Carrier Shape Matters: Filomicelles, Long-circulation, and the EPR effect

载体形状很重要：丝状胶束、长循环和 EPR 效应

• 批准号: 7642477
• 负责人: Dennis E. Discher
• 金额: $ 34.28万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-15 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7642477
• 关键词: Address; Apoptosis; Apoptosis Promoter; Area Under Curve; Benchmarking; Binding; Biocompatible Materials; Biodistribution; Biological; Biological Assay; Biological Models; Blood; Blood Circulation; Blood capillaries; Buffers; Caliber; Cancerous; Cardiac Myocytes; Cell Communication; Cell Culture Techniques; Cells; Cereals; Charge; Chemistry; Clinical; Complement; Complement Activation; Cryopreservation; Cytolysis; Devices; Dose; Doxorubicin; Drug Delivery Systems; Drug Kinetics; Dyes; Exhibits; Fluorescence; Gel; High Pressure Liquid Chromatography; Human; Image; In Vitro; Infarction; Injection of therapeutic agent; Kinetics; Label; Lead; Length; Ligands; Liposomes; Literature; Liver; Lung Neoplasms; Malignant neoplasm of lung; Maps; Measures; Methods; Micelles; Mitotic; Modeling; Monitor; Morphology; Muscle; Myocardial Infarction; Myocardium; Nude Mice; Oxidation-Reduction; Paclitaxel; Partition Coefficient; Pathway interactions; Peptides; Phagocytes; Pharmaceutical Preparations; Polyesters; Polymers; Property; Proteins; Radial; Rattus; Receptor Cell; Reporting; Research Personnel; Rodent; Series; Shapes; Solid Neoplasm; Spleen; Sterility; Surface; System; Testing; Time; Tissues; Toxic effect; Transferrin; Vesicle; Water; Whole Blood; Work; Xenograft Model; base; cancer cell; capillary; computer design; copolymer; design; di-block copolymer; drug testing; flexibility; fluorescence imaging; in vivo; intravenous injection; killings; macrophage; mimetics; molecular dynamics; monomer; mortality; mouse model; nano; nanocarrier; nanoparticle; novel; particle; polymerization; programs; receptor; self assembly; simulation; therapeutic development; trafficking; tumor; uptake

DESCRIPTION (provided by applicant): The ultimate question to be addressed here is what range of filamentous shapes & flexibilities are 'nano' in the circulation and in permeating tumors or other porous tissues? Our worm-like 'Filomicelles' are made from amphiphilic PEG-based polymers similar to those in clinical use and similar to those used to make polymer vesicles, but our cylindrical Filomicelles already appear to possess surprisingly distinct and advantageous pharmacokinetic properties. While the biomaterials literature currently suggests that a particle radius much greater than approximately 100-200 nm leads to rapid clearance by phagocytes of the liver and spleen, we find that Filomicelles many microns long can "worm" through the capillaries and circulate in vivo for a week or more - longer than any synthetic carrier yet reported. Mapping out the limits of this long circulation - length, diameter, flexibility, surface charge, drug retention, and ligand-targeting - is our pen-ultimate Aim in vivo. Long circulating Filomicelles should greatly increase the 'Area Under the Curve' for drug delivery, and we indeed already find that a single injection of PEG-polyester, 8 mu m-long Filomicelles loaded with the hydrophobic anti-mitotic drug taxol shrinks a solid tumor by almost half ... And this is found at a 'TAX' dose (in mg/kg) which is ineffective as free drug. Filomicelles also appear more potent than a single injection of polymer vesicles loaded with both TAX and Doxorubicin. Since our two types of polymer-based carriers are made from copolymers that differ in PEG fraction by only 5-10%, we can more directly compare effects of carrier morphology in delivery. For either system however, we do not yet know how much TAX is (i) released directly in the circulation, (ii) released gradually with sphere micelles from degrading carriers in circulation, or (iii) released from Filomicelles or vesicles that have permeated the tumor. Our ultimate Aim here is to address how the Filomicelles (vs polymer vesicles) might take advantage of the Enhanced Permeation and Retention ('EPR') effect in passive delivery to tumors - specifically lung tumors (with 80- 90% mortality in humans) in a xenograft model. The generality of the EPR effect with these carriers will be examined in limited studies of their permeation into non-cancerous 'porous' tissues such as damaged myocardium and dystrophic muscle. In parallel with the in vivo studies above, we propose to further the designs (with atomistic simulation), make, load, characterize (stability, release, etc.), and target novel block copolymer carriers. Targeted worm-like Filomicelles are already seen to cooperatively zip up on surfaces displaying suitable receptors, at least with model systems in vitro. Subsequent internalization by the cell can then lead to delivery of a large amount of drug all at once from a single micelle - enough to kill a single cell, in principle. In our initial Aims we seek to test this hypothesis of potency by first clarifying precepts of block copolymer self-assembly and shape stability, and then assessing copolymer degradation, cellular trafficking and transport. We propose a focused development of therapeutic ligands, including targeted apoptosis-inducers, as we ultimately seek a wider range of control and targeting (but passive first!) of copolymer assemblies for in vivo studies.

