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

• 批准号: 8012286
• 负责人: Vladimir P Torchilin
• 金额: $ 30.2万
• 依托单位: NORTHEASTERN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-01-11 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012286
• 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

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(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和使用层层(LBL)技术制备新型聚合物包衣，我们预计将获得难溶药物的新剂型，并满足适合父母给药的此类药物对稳定纳米胶体的未满足需求。目前使用的用于难溶药物的胶束载体存在严重问题：(A)药物的载药量低(通常低于5wt)；(B)不同药物无法采用相同的方案；(C)难以控制药物释放速率；(D)扩大技术规模；(E)稳定性不足。另一方面，存在一种通过LBL工艺基于相反电荷的聚电解质的交替吸附在不同颗粒上组装聚电解质多层壳的方法。我们计划用LBL涂层来制备稳定性高、释放速度可控、活性药物含量非常高(高达90%wt)的难溶药物的稳定水胶。为此，对微米级难溶药物的水悬浮液进行超声处理，使其尺寸达到纳米级，并应用LBL涂层形成溶液中稳定的药物纳米颗粒。我们假设药物纳米颗粒周围LBL壳层的形成将导致具有高活性药物含量的稳定的药物制剂。通过改变聚合物上的电荷密度和/或包衣循环次数，可以制备具有不同表面电荷和不同包衣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”表面层将允许特定的配体或报告基团和其他感兴趣的部分附着到药物纳米颗粒上。该建议的具体目标如下：(1)利用LBL技术制备稳定的难溶药物纳米胶体-紫杉醇(PCT)和喜树碱(CPT)-尺寸在100-200 nm，药物含量在75%wt以上，药物释放速度可控；(2)制备LBL纳米胶体，并结合聚乙二醇(以延长寿命)、癌症特异性单抗2C5或TAT肽(TATP)，用于肿瘤靶向或细胞内渗透；(3)研究PCT、CPT非靶向和靶向LBL纳米胶体的性质、细胞毒性、与细胞的相互作用、细胞摄取和细胞内分布；(4)研究非靶向和靶向LBL药物纳米胶体在荷瘤小鼠体内的性质；(5)制备TATP修饰的PCT和CPT LBL纳米胶体，并研究TATP介导的药物纳米胶体在体内外对药物效率的影响。这一提议将开发一种新的平台，用于制备稳定的靶向和非靶向的难溶药物纳米胶体，具有高药物含量和增强药物生物利用度。 与公众健康相关：我们计划通过应用逐层(LBL)技术，通过交替吸附相反电荷的聚电解质，在不同的颗粒上组装聚电解质多层壳，从而获得适合于非肠道给药的难溶药物的新剂型。这将得到稳定性高、释放速度可控、活性药物含量非常高(高达90%wt)的难溶药物的稳定水胶。通过改变聚合物上的电荷密度和/或包衣循环次数，可以制备表面电荷可控、包衣成分不同的微粒，以控制药物释放速率。使用反应性聚合物形成“外”表面层将允许特定的配体或报告基团和其他感兴趣的部分附着到药物纳米颗粒上。该方法将应用于几种难溶的抗癌药物，获得的纳米胶体将被各种配体额外修饰，使其具有长循环、靶向性和细胞内渗透的能力。