Pancreatic Cancer Therapy with GRP Receptor-Targeted Imageable Diphenyl difluorok

使用靶向 GRP 受体的可成像二苯基二氟化合物治疗胰腺癌

• 批准号: 7942920
• 负责人: VIBHUDUTTA AWASTHI
• 金额: $ 7.33万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-29 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7942920
• 关键词: Acetates; Adverse effects; Animals; Antineoplastic Agents; Autopsy; Binding; Biological Assay; Biological Markers; Bombesin; Bombesin Receptor; Cancer Etiology; Cancer Patient; Cancer cell line; Cancerous; Cell Culture Techniques; Cell Survival; Cessation of life; Chelating Agents; Curcuma longa; Curcumin; Cytotoxic agent; Development; Diagnosis; Disease; Dose; Drug Delivery Systems; Early Diagnosis; Ensure; Equilibrium; Erlotinib; Figs - dietary; GRP gene; Goals; Histology; Human; Image; In Vitro; Inhibitory Concentration 50; Investigation; Kinetics; Laboratories; Life; Ligands; Malignant Neoplasms; Malignant neoplasm of pancreas; Mediating; Methods; Minority; Modification; Monitor; Mus; Nature; Neoplasm Metastasis; Nuclear; Nude Mice; Operative Surgical Procedures; Outcome; Pancreatic Adenocarcinoma; Pancreatic carcinoma; Patients; Peptides; Peripheral; Pharmaceutical Preparations; Pharmacologic Substance; Photons; Plasma; Positron-Emission Tomography; Property; Radioisotopes; Radiolabeled; Radionuclide Imaging; Recruitment Activity; Reducing Agents; Research; Scheme; Series; Technetium 99m; Techniques; Testing; Therapeutic; Tissues; Toxic effect; Tumeric; Tumor Volume; United States Food and Drug Administration; Work; Xenograft procedure; analog; anticancer activity; antiproliferative agents; antiproliferative drugs; base; cancer cell; cancer therapy; chemotherapy; cytotoxic; cytotoxicity; design; diphenyl; drug development; fluorodeoxyglucose; gemcitabine; improved; in vitro testing; in vivo; interest; molecular imaging; mouse model; non-invasive monitor; novel; outcome forecast; palliative; pancreatic neoplasm; public health relevance; radiotracer; receptor; research study; response; single photon emission computed tomography; standard of care; stannous chloride; targeted delivery; tomography; tricine; tumor; tumor growth; whole body imaging

DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth leading cause of cancer-related deaths in the USA. While early diagnosis is still a challenge, the standard of care after diagnosis is palliative in nature, and mostly ineffective in improving the prognosis in pancreatic cancer patients. Anticancer drugs are the cornerstone in managing pancreatic cancer, but they can cause severe adverse-effects in therapeutic doses. A more selective delivery of the cytotoxic agents to the primary and metastatic tumors would allow a dose escalation without a parallel increase in peripheral toxicity. It is therefore important not only to develop new chemotherapeutic molecules, but also ensure preferential drug delivery in cancerous tissue. The strategy should also include an in vivo assay to monitor adequacy and selectivity of drug accumulation in cancer. Our goal is to target a recently developed antiproliferative agent in pancreatic cancer, and enable molecular imaging of the targeted agent's distribution in live animals by nuclear techniques. We are developing a series of curcumin-based antiproliferative drugs including a diphenyl difluoroketone (DPDK) compound. DPDK is a potently cytotoxic in several cancer forms; we found it effective against cultured pancreatic cancer cells. We propose to target DPDK through the gastrin-releasing peptide receptors (GRPrs) which are over-expressed in pancreatic cancer tissue. We will modify the DPDK molecule to carry bombesin7-14 peptide which is a ligand for GRPr. The peptide will also harbor a chelator for Tc-99m radionuclide. The Tc-99m radiolabel will allow noninvasive imaging of bombesin-DPDK's distribution after administration. Our null hypothesis is that the targeted DPDK is not more antiproliferative than the non-targeted DPDK. For the rejection of this null hypothesis, the specific aims are: 1. To synthesize bombesin-DPDK conjugate amenable to radiolabeling with 99mTc radionuclide, and 2. To evaluate anticancer activity of bombesin-DPDK in a mouse model of pancreatic cancer. The experiments to accomplish these specific aims are designed to proceed from lab-based synthetic work to in vitro testing of the synthesized compounds in cell culture conditions, and finally to in vivo investigations in a mouse model of xenograft pancreatic tumor. We anticipate that the targeted delivery will help in localized higher concentration of DPDK in pancreatic cancer, allowing efficacy comparable to that achieved by larger doses of non-targeted drug. The strategy to develop a bifunctional molecule that can be monitored by non-invasive imaging is novel application of bombesin-GRPr interaction. The imaging will be useful to assess availability of the drug in the primary/metastatic pancreatic cancer tissue. Recent emphasis by the NCI and the FDA on imaging biomarkers provides support to the utility of imaging in drug development. PUBLIC HEALTH RELEVANCE: Effective non-surgical therapies are needed to alter the outcome and bleak prognosis in pancreatic cancer patients. The proposed research pertains to the development of a novel anticancer drug that can be delivered to the pancreatic cancer tissue in targeted manner, and that such preferential drug delivery can be monitored by non-invasive imaging.

