Layer-by-layer nanocarriers for highly efficient solubilization of insoluble drug

层层纳米载体可高效溶解不溶性药物

基本信息

批准号：
8204760
负责人：
Vladimir P Torchilin
金额：
$ 32.5万
依托单位：
NORTHEASTERN 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：
2010-01-11 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8204760
关键词：
Adsorption Alginates Alkanesulfonates Allylamine Antineoplastic Agents Appearance Architecture Area Biocompatible Biodistribution Biological Availability Blood Blood Circulation Blood capillaries Bovine Serum Albumin Breast Adenocarcinoma Caliber Camptothecin Cancer cell line Cell Culture Techniques Cell Line Cell Membrane Permeability Cells Cellulose Charge Chitosan Chondroitin Clinic Collaborations Colloids Complex Data Deposition Development Dextran Sulfate Dextrans Diagnostic Dosage Forms Dose Drug Carriers Drug Compounding Drug Controls Drug Delivery Systems Drug Formulations Drug Kinetics Drug toxicity Drug usage Engineering Environment Ethylenes Excretory function Experimental Neoplasms Gelatin Goals Hematopoietic Neoplasms Heparin Human Hyaluronic Acid Hydrophobicity Imines In Vitro Individual Laboratories Ligands Liposomes Location Longevity Lymphoma MCF7 cell Malignant Neoplasms Mediating Metabolic Micelles Microcapsules drug delivery system Mind Monitor Monoclonal Antibodies Mus Nude Mice Paclitaxel Participant Penetration Peptides Permeability Pharmaceutical Preparations Pharmacologic Substance Polyethylene Glycols Polylysine Polymers Preparation Process Property Protamine Sulfate Protocols documentation Public Health Reporter Research Personnel Scheme Sodium Solid Solubility Solutions Sonication Surface Suspension substance Suspensions System Techniques Technology Testing Therapeutic Therapeutic Effect Thick Time Treatment Efficacy Ultrasonics Ultrasonography Universities Visit Water Work acrylic acid aqueous base biocompatible polymer cancer cell capsule colloidal nanoparticle controlled release density design dextran drug candidate drug development drug efficacy improved in vivo innovation interest intravenous administration meetings melanoma nano nanoassembly nanocarrier nanocoating nanocolloid nanometer nanoparticle nanoparticulate nanoshell novel novel strategies particle polyallylamine polyanion polycation polyion prevent public health relevance research study scale up skills subcutaneous tumor uptake

项目摘要

DESCRIPTION (provided by applicant): By combining the recent developments in engineering of multifunctional pharmaceutical nanocarriers and in preparing novel types of polymeric coatings using the layer-by-layer (LbL) technology, we expect to obtain new dosage forms of poorly soluble drugs and meet the unmet need for stable nanocolloids of such drugs suitable for parental administration. There exist serious problems with currently used micellar carriers for poorly soluble drugs: (a) low loading efficacy of the drug (usually below 5% wt); (b) impossibility to apply the same protocol for different drugs; (c) difficulties in controlling the drug release rate; (d) scaling up the technology; (e) insufficient stability. On the other hand, there exists an approach to assemble polyelectrolyte multilayer shells on various particles through the LbL process based on an alternate adsorption of oppositely charged polyelectrolytes. We plan LbL coatings to make stable aqueous colloids of poorly soluble drugs with high stability, controllable release rate, and very high content (up to 90% wt) of the active drug. For this, aqueous suspensions of poorly soluble drugs with micron range particles are subjected to ultrasonication to bring their size to the nano level, and stabilized drug nanoparticles in solution are formed by applying the LbL coating. We hypothesize that the formation of LbL shell around drug nanoparticles will result in stable drug preparations with high content of an active drug. By varying the charge density on polymers and/or the number of coating cycles, particles with a different surface charge and different composition of the coat can be prepared to control drug release rate. The use of a reactive polymer to form the "outer" surface layer will allow for the attachment of specific ligands or reporter groups and other moieties of interest to drug nanoparticles. The proposal pursues the following specific aims: (1) To prepare stable nanocolloids of poorly soluble drugs - paclitaxel (PCT), and camptothecin (CPT) - with a size of 100-to-200 nm, drug content of above 75% wt, and controllable drug release rate by using the LbL technology; (2) To prepare drug LbL nanocolloids with attached polyethylene glycol (for increased longevity), cancer-specific monoclonal antibody 2C5 or TAT peptide (TATp), for cancer targeting or intracellular penetration; (3) To investigate the properties, cytoxicity, interaction with cells, and cellular uptake and intracellular distribution of non-targeted and targeted LbL nanocolloids of PCT, and CPT in cancer cells in vitro; (4) To investigate the properties of non-targeted and targeted LbL drug nanocolloids in vivo in mice with experimental tumors; and (5) To prepare TATp-modified LbL nanocolloids of PCT, and CPT and study the effect of TATp-mediated intracellular delivery of drug nanocolloids on drug efficiency both in vitro and in vivo. This proposal will develop a novel platform for making stable targeted and non-targeted nanocolloids of poorly soluble drugs with high drug content and enhanced drug bioavailability. PUBLIC HEALTH RELEVANCE: We plan to obtain new dosage forms of poorly soluble drugs suitable for parenteral administration by applying the layer-by-layer (LbL) technology by assembling polyelectrolyte multilayer shells on various particles through the process of an alternate adsorption of oppositely charged polyelectrolytes. This will result in stable aqueous colloids of poorly soluble drugs with high stability, controllable release rate, and very high content (up to 90% wt) of the active drug. By varying the charge density on polymers and/or the number of coating cycles, particles with a controlled surface charge and different composition of the coat can be prepared to control drug release rate. The use of a reactive polymer to form the "outer" surface layer will allow for the attachment of specific ligands or reporter groups and other moieties of interest to drug nanoparticles. The approach will be applied to several poorly soluble anticancer drugs, and the nanocolloids obtained will be additionally modified by various ligands to make them long-circulating, targeted, and capable of intracellular penetration.

