Ongoing work in the lab is focusing on multiple applications of the pHLIP delivery platform:
pHLIP Targeting of Acidic Tissues
Work continues using Alexa Fluor-conjugated pHLIPs to investigate additional pathological and physiological targets of pHLIP, in vivo. By expanding the potential applications of pHLIP in health and disease, we hope to find new ways for pHLIPs to contribute to human health. Imaging experiments using PET are also under way, in collaborations at Sloan Kettering and the University of Rhode Island.
pHLIP-FIRE (Fluorescent Insertion REporter)
Taking advantage of the reducing environment inside of the cell, we are working towards improving imaging contrast by delivering quenched imaging probes on the pHLIP C-terminus, where they can be inserted into targeted cells and their fluorescence activated by the reduction of disulfide bond. Work in this area is in collaboration with the laboratories of Reschetnyak and Andreev at the University of Rhode Island.
pHLIP-DIRECT (Drug Insertion and Reductive Escape in the Cytosol of Tumors)
Traditional chemotherapeutic treatments, while vital to the fight against cancers, carry with them serious side effects due to drug uptake by healthy cells. We are using pHLIPs' low-pH-selective insertion properties to impart tumor specificity on traditional chemotherapeutic agents in an attempt to improve the efficacy and decrease the side effects of chemotherapy. Additionally, pHLIP is able to translocate normally cell-impermeable cargos into cells, even large and polar molecules such as peptide nucleic acids. Ongoing studies are investigating the delivery of non-traditional therapeutic molecules, such as oncogenic microRNA-targeted peptide nucleic acid therapies in several mouse models of cancer. Work in this area is also in collaboration with the Rhode Island groups.
Computational Simulations of Transmembrane Peptide Properties
In collaboration with the DiMaio lab at the Yale School of Medicine and others, the Engelman lab is investigating the interactions between the transmembrane domains of signaling proteins using Molecular Dynamics simulations and Rosetta Membrane modeling. We also aim to apply these technologies toward further investigations of pHLIP insertion activity.