Complexes of Indomethacin with 4-Carbomethoxy-pyrrolidone PAMAM Dendrimers Show Improved Anti-Inflammatory Properties and Temperature Dependent Binding and Release Profile

Mario Ficker; J. M. Theeuwen Matthijs; Anna Janaszewska; Michał Gorzkiewicz; Søren Wedel Svenningsen; Barbara  Klajnert-Maculewicz; Jørn Bolstad Christensen

doi:10.1021/acs.molpharmaceut.8b00567

Complexes of Indomethacin with 4-Carbomethoxy-pyrrolidone PAMAM Dendrimers Show Improved Anti-Inflammatory Properties and Temperature Dependent Binding and Release Profile

Mario Ficker, J. M. Theeuwen Matthijs, Anna Janaszewska, Michał Gorzkiewicz, Søren Wedel Svenningsen, Barbara Klajnert-Maculewicz, Jørn Bolstad Christensen

7 Citations (Scopus)

Abstract

COX-2 inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common treatment for chronic inflammatory diseases like arthritis and atherosclerosis. However, they are associated with severe side effects such as cardiovascular events or stomach bleeding, due to coinhibition of other enzymes (COX1) and off-target accumulation. PAMAM dendrimers can solubilize lipophilic drugs and increase their circulation time; furthermore, PAMAM dendrimers seem to have some accumulation in inflammatory sides. Three different generations of 4-carbomethoxypyrrolidone (Pyr) surface-modified PAMAM dendrimers were complexed with the NSAID drug indomethacin, and their in-solution thermodynamic profiles were studied by means of NMR experiments. The binding stoichiometry was found dependent on solvent system and dendrimer generation. Larger dendrimers (G3-Pyr) were found to bind indomethacin through entropy driven binding mode, while G1-Pyr and G2-Pyr expressed an enthalpy driven complex formation, which means that the binding constants have a generational temperature dependency. G1/2-Pyr showed reduced binding with increasing temperature, which could be important for drug release at inflammatory sites, which have, in general, elevated temperatures. In vitro studies elucidated that the indomethacin drug remained its activity when delivered as a dendrimer-indomethacin complex. A slight reduction in toxicity profile was noticed for G2/G3-Pyr-indomethacin dendrimers. Both free indomethacin and dendrimer-indomethacin complex inhibited a variety of pro-inflammatory cytokines in LPS treated cells. However, only the indo-dendrimer complexes showed a significant reduction of IL-1β in LPS-treated THP-1 cells, which was not present in the control with free indomethacin.

Original language	English
Journal	Molecular Pharmaceutics
Volume	15
Issue number	8
Pages (from-to)	3573-3582
Number of pages	10
ISSN	1543-8384
DOIs	https://doi.org/10.1021/acs.molpharmaceut.8b00567
Publication status	Published - 6 Aug 2018

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Ficker, M., Theeuwen Matthijs, J. M., Janaszewska, A., Gorzkiewicz, M., Svenningsen, S. W., Klajnert-Maculewicz, B., & Christensen, J. B. (2018). Complexes of Indomethacin with 4-Carbomethoxy-pyrrolidone PAMAM Dendrimers Show Improved Anti-Inflammatory Properties and Temperature Dependent Binding and Release Profile. Molecular Pharmaceutics, 15(8), 3573-3582. https://doi.org/10.1021/acs.molpharmaceut.8b00567

Complexes of Indomethacin with 4-Carbomethoxy-pyrrolidone PAMAM Dendrimers Show Improved Anti-Inflammatory Properties and Temperature Dependent Binding and Release Profile. / Ficker, Mario; Theeuwen Matthijs, J. M.; Janaszewska, Anna et al.
In: Molecular Pharmaceutics, Vol. 15, No. 8, 06.08.2018, p. 3573-3582.

Research output: Contribution to journal › Journal article › Research › peer-review

Ficker, M, Theeuwen Matthijs, JM, Janaszewska, A, Gorzkiewicz, M, Svenningsen, SW, Klajnert-Maculewicz, B & Christensen, JB 2018, 'Complexes of Indomethacin with 4-Carbomethoxy-pyrrolidone PAMAM Dendrimers Show Improved Anti-Inflammatory Properties and Temperature Dependent Binding and Release Profile', Molecular Pharmaceutics, vol. 15, no. 8, pp. 3573-3582. https://doi.org/10.1021/acs.molpharmaceut.8b00567

Ficker M, Theeuwen Matthijs JM, Janaszewska A, Gorzkiewicz M, Svenningsen SW, Klajnert-Maculewicz B et al. Complexes of Indomethacin with 4-Carbomethoxy-pyrrolidone PAMAM Dendrimers Show Improved Anti-Inflammatory Properties and Temperature Dependent Binding and Release Profile. Molecular Pharmaceutics. 2018 Aug 6;15(8):3573-3582. doi: 10.1021/acs.molpharmaceut.8b00567

