טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentRaskin Maya
SubjectPolysaccharide self-assembly nano-biomaterials for the
development of innovative mucoadhesive drug
delivery systems
DepartmentDepartment of Materials Science and Engineering
Supervisor Professor Alejandro Sosnik
Full Thesis textFull thesis text - English Version


Abstract

Poor aqueous solubility of drugs is one of the most challenging drawbacks in pharmaceutical product development. Different nanotechnology platforms have been developed to improve the biological performance of those drugs. Polymeric micelles (PMs), nanostructures generated by the spontaneous arrangement of amphiphilic copolymers blocks above the critical micellar concentration, have emerged as one of the most versatile ones owing the high diversity of hydrophilic and hydrophobic blocks and the chemical flexibility to tailor the amphiphilic structure. PMs were mainly utilized for the intravenous administration of antitumorals drugs and not for mucosal routes because of two main limiting drawbacks: weak interaction with mucus and inability to sustain the release of the encapsulated payload over time. Aiming to extend the application of PMs to non-parenteral administration routes (e.g., oral), this project addressed the design of a novel type of mucoadhesive PM that combines high physical stability and rate-controlling capacity for the delivery of drugs by different mucosal routes. To achieve this, mucoadhesive hydrophilic polysaccharides approved for pharmaceutical were hydrophobized by grafting hydrophobic side-chains made of the thermo-responsive poly(N-Isopropylacrylamide) (pNiPAam) that displays a hydrophilic-to-hydrophobic transition between 30 and 32oC. The graft copolymers were fully characterized by FTIR, 1H-NMR, elemental analysis, DSC and GPC. In addition, the micellization (critical micellar concentration, physical stability, size, size distribution, quantification and visualization of the micelles) was studied by dynamic light scattering and nanoparticle tracking analysis.  Then, the mucoadhesiveness in vitro was evaluated using the mucin method and the cytotoxicity with the Caco2 cell line, an in vitro model of intestinal epithelium. In addition, the encapsulation capacity and release of a model drug was assessed. Finally, the stabilization of the PMs by ionotropic crosslinking was assessed in both drug-free and drug-loaded micelles. Overall results highlight the potential of these novel PMs as a flexible nanotechnology platform for mucosal drug delivery.