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

University Of California-Santa Cruz, Santa Cruz CA

Investigators

Abstract

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.