描述（由申请人提供）：通过结合多功能药物纳米载体工程的最新发展以及使用逐层（LBL）技术准备新型的聚合物涂料的新型类型满足适用于父母给药的此类药物稳定纳米胶体的未满足需求。目前使用的胶束载体用于可溶性差的药物存在严重问题：（a）药物的负荷功效低（通常低于5％wt）；（b）不可能将相同的方案应用于不同的药物；（c）控制药物释放率的困难；（d）扩展技术；（e）稳定性不足。另一方面，存在一种方法，可以基于LBL过程在各种粒子上组装多电解质多层壳，该方法基于相反电荷的聚电解质的替代吸附。我们计划LBL涂层，使稳定的可溶性药物具有高稳定性，可控制的释放速率和高含量（高达90％wt）的稳定水胶体。为此，用微米范围颗粒的水性悬浮液进行超声处理以使其大小达到纳米水平，并通过施加LBL涂层来形成溶液中稳定的药物纳米颗粒。我们假设在药物纳米颗粒周围的LBL壳形成将导致稳定的药物制剂，具有高含量的活性药物。通过改变聚合物的电荷密度和/或涂层周期的数量，可以准备不同的表面电荷和不同成分的颗粒来控制药物释放速率。使用反应性聚合物形成“外部”表面层将允许附着特定的配体或记者基团以及其他感兴趣的部分与药物纳米颗粒相连。该提案追求以下特定目的：（1）准备稳定的可溶性药物的稳定纳米胶体-Paclitaxel（PCT）和Camptothecin（CPT） - 大小为100至200 nm，药物的含量高于75％wt，75％wt，和使用LBL技术可控的药物释放率；（2）用附着的聚乙烯乙二醇（增加寿命），癌症特异性的单克隆抗体2C5或TAT肽（TATP）制备药物LBL纳米胶体，用于靶向癌症或细胞内渗透；（3）研究了非靶标和靶向的LBL纳米胶体的特性，细胞毒性，与细胞的相互作用以及细胞内分布和细胞内分布以及在体外癌细胞中的CPT；（4）研究具有实验性肿瘤的小鼠体内非靶向和靶向的LBL药物纳米胶体的特性；（5）准备PCT的TATP修饰的LBL纳米胶体，并研究TATP介导的药物纳米胶体细胞内递送对体外和体内药物效率的影响。该提案将开发一个新的平台，用于使稳定的靶向且非靶向的纳米胶体固定溶解性药物含量高，药物含量高并增强了药物的生物利用度。公共卫生相关性：我们计划通过在各种粒子上通过替代电荷的多层粒子在各种粒子上组装多层多层壳，从而获得适用于肠胃外管理的新剂型的可溶性药物的新剂型。。这将导致稳定的可溶性药物水胶体，具有高稳定性，可控制的释放速率和高含量（高达90％wt）的活性药物。通过改变聚合物的电荷密度和/或涂层循环的数量，具有控制表面电荷的颗粒以及外套的不同成分可以准备好控制药物释放速率。使用反应性聚合物形成“外部”表面层将允许附着特定的配体或记者基团以及其他感兴趣的部分与药物纳米颗粒相连。该方法将应用于几种可溶的抗癌药物，并且获得的纳米胶体将通过各种配体进行修饰，以使其长期循环，靶向且能够具有细胞内穿透性。