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Molecular pharmaceutics [journal]
- Folate receptor-β in activated macrophages: Ligand binding and receptor recycling kinetics. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 28.
Activated macrophages overexpress a receptor for the vitamin folic acid termed the folate receptor β (FR-β). Because conjugation of folate to low molecular weight drugs, genes, liposomes, nanoparticles, and imaging agents has minor effects on FR binding, the vitamin can be exploited to target both therapeutic and imaging agents to activated macrophages without promoting their uptake by other healthy cells. In this paper we characterize the binding, internalization and recycling kinetics of FR-β on activated macrophages in inflamed tissues of rats with adjuvant-induced arthritis. Our results demonstrate that saturation of macrophage FR is achieved at injection doses of ~150-300 nmol/kg, with more rapidly perfused tissues saturating at lower doses than inflamed appendages. After binding, FR-β internalizes and recycles back to the cell surface every ~10-20 minutes, providing empty receptors for additional folate conjugate uptake. Because the half-life of low molecular weight folate conjugates in the vasculature is usually <1 hour, these data suggest that targeting of folate conjugates to activated macrophages in vivo can be maximized by frequent dosing at conjugate concentrations that barely saturate FR (~150 nmol/kg), thereby minimizing nonspecific binding to receptor-negative tissues and maximizing the probability that unoccupied cell surface receptors will be exposed to folate-drug conjugate.
- Effect of Surface Functionality of Silica Nanoparticles on Cellular Uptake and Cytotoxicity. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 28.
Mesoporous silica nanoparticles (MCM-41) with different surface chemistry were used as carrier system to study its influence on drug delivery and anticancer activity of curcumin (CUR). CUR was encapsulated in pristine MCM-41 (hydrophilic and negatively charged), amino functionalized MCM-41 (MCM-41-NH2 which is hydrophilic and positively charged) and methyl functionalized MCM-41 (MCM-41-CH3 which is hydrophobic and negatively charged) and evaluated for in vitro release and cell cytotoxicity in human squamous cell carcinoma cell line (SCC25). Various techniques were employed to evaluate the performance of these materials on cellular uptake and anticancer activity in SCC25 cell line. Both positively and negatively charged surface demonstrated enhanced drug release and anticancer activity compared to pure curcumin. Positively charged nanoparticles showed higher cell uptake compared to negatively charged nanoparticles owing to its electrostatic interaction with cells. However, hydrophobic surface modified nanoparticles (MCM-41-CH3) showed no improvement in drug release and anticancer activity due to its poor wetting effect. Cell cycle analysis and cell apoptosis studies revealed different pathway mechanisms followed by the positively and negatively charged nanoparticles but exhibiting similar anticancer activity in SCC25 cells.
- On the Barrier Properties of the Cornea: A Microscopy Study of the Penetration of Fluorescently Labeled Nanoparticles, Polymers, and Sodium Fluorescein. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 28.
Overcoming the natural defensive barrier functions of the eye remains one of the greatest challenges of ocular drug delivery. Cornea is a chemical and mechanical barrier preventing the passage of any foreign bodies including drugs into the eye, but the factors limiting penetration of permeants and nanoparticulate drug delivery systems through the cornea are still not fully understood. In this study, we investigate these barrier properties of the cornea using thiolated and PEGylated (750 and 5000 Da) nanoparticles, sodium fluorescein, and two linear polymers (dextran and polyethylene glycol). Experiments used intact bovine cornea in addition to bovine cornea de-epithelialized or tissues pretreated with cyclodextrin. It was shown that corneal epithelium is the major barrier for permeation; pretreatment of the cornea with β-cyclodextrin provides higher permeation of low molecular weight compounds, such as sodium fluorescein, but does not enhance penetration of nanoparticles and larger molecules. Studying penetration of thiolated and PEGylated (750 and 5000 Da) nanoparticles into the de-epithelialized ocular tissue revealed that interactions between corneal surface and thiol groups of nanoparticles were more significant determinants of penetration than particle size (for the sizes used here). PEGylation with polyethylene glycol of a higher molecular weight (5000 Da) allows penetration of nanoparticles into the stroma, which proceeds gradually, after an initial 1 h lag phase.
