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，在血液循环中以及在渗透肿瘤或其他多孔组织时，丝状形状和柔韧性是什么范围？我们的蠕虫状“丝状胶束”是由两亲聚乙二醇基聚合物制成的，类似于临床使用的聚合物，也类似于用于制造聚合物囊泡的聚合物，但我们的圆柱形丝状胶束似乎已经具有令人惊讶的独特和有利的药代动力学特性。虽然目前的生物材料文献表明，远大于约100-200纳米的颗粒半径会导致肝和脾的吞噬细胞快速清除，但我们发现，长达数微米的丝状胶束可以在毛细血管中“蠕虫”，并在体内循环一周或更长时间--比迄今报道的任何合成载体都要长。绘制出这种长循环的极限--长度、直径、灵活性、表面电荷、药物滞留和配体靶向--是我们在体内的终极目标。长循环的丝状胶束应该会大大增加给药的曲线下面积，我们确实已经发现，一次注射8微米长的聚乙二醇聚酯丝状胶束，装载着疏水的抗有丝分裂药物紫杉醇，可以使实体肿瘤缩小近一半……这是在“税”剂量(以毫克/公斤为单位)发现的，作为免费药物，这是无效的。丝状胶束似乎也比单次注射同时含有紫杉醇和阿霉素的聚合物微囊更有效。由于我们的两种聚合物载体是由聚乙二醇组分仅相差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输送过程中的影响。然而，对于任何一种系统，我们还不知道有多少税收是(I)直接在循环中释放，(Ii)随着球状胶束从循环中的降解载体逐渐释放，或(Iii)从渗透到肿瘤的丝状胶束或囊泡中释放。我们的最终目标是解决丝状胶束(VS聚合物囊泡)如何利用被动传递到肿瘤中的增强渗透和滞留(EPR)效应-特别是在异种移植模型中的肺癌(在人类中死亡率为80%-90%)。这些载体的EPR效应的普遍性将在有限的研究中被检验，这些研究是关于它们对非癌症的“多孔”组织的渗透，例如受损的心肌和营养不良的肌肉。在进行上述体内研究的同时，我们建议进一步进行设计(原子模拟)、制备、加载、表征(稳定性、释放等)和目标新型嵌段共聚载体。靶向的蠕虫样的丝状胶束已经被看到协同拉链在显示合适的受体的表面，至少在体外的模型系统中是这样。随后细胞的内化可以导致大量药物从单个胶束中一次性释放--原则上足以杀死一个细胞。在我们最初的目标中，我们试图通过首先澄清嵌段共聚物自组装和形状稳定性的规则，然后评估共聚物的降解、细胞运输和运输来检验这一效力假说。随着我们最终寻求更广泛的控制和靶向(但首先是被动的！)，我们建议集中开发治疗配体，包括靶向凋亡诱导剂。用于活体研究的共聚组件。