טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentOss-Ronen Liat
SubjectAffinity-Based Drug Delivery Using Bio-Synthetic Hydrogels
Formed from PEGylated Proteins
DepartmentDepartment of Biomedical Engineering
Supervisor Professor Dror Seliktar
Full Thesis textFull thesis text - English Version


Abstract

In this work we present the development of hydrogels for drug delivery applications, based on the affinity of drugs to poly(ethylene glycol) (PEG) conjugated albumin. Both of these constituents are widely available, inexpensive and FDA approved. This hydrogel system is photo-polymerizable, thus allowing minimally invasive administration for local sustained drug release at the target tissue. We used PEG and albumin to produce a few variations of hydrogels, including wild-type albumin mixed with PEG, multi-PEGylated albumin, and mono-PEGylated albumin. Furthermore, we performed PEGylation reactions using PEG of different molecular weights, and integrated the PEGylated albumin precursor with PEGylated fibrinogen, which is known for its tissue regeneration and cell adhesion properties. The physicochemical properties of the various hydrogels were characterized. In addition, drug release experiments were designed and performed in order to study the effect of several hydrogel design parameters on the release kinetics from the hydrogels, including: the drug affinity to albumin; the molecular weight of the drug; the molecular weight of the PEG conjugated to albumin; the addition of free PEG-DA molecules to the hydrogel matrix; the molecular interactions between the polymer and the protein, i.e. degree of PEGylation; and the presence of a degrading enzyme. The degradation properties of the hydrogels, as well as their biocompatibility, were also examined in vitro and in vivo.

Results of these experiments indicated that mono-PEGylation of albumin conserves the drug binding properties of the protein while allowing its covalent conjugation within the hydrogel matrix. PEGylation reaction using lower molecular weight PEG resulted in slower drug release kinetics. Thus, the ability to control the release properties of PEGylated albumin hydrogels was obtained through the PEGylation degree, the molecular weight of PEG conjugated to the protein, and the addition of free difunctionalized PEG molecules. Moreover, by using a composite hydrogel system including both mono-PEGylated albumin and PEGylated fibrinogen, we showed sustained drug delivery properties for a hydrogel which also holds cell culture abilities. This combination opens up a broader spectrum of potential uses for the presented system, in cases where drug release and tissue regeneration are required. The rate of both processes may be optimized through the composition of the hydrogel to give an accurate treatment for such specific needs.