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: 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
• 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

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和利用层层（LbL）技术制备新型聚合物涂层的最新进展，我们期望获得难溶性药物的新剂型，并满足此类药物对适合肠胃外给药的稳定纳米胶体的未满足的需求。 目前使用的难溶性药物的胶束载体存在严重的问题：(a)药物的载药效率低(通常低于5％wt)； (b) 不可能对不同的药物应用相同的方案； (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，存在一种通过基于带相反电荷的聚电解质的交替吸附的LbL过程在各种颗粒上组装聚电解质多层壳的方法。我们计划LbL包衣来制备难溶性药物的稳定水胶体，具有高稳定性、可控释放速率和非常高的活性药物含量（高达90%wt）。为此，对微米级颗粒的难溶性药物的水悬浮液进行超声波处理，使其尺寸达到纳米水平，并通过应用 LbL 涂层形成溶液中稳定的药物纳米颗粒。 我们假设药物纳米粒子周围形成 LbL 壳将产生活性药物含量高的稳定药物制剂。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组成的颗粒以控制药物释放速率。使用反应性聚合物形成“外”表面层将允许将特定配体或报告基团以及其他感兴趣的部分附着到药物纳米颗粒上。 该提案追求以下具体目标：（1）利用LbL技术制备稳定的难溶性药物紫杉醇（PCT）和喜树碱（CPT）纳米胶体，其尺寸为100至200 nm，药物含量在75% wt以上，并且药物释放速率可控； （2）制备附有聚乙二醇（延长寿命）、癌症特异性单克隆抗体2C5或TAT肽（TATp）的药物LbL纳米胶体，用于癌症靶向或细胞内渗透； (3) 体外研究PCT、CPT非靶向和靶向LbL纳米胶体的性质、细胞毒性、与细胞的相互作用以及细胞摄取和细胞内分布； (4) 研究非靶向和靶向LbL药物纳米胶体在实验性肿瘤小鼠体内的特性； (5)制备TATp修饰的PCT和CPT的LbL纳米胶体，并研究TATp介导的药物纳米胶体的细胞内递送对体外和体内药效的影响。 该提案将开发一个新的平台，用于制备具有高药物含量和增强的药物生物利用度的难溶性药物的稳定的靶向和非靶向纳米胶体。 公共卫生相关性：我们计划通过应用层层（LbL）技术，通过带相反电荷的聚电解质的交替吸附过程，在各种颗粒上组装聚电解质多层壳，获得适合肠外给药的难溶性药物的新剂型。这将产生难溶性药物的稳定水胶体，具有高稳定性、可控释放速率和非常高的活性药物含量（高达 90% wt）。通过改变聚合物上的电荷密度和/或包衣循环次数，可以制备具有受控表面电荷和不同包衣组成的颗粒以控制药物释放速率。使用反应性聚合物形成“外”表面层将允许将特定配体或报告基团以及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性抗癌药物，获得的纳米胶体将通过各种配体进行额外修饰，使其具有长循环性、靶向性和细胞内渗透能力。