Mechanism of Cooperativity and Nonlinear Release Kinetics in Multivalent Dendrimer鈥揂tropine Complexes
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- 作者：Jhindan Mukherjee ; Pamela T. Wong ; Shengzhuang Tang ; Kristina Gam ; Alexa Coulter ; James R. Baker Jr. ; Seok Ki Choi
- 刊名：Molecular Pharmaceutics
- 出版年：2015
- 出版时间：December 7, 2015
- 年：2015
- 卷：12
- 期：12
- 页码：4498-4508
- 全文大小：650K
- ISSN：1543-8392
文摘
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 1H 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鈥揗S/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 鈭?00 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 (鈮?.1) displayed greater atropine affinity (KD 鈮?渭M) 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.