ABSTRACT
Microencapsulation technology has been increasingly applied toward the development of self-healing paints. Added to paint as a dry powder prior to spraying, the microcapsules store a liquid that can repair the protective barrier layer if released into a scratch. However, self-healing will not occur unless the microcapsules can withstand spray-painting, aggressive solvents in the paint, and long-term exposure to the elements. We have therefore developed a one-pot synthesis for the production of Pickering microcapsules with outstanding strength, solvent resistance, and barrier properties. Octadecyltrimethoxysilane-filled (OTS) microcapsules form via standard interfacial polycondensation, except that silica nanopowder (10-20 nm diameter) replaces the conventional surfactant or hydrocolloid emulsifier. Isophorone diisocyanate (IPDI) in the OTS core reacts with diethylenetriamine, polyethylenimine, and water to form a hard polymer shell along the interface. Compared to pure polyurea, the silica-polyurea composite improves the shelf life of the OTS by 10 times. The addition of SiO2 prevents leaching of OTS into xylenes and hexanes for up to 80 days, and the resulting microcapsules survive nebulization through a spray gun at 620 kPa in a 500 cSt fluid.
ABSTRACT
This study reports the synthesis of the mercapto-hapten (S)-N-(2-(mercaptoethyl)-6-(3-(2-(methylamino)propyl)phenoxy)hexanamide [3, (+)-METH HSMO9] and its use to prepare METH-conjugated vaccines (MCV) from maleimide-activated proteins. MALDI-TOF mass spectrometry analysis of the MCV synthesized using 3 showed there was a high and controllable epitope density on two different carrier proteins. In addition, the MCV produced a substantially greater immunological response in mice than previous METH haptens, and a monoclonal antibody generated from this MCV in mice showed a very high affinity for (+)-METH (K(D) = 6.8 nM). The efficient covalent coupling of (+)-METH HSMO9 to the activated carrier proteins suggests that this approach could be cost-effective for large-scale production of MCV. In addition, the general methods described for the synthesis of (+)-METH HSMO9 (3) and its use to synthesize MCV will be applicable for conjugated vaccines of small molecules and other substances of abuse such as morphine, nicotine, and cocaine.
Subject(s)
Haptens/chemistry , Methamphetamine/analogs & derivatives , Methamphetamine/chemical synthesis , Sulfhydryl Compounds/chemical synthesis , Vaccines/chemical synthesis , Animals , Antibodies, Monoclonal/chemistry , Antibodies, Monoclonal/immunology , Drug Carriers , Epitopes , Female , Haptens/immunology , Maleimides/chemistry , Methamphetamine/immunology , Mice , Mice, Inbred BALB C , Ovalbumin/chemistry , Serum Albumin, Bovine/chemistry , Stereoisomerism , Sulfhydryl Compounds/immunology , Vaccines/immunology , Vaccines, Conjugate/chemistry , Vaccines, Conjugate/immunologyABSTRACT
In addition to addiction, the repeated use of (+)-methamphetamine [(+)-METH], (+)-amphetamine [(+)-AMP], or (+/-)-3,4-methylenedioxymethamphetamine ((+/-)-MDMA, commonly called ecstasy) can lead to life-threatening medical problems including cardiovascular injury, severe depression, and psychosis. Currently, there are no specific pharmacotherapies to treat these medical problems. In this study, we report the design and synthesis of two haptens, (S)-(+)-3-(9-carboxynonyloxy)methamphetamine (3a, (+)-METH MO10) and (S)-(+)-3-(5-carboxypentyloxy)methamphetamine (3b, (+)-METH MO6), and their use in generating high affinity (low K(D) value) monoclonal antibodies (mAbs) against (+)-METH, (+)-AMP, and/or (+)-MDMA. On the basis of results from the determination of mAb K(D) values and ligand specificity, the mAbs generated from hapten 3a showed the greatest promise for generating active and passive immunotherapies for treating overdose or addiction from (+)-METH-like stimulants.
Subject(s)
Antibodies, Monoclonal/immunology , Antibodies, Monoclonal/therapeutic use , Drug Discovery , Haptens/chemistry , Haptens/immunology , Methamphetamine , Substance-Related Disorders/immunology , Animals , Carrier Proteins/metabolism , Cattle , Cell Line , Female , Haptens/metabolism , Immunization , Mice , Ovalbumin/metabolism , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Substrate SpecificityABSTRACT
Synthetic methods were developed for the synthesis of the 3beta-(4-substituted phenyl)-2 beta-[5-(substituted phenyl)thiazol-2-yl]tropanes (4a-s). The compounds were evaluated for their monoamine transporter binding and monoamine uptake inhibition properties using both rat brain tissue and cloned transporter assays. In general, the compounds showed higher dopamine transporter (DAT) affinity relative to the serotonin and norepinephrine transporters (SERT and NET, respectively) and greater [3H]dopamine uptake inhibition potency relative to [3H]serotonin and [3H]norepinephrine uptake inhibition. Several compounds were DAT selective relative to the SERT and NET in the monoamine transporter binding assays. The most potent and selective analog in the functional monoamine uptake inhibition test was 3beta-(4-methylphenyl-2 beta-[5-(3-nitrophenyl)thiazol-2-yl]tropane (4p).
Subject(s)
Dopamine Plasma Membrane Transport Proteins/metabolism , Thiazoles/chemical synthesis , Tropanes/chemical synthesis , Adrenergic Uptake Inhibitors/chemical synthesis , Adrenergic Uptake Inhibitors/chemistry , Adrenergic Uptake Inhibitors/pharmacology , Animals , Binding, Competitive , Cell Line , Corpus Striatum/metabolism , Dopamine Uptake Inhibitors/chemical synthesis , Dopamine Uptake Inhibitors/chemistry , Dopamine Uptake Inhibitors/pharmacology , Frontal Lobe/metabolism , Humans , In Vitro Techniques , Male , Mesencephalon/metabolism , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Radioligand Assay , Rats , Rats, Sprague-Dawley , Serotonin Plasma Membrane Transport Proteins/metabolism , Selective Serotonin Reuptake Inhibitors/chemical synthesis , Selective Serotonin Reuptake Inhibitors/chemistry , Selective Serotonin Reuptake Inhibitors/pharmacology , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/pharmacology , Tropanes/chemistry , Tropanes/pharmacologyABSTRACT
[reaction: see text] The copper metallomicellar hydrolysis of O-methyl O-4-nitrophenyl phenylphosphonothioate to O-methyl phenylphosphonothioic acid takes place with effectively complete inversion at phosphorus.
