טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
Ph.D Thesis
Ph.D StudentBalter Adi
SubjectNano-Structured Porous Silicon Scaffolds for Controlled
Delivery of Antineoplastic Drugs
DepartmentDepartment of Biotechnology
Supervisor Professor Ester H. Segal
Full Thesis textFull thesis text - English Version


Abstract

Nanostructured porous Si (PSi) has emerged over the past decade as a promising material for biomedical applications. We show that PSi can be rationally designed for carrying therapeutic cargos and administered as implantable devices or processed into injectable particles to support local drug release. We engineer the material properties and load a model anticancer drug, Mitoxantrone (MTX), into the nanostructures. We show that chemical modifications have a significant effect on the drug release behavior and the Si scaffold erosion kinetics. Thus, using simple surface chemistry techniques and different loading approaches the release profile of the drug can be tailored from a few hours to several weeks. Furthermore, our in vitro cytotoxicity experiments demonstrate that the MTX released maintains its cytotoxic effect towards breast carcinoma cells, in comparison to the low toxicity of the PSi carriers.

Next, we designed a new therapeutic strategy for an effective delivery of therapeutics into cancer cells, we demonstrate for the first time the application of biolistics for highly controlled delivery of drug payloads carried by PSi particles. Our study reveals significant cytotoxicity towards target human breast carcinoma cells following the delivery of drug-loaded carriers, while administrating empty particles results in no effect on cell viability.

When progressing to in vivo models, we revealed that correlation between in vitro and in vivo behavior of PSi persists only under specific conditions that mimic local oxidative stress manifested by the tumor microenvironment. Under these conditions PSi erosion is enhanced compared to healthy state. Using our model system, we identify determinant factors that modulate material erosion to begin to unravel the importance of the physiological microenvironment in determining device performance and therapeutic capacity.

To elucidate the specific release mechanisms of molecular species from PSi carriers, we have developed a novel mathematical model. In this empirical macroscopic model we adapt the Crank model to lump the effects of temporal changes in molecular interactions and carrier scaffold erosion into a comprehensive model of hindered drug diffusion from nano-scale porous systems. By capturing scaffold degradation, occurring on the same time-scale as drug diffusion, we show that drug diffusivity significantly varies with time. Furthermore, a comparison of the experimental and model results shows accurate representation of the data, emphasizing the reliability of the model. Our generalized model can be easily adapted for other erodible nanostructured drug carriers, to describe their release behavior.