Roles of Nonpolar and Polar Intermolecular Interactions in the Improvement of the Drug Loading Capacity of PEO-b-PCL with Increasing PCL Content for Two Hydrophobic Cucurbitacin Drugs

Abstract

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.

Chemical Modification of Hydrophobic Block in Poly(Ethylene Oxide) Poly(Caprolactone) Based Nanocarriers: Effect on the Solubilization and Hemolytic Activity of Amphotericin B

“…This can be attributed to non-polar interactions between AmB and stearyl groups of the nanocarriers [23] and/or polar interactions between AmB and unconjugated COOH groups or extra carbonyl groups in MePEO-b-PStCL (in comparison to MePEO-b-PCL). [33,34] Nonetheless, the presence of free carboxyl groups on PCL block seemed to positively impact AmB solubilization, as block copolymers with >90% stearyl substitution showed reduced AmB solubilization (data not shown). In general, the extent of AmB solubilization achieved by MePEO-b-PCL, MePEO-b-PCCL, and MePEO-bPStCL nanocarriers at a polymer concentration of 2.5 mgÁmL À1 under current study, appears to be higher than AmB water solubility levels achieved by previously reported polymeric nanocarriers.…”

“…Therefore, both polar and non-polar interactions with the polymer are expected to affect the extent of AmB solubilization as well as release from its polymeric carrier. [33] On the other hand, MePEO-b-PStCL copolymer showed higher encapsulation efficiency compared to MePEO-b-PCL, despite a shorter PCL backbone. This can be attributed to non-polar interactions between AmB and stearyl groups of the nanocarriers [23] and/or polar interactions between AmB and unconjugated COOH groups or extra carbonyl groups in MePEO-b-PStCL (in comparison to MePEO-b-PCL).…”

Pegylated Phospholipids-Based Self-Assembly with Water-Soluble Drugs

“…al. had investigated the roles of nonpolar and polar intermolecular interactions in the improvement of the hydrophobic drug loading capacity of PEG-PCL with increasing PCL content (24).…”

Computational Amphiphilic Materials for Drug Delivery

“…With increasing PCL/PEO ratio, both drugs showed an increase in solubility. This was attributed to the increase in favorable polar interactions and to the formation of additional hydrogen bonds between drugs and PCL rather than to the increase in hydrophobic characteristics (Patel et al, 2009). In their subsequent study, PCL was branched and linked to PEO as PEO-b-3PCL and tested for various drug encapsulations.…”