ABSTRACT
A strategy to prepare compounds with multiple chirality axes, which has led to a concise total synthesis of compound 1A with complete stereocontrol, is reported.
ABSTRACT
With an ever increasing number of people taking numerous medications, the need to safely administer drugs and limit unintended side effects has never been greater. Antidote control remains the most direct means to counteract acute side effects of drugs, but, unfortunately, it has been challenging and cost prohibitive to generate antidotes for most therapeutic agents. Here we describe the development of a set of antidote molecules that are capable of counteracting the effects of an entire class of therapeutic agents based upon aptamers. These universal antidotes exploit the fact that, when systemically administered, aptamers are the only free extracellular oligonucleotides found in circulation. We show that protein- and polymer-based molecules that capture oligonucleotides can reverse the activity of several aptamers in vitro and counteract aptamer activity in vivo. The availability of universal antidotes to control the activity of any aptamer suggests that aptamers may be a particularly safe class of therapeutics.
Subject(s)
Anticoagulants/adverse effects , Antidotes/pharmacology , Aptamers, Nucleotide/pharmacology , Oligonucleotides/pharmacology , Anticoagulants/pharmacology , Antidotes/administration & dosage , Aptamers, Nucleotide/classification , Drug Delivery Systems , Drug Design , Factor IX/antagonists & inhibitors , Factor Xa Inhibitors , Humans , Nucleic Acid Conformation/drug effects , Protamines/pharmacology , Time FactorsABSTRACT
IT-101, a cyclodextrin polymer-based nanoparticle containing camptothecin, is in clinical development for the treatment of cancer. Multiorgan pharmacokinetics and accumulation in tumor tissue of IT-101 is investigated by using PET. IT-101 is modified through the attachment of a 1,4,7,10-tetraazacyclododecane-1,4,7-Tris-acetic acid ligand to bind (64)Cu(2+). This modification does not affect the particle size and minimally affects the surface charge of the resulting nanoparticles. PET data from (64)Cu-labeled IT-101 are used to quantify the in vivo biodistribution in mice bearing Neuro2A s.c. tumors. The (64)Cu-labeled IT-101 displays a biphasic plasma elimination. Approximately 8% of the injected dose is rapidly cleared as a low-molecular-weight fraction through the kidneys. The remaining material circulates in plasma with a terminal half-life of 13.3 h. Steadily increasing concentrations, up to 11% injected dose per cm(3), are observed in the tumor over 24 h, higher than any other tissue at that time. A 3-compartment model is used to determine vascular permeability and nanoparticle retention in tumors, and is able to accurately represent the experimental data. The calculated tumor vascular permeability indicates that the majority of nanoparticles stay intact in circulation and do not disassemble into individual polymer strands. A key assumption to modeling the tumor dynamics is that there is a "sink" for the nanoparticles within the tumor. Histological measurements using confocal microscopy show that IT-101 localizes within tumor cells and provides the sink in the tumor for the nanoparticles.
Subject(s)
Camptothecin/pharmacokinetics , Cyclodextrins/pharmacokinetics , Nanoparticles , Neoplasms/pathology , Polymers/pharmacokinetics , Positron-Emission Tomography , Whole Body Imaging , Animals , Cell Line, Tumor , Copper/pharmacokinetics , Fluorescent Antibody Technique , Kidney/metabolism , Mice , Mice, SCID , Models, Biological , Tissue DistributionABSTRACT
Biodegradable filaments (diameters of 250-300 microm) for the controlled delivery of dexamethasone or levofloxacin are described. Filaments are prepared by wet-spinning solutions of poly(lactide-co-glycolide) (PLGA) and drug dissolved in dimethyl sulfoxide (DMSO) into a coagulation bath of water. Compositional analyses of the filaments by independent measurements of drug, DMSO, water, and polymer give drug loadings up to 40% of filament mass and drug retention (drug in filament per drug in solution) greater than 40%. Drug release kinetics, and thermal and mechanical properties, of the filaments are reported. Three filaments with levofloxacin contents of 46+/-2, 85+/-4, and 36+/-2 microg/cm (denoted 506-L1, 506-L2, and 506-L3, respectively) are implanted in the conjunctiva of New Zealand white rabbits. The time dependent, in-vivo tear concentrations of levofloxacin from filament implants in New Zealand white rabbit eyes are in general agreement with the results from the in-vitro release profiles, with one of the filaments (506-L1) showing effective levels of levofloxacin in the tears for 6 days. The filaments are generally well tolerated by the rabbits. Filament failure occurs at 6-8 days within the rabbit eyes, essentially the same time to failure observed from in-vitro mechanical properties testing results.
