How useful is mass spectrometry for the characterization of dendrimers?

Baytekin, Bilge; Werner, Nicole; Luppertz, Friedhelm; Engeser, Marianne; Brüggemann, Jens; Bitter, Stephan; Henkel, Roman; Felder, Thorsten; Schalley, Christoph A.

doi:10.1016/j.ijms.2006.01.016

Cited by 49 publications

(24 citation statements)

References 71 publications

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“…Direct analysis of PAMAM dendrimers by MALDI 6, 18–22 and ESI 2, 23 has also been reported. While these techniques are useful they are not sufficient for evaluating the purity, stability and detecting individual components of complex dendrimer mixtures.…”

Section: Introductionmentioning

confidence: 99%

Characterization of polyamidoamino (PAMAM) dendrimers using in-line reversed phase LC electrospray ionization mass spectrometry

2016

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Generation 3 (G3) PAMAM dendrimers are symmetrical, highly branched polymers widely reported in the scientific literature as therapeutic agents themselves or as carrier scaffolds for various therapeutic agents. A large number of analytical techniques have been applied to study PAMAM dendrimers, but one that has been missing is in-line reversed phase LC electrospray ionization mass spectrometry (RP/LC/ESI/MS). To translate PAMAM dendrimers into therapeutic agents, a better understanding of their purity, stability and structure is required, and in-line RP/LC/ESI/MS is widely applied to all three of these analytical questions. In this study, we developed a robust in-line RP/LC/ESI/MS method for assessing stability, purity and structure of the G3 PAMAM dendrimers, and we also examined the reasons why previous attempts at method development failed. Using the RP/LC/ESI/MS method we uncovered several unique aspects of the chemistry of G3 PAMAM dendrimers. They are interconverted between two isomeric forms by dialysis, and under higher concentration levels there is an inter-molecular displacement reaction resulting, which degrades PAMAM dendrimers. Purification of G3 dendrimers by RP/LC was also previously unreported; so we slightly modified the LC/MS method for isolating individual components from a complex dendrimer mixture. Thus, we have developed a robust, comprehensive method for characterizing PAMAM dendrimers and their degradation.

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Section: Introductionmentioning

confidence: 99%

Characterization of polyamidoamino (PAMAM) dendrimers using in-line reversed phase LC electrospray ionization mass spectrometry

2016

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“…Dendrimers have thus been ionized by fast atom bombardment (FAB‐MS),10 matrix‐assisted laser desorption/ionization (MALDI),11 and electrospray ionization (ESI) 12. The two latter techniques involve very gentle ionization that minimizes the fragmentation of the analyte molecules, although there are examples for artifacts formed during electrospray ionization13 and through the destruction of dendrons and dendrimers during the MALDI process 14…”

Section: Introductionmentioning

confidence: 99%

Cover Picture: Cooperative Catalytic Reactions Using Organocatalysts and Transition‐Metal Catalysts: Enantioselective Propargylic Alkylation of Propargylic Alcohols with Aldehydes (Angew. Chem. Int. Ed. 40/2010)

Ikeda¹,

Miyake²,

Nishibayashi³

2010

Angew Chem Int Ed

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“…Dendritech, Inc has provided us with the analytical measurements on their PAMAM dendrimer products which are given in Figures S5 and S6. However even though mass spectrometry is often considered as the main method to characterize the presence and nature of defects in the dendrimer structure, it was demonstrated that “dendrimer purity needs to be interpreted with care and may be misleading in the sense that falsely negative results are obtained” [80]. …”

Section: Methodsmentioning

confidence: 99%

Impact of Dendrimer Terminal Group Chemistry on Blockage of the Anthrax Toxin Channel: A Single Molecule Study

Yamini

Kalu

Nestorovich

2016

Toxins

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Nearly all the cationic molecules tested so far have been shown to reversibly block K+ current through the cation-selective PA63 channels of anthrax toxin in a wide nM–mM range of effective concentrations. A significant increase in channel-blocking activity of the cationic compounds was achieved when multiple copies of positively charged ligands were covalently linked to multivalent scaffolds, such as cyclodextrins and dendrimers. Even though multivalent binding can be strong when the individual bonds are relatively weak, for drug discovery purposes we often strive to design multivalent compounds with high individual functional group affinity toward the respective binding site on a multivalent target. Keeping this requirement in mind, here we perform a single-channel/single-molecule study to investigate kinetic parameters of anthrax toxin PA63 channel blockage by second-generation (G2) poly(amido amine) (PAMAM) dendrimers functionalized with different surface ligands, including G2-NH2, G2-OH, G2-succinamate, and G2-COONa. We found that the previously reported difference in IC50 values of the G2-OH/PA63 and G2-NH2/PA63 binding was determined by both on- and off-rates of the reversible dendrimer/channel binding reaction. In 1 M KCl, we observed a decrease of about three folds in kon and a decrease of only about ten times in tres with G2-OH compared to G2-NH2. At the same time for both blockers, kon and tres increased dramatically with transmembrane voltage increase. PAMAM dendrimers functionalized with negatively charged succinamate, but not carboxyl surface groups, still had some residual activity in inhibiting the anthrax toxin channels. At 100 mV, the on-rate of the G2-succinamate binding was comparable with that of G2-OH but showed weaker voltage dependence when compared to G2-OH and G2-NH2. The residence time of G2-succinamate in the channel exhibited opposite voltage dependence compared to G2-OH and G2-NH2, increasing with the cis-negative voltage increase. We also describe kinetics of the PA63 ion current modulation by two different types of the “imperfect” PAMAM dendrimers, the mixed-surface G2 75% OH 25% NH2 dendrimer and G3-NH2 dendron. At low voltages, both “imperfect” dendrimers show similar rate constants but significantly weaker voltage sensitivity when compared with the intact G2-NH2 PAMAM dendrimer.

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How useful is mass spectrometry for the characterization of dendrimers?

Cited by 49 publications

References 71 publications

Characterization of polyamidoamino (PAMAM) dendrimers using in-line reversed phase LC electrospray ionization mass spectrometry

Characterization of polyamidoamino (PAMAM) dendrimers using in-line reversed phase LC electrospray ionization mass spectrometry

Cover Picture: Cooperative Catalytic Reactions Using Organocatalysts and Transition‐Metal Catalysts: Enantioselective Propargylic Alkylation of Propargylic Alcohols with Aldehydes (Angew. Chem. Int. Ed. 40/2010)

Impact of Dendrimer Terminal Group Chemistry on Blockage of the Anthrax Toxin Channel: A Single Molecule Study

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