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排序方式: 共有235条查询结果,搜索用时 15 毫秒
231.
Tuesca Anthony D. Reiff Collin Joseph Jeffrey I. Lowman Anthony M. 《Pharmaceutical research》2009,26(3):727-739
Purpose This work evaluated the feasibility of combining insulin PEGylation with pH responsive hydrogels for oral insulin delivery.
Methods A mono-substituted PEG–insulin conjugate was synthesized and purified. The site of conjugation was determined by MALDI-TOF
MS. Uptake and release of PEGylated insulin was performed in complexation hydrogels to simulate oral dosing. The bioactivity
of the conjugate and PK/PD profile was measured in vivo in rats.
Results PEGylation was confirmed to be specifically located at the amino terminus of the B-chain of insulin. Higher loading efficiency
was achieved with PEGylated insulin than regular human insulin in pH responsive hydrogels. The release of PEGylated insulin
was lower than that of human insulin at all pH levels considered. Full retention of bioactivity of the PEG–insulin conjugate
was confirmed by intravenous dosing while subcutaneous dosing exhibited a relative hypoglycemic effect 127.8% that of human
insulin.
Conclusions Polyethylene glycol conjugated specifically to the amino terminus of the B-chain of insulin maintained the bioactivity of
the protein and significantly extended the duration of the hypoglycemic effect. Used in combination with pH responsive hydrogels,
PEGylated insulin has significant potential for oral delivery. 相似文献
232.
Adams EL Rice PJ Graves B Ensley HE Yu H Brown GD Gordon S Monteiro MA Papp-Szabo E Lowman DW Power TD Wempe MF Williams DL 《The Journal of pharmacology and experimental therapeutics》2008,325(1):115-123
Glucans are structurally diverse fungal biopolymers that stimulate innate immunity and are fungal pathogen-associated molecular patterns. Dectin-1 is a C-type lectin-like pattern recognition receptor that binds glucans and induces innate immune responses to fungal pathogens. We examined the effect of glucan structure on recognition and binding by murine recombinant Dectin-1 with a library of natural product and synthetic (1-->3)-beta/(1-->6)-beta-glucans as well as nonglucan polymers. Dectin-1 is highly specific for glucans with a pure (1-->3)-beta-linked backbone structure. Although Dectin-1 is highly specific for (1-->3)-beta-d-glucans, it does not recognize all glucans equally. Dectin-1 differentially interacted with (1-->3)-beta-d-glucans over a very wide range of binding affinities (2.6 mM-2.2 pM). One of the most striking observations that emerged from this study was the remarkable high-affinity interaction of Dectin-1 with certain glucans (2.2 pM). These data also demonstrated that synthetic glucan ligands interact with Dectin-1 and that binding affinity increased in synthetic glucans containing a single glucose side-chain branch. We also observed differential recognition of glucans derived from saprophytes and pathogens. We found that glucan derived from a saprophytic yeast was recognized with higher affinity than glucan derived from the pathogen Candida albicans. Structural analysis demonstrated that glucan backbone chain length and (1-->6)-beta side-chain branching strongly influenced Dectin-1 binding affinity. These data demonstrate: 1) the specificity of Dectin-1 for glucans; 2) that Dectin-1 differentiates between glucan ligands based on structural determinants; and 3) that Dectin-1 can recognize and interact with both natural product and synthetic glucan ligands. 相似文献
233.
Lu Y Vernes JM Chiang N Ou Q Ding J Adams C Hong K Truong BT Ng D Shen A Nakamura G Gong Q Presta LG Beresini M Kelley B Lowman H Wong WL Meng YG 《Journal of immunological methods》2011,365(1-2):132-141
Clinical response to the anti-CD20 antibody rituximab has been demonstrated to correlate with the polymorphism in the FcγRIIIa receptor where patients homozygous for the higher affinity V158 allotype showed a better response rate. This finding suggests that engineering of anti-CD20 for increased FcγRIIIa affinity could result in improved clinical outcome. To identify variants with increased affinity to FcγRIIIa, we developed quantitative assays using soluble receptors as well as engineered cell lines expressing FcγRI or FcγRIIIa on the cell surface. We assayed a set of anti-CD20 IgG(1) variants that had identical Fab regions, but alterations in the Fc regions, in both the soluble receptor-based and cell-based FcγRIIIa binding assays. We obtained similar relative binding affinity increases and assay precisions. The increase in affinity for FcγRIIIa correlated with the increase in activity in the antibody-dependent cellular cytotoxicity assay. These variants had unaltered FcγRI binding. In addition to Fcγ receptors, IgG also binds to FcRn, the receptor responsible for the long circulating half-life of IgG. The mutations in the anti-CD20 variants were previously found not to affect FcRn binding in the soluble receptor-based assays; consequently, we used anti-Her2 variants with different binding affinities to FcRn to study FcRn binding assays. We generated a cell line expressing FcRn on the cell surface to measure IgG binding and obtained similar ranking of these anti-Her2 variants in the cell-based and the soluble receptor-based FcRn binding assays. In conclusion, both the soluble receptor-based and cell-based binding assays can be used to identify IgG(1) variants with increased affinity to FcγRIIIa and unaltered affinity to FcγRI and FcRn. 相似文献
234.
An osmotic solution was used to evaluate poly(vinyl alcohol) (PVA) hydrogels as potential non-degradable soft tissue replacements in vitro. Osmotic solutions are necessary in order to mimic the swelling pressure observed in vivo for soft tissues present in load-bearing joints. In vitro studies indicated that PVA hydrogels experience minimal changes in swelling with a polymer concentration of 20 wt.% PVA in phosphate-buffered saline solution (0 atm) and between 30 and 35 wt.% PVA in osmotic solution with a pressure of 0.95 atm. Swelling in osmotic pressure solutions caused decreases in the equilibrium hydrogel hydration. An investigation of hydrogel compressive modulus indicated that PVA hydrogels are within the range of articular cartilage, meniscal tissue, and the temporomandibular joint disk. Furthermore, it is possible to tailor PVA hydrogels through careful modification of the polymer concentration and freeze-thaw cycles during hydrogel preparation to match both a desired swelling ratio and a desired compressive modulus or porosity. The microstructure of the PVA hydrogels was also evaluated as a function of freeze-thaw cycles and polymer concentration to give an insight into the processes occurring during synthesis and swelling in osmotic solutions. 相似文献
235.