Peptide dendrimer-conjugates of ketoprofen: Synthesis and ex vivo and in vivo evaluations of passive diffusion, sonophoresis and iontophoresis for skin delivery

Aswathi R. Hegde, Prarthana V. Rewatkar, Jyothsna Manikkath, Karnaker Tupally, Harendra S. Parekh, Srinivas Mutalik

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

The aim of this study was to evaluate skin delivery of ketoprofen when covalently tethered to mildly cationic (2+or 4+) peptide dendrimers prepared wholly by solid phase peptide synthesis. The amino acids glycine, arginine and lysine formed the dendrimer with ketoprofen tethered either to the lysine side-arm (Nε) or periphery of dendrimeric branches. Passive diffusion, sonophoresis- and iontophoresis-assisted permeation of each peptide dendrimer-drug conjugate (D1–D4) was studied across mouse skin, both in vitro and in vivo. In addition, skin toxicity of dendrimeric conjugates when trialed with iontophoresis or sonophoresis was also evaluated. All dendrimeric conjugates improved aqueous solubility at least 5-fold, compared to ketoprofen alone, while also exhibiting appreciable lipophilicity. In vitro passive diffusion studies revealed that ketoprofen in its native form was delivered to a greater extent, compared with a dendrimer-conjugated form at the end of 24 h (Q24 h(μg/cm2): ketoprofen (68.06 ± 3.62) > D2 (49.62 ± 2.92) > D4 (19.20 ± 0.89) > D1 (6.45 ± 0.40) > D3 (2.21 ± 0.19). However, sonophoresis substantially increased the skin permeation of ketoprofen-dendrimer conjugates in 30 min (Q30 min(μg/cm2): D4 (122.19 ± 7.14) > D2 (66.74 ± 3.86) > D1 (52.10 ± 3.22) > D3 (41.66 ± 3.22)) although ketoprofen alone again proved superior (Q30 min: 167.99 ± 9.11 μg/cm2). Next, application of iontophoresis was trialed and shown to considerably increase permeation of dendrimeric ketoprofen in 6 h (Q6 h(μg/cm2): D2 (711.49 ± 39.14) > D4 (341.23 ± 16.43) > D3 (89.50 ± 4.99) > D1 (50.91 ± 2.98), with a Q6 hvalue of 96.60 ± 5.12 μg/cm2for ketoprofen alone). In vivo studies indicated that therapeutically relevant concentrations of ketoprofen could be delivered transdermally when iontophoresis was paired with D2 (985.49 ± 43.25 ng/mL). Further, histopathological analysis showed that the dendrimeric approach was a safe mode as ketoprofen alone. The present study successfully demonstrates that peptide dendrimer conjugates of ketoprofen, when combined with non-invasive modalities, such as iontophoresis can enhance skin permeation with clinically relevant concentrations achieved transdermally.

Original languageEnglish
Pages (from-to)237-249
Number of pages13
JournalEuropean Journal of Pharmaceutical Sciences
Volume102
DOIs
Publication statusPublished - 01-05-2017

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Ketoprofen
Dendrimers
Iontophoresis
Skin
Peptides
Lysine
Solid-Phase Synthesis Techniques
Solubility
Glycine
Arginine

