影响其生物分布，尽管在动物模型中发现具有甚至短t1/2的复合物在人类肿瘤异种移植物中产生良好的抗肿瘤活性。该提案将对许多SWCNT/siRNA制剂进行全面检查，以确定静脉内给药后它们的肿瘤和组织分布。将使用针对KRAS的siRNA进一步检查具有最有希望的肿瘤与组织分布的制剂的抗肿瘤效力。突变型KRAS（mut-KRAS）是原型的不可治疗的癌症靶标。在许多癌症类型的25%的患者肿瘤中发现，2012年美国估计有320，000人将被诊断患有mut-KRAS，其中大多数人将死于他们的疾病。KRAS没有治疗方法，寻找KRAS的有效疗法可以说是当今癌症中最重要的未满足的医疗需求。因此，通过SWCNT递送的siRNA减少其存在提供了解决这一致命问题的方法。因此，该项目将广泛评估全身递送的许多SWCNT复合物的生物分布特性，并将提供关于SWCNT/siRNA复合物在肿瘤中的功效的数据。最终，这项工作将为使用一种强大的新siRNA递送系统铺平道路，该系统具有在临床环境中抑制许多不同的致癌靶点以治疗癌症的潜力。 公共卫生相关性：仍然需要新的选择性癌症疗法来改善患者的预后，而不会产生不必要的毒副作用。短干扰RNA（siRNA）是一种潜在的方式，因为它可以阻断癌症所必需的基因的活性 生长，而不是正常组织。然而，临床siRNA疗法开发的主要障碍是缺乏有效的递送机制来将其施用给患者并将其携带到肿瘤细胞中。Ensysce的研究表明，单壁碳纳米管（SWCNT）可以与siRNA复合，并作为运载工具将siRNA携带到癌细胞中，从而提供选择性的治疗结果。为了确保siRNA递送至肿瘤，已经发现复合物的循环时间（半衰期）是重要的。该提案将对具有一系列循环半衰期的许多单壁碳纳米管制剂进行全面检查，以确定静脉给药后的肿瘤和组织分布。将进一步检查具有最有希望的肿瘤与组织分布的制剂与另一种癌症治疗组合的抗肿瘤活性。这些关键研究将使这项新技术更接近完全的临床前开发，并最终进入临床试验研究。