Hybrid Composites for Light-Controlled CO and Silver Delivery to Malignant Sites and Infection

非技术性：该奖项由加州大学圣克鲁斯材料研究部生物材料项目授予，用于开发具有光敏一氧化碳供体的生物相容性纳米颗粒，该纳米颗粒可以根据浓度引起细胞恢复或死亡。虽然一氧化碳（CO）通常被称为“无声的杀手”，但近年来，低剂量的这种有毒气体在缺氧组织（如中风或心脏病发作）和器官移植中的有益作用已经得到证实。这一令人惊讶的发现促使研究界开发新的递送模式，其中可以将受控剂量的CO递送到生物靶点。由于CO在升高的水平下诱导癌细胞中的程序性细胞死亡，因此还尝试在恶性部位选择性地递送高剂量的CO以对抗癌症。这项研究的重点是开发基于二氧化硅的纳米粒子与光活性CO供体，可以引起细胞恢复或死亡取决于浓度。CO供体在多孔纳米颗粒内的捕获将确保来自药物副产物的非常小的副作用。研究还将致力于开发一种纤维素基绷带材料，该材料含有另一种有益的物质，即银。绷带材料将用荧光银化合物浸渍，以跟踪银向烧伤受害者经常遇到的感染伤口的持续递送。这种新的输送模式将允许监测伤口愈合过程以及施加到伤口部位的银的时间和量。这些复合材料将为治疗炎症、移植失败、恶性肿瘤和慢性伤口感染提供新的便捷方法。技术：在该项目的第一部分，主要研究者（PI）团队设计的光活性一氧化碳（CO）供体金属配合物将被纳入50-70 nm介孔二氧化硅基纳米颗粒的孔隙中，用于按需将CO输送到：a）在低通量方案下对氧化损伤部位提供保护（如在局部缺血和球囊血管成形术中）;和B）在高剂量条件下根除恶性细胞（结肠癌或乳腺癌）。纳米颗粒的表征将利用共同PI小组的专业知识，而生物测定将在PI实验室完成。将CO源限制在纳米颗粒中将确保在每种情况下来自CO供体的副产物的毒性非常小，并且纳米颗粒的增强的摄取将允许在后一种应用中优先杀死癌细胞。该项目的第二部分旨在开发含荧光银化合物的羧甲基纤维素绷带材料，以跟踪银向烧伤患者感染伤口的输送。这项研究工作将使用设计的荧光配体的银络合物来缓慢释放银（以避免沉淀，如普通银盐的情况）并通过荧光的开启或关闭来跟踪药物递送的程度。参与这些项目将使研究生和本科生（一些来自代表性不足的群体）获得广泛领域的经验，包括化学合成，生物化学，材料科学，药物设计和分析，以及细胞生物学。这项工作的成功完成将提供新的生物相容性复合材料，可用于输送CO（一种在医院环境中难以处理的气体）和银，用于各种高影响力的生物医学应用，如治疗感染，血管舒张，细胞保护免受氧化和炎症损伤，以及癌症治疗。

Nontechnical: This award by the Biomaterials Program in the Division of Materials Research to University of California Santa Cruz is for the development of biocompatible nanoparticles with photoactive carbon monoxide-donors that can elicit either cell recovery or death depending on the concentration. Although carbon monoxide (CO) is commonly known as the 'silent killer', in recent years salutary effects of low doses of this noxious gas have been demonstrated in oxygen-deprived tissues (as in stroke or heart attack) and in organ transplants. This surprising discovery has prompted the research community to develop new delivery modes in which controlled doses of CO can be delivered to biological targets. Because CO induces programmed cell death in cancer cells at elevated levels, attempts are also being made to deliver high doses of CO selectively at malignant sites to combat cancer. This research focuses on development of silica-based nanoparticles with photoactive CO-donors that can elicit either cell recovery or death depending on the concentration. Entrapment of the CO-donor within the porous nanoparticles will ensure very little side effects from the byproducts of the drug. Research will also be directed toward development of a cellulose-based bandage material that incorporates another salutary agent, namely silver. The bandage material will be impregnated with fluorescent silver compounds to track the sustained delivery of silver to infected wounds, often encountered on burn victims. This new delivery mode will allow monitoring of the wound healing process with time and amount of silver applied to the wound site. Together, these composite materials will provide new and convenient ways to treat inflammation, transplant failures, malignancies, and chronic wound infections.Technical: In the first part of the project, photoactive carbon monoxide (CO)-donating metal complexes designed in the Principal Investigator's (PI) group, will be incorporated into the pores of 50-70 nm mesoporous silica-based nanoparticles for on-demand CO delivery to: a) provide protection to oxidatively-damaged sites (as in ischemia and balloon angioplasty) under low-flux regimen; and b) eradicate malignant cells (colon or breast cancer) under high dose conditions. Characterization of the nanoparticle will utilize the expertise of the co-PI's group while the biological assays will be completed in the PI's laboratory. Confinement of the CO sources in the nanoparticles will ensure very little toxicity from the byproducts of the CO-donors in each case and the enhanced uptake of the nanoparticles will allow preferential kill of cancer cells in the latter application. The second part of the project is intended to develop carboxymethyl cellulose bandage materials with impregnated fluorescent silver compounds to track silver delivery to infected wounds, often seen in burn victims. This research effort will use designed silver complexes of fluorescent ligands for slow release of silver (to avoid precipitation as is the case with ordinary silver salts) and tracking the extent of drug delivery through turn-on or turn-off of fluorescence. Participation in these projects will allow the graduate and undergraduate students (some from underrepresented groups) to acquire experience in a wide range of fields including chemical synthesis, biochemistry, materials science, drug-design and assays, and cell biology. Successful completion of the work will afford new biocompatible composites that could be employed to deliver CO (a difficult gas to handle in hospital settings) and silver for various high-impact biomedical applications such as the treatment of infections, vasorelaxation, cytoprotection from oxidative and inflammatory damage, and cancer therapy.