All Science Journal Classification (ASJC) codes

  • Pharmaceutical Science

Cite this

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title = "Peptide dendrimer-conjugates of ketoprofen: Synthesis and ex vivo and in vivo evaluations of passive diffusion, sonophoresis and iontophoresis for skin delivery",
abstract = "The aim of this study was to evaluate skin delivery of ketoprofen when covalently tethered to mildly cationic (2+or 4+) peptide dendrimers prepared wholly by solid phase peptide synthesis. The amino acids glycine, arginine and lysine formed the dendrimer with ketoprofen tethered either to the lysine side-arm (Nε) or periphery of dendrimeric branches. Passive diffusion, sonophoresis- and iontophoresis-assisted permeation of each peptide dendrimer-drug conjugate (D1–D4) was studied across mouse skin, both in vitro and in vivo. In addition, skin toxicity of dendrimeric conjugates when trialed with iontophoresis or sonophoresis was also evaluated. All dendrimeric conjugates improved aqueous solubility at least 5-fold, compared to ketoprofen alone, while also exhibiting appreciable lipophilicity. In vitro passive diffusion studies revealed that ketoprofen in its native form was delivered to a greater extent, compared with a dendrimer-conjugated form at the end of 24 h (Q24 h(μg/cm2): ketoprofen (68.06 ± 3.62) > D2 (49.62 ± 2.92) > D4 (19.20 ± 0.89) > D1 (6.45 ± 0.40) > D3 (2.21 ± 0.19). However, sonophoresis substantially increased the skin permeation of ketoprofen-dendrimer conjugates in 30 min (Q30 min(μg/cm2): D4 (122.19 ± 7.14) > D2 (66.74 ± 3.86) > D1 (52.10 ± 3.22) > D3 (41.66 ± 3.22)) although ketoprofen alone again proved superior (Q30 min: 167.99 ± 9.11 μg/cm2). Next, application of iontophoresis was trialed and shown to considerably increase permeation of dendrimeric ketoprofen in 6 h (Q6 h(μg/cm2): D2 (711.49 ± 39.14) > D4 (341.23 ± 16.43) > D3 (89.50 ± 4.99) > D1 (50.91 ± 2.98), with a Q6 hvalue of 96.60 ± 5.12 μg/cm2for ketoprofen alone). In vivo studies indicated that therapeutically relevant concentrations of ketoprofen could be delivered transdermally when iontophoresis was paired with D2 (985.49 ± 43.25 ng/mL). Further, histopathological analysis showed that the dendrimeric approach was a safe mode as ketoprofen alone. The present study successfully demonstrates that peptide dendrimer conjugates of ketoprofen, when combined with non-invasive modalities, such as iontophoresis can enhance skin permeation with clinically relevant concentrations achieved transdermally.",
author = "Hegde, {Aswathi R.} and Rewatkar, {Prarthana V.} and Jyothsna Manikkath and Karnaker Tupally and Parekh, {Harendra S.} and Srinivas Mutalik",
year = "2017",
month = "5",
day = "1",
doi = "10.1016/j.ejps.2017.03.009",
language = "English",
volume = "102",
pages = "237--249",
journal = "European Journal of Pharmaceutical Sciences",
issn = "0928-0987",
publisher = "Elsevier",

}

TY - JOUR

T1 - Peptide dendrimer-conjugates of ketoprofen

T2 - Synthesis and ex vivo and in vivo evaluations of passive diffusion, sonophoresis and iontophoresis for skin delivery

AU - Hegde, Aswathi R.

AU - Rewatkar, Prarthana V.

AU - Manikkath, Jyothsna

AU - Tupally, Karnaker

AU - Parekh, Harendra S.

