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Multi-Color Exchange Transfer Imaging of Drug Delivery Nanocarriers
This project focuses on the design of biodegradable contrast agents, based on peptides and heterocycles, to be used for the labeling of drug delivery vehicles such as liposomes and polymeric particles. Drugs for systemic and local administration of chemotherapy will be packaged together with these CEST agents, and monitored using multiple exchangeable protons at different frequencies, in a manner similar to multiple colors in optical imaging. As a first application, this technology will be used to monitor two different anti-cancer drugs: paclitaxel and doxorubicin enclosed in PLGA-PEG and liposome nanoparticles for the treatment of cervical tumors.
In AIM1, we will fine tune our library of polypeptides and organic heterocycle CEST agents for incorporation into liposomes and polymeric particles. These agents will be synthesized, screened using MRI in vitro, and used in Aims 2 and 3. The new peptide sequences that produce the strongest CEST contrast will be the intended product for the reporter genes outlined in Project 3.
In AIM2, the best CEST agents from AIM 1 will be incorporated into stealth doxorubicin-loaded liposomes and stealth poly(lactic-co-glycolic acid)-copolyethylene glycol (PLGA-PEG) nanoparticles containing paclitaxel. Using MRI, -5-8 selected CEST agents per year (from Aim 1) will be incorporated into particles and screened in vitro, now within particles, and those showing strong contrast will be tested in vivo following tail vein injection in mice bearing cervical tumors. We will test the hypothesis that the CEST contrast agents can be used to label nanoparticles and monitor their biodistribution and persistence in the tumors.
In AIM3, as in AIM2, selected CEST agents from AIM1 will be incorporated into drug loaded liposome and polymer particles, screened using MRI in their new particle form in vitro, and those showing strong contrast tested in vivo following local administration into the vaginal tract of mice bearing cervical tumors. The polymer-based PLGA-PEG particles we will use are able to rapidly penetrate human mucus secretions, allowing them to avoid rapid clearance from the vagina, which we have shown leads to greatly enhanced efficacy against cervical tumors compared to conventional nanoparticles. We will test the hypothesis that CEST labels will allow us to monitor the distribution and persistence of nanoparticles in the cervicovaginal tract. We will also test the hypothesis that we can use "Multicolor" CEST imaging to distinguish between two nanocarriers at once, with one carrier administered systemically, and a second administered locally.