Phage-Mimetic Nanorods for Targeted Breast Cancer Treatment

用于靶向乳腺癌治疗的噬菌体模拟纳米棒

• 批准号: 7904784
• 负责人: Chuanbin Mao
• 金额: $ 21.27万
• 依托单位: UNIVERSITY OF OKLAHOMA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7904784
• 关键词: Ablation; Affinity; Aftercare; Amino Acids; Animal Model; Animals; Antineoplastic Agents; Automobile Driving; Bacteria; Bacteriophages; Binding; Biocompatible; Biological; Biomimetics; Brain; Breast; Breast Cancer Cell; Breast Cancer Treatment; C-terminal; Capsid Proteins; Carbon; Cells; Chemicals; DNA; Data; Disease; Distal; Electrostatics; Engineering; Environment; Figs - dietary; Genetic; Goals; Gold; Hand; Heart; Heating; Histologic; Home environment; Homing; Hydrophobic Interactions; Image; Immune response; Length; Libraries; Light; Malignant Neoplasms; Mammalian Cell; Mammary Neoplasms; Minor; Monitor; Mus; N-terminal; Nanotechnology; Organ; Outcome; Peptides; Phage Display; Phosphate Buffer; Process; Proteins; Random Peptide Libraries; Rest; Saline; Side; Silver Staining; Silver stain method; Specificity; Structure; Surface; Survival Analysis; Technology; Temperature; Testing; Tetanus Helper Peptide; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Tumor Tissue; Virus; base; cancer cell; cancer therapy; design; driving force; in vivo; innovation; irradiation; killings; malignant breast neoplasm; mimetics; nano; nanomaterials; nanomedicine; nanoparticle; nanorod; nanoscale; novel; novel strategies; novel therapeutics; particle; physical property; public health relevance; research study; response; retinal rods; self assembly; treatment strategy; tumor

DESCRIPTION (provided by applicant): In vivo phage display can identify tumor-homing proteins that are specific to the vasculature of a specific tumor tissue and the tumor vasculature is a suitable target for cancer therapy. However, such tumor-homing proteins cannot destruct tumors directly without being conjugated with anti-cancer agents. On the other hand, nanomaterials such as gold nanorods (AuNRs) can rapidly convert tissue-penetrating near infrared (NIR) irradiation into heat to raise the local temperature and thermally destruct tumors. However, AuNRs lack biological recognitions that can allow them to target and attack tumors specifically. This project is innovative because it integrates the tumor-homing proteins established by in vivo phage display and tumor-destructing AuNRs. The objectives of this application are (1) to mimic how proteins and DNA are assembled into a nanorod-like phage particle to assemble target-specific phage coat proteins and a DNA-immobilized AuNR into a phage-mimetic nanorod (PMNR) which can serve as a nano-tumor-heater and (2) to impart the breast tumor-homing specificity to the PMNR through genetically identifying tumor-homing phage coat proteins by using in vivo major coat phage display technology. The overall hypotheses of this project are that (1) major coat protein (pVIII) of nanorod-like fd-tet phage, which is genetically engineered to home to breast tumor through major coat phage display technology, can biomimetically self-assemble on the DNA-immobilized gold nanorods (AuNRs) with tumor-homing peptide motif protruding from the surface and (2) the resultant multi-functional PMNR will serve as a breast tumor-targeting nano-heater to selectively destruct breast tumor upon NIR irradiation. Three specific aims are designed to test our central hypotheses: Aim 1: Identify tumor-homing peptides that are fused to pVIII of nanorod-like phage from a phage-displayed random peptide library. Aim 2: Establish the biomimetic assembly of tumor-homing phage proteins on the DNA-immobilized AuNRs to form tumor-homing PMNRs by mimicking how pVIII is assembled along DNA during natural phage assembly. Aim 3: Test the targeted photothermal ablation of breast tumors using the tumor-targeting PMNRs. This project will result in a new tumor-homing anti-cancer agent and a novel strategy for targeted breast cancer therapy. It will also generate a novel biomimetic strategy for imparting biological recognitions to nanomaterials in nanomedicine. PUBLIC HEALTH RELEVANCE: Phage-mimetic nanorods for targeted breast cancer treatment Project Narrative This project will use a biomimetic strategy to bring together tumor-homing proteins and tumor-destructing nanomaterials to develop a new anti-cancer agent. The new therapeutic agent can recognize breast tumors and destruct the tumors in response to a tissue-penetrating light. It will result in a novel nanotechnological strategy for targeted breast cancer therapy.

描述（由申请人提供）：体内噬菌体展示可以鉴定特定肿瘤组织的脉管系统特异的肿瘤归巢蛋白，并且肿瘤脉管系统是癌症治疗的合适靶点。然而，这种肿瘤归巢蛋白在不与抗癌剂结合的情况下不能直接破坏肿瘤。另一方面，金纳米棒（AuNR）等纳米材料可以快速将组织穿透的近红外（NIR）辐射转化为热量，从而提高局部温度并热破坏肿瘤。然而，AuNR 缺乏生物识别能力，无法特异性地靶向和攻击肿瘤。该项目具有创新性，因为它整合了通过体内噬菌体展示建立的肿瘤归巢蛋白和肿瘤破坏性 AuNR。该应用的目标是 (1) 模拟蛋白质和 DNA 组装成纳米棒状噬菌体颗粒的方式，将目标特异性噬菌体外壳蛋白和 DNA 固定的 AuNR 组装成噬菌体模拟纳米棒 (PMNR)，该纳米棒可用于作为纳米肿瘤加热器，(2) 通过使用体内主外壳噬菌体展示从基因上鉴定肿瘤归巢噬菌体外壳蛋白，从而赋予 PMNR 乳腺肿瘤归巢特异性 技术。该项目的总体假设是：（1）纳米棒状fd-tet噬菌体的主要外壳蛋白（pVIII），通过主要外壳噬菌体展示技术进行基因工程改造，使其能够归巢于乳腺肿瘤，可以在DNA上进行仿生自组装-具有从表面突出的肿瘤归巢肽基序的固定金纳米棒（AuNR），（2）由此产生的多功能PMNR将作为乳腺肿瘤靶向纳米加热器在近红外辐射下选择性破坏乳腺肿瘤。设计了三个具体目标来检验我们的中心假设： 目标 1：从噬菌体展示的随机肽库中识别与纳米棒状噬菌体 pVIII 融合的肿瘤归巢肽。目标 2：通过模拟自然噬菌体组装过程中 pVIII 沿着 DNA 组装的方式，在 DNA 固定的 AuNR 上建立肿瘤归巢噬菌体蛋白的仿生组装，以形成肿瘤归巢 PMNR。目标 3：使用肿瘤靶向 PMNR 测试乳腺肿瘤的靶向光热消融。该项目将产生一种新的肿瘤归巢抗癌药物和乳腺癌靶向治疗的新策略。它还将产生一种新颖的仿生策略，为纳米医学中的纳米材料赋予生物识别能力。 公共健康相关性：用于乳腺癌靶向治疗的噬菌体模拟纳米棒 项目叙述 该项目将采用仿生策略，将肿瘤归巢蛋白和肿瘤破坏纳米材料结合在一起，开发一种新的抗癌剂。新的治疗剂可以识别乳腺肿瘤并响应组织穿透光破坏肿瘤。它将产生一种用于乳腺癌靶向治疗的新型纳米技术策略。