Design and Application of Photoresponsive Modules in Circulating Erythrocytes

循环红细胞光响应模块的设计与应用

• 批准号: 10610352
• 负责人: DAVID S. LAWRENCE
• 金额: $ 72.08万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10610352
• 关键词: Address; Adverse effects; Attention; Behavior; Biochemistry; Biological; Cardiovascular system; Cell surface; Cells; Circulation; Clinical Trials; Combined Modality Therapy; Disease; Drug Delivery Systems; Drug Kinetics; Elements; Enzymatic Biochemistry; Erythrocytes; Eye; Face; Generations; Half-Life; Light; Malignant Neoplasms; Mediating; Metabolic; Metabolism; Modification; Molecular; Optics; Organism; Parents; Penetrance; Penetration; Peptides; Pharmaceutical Preparations; Phototherapy; Plasma; Positioning Attribute; Prodrugs; Property; Proteins; Reactive Oxygen Species; Reporting; Research; Site; Surface; System; Technology; Therapeutic; Therapeutic Agents; Tissues; Toxic effect; Treatment Efficacy; Vitamin B 12; absorption; aggressive therapy; analog; design; dosage; drug action; drug disposition; fluorophore; functional group; improved; in vivo; inhibitor; interest; new technology; peptide drug; photolysis; programs; scaffold; side effect; small molecule; small molecule therapeutics; standard of care; targeted delivery; targeted treatment; therapeutic protein; water solubility

Project Summary The use of light to activate therapeutic agents at diseased sites offers the advantage of aggressive treatment with exquisite spatial and temporal control, thereby reducing potential deleterious side effects at unintended sites. Although photo-activated pro-drugs have been reported, these species require short wavelengths (<450 nm) for activation. However, maximal tissue penetrance by light occurs within the “optical window of tissue” (600 – 900 nm), well beyond the wavelength range of existing photo-cleavable functional groups. We’ve developed a new technology that transforms drugs into light responsive “phototherapeutics” that are conveyed by circulating erythrocytes. The proposed research program seeks to address several fundamental questions associated with light responsive therapeutics: (1) What is the mechanism of light capture and drug release in the B12-based molecular scaffolds, (2) what is the optimized structural relationship between the light capturing antennas and the photolysis of the B12-drug bond, (3) what is the scope of therapeutic agents that are amenable to this photo-technology, (4) do phototherapeutics furnish an enhanced therapeutic window relative to the standard of care, and (5) what is the relationship between the activation wavelength and the therapeutic window?

项目摘要 在疾病部位使用光来激活治疗剂的优点是 通过精细的空间和时间控制进行积极的治疗，从而减少 对非预期地点的潜在有害副作用。虽然光激活的前药物 已经报道，这些物种需要短波长(&lt；450 nm)才能激活。 然而，光对组织的最大透过率发生在“组织的光学窗口”内。 (600-900 nm)，远远超出现有可光裂解官能团的波长范围 组。我们已经开发出一种新技术，可以将药物转化为对光有反应的 “光疗”是由循环中的红细胞传递的。建议数 研究计划试图解决与光相关的几个基本问题 反应疗法：(1)光捕捉和药物释放的机制是什么？ B12基分子支架，(2)优化的结构关系是什么 在光捕捉天线和B12-药物键的光解之间，(3)什么 适用于这种光技术的治疗剂的范围，(4)是否 光疗法提供了一个相对于标准的增强的治疗窗口 CARE，以及(5)激活波长与 治疗窗口？

项目成果

Taking phototherapeutics from concept to clinical launch.

• DOI: 10.1038/s41570-021-00326-w
• 发表时间: 2021-11
• 期刊: Nature reviews. Chemistry
• 作者: Vickerman BM;Zywot EM;Tarrant TK;Lawrence DS
• 通讯作者: Lawrence DS

Assessment of Photoreleasable Linkers and Light-Capturing Antennas on a Photoresponsive Cobalamin Scaffold.

• DOI: 10.1021/acs.joc.1c02931
• 发表时间: 2022-04-15
• 期刊: JOURNAL OF ORGANIC CHEMISTRY
• 影响因子: 3.6
• 作者: Welfare, Joshua G.;Mortelliti, Michael J.;McGlade, Caylie A.;Hartman, Timothy W.;Dempsey, Jillian L.;Lawrence, David S.
• 通讯作者: Lawrence, David S.