16 research outputs found
Fatty acids as therapeutic auxiliaries for oral and parenteral formulations
Many drugs have decreased therapeutic activity due to issues with absorption, distribution, metabolism and excretion. The co-formulation or covalent attachment of drugs with fatty acids has demonstrated some capacity to overcome these issues by improving intestinal permeability, slowing clearance and binding serum proteins for selective tissue uptake and metabolism. For orally administered drugs, albeit at low level of availability, the presence of fatty acids and triglycerides in the intestinal lumen may promote intestinal uptake of small hydrophilic molecules. Small lipophilic drugs or acylated hydrophilic drugs also show increased lymphatic uptake and enhanced passive diffusional uptake. Fatty acid conjugation of small and large proteins or peptides have exhibited protracted plasma half-lives, site-specific delivery and sustained release upon parenteral administration. These improvements are most likely due to associations with lipid-binding serum proteins, namely albumin, LDL and HDL. These molecular interactions, although not fully characterized, could provide the ability of using the endogenous carrier systems for improving therapeutic outcomes
Proinsulin-Transferrin Fusion Protein as a Novel Long-Acting Insulin Analog for the Inhibition of Hepatic Glucose Production
Diplomski rad pod nazivom Disocijacija nastao je kao reakcija i vizualizacija normativnih disocijativnih stanja koja su dio naše svakodnevice.
Izveden je u obliku 12 crteža olovkom koji čine jednu cjelinu. Crteži su vizualni zapisi emocija i disocijativnih stanja u kojima sam se nalazila tijekom crtanja. Oni su ustvari vizualizacija sanjarenja i maštanja, ali ne u doslovnom smislu već metaforičkom. Glavni motiv na njima su životinje koje svojom gestikulacijom, položajem tijela i smještajem u kompoziciji prikazuju emocije, likove ili situacije u kojima sam se našla u svojim mislima
Proinsulin–Transferrin Fusion Protein Exhibits a Prolonged and Selective Effect on the Control of Hepatic Glucose Production in an Experimental Model of Type 1 Diabetes
An ideal basal insulin (INS) replacement
therapy requires the distribution
or action of exogenous INS to more closely mimic physiological INS
in terms of its preferential hepatic action. In this paper, we introduce
a novel strategy to exert liver-specific INS action by hepatic activation
of INS’s precursor, proinsulin (ProINS). We demonstrated the
conversion of human ProINS–transferrin (Tf) fusion protein,
ProINS–Tf, into an active and immuno-reactive form of INS–Tf
in the liver via the slow Tf receptor mediated recycling pathway.
ProINS–Tf displayed prolonged basal blood glucose lowering
effects for up to 40 h in streptozotocin-induced type 1 diabetic mice
following a single subcutaneous injection. The effect of ProINS–Tf
on blood glucose levels was observed predominantly under fasting conditions,
with little effect under free-feeding conditions. In addition, both
the pyruvate tolerance assay in normal mice and the Akt-phosphorylation
assay in H-4-II-E hepatoma cells indicated that the hepatic-activated
ProINS–Tf possessed a much longer effect on the control of
hepatic glucose production than INS. These results indicated that
ProINS–Tf may serve as an effective and safe hepatoselective
INS analog to reduce the frequency of INS injections as well as avert
severe hypoglycemia episodes and other side effects frequently encountered
with long-acting INS therapeutics due to their peripheral action
Proinsulin-Transferrin Fusion Protein as a Novel Long-Acting Insulin Analog for the Inhibition of Hepatic Glucose Production
Characterization of transferrin receptor-mediated endocytosis and cellular iron delivery of recombinant human serum transferrin from rice (<it>Oryza sativa</it> L.)
