ABSTRACT
Liposomal formulations have been developed for a highly cytotoxic platinum-acridine agent, [PtCl(pn)(C18 H21 N4 )](NO3 )2 (PA, pn=propane-1,3-diamine), and fully characterized. Nanoliposomes consisting of hydrogenated soybean phosphatidylcholine (HSPC), 1,2-dihexadecanoyl-sn-glycero-3-phospho-(1'-rac-glycerol) (DPPG), and polyethylene glycol-2000-distearoylphosphatidylethanolamine (DSPE-mPEG2k ) were able to stably encapsulate PA at payload-to-lipid ratios of 2-20 %. The fusogenic properties of the liposomes promote efficient cellular uptake of PA across the plasma membrane, which results in vesicular transport of payload to the nucleus in cultured lung cancer cells. Unencapsulated PA and one of the newly designed liposomal formulations show promising tumor growth inhibition in tumor xenografts derived from A549 lung adenocarcinoma cells of 76 % and 72 %, respectively. Cisplatin showed no significant efficacy at a 10-fold higher dose. These findings underscore the utility of platinum-acridine agents for treating aggressive, chemoresistant forms of cancer and validate nanoliposomes as a biocompatible, expandable platform for their intravenous delivery and other potential routes of administration.
Subject(s)
Acridines/pharmacology , Adenocarcinoma of Lung/drug therapy , Antineoplastic Agents/pharmacology , Lung Neoplasms/drug therapy , Models, Biological , Organoplatinum Compounds/pharmacology , Platinum/pharmacology , A549 Cells , Acridines/chemistry , Adenocarcinoma of Lung/pathology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Drug Compounding , Drug Screening Assays, Antitumor , Female , Humans , Liposomes/chemistry , Lung Neoplasms/pathology , Mice , Mice, Nude , Molecular Structure , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Organoplatinum Compounds/chemical synthesis , Organoplatinum Compounds/chemistry , Platinum/chemistryABSTRACT
Two competing predictions of matching theory and an evolutionary theory of behavior dynamics, and one additional prediction of the evolutionary theory, were tested in a critical experiment in which human participants worked on concurrent schedules for money (Dallery et al., 2005). The three predictions concerned the descriptive adequacy of matching theory equations, and of equations describing emergent equilibria of the evolutionary theory. Tests of the predictions falsified matching theory and supported the evolutionary theory.
Subject(s)
Biological Evolution , Models, Psychological , Psychological Theory , Humans , Reinforcement Schedule , Reinforcement, PsychologyABSTRACT
Phosducin-like protein (PhLP) is a widely expressed binding partner of the G protein betagamma subunit complex (Gbetagamma) that has been recently shown to catalyze the formation of the Gbetagamma dimer from its nascent polypeptides. Phosphorylation of PhLP at one or more of three consecutive serines (Ser-18, Ser-19, and Ser-20) is necessary for Gbetagamma dimer formation and is believed to be mediated by the protein kinase CK2. Moreover, several lines of evidence suggest that the cytosolic chaperonin complex (CCT) may work in concert with PhLP in the Gbetagamma-assembly process. The results reported here delineate a mechanism for Gbetagamma assembly in which a stable ternary complex is formed between PhLP, the nascent Gbeta subunit, and CCT that does not include Ggamma. PhLP phosphorylation permits the release of a PhLP x Gbeta intermediate from CCT, allowing Ggamma to associate with Gbeta in this intermediate complex. Subsequent interaction of Gbetagamma with membranes releases PhLP for another round of assembly.
