In Vitro Blood-Brain-Barrier Permeability and Cytotoxicity of 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.<br>

Biological activity In vitro, absorption, BBB penetration and toxicity of nanoformulation of BT44, a RET agonist with disease-modifying potential for the treatment of neurodegeneration

“…For better comparison, the 1 H-NMR spectra of the pristine BT44, plain A-pPentOx-A polymer and the (lyophilized) precipitate in chloroform-D (CDCl3) as non-selective solvent (no micelles formation) were obtained (Figure S4). The 1 H-NMR spectra of plain polymer clearly presented all the signals suggesting that polymer existed as unimers in nonaggregated form (Figure S4 green spectra) and it was also evident that the precipitate contained not only the drug but also the hydrophilic polymer (Figure S4 red spectra), corroborating our previous findings [26,43,86]. However, the precipitate was significantly enriched in BT44 compared to the formulation.…”

“…Initially the 1 H-NMR spectra of all the three triblock copolymers used in this study were obtained (at concentration of 10 g/L) (Figure S5). while the CUR signals were completely attenuated [43].The 1 H-NMR spectroscopy also revealed a similar pattern for PTX [80] and atorvastatin (ATV) [86] loaded A-pBuOx-A and A-pBuOzi-A ((poly(2-nbutyl-2-oxazine)) micellar formulations, respectively. However, in the absence of drug, small angle neutron scattering (SANS) revealed that the plain A-pBuOzi-A polymer existed as spherical selfassemblies without well-defined core-shell architectures.…”

Tuning the Thermogelation and Rheology of Poly(2-Oxazoline)/poly(2-Oxazine)s Based Thermosensitive Hydrogels for 3D Bioprinting.

“…In the present contribution, we have synthesized a thermoresponsive diblock copolymer which is based on thermosensitive pEtOx as hydrophilic (A) and pPrOzi more hydrophobic, yet still thermoresponsive block (B), respectively. As discussed previously, replacing the pMeOx with pEtOx in ABA triblock copolymers, significantly affected (reduced) the drug loading for the same drug [56] while presently, the thermogelling properties of AB diblock copolymer were investigated while exchanging the pMeOx with pEtOx.…”

“…A plethora of studies show the utilization of pMeOx and pEtOx as hydrophilic polymer for the development of hydrogels [26,[45][46][47], electrospun fibres [48], polymer brushes [49], nanoparticles [50], micelles for drug delivery [51][52][53][54][55][56] and for melt electrowriting [57]. Bloksma et al also investigated the thermoresponsive behaviour of few POzi based homopolymers [20].…”

Synthesis and investigation of chiral poly(2,4-disubstituted-2-oxazoline) based triblock copolymers, their self-assembly and formulation with chiral and achiral drugs

“…[70][71] Among the plethora of drug delivery systems for formulation of PTX and CUR, some POx and POzi based formulations stand out for their extraordinary high drug loading capacity and overall solubilisation for PTX and CUR. 43,47,[72][73][74] While CUR is achiral, PTX is chiral with multiple chiral centers but, to the best of our knowledge, does not have a known enantiomer. The formulations were prepared by the thin film hydration method.…”