טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentCroitoru-Sadger Tsuf
SubjectDevelopment of Short 4-Armed Polymers for Biotechnological
Systems
DepartmentDepartment of Biotechnology and Food Engineering
Supervisor Professor Boaz Mizrahi


Abstract

Low molecular weight (Mw = 2 kDa) multi armed poly(ethylene glycol) (PEG4) has drawn much attention due to its exceptional characteristics: stability in aqueous media and liquidity at room temperature, transparency and biocompatibility. In this research, short PEG4 was used for the development of different biotechnological systems.

The main goals of this research included: (1) Synthesis of PEG4 and substitution with poly(caprolactone) (PCL) and other functional groups; (2) Characterization and monitoring of copolymers’ behavior in aqueous media; (3) Development of a three dimensional printing technique that does not involve the use of heat, Ultra-Violet (UV) irradiation or organic solvents; (4) Study of the size and morphology of the formed structures; (5) Development of an elastomer without the need of aqueous media; (6) Drug-loading of the different polymers with various model drugs and study the relationship between the drugs’ chemical structure and their release profiles.

A series of copolymers consisting of a PEG4 core with appended PCL segments of various lengths were synthesized. These copolymers are capable of undergoing self-assembly in water, forming stable, nano-sized rod or spherical polymersomes. By increasing the Mw of the PCL hydrophobic moieties, the critical micelle concentration value decreases and tend to form a more spherical structure. Campothecin, a poorly water-soluble drug, was loaded into the polymersomes, resulting in a high drug loading efficiency and sustained release for a 7 day period.

Later, a unique 3D printing technique for oral drug delivery systems was developed using PEG4 as the matrix. This system successfully overcomes the disadvantages of the current techniques (solidification of the injected materials by UV irradiation, evaporation of organic solvents, harsh heating and cooling processes, etc.). The ability to print many sensitive bio-active molecules, such as proteins or peptides, is limited by these methods. The PEG4 -PCL copolymers were substituted with two functional groups that cross-link spontaneously. The copolymers were inserted into 3D printer and used to obtain3D pills loaded with different drugs. The printed pills were characterized and examined in a digestive system mimicking apparatus, showing a rapid drug release profile.

Next, PEG4 was used to form a transparent stiff matrix, an elastomer, by substitution with methacrylic anhydride (MA) group through radical polymerization mechanism. This polymer contains double bonds that can be cross-linked by UV irradiation using Irgacure? 2959. To determine the cross-linking time, the polymer was mixed with photo-initiators of different weight percentages. Then, the samples were UV-irradiated for one or five minutes, showing no significant difference between the different photo-initiator percentages. The elastomers exhibited a swallowing capacity of about 150% from their original weight. In addition, the elastomers were loaded with the hydrophilic drug Bupivacaine, which is used for local anesthesia, and showed a sustained release pattern for a 10 day period.

To conclude, PEG4 was used as core molecule for the development of several biocompatible systems. The obtained biomaterials showed desirable properties for their use in various biomedical applications.