NANOPARTICLE-BOUND DOXORUBICIN FOR CHEMOTHERAPY OF GLIOBLASTOMA
Author 1: S. Gelperina, address: 1) Drug Technology Ltd., Khimki, Moscow Region, Russia; 2) Nanosystem Ltd., Moscow, Russia
Author 2: A. Khalansky, address: Institute of Human Morphology, Moscow, Russia
Author 3: O. Maksimenko, address: Nanosystem Ltd., Moscow, Russia
Author 4: Y. Malinovskaya, address: Nanosystem Ltd., Moscow, Russia
Author 5: V. Razzhivina, address: Drug Technology Ltd., Khimki, Moscow Region, Russia
Author 6: V. Balabanyan, address: Drug Technology Ltd., Khimki, Moscow Region, Russia
Insufficient efficacy of the chemotherapy of brain diseases is often due to the limited ability of many drugs to circumvent the blood–brain barrier (BBB). Thus poor brain uptake of doxorubicin is perhaps the main reason why this potentially active anti-tumour antibiotic is not used for the chemotherapy of glioblastoma.
Our previous studies demonstrated that the promising approach to the non-invasive brain delivery is the drug binding to nanoparticles. In particular, intravenous administration of doxorubicin bound to the surfactant-coated poly(lactide-co-glycolide) nanoparticles (Dox-PLGA) enabled considerable growth inhibition of the intracranially implanted 101.8 glioblastoma in rats and long-term remission in >20% animals, whereas the conventional formulation was only marginally effective. This antitumour action was also confirmed by histology. The microscopical studies revealed the effective intratumoral penetration and accumulation of the nanoparticles.
Preclinical studies demonstrated that Dox-PLGA has a favourable toxicological profile. The most important finding is the reduction of cardiotoxicity, evidenced by both functional and histological assessment. The lower toxicity of the nanoparticle formulation is most probably explained by the altered biodistribution of the drug mediated by the nanoparticles.
A Phase 1 trial of the doxorubicin formulation based on PLGA nanoparticles coated with poloxamer 188 is currently on-going in Russia.