Enhanced anti-angiogenic effects of bevacizumab in glioblastoma treatment upon intranasal administration in polymeric nanoparticles

Glioblastoma multiforme (GBM) is one of the most aggressive cancers, where the aggressiveness of tumor has been associated to its high vascularization rate. Bevacizumab (Avastin (R)), an anti-angiogenic monoclonal antibody, has been used to decrease the angiogenic profile. To circumvent the blood-brain barrier (BBB) and decrease off-target organ toxicity, bevacizumab-loaded poly(D,L-lactic-co-glycolic acid) nanoparticles (PLGA NP) were developed and intranasally administrated in CD-1 mice to study their pharmacokinetic and pharmacodynamic profile. After 7 days of administration, PLGA NP showed a higher brain bioavailability of bevacizumab when compared to intranasally administrated free bevacizumab. On the other hand, bevacizumab-loaded PLGA NP were able to increase the penetration (higher Cmax) and the residence time of bevacizumab into the brain (higher Clast). Furthermore, PLGA NP formulation totally prevented bevacizumab systemic exposure. The efficacy of this nanosystem was next evaluated in a validated orthotopic GBM nude mice model, studying the tumor growth over time by bioluminescence and the anti-angiogenic effects. After 14 days, bevacizumab-loaded PLGA NP demonstrated a reduction in the tumor growth accompanied by a higher anti-angiogenic effect compared to the free bevacizumab. These results can be explained by the fact that bevacizumab was found in the brain just for bevacizumab-loaded PLGA NP group, after 14 days of formulation administration. Therefore, we believe that our strategy would be an efficient alternative to improve GBM treatment with high impact for patient life quality and survival.