Nanospheres as Delivery Vehicles for Psoriasis Therapeutics

纳米球作为银屑病治疗的递送载体

• 批准号: 7619164
• 负责人: BOZENA B MICHNIAK-KOHN
• 金额: $ 36.33万
• 依托单位: RUTGERS, THE STATE UNIV OF N.J.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7619164
• 关键词: Address; Adverse effects; Affinity; Anti-Inflammatory Agents; Anti-inflammatory; Betamethasone; Binding; Biocompatible; Biological; Biological Markers; Blood Vessels; Cadaver; Calcipotriene; Cell secretion; Cells; Characteristics; Chemicals; Clinical; Complex; Consensus; Cutaneous; Dermal; Development; Dimethyl Sulfoxide; Disease; Dose; Drug Delivery Systems; Drug Evaluation; Drug Formulations; Drug usage; Drug vehicle; Effectiveness; Esters; Ethylene Glycols; Exposure to; Feasibility Studies; Future; Goals; Hour; Human; Hydration status; Hydrophobicity; In Vitro; Inflammatory; Label; Modeling; Modification; Mus; Nanosphere; Necrosis; Oligonucleotides; Oral; Organic solvent product; Paclitaxel; Particulate; Penetration; Pharmaceutical Preparations; Physiological; Play; Polymers; Porosity; Property; Psoriasis; Rheumatoid Arthritis; Role; Sampling; Skin; Source; Structure; System; Tail; Techniques; Therapeutic; Tissues; Topical agent; Topical application; Toxic effect; Tyrosine; absorption; base; biodegradable polymer; cell behavior; copolymer; cytokine; cytotoxic; cytotoxicity; design; drug distribution; drug efficacy; ethylene glycol; improved; in vitro testing; in vivo; keratinocyte; lipophilicity; nanosized; nile red; novel; novel strategies; novel therapeutics; pre-clinical; response; self assembly; tool; trafficking

DESCRIPTION (provided by applicant): The clinical utility of topical drug administration is critically dependent on improved delivery systems that will allow the administration of therapeutics that are difficult for the body to take up. Within this context, amphiphilic, biodegradable polymers that can self assemble into nano-sized structures have been identified as a promising platform for the development of cutaneous delivery carriers. There is also consensus that a better understanding of the complex interactions that control the biological responses of cells and tissue to nano- sized carriers is of high importance. This application addresses both issues. Our unique nanosphere system is based on a biodegradable, biocompatible, and non-cytotoxic polymer that provides a high degree of structural versatility for complexing lipophilic therapeutics. The nanospheres were formed by the self-assembly of ABA- type amphiphilic triblock copolymer derived exclusively from natural metabolites. A-blocks are poly(ethylene glycol), PEG, and hydrophobic B-blocks are oligomers of desaminotyrosyl-tyrosine alkyl esters (DTR) and non- toxic diacids. The choice of oligo(DTR-diacid) for the middle block was based on its tunable hydrophobicity and degradability under physiological conditions. Modulation of cell behavior and non-fouling characteristics of non- cytotoxic and biocompatible PEG makes it attractive for in vivo applications. Additionally, the presence of PEG could provide superior hydration of the skin thereby increasing the skin permeation ability of nanospheres. No other group has demonstrated successful topical skin delivery in vitro using hollow nanospheres based on a fully biodegradable, self-assembling triblock copolymer that possesses immunomodulatory activities of tissue necrosis factor antagonists. Our nanospheres significantly enhanced skin penetration of highly lipophilic model agents in human cadaver skin compared to a non-particulate formulation. No detectable transdermal permeation was observed even after 24 hours application, suggesting that these nanospheres can be used in topical drug delivery. In addition, major advantages of the polymeric system proposed here include (i) ease of formulation of nano-sized hollow spheres in an ideal size range and narrow distribution, (ii) complete degradability, (iii) non-toxicity, and (iv) chemical diversity allowing for structural modifications and optimization. We plan to use this novel approach to identify a set of generally applicable design parameters for the development of optimized and biologically compatible topical delivery carriers. Our goal is to study the feasibility of tyrosine-derived nanospheres as delivery vehicles for a wide range of lipophilic drugs into the skin as well as nanospheres interactions with healthy and diseased skin. This would result in better understanding of the barriers to efficient topical delivery and promote the design of a formulation for the delivery of psoriasis therapeutics. If successful, the concepts proposed here have the potential to contribute significantly to the future development of skin-targeted applications. Biodegradable non-cytotoxic nanospheres loaded with lipophilic therapeutics will be prepared and optimized for the efficient delivery of drugs into the skin. These topical agents will provide new therapeutic avenues for the treatment of psoriasis while minimizing systemic cytotoxicity of harsh therapeutics. The nanosphere design is highly versatile and will significantly contribute to topical drug delivery applications.

描述（由申请人提供）：局部药物给药的临床实用性取决于改进的递送系统，这将使人体难以服用的治疗剂。在这种情况下，可以自我组装成纳米大小的结构的两亲性，可生物降解的聚合物已被确定为开发皮肤递送载体的有前途的平台。还达成共识，即更好地理解控制细胞和组织对纳米载体的生物学反应的复杂相互作用是很重要的。该应用程序解决了这两个问题。我们独特的纳米球系统基于可生物降解，生物相容性和非环毒性聚合物，该聚合物为络合亲脂性疗法提供了高度的结构多功能性。纳米球是由仅从天然代谢物衍生而来的Aba-型两亲性三嵌段共聚物的自组装形成的。 A块是聚（乙二醇），PEG和疏水性B块是Deaminotyrosyl-酪氨酸烷基烷基酯（DTR）和非毒性二氧化氢的低聚物。在生理条件下，对中间块的寡核酸（DTR-DIACID）的选择是基于其可调节的疏水性和降解性。非细胞毒性和生物相容性PEG的细胞行为和非污染特征的调节使其对体内应用有吸引力。另外，PEG的存在可以提供皮肤的优质水合，从而提高纳米球的皮肤渗透能力。没有其他小组在基于完全可生物降解的，自组装的三嵌段共聚物基于空心纳米球的体外表现出成功的局部皮肤递送，该共聚物具有组织坏死因子拮抗剂的免疫调节活性。与非参数配方相比，我们的纳米球显着增强了人尸体皮肤中高度亲脂性模型的皮肤渗透。即使在24小时后，也没有观察到可检测的透皮渗透，这表明这些纳米球可用于局部药物递送。此外，此处提出的聚合系统的主要优势包括（i）在理想尺寸范围和狭窄分布中易于制定纳米尺寸的空心球，（ii）完全降解性，（iii）无毒性，（iiv）化学多样性，允许结构修饰和优化。我们计划使用这种新颖的方法来确定一组普通的设计参数，以开发优化和生物学上兼容的局部递送载体。我们的目标是研究酪氨酸衍生的纳米球作为递送车的可行性，用于将多种亲脂性药物用于皮肤，以及纳米球与健康和患病的皮肤相互作用。这将更好地理解有效的局部交付的障碍，并促进牛皮癣治疗剂的配方设计。如果成功的话，这里提出的概念有可能为靶向皮肤的应用的未来发展做出重大贡献。可以为有效递送药物进入皮肤的可生物降解的非毒性纳米球，并为有效递送药物提供并进行优化。这些局部药物将为治疗牛皮癣提供新的治疗途径，同时最大程度地减少严厉的治疗疗法的全身细胞毒性。纳米球设计用途高，将有助于局部药物输送应用。