Search

Purpose. Drug delivery to the central nervous system (CNS) is limited by the blood-brain barrier (BBB). Thus, a noninvasive and reversible method to enhance BBB permeation of drugs is highly desirable. In the present work, we studied if ultrasound-induced mild hyperthermia (USHT, 0.4 watts (W)/cm2 at 41°C) can enhance drug absorption in BBB endothelial cells, and we elucidated the mechanism of USHT on cellular accumulation.

Purpose. Localized hyperthermia has been shown previously to augment the cytotoxicity of some lipophilic anticancer drugs. Because many of the substrates for the multi-drug resistance (MDR) transporter P-glycoprotein (P-gp) are lipophilic in nature, studies were conducted to test the hypothesis that hyperthermia induced by ultrasound could also increase cellular uptake and cytotoxicity of P-gp substrates by P-gp-expressing cells.

Purpose. To establish whether anionic liposomes interact with the low-density lipoprotein (LDL) receptor, to determine the role of lipoproteins in this interaction, and whether the association causes functional delivery of encapsulated drugs.

With the exception of various central nervous system (CNS)-required nutrients for which specific, saturable transport systems exist, the passage of most water-soluble solutes through the blood–brain barrier (BBB) is believed to depend largely on the lipid solubility of the solutes. Most peptides, therefore, do not enter the CNS because of their hydrophilic character. Recently, utilizing homologous series of model peptides and Caco-2 cell monolayers as a model of the intestinal mucosa, it was concluded that the principal determinant of peptide transport across the intestinal cellular membrane is the energy required to desolvate the polar amide bonds in the peptide (P. S. Burton et al., Adv. Drug Deliv. Rev. 7:365–386, 1991). To determine whether this correlation can be extended to the BBB, the permeabilities of the same peptides were determined using an in vitro as well as an in situ BBB model. The peptides, blocked on the N- and C-terminal ends, consisted of D-phenylalanine (F) residues: AcFNH2, AcF2NH2, AcF3NH2, AcF2(NMeF)NH2, AcF(NMeF)2NH2, Ac(NMeF)3NH2, and Ac(NMeF)3NHMe. A good correlation among the permeabilities of these model peptides across the bovine brain microvessel endothelial cell (BBMEC) monolayers, an in vitro model of the BBB, and their permeabilities across the BBB in situ was observed (r = 0.928, P < 0.05). The permeabilities of these peptides did not correlate with the octanol–buffer partition coefficients of the peptides (r = 0.389 in vitro and r = 0.155 in situ; P < 0.05). However, correlations were observed between the permeabilities of these peptides and the number of potential hydrogen bonds the peptides can make with water (r = 0.837 in vitro and r = 0.906 in situ; P < 0.05), suggesting that desolvation of the polar bonds in the molecule is a determinant of permeability. Consistent with this, good correlations were found between the permeabilities of these peptides and their partition coefficients between heptane–ethylene glycol (r = 0.981 in vitro and r = 0.940 in situ ; P < 0.05) or the differences in partition coefficients between octanol–buffer and isooctane–buffer (ΔlogPC) (r = 0.961 in vitro and r = 0.962 in situ; P < 0.05), both of which are experimental estimates of hydrogen bond or desolvation potential. These results suggest that the permeability of peptides through the BBB is governed by the same physicochemical parameter (hydrogen bonding potential) as their permeability through the intestinal mucosa.

The aim of this study was to develop sucrose ester (SE)-stabilized oleanolic acid (OA) nanosuspensions (NS) for enhanced delivery.SEOA NS were prepared via O/W emulsion and organic solvent evaporation methods. The particles' size and polydispersity index were measured by nanosizer. Their percent encapsulation efficiency, saturation solubility and in vitro dissolution rate were obtained via HPLC. The in vitro bioefficacy was analyzed by MTT measurements in A549 human non-small-cell lung cancer cell line. The cellular uptake of OA and in vivo pharmacokinetics profile were determined using LC-ESI-MS/MS.Spherical SEOA NS particles (~100 nm in diameter) were produced and found to be physicochemically stable over a month at 4°C. In particular, SEOA 4121 NS (SEL: SEP at 4:1 w/w; SE: OA at 2:1 w/w) produced the greatest increase in saturation solubility (1.89 mg/mL vs. 3.43 μg/mL), dissolution rate, cytotoxicity and bioavailability. Preliminary studies indicated that cellular uptake of SEOA NS by A549 cells was temperature-, concentration- and time-dependent.Preparing OA as SE-stabilized NS particles provides a novel method to enhance saturation solubility, in vitro dissolution rate, bioefficacy and in vivo bioavailability of free OA and/or other potentially useful hydrophobic drugs.

This study aimed at the investigation of the impact of aqueous solubility and dose manipulation on the pharmacokinetics of resveratrol.Water soluble intravenous and oral formulations of resveratrol were prepared with hydroxypropyl-beta-cyclodextrin (HP-beta-CD) and randomly methylated-beta-cyclodextrin (RM-beta-CD), respectively. Sodium salt and suspension of resveratrol in carboxymethyl cellulose (CMC) were used as the reference intravenous and oral formulations, respectively. The pharmacokinetics of resveratrol was assessed in Sprague-Dawley rats. Plasma resveratrol concentrations were measured by high performance liquid chromatography (HPLC).Both HP-beta-CD and RM-beta-CD enhanced the aqueous solubility of resveratrol. After intravenous administration, rapid elimination of resveratrol was observed at all tested doses (5, 10, and 25 mg kg(-1)) regardless of formulation types; with non-linear elimination occurring at the dose of 25 mg kg(-1). RM-beta-CD significantly increased the maximal plasma concentration of orally administered resveratrol, but, it did not increase the oral bioavailability in comparison with the CMC suspension. Furthermore, the oral bioavailability remained unchanged among all tested doses (15, 25, and 50 mg kg(-1)).Aqueous solubility barrier might affect the speed but not the extent of resveratrol absorption. Further, dose manipulation (up to 50 mg kg(-1)) did not have a significant impact on the oral bioavailability of resveratrol.

Drug delivery to the central nervous system (CNS) is limited by the blood-brain barrier (BBB). Thus, a noninvasive and reversible method to enhance BBB permeation of drugs is highly desirable. In the present work, we studied if ultrasound-induced mild hyperthermia (USHT, 0.4 watts (W)/cm2 at 41 degrees C) can enhance drug absorption in BBB endothelial cells, and we elucidated the mechanism of USHT on cellular accumulation.To accomplish these aims, we studied the effects of hyperthermia (41 degrees C), USHT, P-glycoprotein (P-gp) modulator (PSC 833), and combination of USHT and PSC 833 on accumulation of P-gp substrate (R123) and non-P-gp substrates (sucrose, 2-deoxyglucose, and antipyrine) in monolayers of primary bovine brain microvessel endothelial cells (BBMEC).USHT, through its thermal effect, produces a significant (relative to controls; no USHT) and comparable increase in R123 accumulation with PSC 833. We also demonstrate that USHT increases permeability of hydrophobic (R123 and [14C]-antipyrine) and not hydrophilic molecules ([14C]-sucrose and 2-[3H]-deoxy-D-glucose). The enhanced permeability is reversible and size dependent, as USHT produces a much larger effect on cellular accumulation of [14C]-antitpyrine (molecular weight of 188 D) than that of R123 (molecular weight of 380.8 D). Although USHT increases membrane permeability, it did not affect P-gp activity or the activity of glucose transporters.Our results point to the potential use of USHT as a reversible and noninvasive approach to increase BBB permeation of hydrophobic drugs, including P-gp-recognized substrates.