A Micellar Mitotane Formulation with High Drug‐Loading and Solubility: Physico‐Chemical Characterization and Cytotoxicity Studies in 2D and 3D In Vitro Tumor Models

Abstract

Conflict of InterestR.L. is listed as co-inventor of several patents pertinent to the present contribution and is co-founder of Delaqua Pharmaceutical Inc. intending commercial development of poly(2-oxazoline)-based drug delivery systems.

In Vitro Blood-Brain-Barrier Permeability and Cytotoxicity of Atorvastatin-Loaded Nanoformulation Against Glioblastoma in 2D and 3D Models

“…Interestingly, a recently reported micellar mitotane nanoformulation of A-pBuOx-A was also slightly more active than mitotane simply dissolved in EtOH against adrenocortical NCI-H295R cells in a 3D tumor spheroid model (IC 50,48h = 43 µM & 47 µM for nanoformulated & EtOH-dissolved mitotane, respectively). [57] Important to note, the pronounced cytotoxicity of A-pBuOzi-A/ATV after 72 h treatment determined by CellTiterGlo®-3D luminescence assay was confirmed when quantifying the cell-viability by the intrinsic fluorescence of the GFP expressing bRiTS-G2 cells (inset Figure 6d). Although the absolute values slightly differed, both measurement techniques gave comparable results.…”

“…ATV solubilization As reported recently, poly(2-oxazoline) (POx) and poly(2-oxazine) (POzi) based ABA triblock copolymers, all comprising the same hydrophilic poly(2-methyl-2-oxazoline) (PMeOx) shell A and structurally very similar, hydrophobic cores B exhibit different loading capacities for various hydrophobic drugs [50,[53][54][55][56][57] as well as varying drug/polymer interactions in dependence of the drug-loading [58,59] . Whereas the triblock copolymer with a barely hydrophobic poly(2-n-butyl-2-oxazoline) (pBuOx, = A-pBuOx-A) core enabled moderately high loadings of 24 wt.% of the hydrophobic compound curcumin (CUR), its structural isomer with a poly(2-n-propyl-2-oxazine) (pPrOzi; = A-pPrOzi-A) core was able to yield exceptionally high loadings up to 54 wt.%.…”

“…However, cancer cells grown in 3D cell-clusters such as spheroids can behave significantly different from their monolayer counterparts [73] and we have recently reported differences in tumor spheroids depending whether the API was administered in polymer micelles or added as a ethanolic solution. [57] The multi-cellular structures resemble actual tissues better in terms of structural and functional properties and often exhibit an enhanced resistance against therapeutic compounds. [74] CT-2A cells were chosen due to their ability to form spheroids without the need of specialized devices or additives.…”

Poly(2‐oxazoline)‐ and Poly(2‐oxazine)‐Based Self‐Assemblies, Polyplexes, and Drug Nanoformulations—An Update

“…developed mitotane formulation for potentially improved treatment of adrenocortical carcinoma. [ 177 ] The authors screened a small library of different POx and POzi triblock copolymers and selected pMeOx‐ b ‐pBuOx‐ b ‐pMeOx based on its highest loading capacity 36 wt% (solubilization 5.71 ± 0.11 g L −1 ). However, the loading capacity dramatically decreased after 24 h of storage, caused by drug precipitation.…”

“…Reproduced with permission. [ 177 ] Copyright 2019, Wiley‐VCH GmbH. B) A‐pPrOzi‐A‐formulated CUR (50 µ m ) leads to reduced SW480 cell numbers under 3D but not 2D conditions and has anti‐metastatic effects in a metastasis model of colorectal cancer.…”