Phage-Mimetic Nanorods for Targeted Breast Cancer Treatment

描述（由申请人提供）：体内噬菌体展示可以识别特定肿瘤组织的脉管系统特异性肿瘤归巢蛋白，肿瘤脉管系统是癌症治疗的合适靶点。然而，如果不与抗癌药物结合，这种肿瘤归巢蛋白不能直接破坏肿瘤。另一方面，像金纳米棒（aunr）这样的纳米材料可以将穿透组织的近红外（NIR）辐射迅速转化为热量，从而提高局部温度并热破坏肿瘤。然而，aunr缺乏能够使它们特异性靶向和攻击肿瘤的生物学识别。该项目的创新之处在于，它将体内噬菌体展示建立的肿瘤归巢蛋白和肿瘤破坏aunr结合在一起。本应用程序的目的是：(1)模拟蛋白质和DNA如何组装成纳米棒状噬菌体颗粒，将靶向噬菌体外壳蛋白和DNA固定的AuNR组装成可作为纳米肿瘤加热器的噬菌体模拟纳米棒（PMNR）；(2)通过使用体内主要外壳噬菌体展示技术，通过基因鉴定肿瘤归巢噬菌体外壳蛋白，赋予PMNR乳腺肿瘤归巢特异性。本项目的总体假设是：(1)纳米棒样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对其进行基因工程改造，使其进入乳腺肿瘤；可以在表面突出肿瘤自导肽基序的dna固定金纳米棒（aunr）上进行仿生自组装；(2)所得到的多功能PMNR将作为乳腺肿瘤靶向纳米加热器，在近红外照射下选择性破坏乳腺肿瘤。我们设计了三个特定的目标来验证我们的中心假设：目标1：从噬菌体展示的随机肽库中鉴定融合到纳米棒样噬菌体pVIII的肿瘤归家肽。目的2：通过模拟天然噬菌体组装过程中pVIII沿着DNA组装的过程，在DNA固定的aunr上建立肿瘤归家噬菌体蛋白的仿生组装，形成肿瘤归家pmnr。目的3：利用肿瘤靶向pmnr检测乳腺肿瘤光热消融。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。它还将产生一种新的仿生策略，用于赋予纳米医学中纳米材料的生物识别。

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.