查看更多>>摘要：The increasing prevalence of antibiotic resistance in Gram-negative bacteria calls for the discovery of novel effective therapeutic strategies urgently. Mastoparan-C (MP-C), a typical cationic alpha-helical antimicrobial peptide, possesses remarkable broad-spectrum antimicrobial activity. However, its high cytotoxicity toward normal mammalian cells precludes it for further development. In this study, to avoid non-specific membrane lysis and investigate the structure-function relationships of each amino acid of MP-C, a series of new MP-C analogs were rationally designed by amino acid substitution and peptide truncation. Three potential newly designed peptides L(1)G, L(7)A, and L(1)GA(5)K with excellent bioactivity, modest cell toxicity, low resistance tendency, and moderate stability to physiological salts and proteases were screened out. Moreover, the newly designed peptides showed synergy or additive effects against Gram-negative bacteria, when they combined with conventional antibiotics gentamicin, rifampin, and polymyxin B. The results from the time-kill kinetics, outer/inner membrane permeabilization, scanning electron microscope (SEM), and flow cytometry demonstrated that the newly designed peptides could kill bacteria rapidly by membrane destruction and intracellular contents leakage in a concentration and time-dependent manner. Specifically, the most cell-selective peptide L(1)GA(5)K exhibited potent antimicrobial activity against rifampin-resistant E. coli (RRE) and prevented the emergence of rifampin resistance in Enterobacter. Besides, L(1)GA(5)K was capable of reversing rifampin resistance in RRE through the outer membrane permeabilization when used in combination with rifampin. Collectively, our results suggested that the newly designed peptides are hopeful antibiotic alternatives, and the usage of them as an adjuvant to prevent and reverse antibiotic resistance is a promising strategy for tackling the risk of drug-resistant Gram-negative bacteria.
查看更多>>摘要：Vandetanib (ZD6474, Zactima (R), Caprelsa (R)) is a newly developed dual tyrosine kinase inhibitor of vascular endothelial growth factor and epidermal growth factor receptor. Recently, several reports have indicated the interaction of vandetanib with tyrosine kinase inhibitors and transporters. However, these characteristics of vandetanib remain unclear. We examined the interaction of vandetanib with the human organic cation transporter 2 (hOCT2) stably expressed in human embryonic kidney (HEK) 293 cells. The specific uptake of vandetanib was not observed in hOCT2-expressing HEK293 cells. Vandetanib inhibited the uptake of creatinine mediated by hOCT2 in a dose-dependent manner. The IC50 value for vandetanib inhibition of creatinine uptake by hOCT2 was 3.7 +/- 1.0 mu M (average +/- SE of three separate experiments). The IC50 value of cimetidine and trimethoprim for hOCT2 were 100 +/- 13.5 and 52.1 +/- 8.0 mu M, respectively. Vandetanib showed markedly higher affinity for hOCT2 than cimetidine and trimethoprim. These results suggest that hOCT2 may play a crucial role in elevating the serum creatinine levels, as well as increasing the risk of renal impairment during vandetanib administration.
查看更多>>摘要：The objective of this study was to prepare a co-amorphous formulation of piroxicam (PIR), a non-steroidal anti-inflammatory drug, and citric acid (CA), and evaluate its skin permeation ability. A spray-drying method was employed to prepare the co-amorphous formulation and its physical properties were characterized. X-ray powder diffraction and thermal analysis confirmed a homogeneous amorphous state, and the infrared spectra revealed intermolecular interactions between PIR and CA, suggesting formation of a co-amorphous formulation of PIR and CA. The PIR-CA co-amorphous formulation exhibited no crystallization for 60 days at 4/25/40 degrees C with silica gel. The PIR-CA co-amorphous formulation increased the solubility of PIR in polyethylene glycol 400 compared with that of the pure drug, and physical mixture (PM) of PIR and CA, confirming a supersaturated state in the formulation. The PIR-CA co-amorphous formulation demonstrated higher skin permeation than PIR alone or PM of PIR and CA, and the flux value was consistent with the degree of saturation. Thus, the increase in the skin permeation of PIR from the PIR-CA co-amorphous formulation directly depended on the increased thermodynamic activity by supersaturation in the absence of interactions between the drug and co-former in the vehicle.
查看更多>>摘要：SNAC and C-10 are intestinal permeation enhancers (PEs) used in formulations of peptides for oral delivery in clinical trials. Our aims were to compare their: (i) mechanism of action in isolated rat intestinal mucosae mounted in Ussing chambers and in non-everted gut sacs, (ii) effects on mucosa integrity in those models and also in in situ intra-jejunal instillations and (iii) interactions with intestinal mucus. SNAC increased the apparent permeability coefficient (P-app) of the paracellular marker, FITC-dextran 4000 (FD4), across isolated rat gastric mucosae in concentration-dependent fashion, whereas C-10 did not, while both reduced the transepithelial electrical resistance (TEER). In isolated jejunal and colonic mucosae, both agents increased the P-app of [C-14]mannitol and FD4 whereas C-10 but not SNAC reduced TEER. 20 mM SNAC was required to achieve the efficacy of 10 mM C-10 in jejunal and colonic mucosae. In isolated non-everted jejunal and colonics sacs, FD4 flux increases were observed in the presence of both PEs. Histology of mucosae revealed that both PEs induced minor epithelial damage to the mucosa at concentrations that increased fluxes. Jejunal tissue withstood epithelial damage in the following order: intra jejunal in situ instillations > jejunal sacs > isolated jejunal mucosae. Both PEs modulated viscoelastic properties of porcine jejunal mucus without altering rheological properties. In conclusion, SNAC and C-10 are reasonably efficacious PEs in rat intestinal tissue with common overall mechanistic features. Their potency and toxic potential are low, in agreement with clinical trial data.