描述（由申请人提供）：这里要解决的最终问题是循环中以及渗透到肿瘤或其他多孔组织中的丝状形状和灵活性范围是什么？我们的类似蠕虫的“纤维细胞”是由类似于临床用途的两亲性钉的聚合物制成的，类似于用于制造聚合物囊泡的聚合物，但是我们的圆柱形纤维细胞似乎已经具有令人惊讶的独特和有利的药物代动力学特性。尽管生物材料文献目前表明，粒子半径大于大约100-200 nm的粒子半径会导致肝脏和脾脏的吞噬细胞的快速清除，但我们发现，许多微米长的丝细胞可以通过毛细血管“蠕虫”通过毛细血管“蠕虫”，并在体内循环一周或更长的合成载体。绘制这一长循环的限制 - 长度，直径，柔韧性，表面电荷，药物保留和靶向配体 - 是我们在体内的笔迹目标。长期循环的纤维细胞应大大增加“曲线下的面积”以进行药物输送，并且我们确实已经发现，单次注射钉蛋白酶，8 mu m-m-long filomicelles装有疏水性抗微质药物紫杉醇的甲醇将固体肿瘤缩小了几乎一半...并在“税收”剂量上（在MG/KG中）发现了这一点。丝状细胞看起来也比单个含有税收和阿霉素的聚合物囊泡的注入更有效。由于我们的两种基于聚合物的载体是由PEG分数仅相差5-10％的共聚物制成的，因此我们可以更直接地比较载体形态在递送中的影响。但是，对于任何一种系统，我们尚不知道直接在循环中释放多少税（i），（ii）逐渐用循环中降解载体的球胶束释放，或（iii）从已渗透到肿瘤的纤维细胞或囊泡中。我们在这里的最终目的是解决如何在被动递送到肿瘤的肿瘤中（特别是肺肿瘤（人类的80-90％死亡率）中的渗透渗透和保留效应（'EPR'）如何利用filomicelles（VS聚合物囊泡）如何利用增强的优势。这些载体的EPR效应的普遍性将在有限的渗透到非癌性“多孔”组织（如受损的心肌和营养不良的肌肉）中进行检查。与上面的体内研究同时，我们建议进一步设计（具有原子模拟），制造，负载，表征（稳定性，释放等）和靶向新型嵌段共聚物载体。至少在体外模型系统的情况下，已经看到了靶向蠕虫样的纤维细胞在显示合适受体的表面上进行拉链。然后，细胞的后续内部化可以导致一次从单个胶束中递送大量药物 - 原则上足以杀死一个单元。在我们的最初目标中，我们试图通过首先阐明块共聚物自组装和形状稳定性的戒律来检验这种效力的假设，然后评估共聚物降解，细胞运输和运输。我们提出了针对治疗配体的重点发展，包括靶向细胞凋亡诱导者，因为我们最终寻求对体内研究的共聚物组件的更广泛的控制和靶向（但首先是被动的！）。