In the present work, molecular dynamics (MD) simulation was applied to study the solubility of two water-insoluble drugs, fenofibrate and nimodipine, in a series of micelle-forming PEO-b-PCL block copolymers with combinations of blocks having different molecular weights. The solubility predictions based on the MD results were then compared with those obtained from solubility experiments and by the commonly used group contribution method (GCM). The results showed that Flory-Huggins interaction parameters computed by the MD simulations are consistent with the solubility data of the drug/PEO-b-PCL systems, whereas those calculated by the GCM significantly deviate from the experimental observation. We have also accounted for the possibility of drug solubilization in the PEO block of PEO-b-PCL.

An increase in the degree of chemical compatibility between drug and polymeric structure in the core has been shown to raise the encapsulation efficiency and lower the rate of drug release from polymeric micelles. In this study, to achieve an optimized polymeric micellar delivery system for the solubilization and controlled delivery of cucurbitacin I (CuI), the Flory-Huggins interaction parameter (chi(sc)) between CuI and poly(epsilon-caprolactone) (PCL), poly(alpha-benzylcarboxylate-epsilon-caprolactone) (PBCL) and poly(alpha-cholesteryl carboxylate-epsilon-caprolactone) (PChCL) structures was calculated by group contribution method (GCM) as an indication for the degree of chemical compatibility between different micellar core structures and CuI. The results pointed to a better compatibility between CuI and PChCL core rationalizing the synthesis of self-associating methoxy poly(ethylene oxide)-b-poly(alpha-cholesteryl carboxylate-epsilon-caprolactone) block copolymer (MePEO-b-PChCL). Novel block copolymer of MePEO-b-PChCL was synthesized through, first, preparation of substituted monomer, that is, alpha-cholesteryl carboxylate-epsilon-caprolactone, and further ring opening polymerization of this monomer by methoxy PEO (5000 g mol(-1)) using stannous octoate as catalyst. Synthesized block copolymers were characterized for their molecular weight and polydispersity by (1)H NMR and gel permeation chromatography. Self-assembled MePEO-b-PChCL micelles were characterized for their size, morphology, critical micellar concentration (CMC), capacity for the physical encapsulation of CuI, and mode of CuI release in comparison to MePEO-b-PCL and MePEO-b-PBCL micelles. Overall, the experimental order for the level of CuI encapsulation in different polymeric micellar formulations was consistent with what was predicted by the Flory-Huggins interaction parameter. Although MePEO-b-PChCL micelles exhibited the highest level of CuI loading, this structure did not show any significant superiority over MePEO-b-PCL in controlling CuI release. The most efficient control over the rate of CuI release was achieved by MePEO-b-PBCL micelles that had more viscous cores than that of MePEO-b-PChCL, instead. The results point to a potential for MePEO-b-PChCL micelles for the solubilization of cholesterol compatible drugs. It also highlights the inadequacy of the Flory-Huggins interaction parameter calculated by GCM in predicting the order of drug release from different polymeric micellar structures.

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Molecular dynamics (MD) simulation was used to study the roles of nonpolar and polar intermolecular interactions in the improvement of the drug loading capacity of poly(ethylene oxide)-b-poly(epsilon-caprolactone) (PEO-b-PCL) with increasing PCL content for two water insoluble anticancer drugs: Cucurbitacin B (CuB) and Cucurbitacin I (CuI). In particular, random binary mixture models containing 10-12 wt % drug and remaining PEO-b-PCL with three different PCL/PEO (w/w) ratios (0.5, 1, and 2) were used to calculate their Flory-Huggins interaction parameters (chi). The MD simulation results show that, for both CuB and CuI, the computed chi decreases (i.e., affinity increases) with increasing PCL/PEO ratio. Such results are consistent with our experimental observation that increasing the PCL/PEO (w/w) ratio from 1 to 4.8 significantly increases the drug loading capacity of micelles formed by PEO-b-PCL for both drugs. Analysis of the energy data shows that increasing affinity (loading) at higher PCL/PEO ratio is attributed to the increase in favorable polar interactions and to the formation of additional hydrogen bonds (H-bonds) between the drugs and the PCL block rather than to the increase in the hydrophobic characteristics of the diblock copolymer as one would normally expect. In fact, the nonpolar intermolecular interactions became more unfavorable at higher PCL/PEO ratio. Analysis of the radial distribution functions of the model mixtures indicates that at high PCL/PEO ratio, multiple H-bond sites on the PCL block interacted with single H-bond sites on the drug molecules. However, at low PCL/PEO ratio, only single H-bonds formed between various H-bond sites on the drug molecules and those of the PCL and PEO blocks. It seems that formation of H-bonds between multiple H-bond sites on the PCL block and single H-bond sites on the drug molecules is responsible for inducing drug/PEO-b-PCL affinity. The finding also explains the experimental observation that release rates of both drugs decrease with increasing PCL/PEO ratio and that the decrease in the release rate of CuB is more pronounced than that of CuI. Our simulation results show that the number of H-bonds formed between CuB and the PCL block is much higher than that of CuI at high PCL/PEO ratio.

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