查看更多>>摘要：Melanoma anti-tumor therapy remains a challenge. SiRNA-based therapies provide a powerful means, but limitations remain in its pharmaceutical applications owing to the lack of highly efficient delivery systems. In this study, to improve the siRNA delivery efficiency of chitooligosaccharide (COS), phenylboronic acid (PBA)-modified COS was synthesized and structurally characterized. PBA-modified COS was used to deliver survivin-targeted siRNA for melanoma treatment. The siRNA-loaded nanoparticles were prepared by a synergetic assembly of electrostatic complexation and chemical cross-linking. The particle size and zeta potential were characterized by dynamic light scattering, and transmission electron microscopy was utilized to observe the morphology of the nanoparticles. The cellular uptake of nanoparticles on B16F10 cells was studied by flow cytometry and confocal laser scanning microscopy. A luciferase reporter gene assay determined the gene silencing efficiency of different nanoparticles. As a result, the novel nanoparticles remarkably inhibited the proliferation of B16F10 cells in vitro and significantly inhibited the growth and metastasis of melanoma in vivo. In conclusion, PBA-modified COS can serve as a promising carrier for siRNA delivery in the field of anti-tumor therapy.
查看更多>>摘要：Conventional treatment options for lung cancer treatment were restricted due to non-specific nature and side effects, with this associated problem and to overcome this we had developed lumefantrine with nano calcium phosphate loaded lipid nanoparticles (LF-CaP-Ls) affording pH sensitive mechanism. Herein, the present study the in vivo anti-cancer property of LF-CaP-Ls was checked in mice models. Further, reduced lung cancer progression of lumefantrine with nano calcium phosphate loaded lipid nanoparticles (LF-CaP-Ls) treated mice were assessed by measuring the 5-methyltetrahydrofolate (MTHF) in serum. Moreover, LF-CaP-Ls showed substantially a anticancer effect compared to that of lumefantrine loaded lipid nanoparticles (LF-Ls) and free lumefantrine (LF) by exhibiting higher effects in lung tumor bearing mice model as confirmed by reduced tumor progression. Histopathological examination of lungs supported with H&E staining proved the reduced tumor vasculature and reduced inflammatory cells for LF-CaP-Ls compared to that of free LF and LF-Ls. Further, visual inspection with acetic acid test confirmed the reduced tumor progression for LF-CaP-Ls compared to that of free LF and LF-Ls. Altogether, the overall results suggested that the developed LF-CaP-Ls may acts as a better therapeutic molecule for lung cancer due to its maintenance of increased level of 5-MTHF levels, reduced tumor weight. Further, hematological and biochemical parameters were measured and supports our in-vivo therapeutic effect of LF-CaP-Ls.
查看更多>>摘要：Hot-melt extruded (HME) filaments are an essential intermediate product for the threedimensional (3D) printing of drug delivery systems (DDSs) by the fused deposition modelling (FDM) process. The aim of this study was to design novel polymeric 3D-printable HME filaments loaded with active pharmaceutical ingredients (APIs). The physical solid-state properties, mechanical properties, drug release and short-term storage stability of the filaments and 3D-printed DDSs were studied. Physical powder mixtures of polycaprolactone (PCL), plasticizer and API were manually blended, extruded by a single-screw extruder, and printed by a table-top FDM 3D-printing system. The composition of PCL and arabic gum (ARA) enabled the incorporation of 20%, 30% and 40% (w/ w) of indomethacin (IND) and theophylline (THEO) into the HME filaments. The uneven distribution of API throughout the filaments impaired 3D printing. The HME filaments loaded with 20% IND or THEO were selected for the further analysis and printing tests (the ratio of PCL, ARA and IND or THEO was 7:1:2, respectively). The IND filaments were yellowish, mechanically strong and flexible, and they had a uniform filament diameter and smooth outer surface. The filaments containing THEO were smooth and off-white. The 3D-printed tablets fabricated from IND or THEO-loaded filaments showed sustained drug release in vitro. The drug release rate, however, significantly increased by changing the geometry of 3D-printed tablets from a conventional tablet structure to an unorthodox lattice ("honeycomb") structure. Overall, the combination of PCL and ARA provides an interesting novel polymeric carrier system for 3D-printable HME filaments and tablets.
NSTL
Elsevier