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

非技术奖项：该奖项由加州大学圣克鲁斯分校材料研究部生物材料项目颁发，用于开发具有光活性一氧化碳捐赠者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“沉默的杀手”，但近年来，在缺氧组织（如中风或心脏病发作）和器官移植中已经证明了低剂量这种有毒气体的有益作用。这一令人惊讶的发现促使研究界开发新的递送模式，在这种模式中，可控剂量的一氧化碳可以递送到生物目标。由于一氧化碳在高水平下诱导癌细胞的程序性细胞死亡，人们也在尝试在恶性部位选择性地输送高剂量的一氧化碳来对抗癌症。本研究的重点是开发具有光活性co供体的硅基纳米颗粒，这种纳米颗粒可以根据浓度引起细胞恢复或死亡。将co供体包裹在多孔纳米颗粒内将确保药物副产物的副作用很小。研究还将针对纤维素为基础的绷带材料的发展，其中包含另一种有益的剂，即银。这种绷带材料将浸渍荧光银化合物，以追踪银持续输送到感染伤口的情况，这种情况经常发生在烧伤患者身上。这种新的递送模式将允许监测伤口愈合过程的时间和数量的银应用于伤口部位。总之，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和方便的方法。技术方面：在项目的第一部分，由首席研究员（PI）小组设计的光活性一氧化碳（CO）供体金属配合物将被纳入50-70纳米介孔硅基纳米颗粒的孔中，用于按需输送CO: a)在低通量方案下为氧化损伤部位（如缺血和球囊血管成形术）提供保护；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副PI组的专业知识，而生物测定将在PI的实验室完成。限制纳米颗粒中的CO源将确保在每种情况下CO供体副产物的毒性很小，并且纳米颗粒的增强吸收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有浸渍荧光银化合物的羧甲基纤维素绷带材料，以跟踪银向感染伤口的输送，这种情况常见于烧伤患者。这项研究工作将使用设计的荧光配体的银复合物来缓慢释放银（避免沉淀，就像普通银盐一样），并通过开启或关闭荧光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，可用于输送一氧化碳（一种在医院环境中难以处理的气体）和银，用于各种高影响的生物医学应用，如治疗感染、血管松弛、防止氧化和炎症损伤的细胞保护，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.