טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentPinhassi Roy
SubjectNano-Sized Polymer-Drug Conjugates for Targeted Delivery
and Target-Activated Release of Anti-Cancer Drugs
DepartmentDepartment of Biotechnology and Food Engineering
Supervisors Professor Yoav Livney
Professor Yehuda Assaraf
Full Thesis textFull thesis text - English Version


Abstract

There is a great demand for innovative drug delivery systems that can better target antitumor drugs and that can overcome drug resistance phenomena.  The state-of-the-art in anti-cancer drug delivery is the use of long-circulating nano-drug-carriers, including polymeric drug carriers, nanoparticles or liposomes using hydrophilic polymers to evade elimination by the immune system. While most nano-vehicles are passive, active targeting mechanisms based on molecular recognition are rapidly advancing, using antibodies or small molecule ligands (e.g. folic acid), for which certain malignant tumors overexpress specific receptors. A great example is folic acid-“decorated” nano-vehicles, which have been shown to undergo receptor-mediated endocytosis into acidic endosomes in the cancer cell, thereby offering a highly effective route for the delivery of various drugs.

Following this approach, folate-based targeted anti-cancer drug delivery systems were herein designed. We first used low molecular weight linkers for the conjugation of folic acid and chemotherapeutic drug(s). These conjugates showed very high affinity for folate receptor α (FRα) and effective and selective cell uptake only to cells that express the receptor.

We have then developed and tested a prototype of folic acid-targeted polymeric nanovehicle and demonstrated its selective uptake by cells that overexpress FRα. This nanocarrier comprised a folic acid "decorated" arabinogalactan-drug conjugate wherein the drug was connected to the polysaccharide by a peptide linker, which is cleavable by endosomal peptidases. This new nanovehicle was found to be an effective and selective anti-cancer targeted delivery system, with a target-activated release mechanism. This new vehicle exhibited selective uptake and a >6-fold higher cytotoxic effect on FRa cells when compared to the control wild type cells lacking FRα overexpression. This carrier has the potential to harbor a combination cargo of anti-cancer drugs that may exhibit a synergistic cytotoxic effect as well as to solubilize hydrophobic antitumor drugs, and thus exhibit enhanced tumor eradication capability.