In VitroBlood–Brain Barrier Permeability and Cytotoxicity of an Atorvastatin-Loaded Nanoformulation Against Glioblastoma in 2D and 3D Models

Abstract

Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase of the family of statins have been suggested as therapeutic options in various tumors. Atorvastatin is a statin with potential to cross the blood-brain-barrier, however, the concentrations necessary for a cytotoxic effect against cancer cells exceeds the concentration achievable via oral administration, which made the development of a novel atorvastatin formulation necessary. We characterized the drug loading and basic physicochemical characteristics of micellar atorvastatin formulations and tested their cytotoxicity against a panel of different glioblastoma cell lines. In addition, activity against tumor spheroids formed from mouse glioma and mouse cancer stem cells, respectively, was evaluated. Our results show good activity of atorvastatin against all tested cell lines. Interestingly, in the 3D models, growth inhibition was more pronounced for the micellar formulation compared to free atorvastatin. Finally, atorvastatin penetration across a blood-brain-barrier model obtained from human induced-pluripotent stem cells was evaluated. Our results suggest that the presented micelles may enable much higher serum concentrations than possible by oral administration, however, if transport across the blood-brain-barrier is sufficient to reach therapeutic atorvastatin concentration for the treatment of glioblastoma via intravenous administration remains unclear.

Cholesterol Metabolic Reprogramming in Cancer and Its Pharmacological Modulation as Therapeutic Strategy

“…A new formulation of atorvastatin was developed in order to cross the blood-brain barrier and target the glioblastoma tumor cells. This new nanoformulation was cytotoxic in mouse and human glioblastoma cells, and was able to reduce the growth in a three-dimensional (3D) tumor model ( 189 ). The anticancer role of statin treatment in combination with conventional anticancer drugs, has been tested in clinical trials for the treatment of different types of tumors, such as breast, prostate, ovarian or lung cancers, bringing to light controversial effects of the association ( Table 3 summarizes some clinical trials on breast, ovarian and prostate cancer).…”

cRGDyK‑modified procaine liposome inhibits the proliferation and motility of glioma cells via the ERK/p38MAPK pathway

“…However, due to the existence of the BBB, the invasion and metastasis of glioma is extremely low (27). However, existing therapeutic drugs are not adequate to meet clinical needs due to the BBB blocking their uptake into the brain (28). Therefore, it is urgently necessary to develop a novel strategy for targeted drug delivery to treat this particular malignancy.…”

Nanomedicine: A Useful Tool against Glioma Stem Cells

“…Additionally, even though this advantage is less common than others, drug delivery systems can in some cases increase the activity of the drugs. Atorvastatine-loaded polymeric micelles were indeed able to inhibit the growth of CSC spheroids compared to the single drug [102]. In the case of zinc-doped copper oxide nanocomposites, the NPs have an intrinsic inhibitory effect, decreasing the colony formation of TMZ-resistant GSCs, but at the same time exerting lower toxicity on normal cells [75].…”