טכניון מכון טכנולוגי לישראל
הטכניון מכון טכנולוגי לישראל - בית הספר ללימודי מוסמכים  
M.Sc Thesis
M.Sc StudentRawan Omar
SubjectAmphiphilic Star PEG-Camptothecin Conjugates for
Intracellular Targeting
DepartmentDepartment of Biotechnology and Food Engineering
Supervisor Assistant Professor Mizrahi Boaz
Full Thesis textFull thesis text - English Version


Abstract

For more than two decades, understanding the biology of cancer led to meaningful improvements in therapy, however, this progress is too moderate. Based on the world health organization reports, it is predicted that in the coming two decades there will be more than 20 million new cancer cases and over 13 million mortalities in all over the world. One of the most promising ways to treat cancer includes the delivery of chemotherapy drugs using nanoscale delivery systems (nano-carriers). 

Nano-carriers have gained much attention owing to their special properties: high surface-to-volume ratio, the ability to stabilize drugs in the body and increase the circulation of drugs in blood stream.  These carriers are also able to improve the pharmacokinetics and pharmacodynamics profiles of drugs and thus to enhance their therapeutic index and safety. However, the use of commonly available nanoscale systems is limited by two main concerns. First, instability of the carrier and unfavorable release kinetics including significant burst release and loss of drug portion before it reaches the tumor site. Second, inefficient encapsulation/loading of the drug, leading to increased potential for long-term accumulation of the carrier and increased risk of toxicity and immunogenicity.

Camptothecin (CPT) is a naturally occurring cytotoxic alkaloid having a broad spectrum of antitumor activity and was chosen as the model drug. Unfortunately, CPT has low bioavailability, low water solubility and low encapsulation efficiency (<5%), limiting its clinical use. Here, we report on our efforts to develop a drug delivery prototype that has new properties compared to conventional nano-carriers. Our system is composed of a short, star hydrophilic polyethylene glycol (PEG4) backbone and hydrophobic drug CPT that together form an amphiphilic PEG4-CPT conjugates.

The amphiphilic conjugate self-assembles in water into stable spherical nanoparticles with a mean diameter of 200 nm and CPT substitution percentage of 27 %w/w. CPT is released in a sustained release profile without burst effect. In addition, PEG4-CPT nanoparticles are able to load a co-drug (additional drug). Water soluble or poor water soluble version of doxorubicin (DOX) were co-loaded into the PEG4-CPT particles and released simultaneously with CPT. The biological evaluation of PEG4-CPT against HeLa cells showed enhanced cellular uptake by the endocytic pathway, compared to free CPT. Thus, in this approach CPT acts in two ways: As the hydrophobic segment that enables self-assembly in water and as a potent anticancer agent. This concept of combining hydrophobic drugs and short star polymers shows great potential for efficient delivery of hydrophobic chemotherapeutic drugs as well as for drugs with inherent stability and pharmacokinetic barriers.