Ultrasound-based diagnostic and monitoring of bladder cancer treatment with drug released from nanoparticles

基于超声的诊断和监测纳米颗粒释放药物治疗膀胱癌

• 批准号: 9618473
• 负责人: Joe Assouline
• 金额: $ 29.52万
• 依托单位: NANOMEDTRIX, LLC
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-07 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9618473
• 关键词: Advanced Malignant Neoplasm; Adverse effects; Anatomy; Antimitotic Agents; Antineoplastic Agents; Artificial nanoparticles; Binding; Biocompatible Materials; Biomedical Engineering; Bladder; Bladder Neoplasm; Bladder Tissue; Carcinoma; Chemicals; Clinic; Clinical; Clinical Trials; Collaborations; Contrast Media; Cultured Tumor Cells; Custom; Cystoscopy; Data; Development; Diagnostic; Documentation; Drug Delivery Systems; Early Diagnosis; Early treatment; Effectiveness; Ensure; Environment; Epirubicin; Exposure to; Faculty; Fluorescent Dyes; Functional Imaging; Gases; Goals; Image; Imaging Techniques; In Vitro; Injections; Intervention; Intravesical Administration; Iowa; Laboratories; Lead; Lesion; MRI Scans; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of urinary bladder; Measurement; Methodology; Methods; Mind; Modality; Modeling; Molecular Weight; Monitor; Monoclonal Antibodies; Mus; Nanotechnology; Nucleosome Core Particle; Outcome; Patient-Focused Outcomes; Patients; Peptides; Pharmaceutical Preparations; Phase; Research; Research Personnel; Resolution; Schedule; Series; Silicon Dioxide; Small Business Innovation Research Grant; Smooth Muscle; Specificity; Speed; Techniques; Technology; Testing; Therapeutic; Therapeutic Agents; Therapeutic Intervention; Time; Transitional Cell Carcinoma; Translating; Transurethral Resection; Treatment Protocols; Tumor Markers; Ultrasonography; United States; Universities; Urology; accurate diagnosis; advanced system; antitumor agent; antitumor drug; base; bladder transitional cell carcinoma; cancer cell; cancer therapy; chemotherapy; clinical application; commercialization; common treatment; contrast enhanced; cost; cost effective; drug synthesis; experimental study; image processing; imaging modality; imaging system; improved; improved outcome; in vivo; in vivo evaluation; intravesical; minimally invasive; molecular imaging; mouse model; nano; nanomaterials; nanoparticle; neoplastic cell; non-invasive monitor; novel; novel strategies; particle; phase 2 study; preclinical study; prognostic; prototype; radiologist; scale up; screening; soft tissue; sound; submicron; success; targeted delivery; tool; tumor; tumor growth

Project Summary/Abstract Transitional cell carcinoma (TCC) of the bladder is the fifth most common form of cancer in the United States, with over 79,000 new cases expected for 2017. For early stage carcinomas, the most common treatment regimen is to initially perform transurethral resection of bladder tumor (TURBT) using an invasive cystoscopic approach with non-specific fluorescent dyes to highlight the lesions. Even then, small lesions are often missed leading to the cancer recurring in up to 70% of patients and further progresses to advanced cancer in up to 20% of patients following TURBT. Compared to cystoscopy, high resolution ultrasound (HRUS) is low-cost, minimally invasive, and provides an in-depth view of the smooth muscle layer and surrounding tissues of the bladder with spatial resolution as low as 30 m. Despite advances in HRUS, current imaging systems are limited to anatomical data, as it can neither provide functional or molecular imaging data, nor facilitate any interventional approach, alone. The implementation of a targeted contrast enhancement is necessary to elevate the data acquired from even the most advanced system. Clinically approved ultrasound contrast agents operate on the principle that the speed of sound is drastically different high molecular weight gases than in soft tissue. While highly echogenic, these agents are too large and too short-lived to be useful for functional imaging. To improve upon this approach, sub-micron ultrasound agents are being used experimentally, though the resulting agents are limited and have not been applied to TCC. Clinical applications resulting from this approach will benefit by 1) improvement of current screening methods (expedited, cheaper and dynamic), and 2) facilitation of specific delivery of intravesical treatment, specifically with non-invasive monitoring. We propose a material based on mesoporous silica nanoparticles (MSN), functionalized for diagnostic HRUS as well as interventional imaging following delivery of a therapeutic agent. We propose a rigorous in vitro / in vivo testing methodology to characterize the MSN and optimize its diagnostic and therapeutic capabilities. Upon completion the MSN would fulfill a desperately needed alternative to the current invasive and TCC treatment. If successful, the end product represents a highly marketable cost effective material that can be deployed clinically, ultimately improving patient outcomes. Our team of biomedical engineers, radiologists, urology researchers and clinicians are uniquely poised to carry out this research. The use of biocompatible materials and a short peptide for targeting, as opposed to many pre-clinical studies which involve monoclonal antibodies, ensures that the proposed material is of immediate clinical and commercial relevance. This proposal paves the way for SBIR Phase II studies, in which long-term survival and the scale-up of synthesis for commercial purposes will be evaluated.

项目总结/摘要 膀胱移行细胞癌（TCC）是美国第五大常见癌症， 预计2017年新增病例将超过79，000例。对于早期癌症，最常见的治疗 方案是首先使用侵入性膀胱镜进行经尿道膀胱肿瘤切除术（TURBT） 使用非特异性荧光染料来突出病变。即使这样，小的病变往往被错过 导致癌症在高达70%的患者中复发，并在高达20%的患者中进一步发展为晚期癌症 TURBT后的患者。与膀胱镜检查相比，高分辨率超声（HRUS）成本低， 侵入性的，并提供了一个深入了解平滑肌层和周围组织的膀胱， 空间分辨率低至30 μ m。尽管HRUS有进步，但目前的成像系统仅限于 解剖数据，因为它既不能提供功能或分子成像数据，也不能促进任何介入治疗。 方法，独自一人。有针对性的对比度增强的实施是必要的，以提高数据 即使是从最先进的系统中获得的。 临床上批准的超声造影剂的工作原理是， 与软组织中不同的高分子量气体。虽然高回声，这些代理太大， 寿命太短，无法用于功能成像。为了改进这种方法，亚微米超声剂 目前正在实验中使用，尽管所得到的药剂是有限的，并且还没有应用于TCC。 这种方法的临床应用将受益于1）改进当前的筛选方法 （快速、便宜和动态），和2）促进膀胱内治疗的特定递送，特别是 非侵入性监测。我们提出了一种基于介孔二氧化硅纳米颗粒（MSN）的材料， 在递送治疗剂之后，其被功能化用于诊断HRUS以及介入成像。 我们提出了一个严格的体外/体内测试方法来表征MSN和优化其诊断 和治疗能力。完成后，MSN将实现一个迫切需要的替代方案， 目前的侵入性和TCC治疗。如果成功，最终产品代表了一个高度适销对路的成本效益 可以在临床上使用的材料，最终改善患者的治疗效果。 我们的团队生物医学工程师，放射科医生，泌尿科研究人员和临床医生是独一无二的准备进行 出这项研究。使用生物相容性材料和短肽进行靶向，而不是许多 涉及单克隆抗体的临床前研究，确保拟定材料具有直接 临床和商业相关性。该提案为SBIR第二阶段研究铺平了道路，在该阶段， 将评价存活率和用于商业目的的合成规模扩大。