Development of new imaging tools for cancer cells in vitro and in vitro is important for advancing cancer research, elucidating drug effects upon cancer cells, and studying cellular processes. We showed that fluorescent carbon dots (C-dots) synthesized from folic acid can serve as an effective vehicle for imaging cancer cells expressing the folate receptor on their surface. The C-dots, synthesized through a simple one-step process from folic acid as the carbon source, exhibited selectivity towards cancer cells displaying the folate receptor, making such cells easily distinguishable in fluorescence microscopy imaging. Biophysical measurements and competition experiments both confirmed the specific targeting and enhanced uptake of C-dots by the folate receptor-expressing cells. The folic acid-derived C-dots were not cytotoxic, and their use in bioimaging applications could aid biological studies of cancer cells, identification of agonists/antagonists, and cancer diagnostics.
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ABSTRACT:Metformin, a commonly used antidiabetic drug, exerts its glucoselowering effect due to metabolic activities at several sites of action (biophases), including liver, intestine, muscle cells, and adipocytes. The relative contribution of the individual biophases to the overall glucose-lowering effect is not known. Thus, the aims of this investigation were to study the influence of mode of drug administration on the kinetics of glucose-lowering action of metformin in diabetic rats and identify the contribution of different sites of action to the overall response. Streptozotocin diabetic rats received metformin in crossover fashion via intraduodenal, intravenous, and intraportal routes as bolus dose or infusion regimens designed to yield similar pharmacokinetic profiles. Metformin plasma concentrations and blood glucose levels were measured following each mode of administration. Despite the similarity in the concentration-time profiles obtained for different routes of metformin administration, intraduodenal administration produced larger response than intraportal metformin infusion, and lowest response was observed following intravenous administration. This finding indicates that a significant "first-pass" pharmacodynamic effect, which occurs in the presystemic sites of action (liver and the gastrointestinal wall), contributes to the overall glucose-lowering response of metformin. We applied a combined pharmacokinetic-pharmacodynamic modeling approach to study the nature of the first-pass pharmacodynamic effect. The observed data were successfully described by a novel integrated indirect response pharmacokinetic-pharmacodynamic model that revealed a correlation between the temporal metformin concentrations that transit the portal vein and through the gut wall rather than with drug concentrations that accumulated in the liver and the intestinal wall.Metformin, a biguanide glucose-lowering agent, is commonly used for management of type 2 diabetes. Despite the wide clinical use of metformin, the mechanism of its action is not fully understood. The glucose-lowering effect of metformin is apparently composed of a combination of several distinct activities in various organs and tissues (Hermann and Melander, 1992;Cusi and DeFronzo, 1998), including: 1) decreased hepatic glucose output due to decreased hepatic gluconeogenesis and increased glycogenesis and lipogenesis (Christiansen and Hellerstein, 1998); 2) reduced rate of intestinal glucose absorption (Wilcock and Bailey, 1991); and 3) increased glucose uptake by muscle cells and adipocytes (Bailey et al., 1996). The multifactorial mechanism of action of metformin and the complex nature of glucose homeostasis in vivo obscures the dose-response relationship of the metabolic effects in individual organs and tissues (Wiernsperger, 1996). As a result, the relative significance of the above-mentioned sites of metformin action (biophases) to produce metabolic effects remains unknown and is still a matter ...
Intracellularly targeted delivery system based on PLGA nanoparticles decorated with endoplasmic reticulum (ER)-targeting or control peptides and encapsulating antigenic peptide and fluorescent marker, was developed and characterized. The cellular uptake by dendritic cells (murine DC2.4 cells), intracellular trafficking, and cross-presentation efficiency of this delivery system were studied in vitro. The prepared nanoparticles (an average diameter of ~350 nm) efficiently encapsulated antigenic peptide and fluorescent marker and gradually released them over several days. Yet, the nanoparticles' size was small enough to allow their efficient endocytosis by the antigen-presenting cells in vitro. Surface conjugation of the targeting or control peptides enhanced the endocytosis of the nanoparticles, affected their intracellular trafficking, and induced prolonged low-magnitude cross-presentation of the antigenic peptide. We demonstrated in vitro that the intracellular fate of nanoparticulate drug delivery systems can be altered by their surface decoration with peptidic targeting residues. More detailed investigation is required to determine the mechanisms and therapeutic potential of intracellular targeting of nanodelivery systems in vivo for the goal of an anticancer vaccine.
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