Abstract Background Transferrin (TF) plays a critical physiological role in cellular iron delivery via the transferrin receptor (TFR)-mediated endocytosis pathway in nearly all eukaryotic organisms. Human serum TF (hTF) is extensively used as an iron-delivery vehicle in various mammalian cell cultures for production of therapeutic proteins, and is also being explored for use as a drug carrier to treat a number of diseases by employing its unique TFR-mediated endocytosis pathway. With the increasing concerns over the risk of transmission of infectious pathogenic agents of human plasma-derived TF, recombinant hTF is preferred to use for these applications. Here, we carry out comparative studies of the TFR binding, TFR-mediated endocytosis and cellular iron delivery of recombinant hTF from rice (rhTF), and evaluate its suitability for biopharmaceutical applications. Result Through a TFR competition binding affinity assay with HeLa human cervic carcinoma cells (CCL-2) and Caco-2 human colon carcinoma cells (HTB-37), we show that rhTF competes similarly as hTF to bind TFR, and both the TFR binding capacity and dissociation constant of rhTF are comparable to that of hTF. The endocytosis assay confirms that rhTF behaves similarly as hTF in the slow accumulation in enterocyte-like Caco-2 cells and the rapid recycling pathway in HeLa cells. The pulse-chase assay of rhTF in Caco-2 and HeLa cells further illustrates that rice-derived rhTF possesses the similar endocytosis and intracellular processing compared to hTF. The cell culture assays show that rhTF is functionally similar to hTF in the delivery of iron to two diverse mammalian cell lines, HL-60 human promyelocytic leukemia cells (CCL-240) and murine hybridoma cells derived from a Sp2/0-Ag14 myeloma fusion partner (HB-72), for supporting their proliferation, differentiation, and physiological function of antibody production. Conclusion The functional similarity between rice derived rhTF and native hTF in their cellular iron delivery, TFR binding, and TFR-mediated endocytosis and intracellular processing support that rice-derived rhTF can be used as a safe and animal-free alternative to serum hTF for bioprocessing and biopharmaceutical applications.</p
Characterization and Oral Delivery of Proinsulin-Transferrin Fusion Protein Expressed Using ExpressTec
Proinsulin-transferrin fusion protein (ProINS-Tf) has been designed and successfully expressed from the mammalian HEK293 cells (HEK-ProINS-Tf). It was found that HEK-ProINS-Tf could be converted into an activated form in the liver. Furthermore, HEK-ProINS-Tf was demonstrated as an extra-long acting insulin analogue with liver-specific insulin action in streptozotocin (STZ)-induced type 1 diabetic mice. However, due to the low production yield from transfected HEK293 cells, there are other interesting features, including the oral bioavailability, which have not been fully explored and characterized. To improve the protein production yield, an alternative protein expression system, ExpressTec using transgenic rice (Oryza sativa L.), was used. The intact and active rice-derived ProINS-Tf (ExpressTec-ProINS-Tf) was successfully expressed from the transgenic rice expression system. Our results suggested that, although the insulin-like bioactivity of ExpressTec-ProINS-Tf was slightly lower in vitro, its potency of in vivo blood glucose control was considerably stronger than that of HEK-ProINS-Tf. The oral delivery studies in type 1 diabetic mice demonstrated a prolonged control of blood glucose to near-normal levels after oral administration of ExpressTec-ProINS-Tf. Results in this report suggest that ExpressTec-ProINS-Tf is a promising insulin analog with advantages including low cost, prolonged and liver targeting effects, and most importantly, oral bioactivity
Selective Intracellular Delivery of Recombinant Arginine Deiminase (ADI) Using pH-Sensitive Cell Penetrating Peptides To Overcome ADI Resistance in Hypoxic Breast Cancer Cells
Interaction between Cell-Penetrating Peptides and Acid-Sensitive Anionic Oligopeptides as a Model for the Design of Targeted Drug Carriers
Pioneering computational culture within pharmacy schools by empowering students with data science and bioinformatics skills
As advancements in digital health lead to the generation of increasingly diverse and voluminous pharmaceutical data, it is increasingly critical that we teach trainee pharmaceutical scientists how to leverage this data to lead future innovations in healthcare and pharmaceutical research. To address this need, the University of Southern California Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences (USC Mann) is incorporating data science and bioinformatics into the graduate and undergraduate curricula through introductory courses tailored for students without prior programming experience. These courses feature a teaching framework designed to make the fundamentals of data science and bioinformatics accessible to pharmacy students through step-by-step, Jupyter-based coding assignments with examples relevant to the pharmaceutical sciences. Here, we outline the design of our framework, discussing the strategies we developed for it and the opportunities it presents to cultivate a computational culture within our institution and beyond