- Successful Entrapping of Liposomes in Glucan Particles: an innovative micron-sized carrier to deliver water soluble molecules. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 27.
Glucan particles (GPs) are monodisperse microspheres derived from baker's yeast, and represent an interesting class of microcarriers for theranostic applications as they show a high affinity towards immune system cells. The typical loading strategy was to harness the ability of the molecule to be loaded to interact with nano- micro-assembled systems through electrostatic or hydrophobic forces. However, small water soluble chemicals could not be steadily retained by the leaky shell of GPs. In this work, we propose an alternative loading approach for small water soluble compounds that is based on their entrapment in the aqueous core of liposomes that are directly formed into the microparticles through the reverse phase evaporation method (REV). The construct obtained may act as biocompatible carrier to deliver and release, even in triggerable way, bioactive compounds.
- Comparison of Binding Characteristics and In Vitro Activities of Three Inhibitors of Vascular Endothelial Growth Factor A. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 27.
The objectives of this study were to evaluate the relative binding and potencies of three inhibitors of vascular endothelial growth factor A (VEGF), used to treat neovascular age-related macular degeneration, and assess their relevance in the context of clinical outcome. Ranibizumab is a 48 kDa antigen binding fragment, which lacks a fragment crystallizable (Fc) region and is rapidly cleared from the systemic circulation. Aflibercept, a 110 kDa fusion protein and bevacizumab, a 150 kDa monoclonal antibody, each contain an Fc region. Binding affinities were determined using Biacore analysis. Competitive binding by sedimentation velocity analytical ultracentrifugation (SV-AUC) was used to support the binding affinities determined by Biacore of ranibizumab and aflibercept to VEGF. A bovine retinal microvascular endothelial cell (BREC) proliferation assay was used to measure potency. Biacore measurements were format dependent, especially for aflibercept, suggesting that biologically relevant, true affinities of recombinant VEGF (rhVEGF) and its inhibitors are yet to be determined. Despite this assay format dependency, ranibizumab appeared to be a very tight VEGF binder in all three formats. The results are also very comparable to those reported previously1-3. At equivalent molar ratios ranibizumab was able to displace aflibercept from preformed aflibercept-VEGF complexes in solution as assessed by SV-AUC, whereas aflibercept was not able to significantly displace ranibizumab from preformed ranibizumab-VEGF complexes. Ranibizumab, aflibercept, and bevacizumab showed dose-dependent inhibition of BREC proliferation induced by 6 ng/ml VEGF, with average IC50 values of 0.088 ± 0.032 nM, 0.090 ± 0.009 nM, and 0.500 ± 0.091 nM, respectively. Similar results were obtained with 3ng/mL VEGF. In summary Biacore studies and SV-AUC solution studies show that aflibercept does not bind with higher affinity than ranibizumab to VEGF as recently reported 4 and both inhibitors appeared to be equipotent with respect to their ability to inhibit VEGF function. 1. Ferrara, N.; Damico, L.; Shams, N.; Lowman, H.; Kim, R. Development of ranibizumab, an anti-vascular endothelial growth factor antigen binding fragment, as therapy for neovascular age-related macular degeneration. Retina 2006, 26, (8), 859-70. 2. Lowe, J.; Araujo, J.; Yang, J.; Reich, M.; Oldendorp, A.; Shiu, V.; Quarmby, V.; Lowman, H.; Lien, S.; Gaudreault, J.; Maia, M. Ranibizumab inhibits multiple forms of biologically active vascular endothelial growth factor in vitro and in vivo. Exp Eye Res 2007, 85, (4), 425-30. 3. Presta, L. G.; Chen, H.; O'Connor, S. J.; Chisholm, V.; Meng, Y. G.; Krummen, L.; Winkler, M.; Ferrara, N. Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders. Cancer Res 1997, 57, (20), 4593-9. 4.Papadopoulos, N.; Martin, J.; Ruan, Q.; Rafique, A.; Rosconi, M. P.; Shi, E.; Pyles, E. A.; Yancopoulos, G. D.; Stahl, N.; Wiegand, S. J. Binding and neutralization of vascular endothelial growth factor (VEGF) and related ligands by VEGF Trap, ranibizumab and bevacizumab. Angiogenesis 2012, 15, (2), 171-85.