AU - Mutalik, Srinivas

PY - 2017/5/1

Y1 - 2017/5/1

N2 - The aim of this study was to evaluate skin delivery of ketoprofen when covalently tethered to mildly cationic (2+or 4+) peptide dendrimers prepared wholly by solid phase peptide synthesis. The amino acids glycine, arginine and lysine formed the dendrimer with ketoprofen tethered either to the lysine side-arm (Nε) or periphery of dendrimeric branches. Passive diffusion, sonophoresis- and iontophoresis-assisted permeation of each peptide dendrimer-drug conjugate (D1–D4) was studied across mouse skin, both in vitro and in vivo. In addition, skin toxicity of dendrimeric conjugates when trialed with iontophoresis or sonophoresis was also evaluated. All dendrimeric conjugates improved aqueous solubility at least 5-fold, compared to ketoprofen alone, while also exhibiting appreciable lipophilicity. In vitro passive diffusion studies revealed that ketoprofen in its native form was delivered to a greater extent, compared with a dendrimer-conjugated form at the end of 24 h (Q24 h(μg/cm2): ketoprofen (68.06 ± 3.62) > D2 (49.62 ± 2.92) > D4 (19.20 ± 0.89) > D1 (6.45 ± 0.40) > D3 (2.21 ± 0.19). However, sonophoresis substantially increased the skin permeation of ketoprofen-dendrimer conjugates in 30 min (Q30 min(μg/cm2): D4 (122.19 ± 7.14) > D2 (66.74 ± 3.86) > D1 (52.10 ± 3.22) > D3 (41.66 ± 3.22)) although ketoprofen alone again proved superior (Q30 min: 167.99 ± 9.11 μg/cm2). Next, application of iontophoresis was trialed and shown to considerably increase permeation of dendrimeric ketoprofen in 6 h (Q6 h(μg/cm2): D2 (711.49 ± 39.14) > D4 (341.23 ± 16.43) > D3 (89.50 ± 4.99) > D1 (50.91 ± 2.98), with a Q6 hvalue of 96.60 ± 5.12 μg/cm2for ketoprofen alone). In vivo studies indicated that therapeutically relevant concentrations of ketoprofen could be delivered transdermally when iontophoresis was paired with D2 (985.49 ± 43.25 ng/mL). Further, histopathological analysis showed that the dendrimeric approach was a safe mode as ketoprofen alone. The present study successfully demonstrates that peptide dendrimer conjugates of ketoprofen, when combined with non-invasive modalities, such as iontophoresis can enhance skin permeation with clinically relevant concentrations achieved transdermally.

AB - The aim of this study was to evaluate skin delivery of ketoprofen when covalently tethered to mildly cationic (2+or 4+) peptide dendrimers prepared wholly by solid phase peptide synthesis. The amino acids glycine, arginine and lysine formed the dendrimer with ketoprofen tethered either to the lysine side-arm (Nε) or periphery of dendrimeric branches. Passive diffusion, sonophoresis- and iontophoresis-assisted permeation of each peptide dendrimer-drug conjugate (D1–D4) was studied across mouse skin, both in vitro and in vivo. In addition, skin toxicity of dendrimeric conjugates when trialed with iontophoresis or sonophoresis was also evaluated. All dendrimeric conjugates improved aqueous solubility at least 5-fold, compared to ketoprofen alone, while also exhibiting appreciable lipophilicity. In vitro passive diffusion studies revealed that ketoprofen in its native form was delivered to a greater extent, compared with a dendrimer-conjugated form at the end of 24 h (Q24 h(μg/cm2): ketoprofen (68.06 ± 3.62) > D2 (49.62 ± 2.92) > D4 (19.20 ± 0.89) > D1 (6.45 ± 0.40) > D3 (2.21 ± 0.19). However, sonophoresis substantially increased the skin permeation of ketoprofen-dendrimer conjugates in 30 min (Q30 min(μg/cm2): D4 (122.19 ± 7.14) > D2 (66.74 ± 3.86) > D1 (52.10 ± 3.22) > D3 (41.66 ± 3.22)) although ketoprofen alone again proved superior (Q30 min: 167.99 ± 9.11 μg/cm2). Next, application of iontophoresis was trialed and shown to considerably increase permeation of dendrimeric ketoprofen in 6 h (Q6 h(μg/cm2): D2 (711.49 ± 39.14) > D4 (341.23 ± 16.43) > D3 (89.50 ± 4.99) > D1 (50.91 ± 2.98), with a Q6 hvalue of 96.60 ± 5.12 μg/cm2for ketoprofen alone). In vivo studies indicated that therapeutically relevant concentrations of ketoprofen could be delivered transdermally when iontophoresis was paired with D2 (985.49 ± 43.25 ng/mL). Further, histopathological analysis showed that the dendrimeric approach was a safe mode as ketoprofen alone. The present study successfully demonstrates that peptide dendrimer conjugates of ketoprofen, when combined with non-invasive modalities, such as iontophoresis can enhance skin permeation with clinically relevant concentrations achieved transdermally.

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