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Size-tunable cancer nanotherapeutics

尺寸可调的癌症纳米疗法

基本信息

批准号：
8657850
负责人：
Juntao Luo
金额：
$ 31.14万
依托单位：
UPSTATE MEDICAL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8657850
关键词：
Abraxane Adverse effects Allergic Allergic Reaction Animal Model Architecture Biodistribution Breast Cancer Model Breast Cancer Treatment Canis familiaris Cell surface Cessation of life Cholic Acids Clinical Cremophor Data Development Drug Delivery Systems Drug Formulations Drug Stability Encapsulated Environment FDA approved Face Future Health Histamine Hour Human Image In Vitro Label Length Ligands Link Liquid substance Literature Liver Lysine Malignant Neoplasms Mammals Micelles Names Neoplasm Metastasis Neoplasms in Vascular Tissue Organ Paclitaxel Particle Size Patients Penetration Permeability Pharmaceutical Preparations Physical condensation Polyethylene Glycols Polymers Powder dose form Precipitation Premedication Process Property Publishing Reaction Reporting Rest Reticuloendothelial System Scintillation Counting Serum Albumin Shapes Site Solubility Solvents Steroids Structure System Testing Therapeutic Toxic effect Transgenic Mice Transgenic Organisms Treatment Efficacy Water Xenograft Model Xenograft procedure amphiphilicity aqueous base cancer cell cancer type chemotherapeutic agent combat cremophor EL cytotoxicity design functional group improved in vivo malignant breast neoplasm mouse model nanocarrier nanoformulation nanoparticle nanotherapeutic novel optical imaging phase 1 study therapeutic target tumor tumor progression tumor xenograft

项目摘要

Paclitaxel is a standard and effective chemotherapeutic agent for many cancer types. However, Cremophor EL in the formulation of PTX (Taxol(R)) causes significant side effects such as allergic reactions. A novel Cremophor-free polymeric nanocarrier is proposed to avoid the side effects and to deliver PTX selectively to the tumor sites to improve the antitumor effects in breast cancer treatment. A linear-dendritic amphiphilic polymer system (named as telodendrimer), composed of a dendritic oligomer of cholic acids linked to a polyethylene glycol (PEG), self-assembles under aqueous environment to form stable micelles that can encapsulate hydrophobic drugs. This telodendrimer system has unique properties that are superior to many published micelle-based nanoparticles, due to the unique facial amphiphilicity of cholic acid and the linear- dendritic shape of the polymer. These telodendrimers have well defined structures and multiple functional groups and the micelles formed by the telodendrimers have tunable sizes, after loaded with high content of PTX. To our knowledge, this telodendrimers has the highest PTX loading capacity (50% w/w drug/polymer) among the conventional polymeric micelle systems reported in literature, such as the most impressive loading of PTX in PEG-PDLLA (25% w/w). Also, the stability of the drug loaded micelle was observed to be very stale in size upon storage, and no further aggregation was observed over six months. Preliminary data of the tumor targeting properties via enhanced permeability and retention (EPR) effects of nanoparticles in transgenic mouse mammary tumor model, syngeneic mammary cancer model as well as xenograft models and the antitumor effects in xenograft models are promising. However, only a limited number of telodendrimers have been tested. We believe there is room for further improvement and optimization. We hypothesize that the in vivo tumor targeting and antitumor effects of these nanotherapeutics are determined by their size, drug loading capacity and their stability, and these properties depend on (i) the number and arrangement of cholic acid molecules and (ii) the PEG chain length and (iii) the hindrance of the oligomer of cholic acid. These PTX- loaded nanoparticles (Nanoxane) have been shown to be targeting therapeutic by themselves via EPR effect. Decorated with cancer targeting ligands, these nanocarriers will be more efficient in delivering drugs to the tumor sites and enhancing the tumor penetration of the therapeutics. In this proposal we will design and combinatorially synthesize 52 novel amphiphilic polymers with various architectures for the optimization of nanocarriers. The physicochemical properties and cytotoxicity of the telodendrimers and resulting nanocarriers will be characterized. The selected polymers will be further screened in the in vivo tumor targeting and biodistribution studies via optical imaging, liquid scintillation counting and microSPECT imaging in mouse models bearing spontaneous or xenograft tumors. Finally, the in vivo toxicity and anti-tumor properties of the optimized Nanoxane and ligand-nanoxanes will be evaluated in animal models.

紫杉醇是许多癌症类型的标准和有效的化疗剂。然而，Cremophor PTX（Taxol（R））制剂中的EL引起显著的副作用，例如过敏反应。一种新型提出了不含聚氧乙烯聚合物纳米载体来避免副作用并选择性地将紫杉醇递送给以提高乳腺癌治疗中的抗肿瘤效果。一种线性-树枝状两亲性聚合物系统（命名为末端树枝状聚合物），由连接到聚乙二醇（PEG）在水性环境下自组装以形成稳定的胶束，包封疏水性药物。这种末端树枝状聚合物系统具有独特的性能，上级许多公开的基于胶束的纳米颗粒，由于胆酸独特的表面两亲性和线性- 聚合物的树枝状形状。这些末端树枝状聚合物具有明确定义的结构和多个功能，基团和胶束形成的末端树枝状聚合物具有可调的大小，在负载高含量的 PTX。据我们所知，这种末端树枝状聚合物具有最高的PTX负载能力（50%w/w药物/聚合物）在文献中报道的常规聚合物胶束体系中，例如最令人印象深刻的负载的PTX的PEG-PDLLA（25%w/w）。此外，观察到载药胶束的稳定性非常不稳定在储存后的大小，并且在六个月内没有观察到进一步的聚集。肿瘤的初步数据通过增强的渗透性和保留（EPR）效应的纳米颗粒在转基因中的靶向性质小鼠乳腺肿瘤模型、同基因乳腺癌模型以及异种移植模型，在异种移植模型中的抗肿瘤作用是有希望的。然而，只有有限数量的末端树枝状聚合物具有被测试过了我们认为还有进一步改进和优化的空间。我们假设这些纳米治疗剂的体内肿瘤靶向和抗肿瘤作用取决于它们的大小、载药量容量和它们的稳定性，并且这些性质取决于（i）胆酸的数量和排列分子和（ii）PEG链长和（iii）胆酸低聚物的阻碍。这些PTX- 负载的纳米颗粒（Nanoxane）已经显示出通过EPR效应自身靶向治疗剂。用癌症靶向配体装饰，这些纳米载体将更有效地将药物递送到患者体内。肿瘤位点和增强治疗剂的肿瘤渗透。在本论文中，我们将设计并组合合成52种新型的两亲性聚合物，用于优化纳米载体的结构。本文研究了该化合物的理化性质和细胞毒性。末端树枝状聚合物和所得纳米载体将被表征。选定的聚合物将进一步筛选在体内肿瘤靶向和生物分布研究中，通过光学成像、液体闪烁计数和在携带自发性或异种移植肿瘤的小鼠模型中的microSPECT成像。最后，体内毒性将在动物模型中评价优化的Nanoxane和配体-Nanoxane的抗肿瘤性质。