描述（由申请人提供）：胰腺癌是美国癌症相关死亡的第四大原因。虽然早期诊断仍然是一个挑战，但诊断后的护理标准本质上是姑息性的，对改善胰腺癌患者的预后大多无效。抗癌药物是治疗胰腺癌的基石，但在治疗剂量下，它们会引起严重的副作用。更有选择性地向原发性和转移性肿瘤递送细胞毒性药物将允许剂量增加而不会同时增加外周毒性。因此，重要的是不仅要开发新的化疗分子，而且要确保在癌组织中优先递送药物。该策略还应包括体内试验，以监测癌症中药物积累的充分性和选择性。我们的目标是针对最近开发的胰腺癌抗增殖药物，并通过核技术实现靶向药物在活体动物中的分布的分子成像。我们正在开发一系列以姜黄素为基础的抗增殖药物，包括一种二苯二氟酮（DPDK）化合物。DPDK对几种癌症形式具有强细胞毒性；我们发现它对培养的胰腺癌细胞有效。我们建议通过在胰腺癌组织中过度表达的胃泌素释放肽受体（grpr）靶向DPDK。我们将对DPDK分子进行修饰，使其携带作为GRPr配体的bombesin7-14肽。该肽还含有Tc-99m放射性核素的螯合剂。Tc-99m放射性标签将允许在给药后对bombesin-DPDK的分布进行无创成像。我们的零假设是靶向DPDK并不比非靶向DPDK更具有抗增殖能力。对于拒绝这一零假设，具体目的是：1。合成可与99mTc放射性核素进行放射性标记的bombesin-DPDK偶联物；目的：评价炸弹素- dpdk在胰腺癌小鼠模型中的抗癌作用。完成这些特定目标的实验设计从实验室合成工作到细胞培养条件下合成化合物的体外测试，最后到异种移植胰腺肿瘤小鼠模型的体内研究。我们预计靶向递送将有助于胰腺癌中高浓度DPDK的局部化，其疗效可与大剂量非靶向药物相媲美。开发一种可以通过非侵入性成像监测的双功能分子的策略是炸弹素- grpr相互作用的新应用。成像将有助于评估药物在原发性/转移性胰腺癌组织中的可用性。最近NCI和FDA对成像生物标志物的重视为成像在药物开发中的应用提供了支持。

项目成果

Liposome-encapsulated EF24-HPβCD inclusion complex: a preformulation study and biodistribution in a rat model.

• DOI: 10.1007/s11051-010-0154-5
• 发表时间: 2011-06-01
• 期刊: JOURNAL OF NANOPARTICLE RESEARCH
• 影响因子: 2.5
• 作者: Agashe, H.;Lagisetty, P.;Sahoo, K.;Bourne, D.;Grady, B.;Awasthi, V.
• 通讯作者: Awasthi, V.

EF24 suppresses maturation and inflammatory response in dendritic cells.

• DOI: 10.1093/intimm/dxr121
• 发表时间: 2012-07
• 期刊: International immunology
• 影响因子: 4.4
• 作者: Prachi Vilekar;S. Awasthi;A. Natarajan;S. Anant;V. Awasthi

CLEFMA-an anti-proliferative curcuminoid from structure-activity relationship studies on 3,5-bis(benzylidene)-4-piperidones.

• DOI: 10.1016/j.bmc.2010.06.055
• 发表时间: 2010-08-15
• 期刊: BIOORGANIC & MEDICINAL CHEMISTRY
• 影响因子: 3.5
• 作者: Lagisetty, Pallavi;Vilekar, Prachi;Sahoo, Kaustuv;Anant, Shrikant;Awasthi, Vibhudutta
• 通讯作者: Awasthi, Vibhudutta

Tumor suppressive activities of solvatochromic 3,3'-azadimethylene dinaphthospiropyran in colon cancer model.

• DOI: 10.1111/cbdd.13785
• 发表时间: 2021-03
• 期刊: Chemical biology & drug design
• 影响因子: 3
• 作者: Lagisetty P;Eeda V;Yadav VR;Nimmo SL;Subramaniam D;Powell DR;Awasthi V
• 通讯作者: Awasthi V