Doctoral defence: Allan Tobi "Development of Smart Nanoparticles for Experimental Treatment of Cancer"

On December 3rd, Allan Tobi will defend his thesis "Development of Smart Nanoparticles for Experimental Treatment of Cancer".

Supervisor:
Professor Tambet Teesalu, University of Tartu

Opponents: 
Cornelis F.M. Sier, Leiden University Medical Centre (Netherlands)

Summary:
Glioblastoma is the most common malignant brain tumor with an unfavorable prognosis and high mortality rate. Standard treatment for glioblastoma consists primarily of tumor surgical resection followed by radiation therapy and concurrent chemotherapy with temozolomide. Increasing attention is being paid to the development of novel therapies based on precision-targeted nanoparticles to improve the efficacy of cancer treatment and reduce side effects.
The research presented in this doctoral thesis focuses on the use of two nanoparticle platforms as tools and drug carriers for preclinical cancer research: silver nanoparticles (AgNP) and iron oxide nanoparticles (NW). We demonstrated that they can be functionalized with tumor homing peptides and used to deliver cytotoxic and proapoptotic drugs. AgNP and NW platforms can be used to enhance in vitro and in vivo assays for the study and validation of targeting ligands. In addition to the development and characterization of the nanocarriers, we identified a tumor homing peptide PL3 (AGRGRLVR) that interacts with the tenascin-C and neuropilin-1 proteins. PL3 peptide enhanced nanoparticle accumulation in tumor tissue and showed efficacy in experimental cancer mouse models. The PL3 peptide has an exposed CendR-motif, which results in healthy tissue accumulation, mainly in the lungs. To address this issue, we used a modified phage display method to identify cryptic proteolytically activatable PL3 derivative peptides: SKLG (AGRGRLVRSKLG) and PL3uCendR (AGRGRLVRSAGGSVA). Cleavage of cryptic derivatives by urokinase (uPA) overexpressed in tumors activated a neuropilin-1 dependent penetration mechanism, while accumulation in healthy lung tissue was reduced.
The results of this work can help develop improved targeted cancer treatments for glioblastoma with reduced side effects.