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Biomacromolecules ; 20(8): 3041-3056, 2019 08 12.
Artigo em Inglês | MEDLINE | ID: mdl-31318531


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 "like-dissolves-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 to isolate the crucial factors determining drug loading. Therefore, the compatibility of 18 different amphiphilic polymers for five different hydrophobic drugs was determined empirically. Subsequently, the obtained specificities were compared to theoretical compatibilities derived from either the Flory-Huggins interaction parameters or the Hansen solubility parameters. In general, the 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 predictive strength of Hansen solubility parameters is clearly unsatisfactory.

Macromol Biosci ; 18(11): e1800155, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30256527


A known limitation of polymer micelles for the formulation of hydrophobic drugs is their low loading capacity (LC), which rarely exceeds 20 wt%. One general strategy to overcome this limitation is to increase the amphiphilic contrast, that is, to make the hydrophobic core of the micelles more hydrophobic. However, in the case of poly(2-oxazoline) (POx)-based amphiphilic triblock copolymers, a minimal amphiphilic contrast was reported to be beneficial. Here, this subject is revisited in more detail using long hydrophobic side chains that are either linear (nonyl) or branched (3-ethylheptyl). Two different backbones within the hydrophobic block are investigated, in particular POx and poly(2-oxazine) (POzi), for the solubilization and co-solubilization of the two highly water insoluble compounds, curcumin and paclitaxel. Even though high loading capacities can be achieved for curcumin using POzi-based triblock copolymers, the solubilization capacity of all investigated polymers with longer side chains is significantly lower compared to POx and poly(2-oxazine)s with shorter side chains. Although the even lower LC for paclitaxel can be somehow improved by co-formulating curcumin, this study corroborates that in the case of POx and POzi-based polymer micelles, an increased amphiphilic contrast leads to less drug solubilization.

Curcumina , Fibroblastos/metabolismo , Oxazóis/química , Paclitaxel , Células Cultivadas , Curcumina/química , Curcumina/farmacocinética , Curcumina/farmacologia , Fibroblastos/citologia , Humanos , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Solubilidade
J Am Chem Soc ; 140(33): 10524-10529, 2018 08 22.
Artigo em Inglês | MEDLINE | ID: mdl-30048122


The coordination chemistry and stability of aminoborylene ligands bearing different N-heterocyclic carbene (NHC) stabilizing groups has been investigated with Group VI and VIII metals. NHC-aminoborylene complexes have been accessed via reduction of NHC-dihaloaminoborane adducts with Na2[M(CO) x] species (M = Fe, Ru, Cr, W). Imidazol-2-ylidene-stabilized aminoborylene ligands were found to afford thermally robust metal-borylene complexes, which are inert to oxidation, hydrolysis, and insertion of unsaturated substrates. Such ligands have additionally been demonstrated to be significantly more electron releasing than NHCs and other carbon-based ligands by infrared spectroscopy, and can be regarded as unique examples of highly nucleophilic borylene ligands isolobal to classical NHCs. In contrast, cyclic alkylaminocarbene (CAAC)-bound dihaloaminoboranes were found to be reduced by one or two electrons upon reaction with Na2[M(CO) x] species to form either a stable borane-centered radical, or the free CAAC-aminoborylene complex, which further reacts to form a carbonyl-stabilized aminoborylene. Borylene-to-CO migration was also observed upon reaction of a ruthenium imidazol-2-ylidene aminoborylene complex with B(C6F5)3, where the product borylene remains trapped by the Ru center.