Polymer micelles offer the possibility to create a nanoscopic environment that is distinct from the bulk phase. They find applications in catalysis, drug delivery, cleaning, etc. Often, one simply distinguishes between hydrophilic and hydrophobic, but fine-tuning of the microenvironment is possible by adjusting the structure of the polymer amphiphile. Here, we investigated a small library of structurally similar amphiphiles based on poly(2-oxazoline)s and poly(2-oxazine)s with respect to their solubilization capacity for two extremely water insoluble drugs, curcumin and paclitaxel. We found very significant and orthogonal specificities even if only one methylene group is exchanged between the polymer backbone and side chain. More strikingly, we observed profound synergistic and antagonistic solubilization patterns for the coformulation of the two drugs. Our findings shed new light on host-guest interaction in polymer micelles and such pronounced host-guest specificities in polymer micelles may not only be interesting in drug delivery but also for applications such as micellar catalysis.
Despite decades of research, our understanding of the molecular interactions between drugs and polymers in drug loaded polymer micelles does not extend much beyond concepts such as "likedissolves-like" or hydrophilic/hydrophobic. However, polymer-drug compatibility strongly affects formulation properties and therefore the translation of a formulation into the clinics. Specific interactions such as hydrogen-bonding, π-π stacking or coordination interactions can be utilized to increase drug-loading. This is commonly based on trial-and-error and eventually leads to an optimized drug carrier. Unfortunately, due to the unique characteristics of each drug, the deduction of advanced general concepts remains challenging. Furthermore, the introduction of complex moieties or specifically modified polymers hampers systematic investigations regarding polymer drug-compatibility as well as clinical translation. In this study, we reduced the complexity in order to isolate crucial factors determining drug-loading. Therefore, the compatibility of 18 different amphiphilic polymers for 5 different hydrophobic drugs was determined empirically. Subsequently, the obtained specificities were compared to theoretical compatibilities derived from either the Flory-Huggins interaction parameter or Hansen solubility parameters. In general, Flory-Huggins interaction parameters were less suited to correctly estimate the experimental drug solubilization compared to the Hansen solubility parameters. The latter were able to correctly predict some trend regarding good and poor solubilizers, yet the overall predicitive strength of Hansen Solubility parameters is clearly unsatisfactory. Materials and Methods Reagents and Solvents All substances for the preparation of the polymers were purchased from Sigma-Aldrich (Steinheim, Germany) or Acros (Geel, Belgium) and were used as received unless otherwise stated. Soluplus® (polyvinyl caprolactame-polyvinyl acetate-polyethylene glycol graft copolymer) and Resomer® (polyethyleneglycol-poly(L-lactide); 35 wt.% PEG) were a generous gift by BASF SE (Ludwigshafen, Germany) and Evonik Industries AG (Essen, Germany), respectively. Curcumin powder from Curcuma longa (turmeric) was purchased from Sigma-Aldrich and analyzed in-house (curcumin = 79%; demethoxycurcumin = 17%, bisdemethoxycurcumin = 4%; determined by HPLC analysis; Figure S22). Paclitaxel (> 99%, HPLC) was purchased from LC Laboratories (Woburn, MA, USA). Efavirenz (> 98%, HPLC) and dexamethasone (> 99%, HPLC) were purchased from TCI (Eschborn, Germany). Tanshinone IIA (> 98%, HPLC) was purchased from Shanghai Yuanye BioTechnology (Shanghai, China). Deuterated chloroform (CDCl 3) for NMR analysis was obtained from Deutero GmbH (Kastellaun, Germany). The monomers 2-iso-propyl-2-oxazoline (iPrOx), 2-iso-propyl-2-oxazine (iPrOzi), 2-n-propyl-2oxazoline (nPrOx), 2-n-propyl-2-oxazine (nPrOzi), 2-cyclo-2-propyl-2-oxazoline (cPrOx), 2-cyclo-2propyl-2-oxazine (cPrOzi), 2-(cyclo-propyl-methylene)-2-oxazoline (cPrMeOx), 2-(cyclo-propylmethylene)-2-oxazine (cPrM...
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