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（由申请人提供）：正常细胞分裂需要形成有丝分裂纺锤体的设备，该设备与微管（MT）组件直接相关。因此，如果MT组件被微管蛋白结合剂抑制，则有丝分裂的纺锤体功能会受到干扰，从而导致有丝分裂的中期/后期过渡过程中细胞分裂的抑制。因此，微管蛋白结合剂是抗癌药物，可以通过扰动MT组装并导致癌细胞死亡来抑制细胞分裂。但是，当前的小管蛋白结合抗癌药无法明确识别癌细胞，并用作成像探针。我们的实验室最近使用噬菌体显示技术成功识别了两种类型的肽：微管蛋白结合肽和SKBR-3乳腺癌细胞靶向/内化肽。此外，我们在合成掺杂纳米颗粒（UCNP）及其用作癌细胞成像探针的合成方面发展了专业知识。与诸如广泛使用的量子点（QD）之类的下转换纳米颗粒相反，UCNP可以通过较长的波长光（例如近红外（NIR）光（例如980 nm）发出较短波长的光（例如，绿光）来激发UCNP。由于它们有能力被NIR光激发，因此可以穿透细胞和组织相对深层，因此可以将UCNP用于细胞/组织成像，而不会引起从或受到光损伤到生物分子，细胞和组织的自动荧光。该项目基于这些成功，并将在UCNP的表面结合微管蛋白结合和靶向癌症/内部化肽。我们的假设是核心壳上转换纳米颗粒（稀疏地掺杂了？-nayf4：yb，yb，er converversion纳米晶体作为核心和硅壳），硅胶作为壳）具有微管蛋白结合和SKBR-3乳腺癌细胞靶向/内化型肽，以表面构成乳腺癌细胞（1）乳腺癌（1）。（2）结合微管与中断细胞内MT组装，抑制细胞增殖并在体外和体内导致细胞死亡；（3）在NIR激发下启用癌细胞和肿瘤组织的选择性荧光成像。我们将执行两个具体的目的：（1）目标1：在具有小管蛋白结合肽和SKBR-3癌细胞靶向/内化肽的UCNP的存在下，评估体外MT组件，以了解细胞靶向细胞靶向的微管蛋白结合UCNP的UCNP UCNP ucnps Introump MT Introump in velro。（2）目标2：评估体外SKBR-3乳腺癌细胞的增殖和细胞周期以及体内靶向癌细胞成像和SKBR-3细胞后与细胞靶向细胞靶向小管蛋白结合UCNP相互作用后的体外杀伤。该项目将通过开发靶向癌症成像和治疗剂来推动靶向癌症治疗和诊断。该项目中开发的癌症靶向小管蛋白结合UCNP是多功能的疗法剂，可以靶向和杀死癌细胞，同时荧光检测并在癌细胞和肿瘤组织中进行荧光检测和跟踪。