טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentZinger Assaf
SubjectDeveloping Bio-Active Nanoparticles for Performing Precise
and Personalized Medical Tasks Inside the Body
DepartmentDepartment of Chemical Engineering
Supervisor Professor Avi Schroeder
Full Thesis textFull thesis text - English Version


Abstract

Surgical blades are common medical tools. However, blades cannot distinguish between healthy and diseased tissue, thereby creating unnecessary damage, lengthening recovery and increasing pain. We propose that surgical procedures can rely on natural tissue remodeling tools - enzymes, which are the same tools our body uses to repair itself. Through a combination of nanotechnology and a controllably activated proteolytic enzyme we performed a targeted surgical task in the oral cavity. More specifically, we engineered nanoparticles that contain collagenase in a deactivated form. Once placed at the surgical site collagenase was released at a therapeutic concentration and activated by calcium, its biological cofactor that is naturally present in the tissue. Enhanced periodontal remodeling was recorded due to enzymatic cleavage of the supracrestal collagen fibers that connect the teeth to the underlying bone. When positioned in their new orientation, natural tissue repair mechanisms supported soft and hard tissue recovery and reduced tooth relapse

We then sought to take advantage of this nanoparticulate tool to treat pancreatic cancer. Using a nanoparticulate proteolytic-enzyme system increases nano-drug uptake into cancer tumor, inside the patient body. More specifically, we encapsulated collagenase inside 100-nm PEGylated liposomes that protected the enzyme from early deactivation and prolonged its release rate to treat overexpressed extra cellular matrix (ECM) in pancreatic ductal adenocarcinoma (PDA) which limits drug penetration into the tumor and is associated with poor prognosis. After being injected into the systemic circulation, the nanoparticles accumulated in the diseased pancreas over a period of 8 hours. We designed the liposomes to release the enzyme on-target at a therapeutic rate by increasing the cholesterol content in the membrane. At the target site, the enzyme degraded the dense collagen matrix, allowing an increase in nano-drug penetration into the pancreas and improving the treatment efficacy. Degrading the ECM did not increase the incidences of circulating tumor cells (CTCs) nor was metastatic disease detected. This suggests that the enzyme degrades the fibrotic tissue in a manner that allows nanotherapeutics to penetrate the tumor but not the cells to escape into circulation. 

A new approach for treating pancreatic cancer through a combination of nanotechnology and tissue-degrading enzymes and chemotherapy is described. Through the combination of nanotechnology and proteolytic enzymes, localized surgical procedures can now be less invasive.