Development of newly synthesized nanoparticle-based drugs for the treatment of glioblastoma

Efficient and safe delivery of siRNA remains a major barrier to effective gene silencing therapies for GBM. This doctoral thesis evaluated two families of cationic nanoparticles-phosphorus-based dendrimers (AK35, AK71, AK72, AK102, AK116, AK120) and dihydropyridine (DHP)-based nanoparticles (MR550-1D, MR563-D, MR564-D, MK044-D, MR618-D, DL-109)-for siRNA complexation, protection, cellular uptake, transfection efficiency, and biocompatibility. Briefly, all dendrimers formed stable complexes with siRNA and provided partial protection from degradation. However, none were able to deliver siRNA effectively or induce gene silencing of p42 or Rheb in T98G and astrocytes. Some dendrimers showed toxicity at high concentrations, and slight hemolytic effects were observed with AK102 and AK120. Due to their lack of functional transfection, dendrimers were not considered suitable for further investigation. In contrast, all DHP-based nanoparticles demonstrated strong siRNA binding, protection from RNases, and high transfection efficiency in T98G cells. MK044-D and DL-109 displayed the best safety profiles in several cell types and were able to silence both target genes effectively. MK044-D exhibited good cellular uptake, no in vivo toxicity in mice, and excellent biodistribution to brain, spinal cord, and intestinal package. These results highlight MK044-D as promising non-viral siRNA carrier for GBM gene therapy.