- One-Pot-Multi-Tracer Synthesis of Novel 18F-Labelled PET Imaging Agents. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 26.
18F labelled phosphonium salts are increasingly important molecular probes for targeting the mitochondrial membrane potential depletion during apoptosis and for detecting myocardial perfusion deficit. Here, we introduce two new tracers, [18F]MitoPhos_04 and [18F]MitoPhos_07, that can act as mitochondrial imaging agents and have the added advantage of being synthesised in the same reaction vial from one radiolabelled synthon. The radiosynthesis of both tracers was carried out on a fully automated system via a facile two-step reaction. Utilising the radiolabelling of an ethyl azide, a copper-mediated 1,3-cycloaddition reaction and isolation via semi-prep HPLC allowed for the simultaneous synthesis of two tracers with a total synthesis time of less than 1 hour. Initial cellular uptake studies demonstrated that the uptake of [18F]MitoPhos_04 was substantially higher than that seen for [18F]MitoPhos_07 in the murine -lymphoma cell line, 38C13.
- PET imaging of neovascularization with 68Ga-3PRGD2 for assessing tumor early response to Endostar anti-angiogenic therapy. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 26.
Objectives: Anti-angiogenic therapy is an effective strategy to inhibit tumor growth. In this study, 68Ga-3PRGD2 targeting integrin αvβ3 was evaluated to be a PET tracer for monitoring the efficacy of Endostar anti-angiogenic therapy in an animal model. Methods: Thirty-two LLC tumor bearing mice were randomly divided into two groups. The mice in treatment group were administrated with Endostar (8 mg/kg/day) via tail vein injection for three weeks, while the mice in control group were administrated with saline. The 68Ga-3PRGD2 PET imaging was performed at 3, 7, 14 and 21 d post-treatment, while using 18F-FDG PET imaging as the control. Immunofluorescence staining and Western blot were carried out to validate the imaging results. Results: Endostar inhibited the newborn vascular endothelial cells, causing the decrease of integrin αvβ3 expression, which led to the decrease of 68Ga-3PRGD2 uptake in tumor. This finding was confirmed by immunofluorescence staining and Western blot results. As compared with control group, 18F-FDG imaging showed the uptake difference on 14 d post-treatment, whereas 68Ga-3PRGD2 imaging showed the uptake difference on 3 d post-treatment. Conclusions: As a specific probe, 68Ga-3PRGD2 targeting integrin αvβ3 can be used to monitor the efficacy of anti-angiogenic therapy. Compared with 18F-FDG metabolic imaging, 68Ga-3PRGD2 PET reflects the tumor response to anti-angiogenic therapy much earlier and more accurately, which provides new opportunities to develop individualized therapeutic approaches, establish optimized dosages and dose intervals for effective treatment that improve the survival rate of patients.
- Protein abundance of clinically relevant multidrug transporters along the entire length of the human intestine. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 26.
