Synthesis and Investigation of Chiral Poly(2,4-disubstituted-2-oxazoline)-Based Triblock Copolymers, Their Self-Assembly, and Formulation with Chiral and Achiral Drugs

Abstract

Considering the largely chiral nature of biological systems, there is interest in chiral drug delivery systems. Here, we investigate for the first time polymer micelles based on poly(2-oxazoline) (POx) ABA-type triblock copolymers with chiral and racemic hydrophobic blocks for the formulation of chiral and achiral drugs. Specifically, poly(2-ethyl-4-ethyl-2oxazoline) (pEtEtOx) and poly(2-propyl-4-methyl-2-oxazoline) (pPrMeOx) were used as hydrophobic block B and poly(2-methyl-2-oxazoline) (pMeOx) as hydrophilic block A. Using these triblock copolymers, nanoformulations of curcumin (CUR), paclitaxel (PTX), and chiral (R and S) and racemic ibuprofen were prepared. For CUR and PTX, the maximum drug loading was significantly dependent on the structure of the hydrophobic repeat units, but not the chirality. In contrast, the maximum drug loading with chiral/racemic ibuprofen was affected neither by the polymer structure nor by chirality, but minor effects were observed with respect to the size and size distribution of the drug-loaded micelles.

POxload: Machine Learning Estimates Drug Loadings of Polymeric Micelles

“…Solubilization data of drug–polymer mixtures from several previous publications ,,− ,− were combined together with in-house data − to create a formulation database of 3700 experimental data points. These are listed in Table S1, which also includes polymer and monomer names used throughout this article.…”

Comparison of the hydrophilicity of water-soluble poly(2-alkyl-2-oxazoline)s, poly(2-alkyl-2-oxazine)s and poly(2,4-dialkyl-2-oxazoline)s

“…[7][8][9][10][11][12] Comparatively few studies have been undertaken for watersoluble POz systems, [13][14][15] though interest in these systems is growing following reports that hydrophilic POz ( poly(2-methyl-2-oxazine) (PMeOz) and poly(2-ethyl-2-oxazine) (PEtOz)) outperform both POx and PEG as antifouling coatings. [16][17][18][19] PdOx systems are yet to be studied in similar applications, and to date have only been utilised as carrier materials in potential therapeutic polymer nanoparticles, 20,21 though initial synthesis papers briefly compared the material properties of these systems to POx and POz isomers. [22][23][24] PCIE can be easily modified in a multitude of ways, ranging from simple changes in initiator, monomer, or termination agent choice, to the incorporation of reactive moieties to form complex architectures or allow for post-polymer modifications.…”

“…7–12 Comparatively few studies have been undertaken for water-soluble POz systems, 13–15 though interest in these systems is growing following reports that hydrophilic POz (poly(2-methyl-2-oxazine) (PMeOz) and poly(2-ethyl-2-oxazine) (PEtOz)) outperform both POx and PEG as antifouling coatings. 16–19 PdOx systems are yet to be studied in similar applications, and to date have only been utilised as carrier materials in potential therapeutic polymer nanoparticles, 20,21 though initial synthesis papers briefly compared the material properties of these systems to POx and POz isomers. 22–24…”

Thionation of poly(2-ethyl-2-oxazoline) and its effect on solubility and cloud point

“…[3][4][5] Poly(2-oxazoline)s (POx) are polymers with tertiary amide repeating units, synthesized by cationic ring opening polymerization. 6,7 This synthetic polymer family has recently received increased attention, as they have been found to have a wide scope of potential applications, including surface coatings, 8,9 indirect food additives, 10,11 drug delivery systems, [12][13][14] and hydrogels. [15][16][17][18][19][20] Recently, a POx-based polymer-drug conjugate successfully completed phase I clinical trials, 21 and a POx-based hemostatic patch was approved for clinical use.…”