טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentShtenberg Yarden
SubjectMucoadhesive Polymer Systems for Controlled and Local
Drug Delivery
DepartmentDepartment of Biotechnology
Supervisor Professor Havazelet Bianco-Peled
Full Thesis textFull thesis text - English Version


Abstract

Mucoadhesive polymers have emerged as a promising platform for non-invasive drug delivery system due to their ability to adhere to the mucus gel layer, which covers all exposed organs in the body. Mucoadhesive polymers are biodegradable, non-toxic, water soluble, inexpensive, allow local and sustained release of the drug at the target site, quickly adhere to most tissues and form strong bonds with the mucus layer.

This research thesis describes three projects aimed to develop new mucoadhesive polymer and drug delivery systems.

In the first project, our goal was to generate a new mucoadhesive carbohydrate-based delivery system composed of alginate backbone covalently attached to polyethylene glycol (PEG) modified with a unique functional end-group (maleimide). The immobilization of PEG-maleimide chains significantly improved the mucoadhesion properties attributed to thioether bonds creation via Michael addition and hydrogen bonding with the mucus glycoproteins. Mucoadhesion studies using tensile and rotating cylinder assays revealed a 3.6-fold enhanced detachment force and a 2.8-fold enhanced retention time compared to the unmodified polymer, respectively. Drug release experiments were used to evaluate the release profiles from alginate-PEG-maleimide tablets in comparison to alginate and alginate-SH tablets. Overall, our studies disclose that PEG-maleimide substitutions on other biocompatible polymers can lead to the development of useful biomaterials for diverse biomedical applications.

In the second project, we aim to develop a new oral mucoadhesive delivery system based on the combination of alginate and liposomes for treating oral cancer. Oral cancers are extremely common among adults with increasing incidences due to human papillomavirus, while treatment modalities are limited. The polymer provides adhesion properties and induces local release of the drug-loaded carriers, while the liposomes protect the drug from degradation and improve its absorption into the cells. Three hybrid alginate/liposomes delivery systems were investigated: a hybrid paste, which presented excellent adhesive capabilities, yet fast burst release; a hybrid hydrogel, demonstrating controllable release rates but poor mucoadhesive properties. These findings led to the development of a hybrid cross-linked paste, an innovative formulation, including both desired characteristics of mucoadhesion and sustained liposomes release, is an important milestone in the development of a new potential treatment for oral cancer.

In the third project, we investigated the effect of polymer type, concentration, functional end group and crosslinking on the liposome release profile from polymer paste.

Native and thiolated polymers presented enhanced mucoadhesion in a wet environment in comparison to acrylated polymers which dissolved rapidly due to the enhanced solubility of PEG chains in water. Paste crosslinking resulted in a pronounced sustained release profile with respect to non-crosslinked pastes. Pectin-SH pastes, especially 3% (w/v), showed a linear release profile which are ascribed to the combination of ionic crosslinking and di-sulfide bridging. By changing polymer type or concentration we can vary the release mechanisms and achieve distinct inherent properties which can be applied for diverse medical applications.