Surface-modification of polymeric micelles with sugar residues for different biomedical applications

David Wang Auditorium, 3rd floor Dalia Maydan Bldg
Alexandra Bukchin, MSc. candidate

Alexandra Bukchin, MSc. candidate Laboratory of Pharmaceutical Nanomaterials Science, Department of Materials Science and Engineering, Technion-Israel Institute of Technology, Haifa, Israel

Low solubility in biological fluids of 50-70% of the marketed drugs represents a significant drawback in drug formulation, administration and bioavailability. Polymeric micelles (PMs) were introduced as a promising nanotechnology platform for the delivery of hydrophobic drugs. Amphiphilic poly(ethylene oxide)-poly(propylene oxide) (PEO-PPO) block copolymers are thermo-responsive, display unique aggregation properties in aqueous medium and therefore may be used as successful solubilizers for poorly water-soluble drugs in the form of PMs. However, their micellization is incomplete and their physical stability jeopardized under extreme dilution. In addition, they are incapable of targeting specific cells. In this work, we investigated the synthesis and characterization of PMs surface-modified with growing sugar residues employing two chemistries – ring opening conjugation using microwave radiation and Steglich esterification reaction – in order to tune the self-assembly properties and increase the uptake by cell expressing sugar receptors. The improved self-assembly was verified by the decrease in the critical micellar concentration (CMC) and the growing micellar size. In addition, the binding of the micelles to sugar receptors was demonstrated in vitro by the concanavalin A agglutination assay. Drug encapsulation in pristine and modified PMs was studied with dasatinib and imatinib, two hydrophobic antitumoral drugs from the tyrosine kinase inhibitor family with different melting temperature and intrinsic aqueous solubility. The solubility of the drugs in water increased by several hundred-folds. First, the targeting features to cells with affinity for glucose and lactose were investigated in an in vitro model of rhabdomyosarcoma (Rh30), a pediatric type of cancer of the connective tissue. Features such as cell compatibility in the presence of the pristine and modified PMs without and with drug were evaluated. Drug-loaded PMs increased by a 100 times the efficiency of the drug to treat Rh30. Then, PMs were assessed in macrophages that are key players in the immune response to foreign body invaders and display high concentration of lectin like receptors (LLR), transmembrane proteins with high affinity binding sites and selectivity for sugar clusters. Results in this research direction are also very promising. Supervisor: Prof. Alejandro Sosnik