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Tubulin-Binding Upconversion Nanoparticles for Breast-Cancer Imaging and Therapy

用于乳腺癌成像和治疗的微管蛋白结合上转换纳米颗粒

基本信息

批准号：
8507732
负责人：
Chuanbin Mao
金额：
$ 21.08万
依托单位：
UNIVERSITY OF OKLAHOMA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-07-15 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8507732
关键词：
Anaphase Antineoplastic Agents Bacteriophages Binding Breast Cancer Cell C-terminal Caliber Carbodiimides Cell Cycle Cell Death Cell Proliferation Cell division Cell physiology Cells Charge Chemistry Chromosome Segregation Chromosomes Colchicine Detection Image In Vitro Ions Lanthanoid Series Elements Light Malignant Neoplasms Mammary Gland Parenchyma Metaphase Methods Methyl Green Microtubule Proteins Microtubules Mitosis Mitotic Spindle Apparatus Mitotic spindle Modification Nanotubes Normal Cell Optics Paclitaxel Peptides Phage Display Pharmaceutical Preparations Plus End of the Microtubule Process Protein Subunits Proteins Quantum Dots Reporting Silicon Dioxide Surface Techniques Therapeutic Agents Time Tissues Travel Tubulin Tubulin Binding Agent Tumor Tissue Visible Radiation Work base cancer cell cancer diagnosis cancer imaging cancer therapy cell killing cellular imaging daughter cell depolymerization imaging probe in vivo killings malignant breast neoplasm nanocrystal nanoparticle polymerization prevent success tau Proteins theranostics uptake

项目摘要

DESCRIPTION (provided by applicant): Normal cell division needs the formation of a mitotic spindle apparatus, which is directly related to microtubule (MT) assembly. Thus, if the MT assembly is inhibited by tubulin-binding agents, the mitotic spindle functions will be perturbed, resulting in the inhibition of cell division at the metaphase/anaphase transition of mitosis. Therefore, tubulin-binding agents are anti-cancer drugs that can inhibit cell division by perturbing the MT assembly and cause cancer cell death. However, the current tubulin-binding anti-cancer drugs cannot specifically recognize cancer cells and serve as imaging probes. Our lab has recently used phage display technique to successfully identify two types of peptides: tubulin-binding peptides and SKBR-3 breast cancer cell-targeting/internalizing peptides. Moreover, we have developed expertise in the synthesis of lanthanide ion doped upconversion nanoparticles (UCNPs) and their utilization as cancer cell imaging probes. In contrast to the down-conversion nanoparticles such as the widely used quantum dots (QDs), the UCNPs can be excited by a longer wavelength light such as near infrared (NIR) light (e.g., 980 nm) to emit a shorter wavelength light (e.g., green light). Due to their ability to be excited by NIR light, whic can penetrate cells and tissues relatively deeply, UCNPs can be used for cell/tissue imaging without causing either autofluorescence from or photodamage to the biomolecules, cells and tissues. This project is based on these successes and will conjugate both tubulin-binding and cancer-targeting/internalizing peptides onto the surface of UCNPs. Our hypothesis is that core-shell upconversion nanoparticles (Rare-earth doped ?-NaYF4:Yb,Er upconversion nanocrystal as a core and silica as a shell) with both tubulin-binding and SKBR-3 breast cancer cell- targeting/internalizing peptides conjugated to the surface will (1) recognize the breast cancer cells and be internalized; (2) bind tubulins to interrupt intracellular MT assembly, inhibit cell proliferation and cause cell death in vitro and in vivo; and (3) enable the selective fluorescent imaging of the cancer cells and tumor tissues under NIR excitation. We will carry out two specific aims: (1) Aim 1: Evaluate the in vitro MT assembly in the presence of UCNPs with both tubulin-binding peptides and SKBR-3 cancer cell-targeting/internalizing peptides conjugated to the surface to understand how cell-targeting tubulin-binding UCNPs interrupt MT assembly in vitro. (2) Aim 2: Evaluate in vitro SKBR-3 breast cancer cell proliferation and cell cycle as well as in vitro and in vivo targeted cancer cell imaging and killing after SKBR-3 cells interact with the cell-targeting tubulin-binding UCNPs in vitro or in vivo. This project will advance the targete cancer treatment and diagnosis by developing targeted cancer imaging and therapeutic agents. The cancer-targeting tubulin-binding UCNPs developed in this project are multi-functional theranostic agents that can target and kill cancer cells and at the same time be fluorescently detected and tracked inside the cancer cells and tumor tissues.

描述（申请人提供）：正常细胞分裂需要形成有丝分裂纺锤体，这与微管（MT）组装直接相关。因此，如果微管蛋白结合剂抑制MT组装，有丝分裂纺锤体功能将受到干扰，导致有丝分裂中期/后期转变时细胞分裂受到抑制。因此，微管蛋白结合剂是一种抗癌药物，可以通过干扰 MT 组装来抑制细胞分裂并导致癌细胞死亡。然而，目前的微管蛋白结合抗癌药物不能特异性识别癌细胞并用作成像探针。我们的实验室最近利用噬菌体展示技术成功鉴定了两种类型的肽：微管蛋白结合肽和SKBR-3乳腺癌细胞靶向/内化肽。此外，我们还开发了稀土离子掺杂上转换纳米颗粒（UCNP）的合成及其作为癌细胞成像探针的应用方面的专业知识。与下转换纳米颗粒（例如广泛使用的量子点（QD））相比，UCNP 可以被较长波长的光（例如近红外（NIR）光（例如，980 nm））激发，以发射较短波长的光（例如，绿光）。由于它们能够被近红外光激发，从而相对较深地穿透细胞和组织，UCNP 可用于细胞/组织成像，而不会引起生物分子、细胞和组织的自发荧光或光损伤。该项目基于这些成功，并将微管蛋白结合肽和癌症靶向/内化肽结合到 UCNP 的表面。我们的假设是，表面缀合有微管蛋白结合肽和 SKBR-3 乳腺癌细胞靶向/内化肽的核壳上转换纳米颗粒（稀土掺杂 ?-NaYF4:Yb,Er 上转换纳米晶体作为核心，二氧化硅作为壳）将 (1) 识别乳腺癌细胞并被内化； (2)在体外和体内结合微管蛋白，中断细胞内MT组装，抑制细胞增殖并导致细胞死亡； (3)在近红外激发下能够对癌细胞和肿瘤组织进行选择性荧光成像。我们将实现两个具体目标：(1) 目标 1：在 UCNP 存在的情况下评估体外 MT 组装，其中 UCNP 与表面缀合有微管蛋白结合肽和 SKBR-3 癌细胞靶向/内化肽，以了解细胞靶向微管蛋白结合 UCNP 如何在体外中断 MT 组装。（2）目标2：评估体外SKBR-3乳腺癌细胞增殖和细胞周期，以及SKBR-3细胞与细胞靶向微管蛋白结合的UCNP在体外或体内相互作用后的体外和体内靶向癌细胞成像和杀伤作用。该项目将通过开发靶向癌症成像和治疗剂来推进靶向癌症治疗和诊断。该项目开发的癌症靶向微管蛋白结合UCNP是多功能治疗诊断剂，可以靶向并杀死癌细胞，同时在癌细胞和肿瘤组织内进行荧光检测和追踪。