Size-tunable cancer nanotherapeutics

尺寸可调的癌症纳米疗法

• 批准号: 8461919
• 负责人: Juntao Luo
• 金额: $ 30.18万
• 依托单位: UPSTATE MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8461919
• 关键词: Abraxane; Adverse effects; Allergic; Allergic Reaction; Animal Model; Architecture; Biodistribution; Breast Cancer Model; Breast Cancer Treatment; Canis familiaris; Cell surface; Cholic Acids; Clinical; Cremophor; Data; Development; Drug Delivery Systems; Drug Formulations; Drug Stability; Encapsulated; Environment; Evaluation; FDA approved; Face; Future; Histamine; Hour; Human; Image; In Vitro; Label; Length; Ligands; Link; Liquid substance; Literature; Liver; Lysine; Malignant Neoplasms; Mammals; Micelles; Names; Neoplasms in Vascular Tissue; Paclitaxel; Particle Size; Patients; Penetration; Permeability; Pharmaceutical Preparations; Physical condensation; Polyethylene Glycols; Polymers; Powder dose form; Precipitation; Premedication; Principal Investigator; Property; Publishing; Reaction; Reporting; 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; cremophor EL; cytotoxicity; design; functional group; improved; in vivo; malignant breast neoplasm; mouse model; nanocarrier; nanoformulation; nanoparticle; nanotherapeutic; novel; optical imaging; phase 1 study; programs; therapeutic target; tumor; tumor xenograft

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.

紫杉醇是治疗多种癌症的标准且有效的化疗药物。然而，香油 在PTX(紫杉醇(R))的配方中，EL会导致严重的副作用，如过敏反应。一本小说 提出了不含克霉酚的聚合物纳米载体，以避免副作用并选择性地将PTX输送到 提高肿瘤部位在乳腺癌治疗中的抗肿瘤效果。一种线状-树枝状两亲化合物 聚合物体系(称为端树状大分子)，由连接到一个 聚乙二醇(PEG)，在水环境中自组装形成稳定的胶束，可以 包装疏水药物。这种端粒系统具有独特的性能，这些性能优于许多 已发表的基于胶束的纳米颗粒，由于胆酸独特的面部两亲性和线性- 聚合物的树枝状。这些端树状分子具有明确的结构和多种功能 端树状大分子形成的基团和胶束在负载了高含量的 PTX。据我们所知，这种端树状大分子具有最高的PTX载药量(50%w/w药物/聚合物) 在文献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 聚乙二醇聚乳酸中的PTX含量(25%w/w)。此外，还观察到载药胶束的稳定性非常陈旧。 在储存后的大小上，在六个月内没有观察到进一步的聚集。肿瘤的初步数据 通过增强纳米颗粒在转基因中的渗透性和滞留(EPR)效应而实现的靶向性 小鼠乳腺肿瘤模型、同基因乳腺癌模型及异种移植瘤模型 在异种移植模型中的抗肿瘤作用是有希望的。然而，只有数量有限的端树突体具有 已经测试过了。我们相信还有进一步改进和优化的空间。我们假设，在 这些纳米药物的体内肿瘤靶向性和抗肿瘤效果取决于它们的大小、载药量 容量及其稳定性，这些性质取决于(I)胆酸的数量和排列 分子和(Ii)聚乙二醇链长度和(Iii)胆酸低聚物的阻挡作用。这些PTX- 载药纳米粒(纳米氧烷)已被证明通过EPR效应自身具有靶向治疗作用。 用癌症靶向配体装饰，这些纳米载体将更有效地将药物输送到 肿瘤部位和增强肿瘤穿透性的治疗药物。 在这个方案中，我们将设计并组合合成52种新型两亲性聚合物，它们具有不同的 用于优化纳米载体的体系结构。黄曲霉毒素的理化性质及细胞毒性 将对端树状分子和由此产生的纳米载体进行表征。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 小鼠自发或异种移植瘤模型的微SPECT成像。最后，体内毒性 优化的纳米氧烷和配体-纳米氧烷的抗肿瘤性能将在动物模型中进行评估。