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

基本信息

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
项目类别：
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

项目摘要

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，在循环系统和渗透性肿瘤或其他多孔组织中，什么范围的丝状形状和灵活性是“纳米”的？我们的蠕虫状“丝状胶束”由两亲性 PEG 聚合物制成，类似于临床使用的聚合物以及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。虽然生物材料文献目前表明，远大于约 100-200 nm 的颗粒半径会导致肝脏和脾脏的吞噬细胞快速清除，但我们发现数微米长的丝状胶束可以“蠕动”通过毛细血管并在体内循环一段时间。一周或更长时间——比迄今为止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、药物保留和配体靶向——是我们体内的最终目标。长循环丝状胶束应该大大增加药物输送的“曲线下面积”，我们确实已经发现，单次注射 PEG-聚酯、8μm长的丝状胶束，负载疏水性抗有丝分裂药物紫杉醇，可以缩小实体瘤几乎一半......这是在“TAX”剂量（以毫克/千克为单位）下发现的，作为游离药物是无效的。丝状胶束似乎也比单次注射负载 TAX 和阿霉素的聚合物囊泡更有效。由于我们的两种聚合物载体由 PEG 含量仅相差 5-10% 的共聚物制成，因此我们可以更直接地比较载体形态在递送中的影响。然而，对于这两种系统，我们尚不知道有多少 TAX 是（i）直接在循环中释放的，（ii）与循环中降解载体中的球形胶束一起逐渐释放的，或（iii）从渗透到循环中的丝状胶束或囊泡中释放的。瘤。我们的最终目标是解决丝状胶束（相对于聚合物囊泡）如何利用增强渗透和保留（“EPR”）效应被动递送至肿瘤——特别是肺肿瘤（人类死亡率为 80-90%）。异种移植模型。这些载体的 EPR 效应的普遍性将在其渗透到非癌性“多孔”组织（例如受损心肌和营养不良的肌肉）的有限研究中进行检验。与上述体内研究并行，我们建议进一步设计（通过原子模拟）、制造、负载、表征（稳定性、释放等）和靶向新型嵌段共聚物载体。人们已经发现，有针对性的蠕虫状丝状胶束可以在显示合适受体的表面上协同收缩，至少在体外模型系统中是这样。随后细胞的内化可以导致从单个胶束一次性释放大量药物——原则上足以杀死单个细胞。在我们最初的目标中，我们试图通过首先阐明嵌段共聚物自组装和形状稳定性的规则，然后评估共聚物降解、细胞运输和运输来测试这种效力假设。我们建议重点开发治疗配体，包括靶向凋亡诱导剂，因为我们最终寻求更广泛的控制和靶向（但首先是被动！）共聚物组装体以进行体内研究。