Nanomedicines for targeted or local drug delivery for cancer treatment (V. Préat)

Bruxelles Woluwe

Polymeric and lipidic nanomedicines are developed for the administration of poorly water soluble drugs, peptides, vaccines and nucleic acids. Our research mainly focuses on (i) intravenous delivery of drug-loaded of nanoparticles targeting the tumoral endothelium and cancer cells ii) local delivery of anticancer drugs.

Several main mechanisms of delivery of drug-loaded nanoparticles to tumors have been reported (Figure 1): (i) passive targeting through leaky vasculature surrounding the tumors, described as the enhanced permeability and retention effect (EPR) (ii) “active” targeting by grafting specific ligands of cancer cells or angiogenic endothelial cells to the surface of the nanocarrier (iii) magnetic targeting of SPIO (small paramagnetic iron oxides) loaded nanoparticles.

Figure 2: Passive, active and magnetic targeting of anticancer drug-loaded nanomedicines

We formulated various nanocarriers (micelles and untargeted or targeted nanoparticles) loaded with several anti-cancer drugs to specifically target tumors and improve the therapeutic index of anti-cancer drugs by nanomedicines. For example, PLGA-based nanoparticles formulated for the delivery of paclitaxel, a new cyclin dependent kinase inhibitor and doxorubicin induced a higher regrowth delay of tumors in vivo than free drugs. Exploiting the αvβ3 integrin overexpression by tumoral endothelium and tumor cells, we designed PLGA-based nanoparticles grafted with the RGD peptide and demonstrated the “active” targeting of these PLGA-based nanoparticles.

We formulated multi-functional nanoparticles for the encapsulation of a therapeutic drug and a contrast agent (SPIO) that can be targeted by magnets and significantly enhanced drug biodistribution in the tumors. Anticancer drug-loaded nanomedicines are developed for the treatment of glioblastoma. In particular lauroyl gemcitabine forming hydrogel significantly improved the survival of glioblastoma bearing mice when perisurgically injected in the resection cavity.
Coentrapment of melanoma-associated antigens and Toll like receptor ligands in mannose-functionalizes nanoparticles potentiated Th1 immune response and decreased tumor growth in therapeutic settings.
Our current projects are focussed on the mechanisms of action of nanomedicines, in particular their effect on the tumor microenvironment.

We also aim to develop formulation (nanoparticles) and physical methods (electroporation) for the delivery of DNA and RNA with a particular interest in vaccination and cancer treatments (Figure 2). Electroporation of DNA was optimized to deliver plasmid vaccines into the skin or the muscle. This potent delivery method allows high level of expression. Optimised plasmids encoding tumor antigens elicited humoral and cellular immune response and induced tumor control or regression. Electroporation of plasmid coding for host defense peptides promoted wound healing in healthy and diabetic mice models.
Our current research focuses now on the combination of optimized anticancer DNA vaccines and immune checkpoint inhibitors.

Figure 3: Plasmid DNA and siRNA delivery