טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentTalal Julia
SubjectNanoparticle-in-Nanoparticle Multimicellar Nanomaterials
for Drug Delivery via Sol-Gel Chemistry
Coupled to Spray-Drying Technology
DepartmentDepartment of Materials Science and Engineering
Supervisor Professor Alejandro Sosnik
Full Thesis textFull thesis text - English Version


Abstract

   Polymeric micelles (PMs) can increase the aqueous solubility of poorly-water soluble drugs, owing to their unique structure of inner hydrophobic core and outer hydrophilic corona. However, one of their most remarkable drawbacks is that they disassemble under dilution in body fluids and struggle to sustain the release of the encapsulated payload. Crosslinking of the micellar corona with mild and selective chemistries that do not compromise the integrity of the cargo is a promising approach to stabilize the micelles and control the release.

   In this work, we investigated a new strategy to produce physically-stable PMs by means of sol-gel chemistry coupled to spray-drying. For this, amphiphilic poly(ethylene oxide)-b-poly(propylene oxide) block copolymers (PEO-PPO) were primarily modified with 3-isocyanatopropyl triethoxysilane (IPTS) and the physicochemical and thermal properties of the derivatives fully characterized by different techniques. Then, the modified copolymers were used to produce PMs. In general, at room temperature, three size populations were measured in pristine and modified polymers, while at 37°C, one single population of 20-30 nm was observed. These results were consistent with the incomplete micellization of the thermo-responsive PEO-PPOs at lower temperature. Then, the ethoxysilane groups in the corona of the micelles were hydrolyzed and the generated silanols condensed by freeze- and spray-drying to form a crosslinked siloxane outer membrane. Freeze-drying resulted in massive crosslinking and the formation of monoliths that were not re-dispersible. Conversely, spray-drying enabled a more controlled process. Moreover, since the spray-drying instrument is based on a vibrating mesh spray with holes in the 4-7 μm size range that produce ultra-fine droplets, the process led to the generation of a fully re-dispersible powder. Investigation of the structure revealed a unique nanoparticle-in-nanoparticle multimicellar nanomaterial with size of 200 and 85 nm at room temperature and 37°C, respectively. Owing to their amphiphilic nature the novel nanomaterials can host poorly-soluble drug in the hydrophobic domains and eventually sustain its release with a more controlled fashion. To support the feasibility of the approach, the hydrophobic anti-human immunodeficiency virus (HIV) drug tipranavir was encapsulated for the first time in both unmodified and modified PMs and the aqueous solubility increased by up to 3 orders of magnitude. Release studies in vitro showed a much more controlled drug release rate from crosslinked PMs, characterized by a zero-order kinetics and deprived of burst effect as opposed to the non-crosslinked micelles that showed the characteristic bimodal release profile of polymeric nanoparticles.