ABSTRACT
PURPOSE: The objective of this study was to compare different techniques to enhance the solubility and dissolution rate, and hence the bioavailability of candesartan cilexetil. METHODS: To achieve this target, various techniques were employed such as solid dispersions, inclusion complexes, and preparation of candesartan nanoparticles. Following the preparations, all samples were characterized for their physicochemical properties, and the samples of the best results were subjected to further bioavailability studies. RESULTS: Results of dissolution studies revealed an increase in the dissolution rate of all samples. The highest dissolution rate was achieved using solid dispersion of the drug with PVP K-90 (1:4). Physicochemical investigations (XR, DSC, and FT-IR) suggested formation of hydrogen bonding and changing in the crystalline structure of the drug. Regarding the inclusion complexes, more stable complex was formed between HP-ß-CD and CC compared to ß-CD, as indicated by phase solubility diagrams. Antisolvent method resulted in the preparation of stable nanoparticles, as indicated by ζ potential, with average particle size of 238.9 ± 19.25 nm using PVP K-90 as a hydrophilic polymer. The best sample that gave the highest dissolution rate (CC/PVP K-90 1:4) was allowed for further pharmacokinetic studies using UPLC MS/MS assay of rabbit plasma. Results showed a significant increase in the bioavailability of CC from ~15% to ~48%. CONCLUSION: The bioavailability of CC was significantly improved from ~15% to ~48% when formulated as SDs with PVP K-90 with 1:4 drug:polymer ratio.
Subject(s)
Antihypertensive Agents/pharmacokinetics , Benzimidazoles/chemistry , Biphenyl Compounds/chemistry , Tetrazoles/chemistry , Animals , Antihypertensive Agents/blood , Antihypertensive Agents/chemistry , Biological Availability , Male , Molecular Structure , Nanoparticles/chemistry , Particle Size , Rabbits , Solubility , Surface PropertiesABSTRACT
We have previously reported the utility of folate-polyethylene glycol-appended dendrimer conjugate with glucuronylglucosyl-ß-cyclodextrin (Fol-PEG-GUG-ß-CDE) (generation 3) as a tumor-selective carrier for siRNA against polo-like kinase 1 (siPLK1) in vitro. In the present study, we evaluated the potential of Fol-PEG-GUG-ß-CDE as a carrier for the low-molecular antitumor drug doxorubicin (DOX). Further, to fabricate advanced antitumor agents, we have prepared a ternary complex of Fol-PEG-GUG-ß-CDE/DOX/siPLK1 and evaluated its antitumor activity both in vitro and in vivo. Fol-PEG-GUG-ß-CDE released DOX in an acidic pH and enhanced the cellular accumulation and cytotoxic activity of DOX in folate receptor-α (FR-α)-overexpressing KB cells. Importantly, the Fol-PEG-GUG-ß-CDE/DOX/siPLK1 ternary complex exhibited higher cytotoxic activity than a binary complex of Fol-PEG-GUG-ß-CDE with DOX or siPLK1 in KB cells. In addition, the cytotoxic activity of the ternary complex was reduced by the addition of folic acid, a competitor against FR-α. Furthermore, the ternary complex showed a significant antitumor activity after intravenous administration to the tumor-bearing mice. These results suggest that Fol-PEG-GUG-ß-CDE has the potential of a tumor-selective co-delivery carrier for DOX and siPLK1.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Dendrimers/chemistry , Doxorubicin/administration & dosage , Drug Carriers/chemistry , Oligosaccharides/chemistry , RNA, Small Interfering/administration & dosage , Animals , Cell Cycle Proteins/antagonists & inhibitors , Cell Survival/drug effects , Doxorubicin/pharmacology , Drug Liberation , Humans , KB Cells , Mice, Nude , Particle Size , Protein Serine-Threonine Kinases/antagonists & inhibitors , Proto-Oncogene Proteins/antagonists & inhibitors , RNA, Small Interfering/pharmacology , Surface Properties , Xenograft Model Antitumor Assays , Polo-Like Kinase 1ABSTRACT
Abstract In this study, we newly synthesized the polyamidoamine STARBURST dendrimer (dendrimer, generation 3: G3) conjugates with 6-O-α-(4-O-α-D-glucuronyl)-D-glucosyl-ß-cyclodextrin [GUG-ß-CDE (G3)] having the various degrees of substitution (DS) of GUG-ß-cyclodextrin of 1.6, 3.0, 3.7, 5.0 and 8.6, and evaluated them as a siRNA transfer carrier. GUG-ß-CDEs (G3) formed the positively charged and nano-order complexes with siRNA. Of the siRNA complexes with five GUG-ß-CDEs (G3), the complex with GUG-ß-CDE (G3, DS 3.7) showed the highest RNAi effect and cellular uptake with negligible cytotoxicity in KB cells at a charge ratio of 20. In addition, the RNAi effect and cellular uptake of the complex with GUG-ß-CDE (G3, DS 3.7) were higher than those of α-CDE (G3, DS 2.4) and comparable to those of Lipofectamine™ 2000. Furthermore, the complex with GUG-ß-CDE (G3, DS 3.7) possessed the endosomal escaping ability, the releasing property of siRNA in the cytoplasm and serum resistance. These results suggest that GUG-ß-CDE (G3, DS 3.7) has the potential as a novel siRNA carrier.