Intestinal transporters are crucial determinants in the oral absorption of drugs. We therefore studied mRNA expression (N=33) and absolute protein content (N=10) of clinically relevant transporters in healthy epithelium of the duodenum, proximal and distal jejunum and ileum and the ascending, transversal, descending and sigmoidal colon of six organ donors (24-54 years). In the small intestine, the abundance of nearly all studied proteins ranged between 0.2-1.6 pmol/mg with the exception of OCT3 (<0.1 pmol/mg) and PEPT1 (2.6-4.9 pmol/mg) which accounted for ~50% of all measured transporters. OATP1A2 was not detected in any intestinal segment. ABCB1, ABCG2, PEPT1 and ASBT were significantly higher abundant in jejunum/ileum than in colon. In contrast to this, ABCC2, ABCC3 and OCT3 expression was found to be highest in colon. Site-dependent expression was confirmed for ABCB1 and ASBT and significant correlations between mRNA and protein levels for ABCG2, ASBT, OCT3 and PEPT1 in the small intestine. Our data provide further physiological pieces in the puzzle required to predict intestinal drug absorption in man.
- Prodrugs of Pioglitazone for Extended-Release (XR) Injectable Formulations. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 26.
N-acyloxymethyl derivatives of pioglitazone (PIO) have been prepared and characterized as model candidates for extended-release injectable formulations. All PIO derivatives prepared are crystalline solids as determined by powder X-ray diffraction, and the solubility in aqueous media is below 1 μM at 37 °C. The melting points steadily increase from 55 oC, for the hexanoyloxymethyl derivative, to 85 °C, for the palmitoyloxymethyl derivative; inversely, the solubilities in ethyl oleate decrease as a function of increasing acyl chain length. The butyroyloxymethyl ester has a higher melting point and a lower solubility in ethyl oleate than expected from the trend. The 13C solid-state NMR spectra of the PIO homologs between the hexanoyloxymethyl derivative and stearoyloxymethyl derivative suggest a common structural motif with the acyl chains exchanging between two distinct conformations, and the rate of exchange is slower for longer chain derivatives. The butyroyloxymethyl derivative is efficiently converted to PIO in in vitro rat plasma with a half-life of < 2 minutes at 37 ° C, while the rate of enzymatic cleavage in rat plasma decreases as the ester chain length increases for the longer acyloxymethyl derivatives. The concentration of PIO in plasma increases rapidly, or "spikes," in the hours following intramuscular (IM) injection of either the HCl salt or the butyroyloxymethyl derivative. In contrast, the more lipophilic palmitoyloxymethyl derivative provides slow growth in the PIO concentration over the first day to reach levels that remain steady for two weeks. Based on its in vivo pharmacokinetic profile, as well as material and solubility properties, the PIO palmitoyloxymethyl derivative has potential as a once-monthly injectable medication to treat diabetes.
- Bacterial cellulose/acrylamide pH-sensitive smart hydrogel: Development, characterization and toxicity studies in ICR mice model. [JOURNAL ARTICLE]
- Mol Pharm 2014 Aug 26.
The objective of this study is to synthesize and evaluate acute toxicity of the bacterial cellulose (BC)/acrylamide (Am) hydrogels as non-cytotoxic and biocompatible oral drug delivery vehicles. A novel series of solubilized BC/Am hydrogels were synthesized using a microwave irradiation method. The hydrogels were characterized by Fourier transform infrared (FTIR), swelling ratio, porosity, drug release, in vitro and in vivo biocompatibility experiments. FTIR spectra revealed that the BC crystallinity and gel fraction decreased as the NaOH concentration increased from 2% to 10% w/v, whereas the optical transparency, pH sensitivity, and porosity were enhanced with increasing alkali concentration. Theophylline was used as a model drug for drug loading and release studies. The percentage of drug released was higher at pH 7.4 compared to pH 1.5. In vitro cytotoxicity and hemolytic tests indicated that the BC/Am hydrogel is non-cytotoxic and hemocompatible. Results of acute oral toxicity tests on ICR mice suggested that the hydrogels are non-toxic up to 2000 mg/kg when administered orally, as no toxic response or histopathological changes were observed in comparison to control mice. The results of this study demonstrated that the pH-sensitive smart hydrogel makes it a possible safe carrier for oral drug delivery.