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）：局部给药的临床效用很大程度上取决于改进的递送系统，该系统将允许施用身体难以吸收的治疗剂。在此背景下，可以自组装成纳米尺寸结构的两亲性可生物降解聚合物已被认为是开发皮肤递送载体的有前途的平台。人们还一致认为，更好地理解控制细胞和组织对纳米尺寸载体的生物反应的复杂相互作用非常重要。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、生物相容性且无细胞毒性的聚合物，为复合亲脂性治疗提供高度的结构多功能性。纳米球是由仅源自天然代谢物的 ABA 型两亲性三嵌段共聚物自组装形成的。 A-嵌段是聚(乙二醇)、PEG，疏水性B-嵌段是脱氨基酪氨酰-酪氨酸烷基酯(DTR)和无毒二酸的低聚物。中间嵌段选择寡聚（DTR-二酸）是基于其在生理条件下可调的疏水性和可降解性。无细胞毒性和生物相容性 PEG 对细胞行为的调节和无污染特性使其在体内应用中具有吸引力。此外，PEG的存在可以为皮肤提供优异的水合作用，从而增加纳米球的皮肤渗透能力。没有其他研究小组证明使用基于完全可生物降解的自组装三嵌段共聚物的中空纳米球在体外成功进行局部皮肤递送，该共聚物具有组织坏死因子拮抗剂的免疫调节活性。与非颗粒制剂相比，我们的纳米球显着增强了高亲脂性模型药物在人体尸体皮肤中的皮肤渗透性。即使在应用 24 小时后也没有观察到可检测到的透皮渗透，这表明这些纳米球可用于局部药物递送。此外，本文提出的聚合物体系的主要优点包括（i）易于配制理想尺寸范围和窄分布的纳米尺寸空心球，（ii）完全降解性，（iii）无毒性，以及（iv）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遍适用的设计参数，用于开发优化且生物相容的局部递送载体。我们的目标是研究酪氨酸衍生的纳米球作为多种亲脂性药物进入皮肤的递送载体的可行性，以及纳米球与健康和患病皮肤的相互作用。这将导致更好地了解有效局部递送的障碍，并促进用于递送牛皮癣治疗剂的制剂的设计。如果成功，这里提出的概念有可能对皮肤针对性应用的未来发展做出重大贡献。将制备和优化负载亲脂性治疗剂的可生物降解的非细胞毒性纳米球，以将药物有效输送到皮肤中。这些外用药物将为治疗牛皮癣提供新的治疗途径，同时最大限度地减少严酷治疗的全身细胞毒性。纳米球设计具有高度通用性，将为局部药物输送应用做出重大贡献。