Mechanism of Cooperativity and Nonlinear Release Kinetics in Multivalent Dendrimer-Atropine Complexes.
Despite extensive studies on drug delivery using multivalent complexation systems, the biophysical basis for release kinetics remains poorly defined. The present study addresses this aspect involved in the complexation of a fifth generation poly(amidoamine) (PAMAM) dendrimer with atropine, an essential antidote used for treating organophosphate poisoning. First, we designed (1)H NMR titration studies for determining the molecular basis of the drug complexation with a glutarate-modified anionic dendrimer. These provide evidence pointing to a combination of electrostatic and hydrophobic interactions as the driving forces for dendrimer complexation with the alkaloid drug molecule. Second, using LC-MS/MS spectrometry, we determined the dissociation constants (KD) at steady state and also measured the drug release kinetics of atropine complexes with four negatively charged dendrimer types. Each of these dendrimers has a high payload capacity for up to ∼ 100 atropine molecules. However, the affinity of the atropine to the carrier was highly dependent on the drug to dendrimer ratio. Thus, a complex made at a lower loading ratio (≤ 0.1) displayed greater atropine affinity (KD ≈ μM) than other complexes prepared at higher ratios (>10), which showed only mM affinity. This negative cooperative variation in affinity is tightly associated with the nonlinear release kinetics observed for each complex in which drug release occurs more slowly at the later time phase at a lower loading ratio. In summary, the present study provides novel insights on the cooperativity as the mechanistic basis for nonlinear release kinetics observed in multivalent carrier systems.
Michigan Nanotechnology Institute for Medicine and Biological Sciences, and Department of Internal Medicine, University of Michigan , Ann Arbor, Michigan 48109, United States.
Jhindan
J
Mukherjee
Michigan Nanotechnology Institute for Medicine and Biological Sciences, and Department of Internal Medicine, University of Michigan , Ann Arbor, Michigan 48109, United States.
Pamela T
PT
Wong
Michigan Nanotechnology Institute for Medicine and Biological Sciences, and Department of Internal Medicine, University of Michigan , Ann Arbor, Michigan 48109, United States.
Shengzhuang
S
Tang
Michigan Nanotechnology Institute for Medicine and Biological Sciences, and Department of Internal Medicine, University of Michigan , Ann Arbor, Michigan 48109, United States.
Kristina
K
Gam
Michigan Nanotechnology Institute for Medicine and Biological Sciences, and Department of Internal Medicine, University of Michigan , Ann Arbor, Michigan 48109, United States.
Alexa
A
Coulter
Michigan Nanotechnology Institute for Medicine and Biological Sciences, and Department of Internal Medicine, University of Michigan , Ann Arbor, Michigan 48109, United States.
James R
JR
Baker
Michigan Nanotechnology Institute for Medicine and Biological Sciences, and Department of Internal Medicine, University of Michigan , Ann Arbor, Michigan 48109, United States.
Seok Ki
SK
Choi
D001285:Atropine / Q000737:chemistry*; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D065546:Drug Liberation; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007624:KB Cells; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D055672:Static Electricity; D053719:Tandem Mass Spectrometry / Q000379:methods
D050091:Dendrimers; D004364:Pharmaceutical Preparations; D001285:Atropine
PAMAM dendrimer; atropine; cooperativity; host−guest complexes; nonlinear release kinetics