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title = "Complexes of Indomethacin with 4-Carbomethoxy-pyrrolidone PAMAM Dendrimers Show Improved Anti-Inflammatory Properties and Temperature Dependent Binding and Release Profile",

abstract = "COX-2 inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common treatment for chronic inflammatory diseases like arthritis and atherosclerosis. However, they are associated with severe side effects such as cardiovascular events or stomach bleeding, due to coinhibition of other enzymes (COX1) and off-target accumulation. PAMAM dendrimers can solubilize lipophilic drugs and increase their circulation time; furthermore, PAMAM dendrimers seem to have some accumulation in inflammatory sides. Three different generations of 4-carbomethoxypyrrolidone (Pyr) surface-modified PAMAM dendrimers were complexed with the NSAID drug indomethacin, and their in-solution thermodynamic profiles were studied by means of NMR experiments. The binding stoichiometry was found dependent on solvent system and dendrimer generation. Larger dendrimers (G3-Pyr) were found to bind indomethacin through entropy driven binding mode, while G1-Pyr and G2-Pyr expressed an enthalpy driven complex formation, which means that the binding constants have a generational temperature dependency. G1/2-Pyr showed reduced binding with increasing temperature, which could be important for drug release at inflammatory sites, which have, in general, elevated temperatures. In vitro studies elucidated that the indomethacin drug remained its activity when delivered as a dendrimer-indomethacin complex. A slight reduction in toxicity profile was noticed for G2/G3-Pyr-indomethacin dendrimers. Both free indomethacin and dendrimer-indomethacin complex inhibited a variety of pro-inflammatory cytokines in LPS treated cells. However, only the indo-dendrimer complexes showed a significant reduction of IL-1β in LPS-treated THP-1 cells, which was not present in the control with free indomethacin.",

author = "Mario Ficker and {Theeuwen Matthijs}, {J. M.} and Anna Janaszewska and Micha{\l} Gorzkiewicz and Svenningsen, {S{\o}ren Wedel} and Barbara Klajnert-Maculewicz and Christensen, {J{\o}rn Bolstad}",

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T1 - Complexes of Indomethacin with 4-Carbomethoxy-pyrrolidone PAMAM Dendrimers Show Improved Anti-Inflammatory Properties and Temperature Dependent Binding and Release Profile

AU - Ficker, Mario

AU - Theeuwen Matthijs, J. M.

AU - Janaszewska, Anna

AU - Gorzkiewicz, Michał

AU - Svenningsen, Søren Wedel

AU - Klajnert-Maculewicz, Barbara

AU - Christensen, Jørn Bolstad

PY - 2018/8/6

Y1 - 2018/8/6

N2 - COX-2 inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common treatment for chronic inflammatory diseases like arthritis and atherosclerosis. However, they are associated with severe side effects such as cardiovascular events or stomach bleeding, due to coinhibition of other enzymes (COX1) and off-target accumulation. PAMAM dendrimers can solubilize lipophilic drugs and increase their circulation time; furthermore, PAMAM dendrimers seem to have some accumulation in inflammatory sides. Three different generations of 4-carbomethoxypyrrolidone (Pyr) surface-modified PAMAM dendrimers were complexed with the NSAID drug indomethacin, and their in-solution thermodynamic profiles were studied by means of NMR experiments. The binding stoichiometry was found dependent on solvent system and dendrimer generation. Larger dendrimers (G3-Pyr) were found to bind indomethacin through entropy driven binding mode, while G1-Pyr and G2-Pyr expressed an enthalpy driven complex formation, which means that the binding constants have a generational temperature dependency. G1/2-Pyr showed reduced binding with increasing temperature, which could be important for drug release at inflammatory sites, which have, in general, elevated temperatures. In vitro studies elucidated that the indomethacin drug remained its activity when delivered as a dendrimer-indomethacin complex. A slight reduction in toxicity profile was noticed for G2/G3-Pyr-indomethacin dendrimers. Both free indomethacin and dendrimer-indomethacin complex inhibited a variety of pro-inflammatory cytokines in LPS treated cells. However, only the indo-dendrimer complexes showed a significant reduction of IL-1β in LPS-treated THP-1 cells, which was not present in the control with free indomethacin.

AB - COX-2 inhibitors such as nonsteroidal anti-inflammatory drugs (NSAIDs) are the most common treatment for chronic inflammatory diseases like arthritis and atherosclerosis. However, they are associated with severe side effects such as cardiovascular events or stomach bleeding, due to coinhibition of other enzymes (COX1) and off-target accumulation. PAMAM dendrimers can solubilize lipophilic drugs and increase their circulation time; furthermore, PAMAM dendrimers seem to have some accumulation in inflammatory sides. Three different generations of 4-carbomethoxypyrrolidone (Pyr) surface-modified PAMAM dendrimers were complexed with the NSAID drug indomethacin, and their in-solution thermodynamic profiles were studied by means of NMR experiments. The binding stoichiometry was found dependent on solvent system and dendrimer generation. Larger dendrimers (G3-Pyr) were found to bind indomethacin through entropy driven binding mode, while G1-Pyr and G2-Pyr expressed an enthalpy driven complex formation, which means that the binding constants have a generational temperature dependency. G1/2-Pyr showed reduced binding with increasing temperature, which could be important for drug release at inflammatory sites, which have, in general, elevated temperatures. In vitro studies elucidated that the indomethacin drug remained its activity when delivered as a dendrimer-indomethacin complex. A slight reduction in toxicity profile was noticed for G2/G3-Pyr-indomethacin dendrimers. Both free indomethacin and dendrimer-indomethacin complex inhibited a variety of pro-inflammatory cytokines in LPS treated cells. However, only the indo-dendrimer complexes showed a significant reduction of IL-1β in LPS-treated THP-1 cells, which was not present in the control with free indomethacin.

U2 - 10.1021/acs.molpharmaceut.8b00567

DO - 10.1021/acs.molpharmaceut.8b00567

M3 - Journal article

C2 - 30011214

SN - 1543-8384

VL - 15

SP - 3573

EP - 3582

JO - Molecular Pharmaceutics

JF - Molecular Pharmaceutics

IS - 8

ER -

Complexes of Indomethacin with 4-Carbomethoxy-pyrrolidone PAMAM Dendrimers Show Improved Anti-Inflammatory Properties and Temperature Dependent Binding and Release Profile

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