title: A Nanotechnology-Based Platform for Extending the Pharmacokinetic and Binding Properties of Anti-methamphetamine Antibody Fragments.
abstract: To address the need for effective medications to aid in the treatment of methamphetamine (METH) abuse, we used a nanotechnology approach to customize the in vivo behavior of an anti-METH single chain antibody (scFv7F9Cys). Anti-METH scFv7F9Cys was conjugated to dendrimer nanoparticles via a polyethylene glycol (PEG) linker to generate high-order conjugates termed dendribodies. We found that the high affinity (KD = 6.2 nM) and specificity for METH was unchanged after nanoparticle conjugation. The dendribodies were administered in an i.v. bolus to male Sprague Dawley rats after starting a s.c. infusion of METH. The PCKN values for clearance and volume of distribution of scFv7F9Cys after conjugation to dendrimers decreased 45 and 1.6-fold respectively, and the terminal elimination half-life increased 20-fold. Organ distribution of scFv7F9Cys and dendribody in blood and urine agreed well with the PCKN data. Renal clearance appeared to be the major route of elimination for both experimental medications. We have thus successfully developed a novel multivalent METH-binding nanomedicine by conjugating multiple anti-METH scFvs to dendrimer nanoparticles, extending the scFv half-life from 1.3 (± 0.3) to 26 (± 2.6) hr. These data suggest that the dendribody design could be a feasible platform for generating multivalent antibodies with customizable PCKN profiles.
authors.affiliation: Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham St., # 611, Little Rock, Arkansas 72205, USA.
authors.forename: Nisha
authors.initials: N
authors.lastname: Nanaware-Kharade
authors.affiliation: Department of Physiology and Biophysics, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham St., # 750, Little Rock, Arkansas 72205, USA.
authors.forename: Shraddha
authors.initials: S
authors.lastname: Thakkar
authors.affiliation: Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham St., # 611, Little Rock, Arkansas 72205, USA.
authors.forename: Guillermo A
authors.initials: GA
authors.lastname: Gonzalez
authors.affiliation: Department of Pharmacology and Toxicology, College of Medicine, University of Arkansas for Medical Sciences, 4301 West Markham St., # 611, Little Rock, Arkansas 72205, USA.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Peterson
mesh_terms: D000818:Animals; D000937:Antigen-Antibody Reactions; D016466:CHO Cells; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D003412:Cricetulus; D050091:Dendrimers / Q000737:chemistry; D004912:Erythrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006207:Half-Life; D006461:Hemolysis / Q000187:drug effects; D008297:Male; D008694:Methamphetamine / Q000097:blood / Q000276:immunology* / Q000378:metabolism; D053758:Nanoparticles / Q000737:chemistry*; D011092:Polyethylene Glycols / Q000737:chemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry / Q000302:isolation & purification; D057127:Single-Chain Antibodies / Q000737:chemistry / Q000276:immunology* / Q000493:pharmacokinetics; D053719:Tandem Mass Spectrometry; D014018:Tissue Distribution
chemical_list: D050091:Dendrimers; C104700:PAMAM Starburst; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies; D011092:Polyethylene Glycols; D008694:Methamphetamine