TARGETING AND DELIVERY

North Dakota State University, Fargo ND

Investigators

Linked publications & trials

Abstract

DESCRIPTION (Adapted from the applicant's abstract): Matrix metalloproteinases (MMFs) play key roles in tissue stability through their maintenance of the extracellular matrix. Consequently, they are implicated in diseases associated with native matrix degradation such as metastatic cancers, arthritis and multiple sclerosis, for which they are attractive targets for therapeutic drug regimens. Nevertheless, effective therapies targeting MMPs remain elusive. This is due at least in part to their broad distribution in both healthy and diseased tissues. The need for a new approach to targeting the MMPs associated with diseased tissues is clear. This project would employ novel strategies that bring chemical, biological and physical expertise to bear on targeting and inhibiting MMPs associated with diseased tissues where MMPs are being over expressed. Project 2 involves design and synthesis of drug delivery systems to target MMPs and synthesis of asymmetric porphyrin chromophores for incorporation into drugs for MMP inhibition. Porphyrins will be supplied to the organic synthesis group for incorporation (see project 1). Candidate drugs will be routed to this project for incorporation into triggered-release delivery vehicles. Polymerized liposomes will be functionalized with MMP substrates or substrate analogs that cross link components of the liposome. The investigators hypothesize that this will render the delivery liposomes susceptible to catalytic rupture via action of the target enzyme on substrates, which stabilize the polymerized liposomes by cross linking component lipids. The encapsulated drugs will then be released into the intercellular space where inhibition of the offending MMPs can occur. Other mildly immunogenic polymerized liposomes will be ornamented with MMP inhibitors so that they can collect multiple MMPs by tight binding of the tethered inhibitors in the enzyme active site. The investigators hypothesize that these "MMP trash cans" will subsequently be expelled from the tissues through normal immune pathways. Promising drugs and delivery systems will be tested by enzymatic assay using isolated enzymes. Those showing reasonable MMP inhibition will be supplied to the biology core group for testing in whole cell cultures. The drugs appended with free-base porphyrins will also be delivered by triggered release liposomes. This should keep them metal free until they are released in the vicinity of MMFs. They will be screened for their ability to bind to and extract Zn2+ from the enzyme active site. Since MMPs are Zn-dependent enzymes, loss of Zn2+ is expected to inactivate the enzyme. Moreover, the free base and metalloporphyrins could be activated with light to serve as photodynamic therapy (PDT) agents. Model systems to study Zn2+ extraction are also proposed.