Prediction of drug solubility in amphiphilic di-block copolymer micelles: the role of polymer-drug compatibility.
ABSTRACT The goal of the current study was to assess the value of predictive computational approaches for estimating drug solubility in hydrated micelles formed from di-block copolymers of polyethylene glycol (PEG) and random copolyesters of epsilon-caprolactone (CL) and trimethylene carbonate (TMC) using drug-polymer compatibility as assessed through the Flory-Huggins interaction parameter (chi). In order to accomplish this, the compatibility of several well-known model drugs (associated with the four biopharmaceutics classification system (BCS) classes) was assessed with both segments of the amphiphilic di-block copolymer PEG-b-P(CL-co-TMC). Compatibilities were estimated based on the Hansen modification of the Hildebrand approach using Molecular Modeling Pro software. Experimental solubilities for model drugs were determined using a shake-flask technique at various polymer concentrations. The solubilities of 8 compounds in 10% w/v micelle solutions were in relatively good agreement with the predicted drug-polymer compatibility. In addition, the approach allows for the selection of a suitable di-block copolymer for optimal solubilization of a specific drug. Furosemide was assessed as a model with results suggesting that it can be best entrapped in a di-block copolyester containing a relatively high CL content. The data suggests that prediction of drug solubilization of block copolymer-based micelles may be facilitated by assessing the compatibility of the drug for the component polymeric domains.
Article: Synthesis, formulation and in vitro evaluation of a novel microtubule destabilizer, SMART-100.[show abstract] [hide abstract]
ABSTRACT: A novel microtubule destabilizer, substituted methoxybenzoyl-ary-thiazole (SMART)-100, was synthesized, which showed good anticancer activity in HepG2 cells. SMART-100 was able to circumvent multidrug resistance (MDR) and effectively inhibited the growth of cell lines that overexpress P-glycoprotein (P-gp). SMART-100 inhibited P-gp activity, which may be responsible for its ability to overcome MDR. Since SMART-100 is poorly soluble in water, it was formulated in polyethylene-b-poly(D,L-lactide) (PEG-PLA) micelles. The solubility of SMART-100 was increased by more than 1.1x10(5) folds. SMART-100 loaded PEG-PLA micelles could effectively inhibit HepG2 cell growth and arrest cell cycle progression at G2/M phase, followed by appearance of a sub-G1 phase, which is indicative of cell apoptosis. Increased Caspase-3 activity was also observed when HepG2 cells were treated with SMART-100. The anticancer activity of SMART-100 loaded PEG-PLA micelles was also evaluated on luciferase expressing C4-2-Luc cell lines by IVIS imaging. Our results suggest that SMART-100 has the potential to treat resistant cancers.Journal of Controlled Release 04/2010; 143(1):151-8. · 5.73 Impact Factor
Article: Encapsulation of docetaxel in oily core polyester nanocapsules intended for breast cancer therapy.[show abstract] [hide abstract]
ABSTRACT: This study is designed to test the hypothesis that docetaxel [Doc] containing oily core nanocapsules [NCs] could be successfully prepared with a high percentage encapsulation efficiency [EE%] and high drug loading. The oily core NCs were generated according to the emulsion solvent diffusion method using neutral Labrafac CC and poly(d, l-lactide) [PLA] as oily core and shell, respectively. The engineered NCs were characterized for particle mean diameter, zeta potential, EE%, drug release kinetics, morphology, crystallinity, and cytotoxicity on the SUM 225 breast cancer cell line by dynamic light scattering, high performance liquid chromatography, electron microscopies, powder X-ray diffraction, and lactate dehydrogenase bioassay. Typically, the formation of Doc-loaded, oily core, polyester-based NCs was evidenced by spherical nanometric particles (115 to 582 nm) with a low polydispersity index (< 0.05), high EE% (65% to 93%), high drug loading (up to 68.3%), and a smooth surface. Powder X-ray diffraction analysis revealed that Doc was not present in a crystalline state because it was dissolved within the NCs' oily core and the PLA shell. The drug/polymer interaction has been indeed thermodynamically explained using the Flory-Huggins interaction parameters. Doc release kinetic data over 144 h fitted very well with the Higuchi model (R2 > 0.93), indicating that drug release occurred mainly by controlled diffusion. At the highest drug concentration (5 μM), the Doc-loaded oily core NCs (as a reservoir nanosystem) enhanced the native drug cytotoxicity. These data suggest that the oily core NCs are promising templates for controlled delivery of poorly water soluble chemotherapeutic agents, such as Doc.Nanoscale Research Letters 12/2011; 6(1):630. · 2.73 Impact Factor