Tacrolimus (TAC) has exhibited promising therapeutic potential in the treatment of pulmonary arterial hypertension (PAH); however, its application is prevented by its poor solubility, instability, poor bioavailability, and negative systemic side effects. To overcome the obstacles of using TAC for the treatment of PAH, we developed nanocomposite microparticles (nCmP) for the pulmonary delivery of tacrolimus in the form of dry powder aerosols. These particles can provide targeted pulmonary delivery, improved solubility of tacrolimus, the potential of penetration through mucus barrier, and controlled drug release. In this system, tacrolimus-loaded polymeric nanoparticles (NP) were prepared via emulsion solvent evaporation and nCmP were prepared by spray drying these NP with mannitol. The NP were approximately 200 nm in diameter with narrow size distribution both before loading into and after redispersion from nCmP. The NP exhibited smooth, spherical morphology and the nCmP were raisin-like spheres. High encapsulation efficacy was achieved both in the encapsulation of tacrolimus in NP and that of NP in nCmP. nCmP exhibited desirable aerosol dispersion properties, allowing them to deposit into the deep lung regions for effective drug delivery. A549 cells were used as in vitro models to demonstrate the non-cytotoxicity of TAC nCmP. Overall, the designed nCmP have the potential to aid in the delivery of tacrolimus for the treatment of PAH.

This work develops a probability-based numerical method for quantifying mechanical properties of non-Gaussian chains subject to uniaxial deformation, with the intention of being able to incorporate polymer–polymer and polymer–filler interactions. The numerical method arises from a probabilistic approach for evaluating the elastic free energy change of chain end-to-end vectors under deformation. The elastic free energy change, force, and stress computed by applying the numerical method to uniaxial deformation of an ensemble of Gaussian chains were in excellent agreement with analytical solutions that were obtained with a Gaussian chain model. Next, the method was applied to configurations of cis- and trans-1,4-polybutadiene chains of various molecular weights that were generated under unperturbed conditions over a range of temperatures with a Rotational Isomeric State (RIS) approach in previous work (Polymer 2015, 62, 129–138). Forces and stresses increased with deformation, and further dependences on chain molecular weight and temperature were confirmed. Compression forces normal to the imposed deformation were much larger than tension forces on chains. Smaller molecular weight chains represent the equivalent of a much more tightly cross-linked network, resulting in greater moduli than larger chains. Young’s moduli computed from the coarse-grained numerical model were in good agreement with experimental results.