D1

Novel multifunctional drug carriers to address novel drugs in heart and pulmonary diseases

Coordinators: E. Fattal, V. Dive
Starting date: January 2012

Nanotechnology applied to drug delivery has proven over the past years to have a dramatic impact in medicine by improving the biodistribution and the target site accumulation while reducing side effects of systematically applied therapeutics. In cancer therapy, most of the nanotechnologies administered to animals or humans take advantage of the enhanced permeation and retention effect (EPR) in which the nanoparticles can cross the leaky neovessels and, due to a poor lymphatic drainage within the tumour, accumulate in the target tissue. An attempt to increase the amount of drug that actually reaches the target tissue was carried out using ligand-addressed nanoparticles. However, one main issue remains the tissue targeting specificity. In the field of tumour targeting by nanotechnologies, rather ubiquitous receptors were addressed such as the folic acid, hyaluronic acid, transferin, or epithelial growth factor receptors. Multifunctional nanoparticles, combining imaging and drug delivery properties hold great promise for the future of therapy, as they could report on the early onset of a disease in each individual patient and deliver a suitable therapeutic agent at the target site. Partner 16 has recently proposed two strategies for the design of multifunctional nanocarriers that could be imaged by MRI or ultrasound imaging. If targeted in a highly specific manner, such nanocarriers could significantly improve the treatment of several diseases that cannot be easily reachable by conventional drugs.

The challenge that we want to meet here is to target drug-carriers to the cardiovascular (CV) sphere and the pulmonary vasculature to improve the treatment of three classes of CV diseases: pulmonary arterial hypertension (PAH), atherosclerosis and ischemic heart disease. Several proteins are specifically expressed in the CV sphere and the pulmonary vasculature and will be used to anchor cargo particles for local drug delivery. The first one is a receptor involved in the pathogenesis of PAH, Tie2. Tie2 is almost exclusively expressed on endothelial cells, and has been recognized as a major signaling pathway that controls vascular remodeling. Thus, Tie2 can be used to target drug-carriers for the treatment of PAH. In the field of atherosclerosis, MMP12 appears as an interesting candidate. MMP12, also called macrophage metalloelastase, is a member of the matrix metalloproteinase (MMP) family. It is highly expressed by macrophages present in atheromatous plaque and has been particularly implicated in plaque progression and rupture in humans and animal models of atherosclerosis. MMP12 thus represents a valuable targeting system to deliver molecules to treat atherosclerosis but also, as discussed below, a therapeutic target on its own. Finally, drug delivery to myocardial cells could be achieved by targeting a protein expressed in the extracellular matrix of cardiac myocytes, the alpha7beta1D integrin. Among the many integrins present in the extracellular matrix, the alpha7beta1D isoform is only found in striated muscle, i.e. heart and fast skeletal muscle. In the skeletal muscle, it is only expressed in the myotendinous junction. Therefore, alpha7beta1D integrin provides a unique way to locally deliver drugs to treat ischemic heart disease or induce cardioprotection.

In addition to the new drugs that will be generated and developed in the CV target project T1, there exists already at least one novel drug family for each of the three CV diseases listed above that will be tested here. The first one includes tyrosine kinase inhibitors to treat PAH. These new compounds already used in cancer therapy are promising in PAH for their action on pulmonary vascular cells. However, they present different levels of toxicity to the heart, and to cardiomyocytes in particular, in experimental models of PAH. Therefore, nanoparticles targeted to the endothelial cells and containing tyrosine kinase inhibitors could treat PAH without inducing these collateral damages. The second one includes inhibitors of MMP12 to treat atherosclerosis. The recent discovery of highly specific inhibitors of MMP-12 by Partner 11 makes it now possible to evaluate the potential therapeutic efficacy of a specific blockade of MMP-12 in animal models of atherosclerosis. Infusion of selective MMP-12 inhibitors through mini-pumps was shown to reduce plaque growth and rupture in a mice model of atherosclerosis. However, optimal exploitation of these inhibitors would require the development of selective delivery systems, entrapping MMP-12 inhibitors, able to concentrate these inhibitors into plaque macrophages. This can be achieved by grafting particle surface with MMP-12 inhibitors. The third one is cyclosporine to prevent ischemia-reperfusion injury after myocardial infarction. Opening of the mitochondrial permeability transition pore (mPTP) appears to be a pivotal event in ischemia-reperfusion injury. Cyclosporine is a classically used immunosuppressive agent which has been shown recently to also inhibit mPTP and reduce infarct size. Cyclosporine is a cyclic peptide with a low stability and a poor intracellular penetration. Therefore, there is a need to address cyclosporine in a specific fashion to the ischemic myocardium in order to potentiate its cardiac action while reducing its immunosuppressive effect.

AIM 1 - DEVELOPING MULTIFUNCTIONAL PARTICLES
Partner 11; Partner 12; Partner 13 (team 3); Partner 16
AIM 2 - PARTICLE CHARACTERISATION
Partner 16
AIM 3 - IN VIVO TRACKING AND PHARMACOLOGICAL EVALUATION
Partner 2; Partner 6; Partner 11; Partner 12