Straight to the core: Intratumoral delivery of pitavastatin and miR-338–5p through lipid nanoparticles inhibits glioblastoma growth

Abstract

Over the last decades, only minimal therapeutic advances in the field of glioblastoma have been achieved. In spite of the approval of temozolomide, the 2-year survival rate of these patients is below 30 %. In this work, the development of cationic nanostructured lipid carriers (NLCs) for the co-delivery of pitavastatin and miR-338–5p, termed _PTNLCs:PAH:miR-338–5p, is explored. The results show an intracellular delivery of the cargo with subsequent transfection, target gene (NDFIP1, RHEB and PPP2R5A) knockdown and cytotoxicity at low µM concentrations of the carrier. This prototype also blocks spheroids growth within 72 h of treatment, resulting in the smallest cell aggregates (524 ± 40 µm vs. 1089 ± 29 µm for the control) at day 17. Biodistribution studies show an increased brain permeation for _PTNLCs after intravenous administration and a significant brain accumulation of _PTNLCs:PAH:miR-338–5p up to 48 h after one intracerebral injection. Lastly, the efficacy of the carriers was assessed in an orthotopic glioblastoma model through magnetic resonance imaging. After three local injections, the carrier was able to promote tumor regression, leading to 80 % of long-term survivors with a median survival over 60 days, contrasting to saline and temozolomide (12 and 41 days, respectively). Altogether, this preclinical proof of concept study opens new perspectives and supports the use of this prototype as a functional and effective tool for drug and gene delivery, with ability to respond to the aggressiveness of glioblastoma.