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鉴定对特定肿瘤组织的脉管系统具有特异性的肿瘤归巢蛋白，并且肿瘤脉管系统是癌症治疗的合适靶标。然而，这样的肿瘤归巢蛋白不能在不与抗癌剂缀合的情况下直接破坏肿瘤。另一方面，纳米材料如金纳米棒（AuNRs）可以迅速将穿透组织的近红外（NIR）辐射转化为热量，以提高局部温度并热破坏肿瘤。然而，AuNR缺乏生物学特性，无法特异性地靶向和攻击肿瘤。该项目是创新的，因为它整合了通过体内噬菌体展示和肿瘤破坏AuNR建立的肿瘤归巢蛋白。本申请的目的是（1）模拟蛋白质和DNA如何组装成纳米棒样噬菌体颗粒，以将靶特异性噬菌体外壳蛋白和DNA固定化的AuNR组装成可用作纳米肿瘤加热器的噬菌体模拟纳米棒（PMNR），和（2）通过遗传鉴定肿瘤靶向蛋白质，赋予PMNR乳腺肿瘤归巢特异性。通过使用体内主要外壳噬菌体展示技术归巢噬菌体外壳蛋白。本项目的总体假设是：（1）通过噬菌体主要外壳展示技术，基因工程改造的纳米棒样fd-tet噬菌体主要外壳蛋白（pVIII），可以在DNA固定的金纳米棒（AuNR）上进行生物仿生自组装，并具有从表面突出的肿瘤归巢肽基序，以及（2）所得的多功能PMNR将用作乳腺肿瘤-靶向纳米加热器，以在NIR照射下选择性地破坏乳腺肿瘤。我们设计了三个具体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与纳米棒样噬菌体pVIII融合的肿瘤归巢肽。目标二：通过模拟自然噬菌体组装过程中pVIII如何沿着DNA组装，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。目的3：利用肿瘤靶向PMNR进行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剂和一种靶向乳腺癌治疗的新策略。它还将产生一种新的仿生策略，用于在纳米医学中赋予纳米材料生物活性。 公共卫生相关性：该项目将使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，以开发一种新的抗癌剂。这种新的治疗剂可以识别乳腺肿瘤，并在组织穿透光的作用下摧毁肿瘤。它将为靶向乳腺癌治疗提供一种新的纳米技术策略。

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.