Theranostic Nanoparticles For Detection and Treatment of Pancreatic Cancer

用于检测和治疗胰腺癌的治疗诊断纳米颗粒

• 批准号: 10140485
• 负责人: Lacey R McNally
• 金额: $ 35.37万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-16 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10140485
• 关键词: Theranostic; Nanoparticles; Detection; Treatment; Pancreatic

 DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDA) is virtually a lethal disease for which no gold-standard detection method exists and virtually no significant treatment improvements have occurred within the last 30 years. Because PDA is associated with metastases at presentation, hypovascularity, desmoplasia, acidosis, overcoming the physical and microenvironmental barriers to deliver efficacious drugs to pancreatic tumor cells remains elusive. In this endeavor, we have developed an ultra-acidic pH-responsive theranostic (UPRT) nanoparticle, whose distribution within mice bearing orthotopic pancreatic tumors can also be quantitatively imaged by Optoacoustic Tomography, enabling whole body, real-time mapping of biodistribution and accumulation. Three innovative aspects in this proposal are: 1) development and characterization of UPRT polymeric drug carriers with a tunable and sharp pH response pH < 0.3 containing both a contrast agent and drug; 2) use of newly-emerging imaging technology, Multispectral Optoacoustic Tomography, for sensitive and specific detection of UPRT nanoparticles with quantitative assessment and innovative image analysis; 3) identification of pharmacokinetic/pharmacodynamics properties of the nanoparticle along with validation of Multispectral Optoacoustic Tomography imaging assays of UPRT nanoparticle delivery using standard methods, i.e. histology and LC-MS. Our overarching hypothesis is that UPRT-nanoparticles will target the acidic pH resulting from excessive lactic acid production associated with hypovascularity in pancreas tumors to deliver drugs to tumor cells and serve as a diagnostic contrast agent in vivo. Because Multispectral Optoacoustic Tomography (MSOT) has high sensitivity, high spatial resolution, increased depth of penetration, potential for whole-body imaging, and potential for longitudinal imaging, MSOT will be utilized to determine biodistribution and pharmacokinetic/pharmacodynamic properties of the proposed polymer-based, theranostic nanoparticles. To test this hypothesis, we will evaluate the following aims: 1) Characterize the biophysical properties, drug/contrast agent loading and release, and in vitro efficacy of UPRT nanoparticle; 2) Optimize design and kinetics of UPRT nanoparticle that delivers NIR dye/drugs to hypovascular tumor areas; 3) Determine spatiotemporal distribution, therapeutic efficacy, and toxicity profiles of UPRT nanoparticle using Multispectral Optoacoustic Tomography in orthotopic models of pancreatic adenocarcinoma which spontaneously metastasize. Detection and treatment of pancreatic cancer with this delivery system will likely constitute an effective approach to improve detection and drug delivery for these currently untreatable patients.

 描述（由申请方提供）：胰腺导管腺癌（PDA）实际上是一种致死性疾病，不存在金标准检测方法，并且在过去30年中几乎没有显著的治疗改进。由于PDA与表现时的转移、血管生成不足、结缔组织增生、酸中毒相关，克服物理和微环境障碍以将有效药物递送至胰腺肿瘤细胞仍然是难以捉摸的。在这项奋进中，我们开发了一种超酸性pH响应性治疗诊断（UPRT）纳米颗粒，其在原位胰腺肿瘤小鼠体内的分布也可以通过光声断层扫描进行定量成像，从而实现全身实时绘制生物分布和积累。该提案中的三个创新方面是：1）开发和表征具有可调和尖锐pH响应pH < 0.3的UPRT聚合物药物载体，其包含造影剂和药物; 2）使用新兴的成像技术，多光谱光声断层扫描，通过定量评估和创新的图像分析来灵敏和特异地检测UPRT纳米颗粒; 3）鉴定纳米颗粒的药代动力学/药效学性质，沿着使用标准方法验证UPRT纳米颗粒递送的多光谱光声断层成像分析，即组织学和LC-MS。我们的总体假设是UPRT-纳米颗粒将靶向由胰腺肿瘤中与血管减少相关的过量乳酸产生引起的酸性pH，以将药物递送至肿瘤细胞，并用作胰腺肿瘤中的诊断造影剂。vivo.由于多光谱光声断层扫描（MSOT）具有高灵敏度、高空间分辨率、增加的穿透深度、全身成像的潜力和纵向成像的潜力，因此MSOT将用于确定所提出的基于聚合物的治疗诊断纳米颗粒的生物分布和药代动力学/药效学特性。为了验证这一假设，我们将评估以下目标：1）表征UPRT纳米颗粒的生物物理性质、药物/造影剂负载和释放以及体外功效; 2）优化将NIR染料/药物递送到低血管肿瘤区域的UPRT纳米颗粒的设计和动力学; 3）确定时空分布、治疗功效，在自发转移的胰腺癌的原位模型中使用多光谱光声断层扫描的UPRT纳米颗粒的毒性概况。用这种递送系统检测和治疗胰腺癌将可能构成改善这些目前无法治疗的患者的检测和药物递送的有效方法。

项目成果

Temozolomide Enhances Triple-Negative Breast Cancer Virotherapy In Vitro.

• DOI: 10.3390/cancers10050144
• 发表时间: 2018-05-17
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Garza-Morales R;Gonzalez-Ramos R;Chiba A;Montes de Oca-Luna R;McNally LR;McMasters KM;Gomez-Gutierrez JG
• 通讯作者: Gomez-Gutierrez JG

Detection of microspheres in vivo using multispectral optoacoustic tomography.

• DOI: 10.1080/10520295.2016.1251611
• 发表时间: 2017
• 期刊: Biotechnic & histochemistry : official publication of the Biological Stain Commission
• 作者: Bhutiani N;Kimbrough CW;Burton NC;Morscher S;Egger M;McMasters K;Woloszynska-Read A;El-Baz A;McNally LR
• 通讯作者: McNally LR

Molecular Imaging of Inflammatory Disease.

• DOI: 10.3390/biomedicines9020152
• 发表时间: 2021-02-04
• 期刊: Biomedicines
• 影响因子: 4.7
• 作者: Jones MA;MacCuaig WM;Frickenstein AN;Camalan S;Gurcan MN;Holter-Chakrabarty J;Morris KT;McNally MW;Booth KK;Carter S;Grizzle WE;McNally LR
• 通讯作者: McNally LR