Abstract
Encapsulation in self-assembled block copolymer (BCP) based nanoparticles (NPs) is a common approach to enhance hydrophobic drug solubility, and nanoprecipitation processes in particular can yield high encapsulation efficiency (EE). However, guiding principles for optimizing polymer, drug, and solvent selection are critically needed to facilitate rapid design of drug nanocarriers. Here, we evaluated the relationship between drug-polymer compatibility and concentration ratios on EE and nanocarrier size. Our studies employed a panel of four drugs with differing molecular structures (i.e., coumarin 6, dexamethasone, vorinostat/SAHA, and lutein) and two BCPs [poly(caprolactone)-b-poly(ethylene oxide) (PCL-b-PEO) and poly(styrene)-b-poly(ethylene oxide) (PS-b-PEO)] synthesized using three nanoprecipitation processes [i.e., batch sonication, continuous flow flash nanoprecipitation (FNP), and electrohydrodynamic mixing-mediated nanoprecipitation (EM-NP)]. Continuous FNP and EM-NP processes demonstrated up to 50% higher EE than batch sonication methods, particularly for aliphatic compounds. Drug-polymer compatibilities were assessed using Hansen solubility parameters, Hansen interaction spheres, and Flory Huggins interaction parameters, but few correlations were EE observed. Although some Hansen solubility (i.e., hydrogen bonding and total) and Flory Huggins interaction parameters were predictive of drug-polymer preferences, no parameter was predictive of EE trends among drugs. Next, the relationship between polymer: drug molar ratio and EE was assessed using coumarin 6 as a model drug. As polymer:drug ratio increased from <1 to 3–6, EE approached a maximum (i.e., ∼51% for PCL BCPs vs. ∼44% PS BCPs) with Langmuir adsorption behavior. Langmuir behavior likely reflects a formation mechanism in which drug aggregate growth is controlled by BCP adsorption. These data suggest polymer:drug ratio is a better predictor of EE than solubility parameters and should serve as a first point of optimization.
Highlights
Hydrophobic drugs are poorly soluble in biological media; drug delivery carriers are often employed to improve their biodistribution profiles (Torchilin, 2007; Kumar et al, 2020)
We investigated block copolymer (BCP) consisting of polyethylene oxide (PEO) as the hydrophilic block and either poly(styrene) (PS) or poly(caprolactone) (PCL) as the hydrophobic block (i.e., PS9.5kDa-b-PEO18kDa and PCL6kDab-PEO5kDa)
We investigated the size distribution of empty micelles and BCP nanocarriers synthesized via electrohydrodynamic mixingmediated nanoprecipitation (EM-NP) versus batch sonication
Summary
Hydrophobic drugs are poorly soluble in biological media; drug delivery carriers are often employed to improve their biodistribution profiles (Torchilin, 2007; Kumar et al, 2020). Amphiphilic block copolymer (BCP) micelles and self-assembled nanoparticles (NPs) consisting of a hydrophobic core and a hydrophilic corona are the most commonly employed hydrophobic drug carriers (Bobo et al, 2016) because of their high drug loading capacity, tunable properties, and potential for controlled and/or stimuli-responsive release (Mura et al, 2013). These self-assembled nanostructures have largely failed to be translated to the clinic (Anselmo and Mitragotri, 2016). It can be challenging to identify the optimal drug, BCP, and solvent combinations and operating conditions to maximize encapsulation efficiency (EE) (Martínez Rivas et al, 2017)
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