Intracellular distribution of drugs
Much of the focus of drug delivery programs has been on promoting drug absorption, enhancing drug distribution, targeting drugs to particular organs and tissues where they are active, and reducing drug exposure to sites of toxicity. These programs have been extremely successful and continue with great momentum within MIPS and elsewhere.
However, with advances in molecular biology and pharmacology, our understanding of drug action is much deeper than the organ level, and is increasingly focused on drug activity within specific subcellular domains and organelles. Alongside this increased understanding of fundamental biology, we are becoming more focused on the mechanisms by which drugs and drug delivery systems are trafficked intracellularly, and how we can manipulate these pathways to better target intracellular sites.
D4 is investigating three major approaches to intracellular drug transport:
- utilising nanoparticulate drug delivery systems to promote intracellular delivery
- understanding and utilising cellular trafficking of endogenous materials via intracellular binding proteins
- vesicular transport networks
Our interest in intracellular binding proteins stems from the realisation that many drug molecules are poorly water soluble and share many physicochemical properties with lipids and lipid soluble vitamins. These are trafficked through most cell types by protein chaperones called intracellular lipid-binding proteins. The best known and most highly expressed of these are the fatty acid binding proteins (FABPs).
In recent years, D4 has shown that a range of drugs bind FABPs selectively and with high affinity, and that this may promote both mass transport and targeting to intracellular locations such as the nucleus. These studies are now expanding to explore drug interactions with a broader range of binding proteins. We ultimately seek to link structural information of drug binding profiles by NMR and crystallography to functional studies obtained using cell and molecular biology measures of intracellular trafficking.
Another major area of interest is in drug targeting to the vesicular distribution network—in particular, the trafficking pathways of G-protein coupled receptors (GPCRs). As known for some time, many GPCRs are taken up into endosomes from the plasma membrane, while endosomes provide a sorting function—marking receptors for degradation or recycling back to the cell surface. More recently, it has become evident that GPCRs can continue to signal from the endosome, generating signals that differ from those emanating from the plasma membrane.
In a broad cross-institute collaboration, drug delivery scientists are collaborating with synthetic chemists and GPCR biologists to better understand these phenomena and to design drug analogues, prodrugs and nanostructured delivery systems to better interact with these emerging targets.