Disulfide-functional poly(amido amine)s with tunable degradability for gene delivery

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Abstract

Controlled degradability in response to the local environment is one of the most effective strategies to achieve spatiotemporal release of genes from a polymeric carrier. Exploiting the differences in reduction potential between the extracellular and intracellular environment, disulfides are frequently incorporated into the backbone of polymeric drug delivery agents to ensure efficient intracellular release of the payload. However, although to a lesser extent, reduction of disulfides may also occur in the extracellular environment and should be prevented to avoid premature release. Accurate control over the stability of disulfide linkages enables the optimization of polymeric carriers for efficient drug delivery. Bioreducible poly(amido amine)s (PAAs) with varying degrees of steric hindrance adjacent to the disulfide bonds (0, 2 or 4 methyl groups) were prepared in order to obtain carriers with controlled stability. The degradation behavior of these PAA-polymers was evaluated under different reducing conditions and their in vitro toxicities and transfection efficiencies were assessed. Degradation of the PAA-based polyplexes consistently required higher reducing strengths as the steric hindrance near the disulfide bonds increased. Polyplexes based on 2-methyl cystamine disulfide based PAA polymer (PAA2m) remained stable under extracellular glutathione concentrations (0.001–0.01 mM), while degrading within 1 h under reducing conditions similar to those in the intracellular environment (1–10 mM glutathione). This polymer exhibited excellent transfection capabilities, with efficiencies up to 90% of transfected cells. PAA0m showed slightly reduced transfection properties compared to PAA2m, likely due to premature degradation. The severely hindered PAA4m, however, displayed increased toxicity, accompanied by reduced transfection efficiency, as a result of its exceptional stability. These results demonstrate the feasibility of introducing steric hindrance near the disulfide moiety to tune polyplex stability against bioreduction, and show that PAA2m is a promising polymer to be further developed for gene therapy.
Original languageEnglish
Pages (from-to)357-365
JournalJournal of controlled release
Volume244
DOIs
Publication statusPublished - 2016

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Disulfides
Amines
Transfection
Polymers
Genes
Glutathione
Cystamine
Drug Carriers
Genetic Therapy
Pharmaceutical Preparations

Keywords

  • IR-101063
  • METIS-317659

Cite this

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title = "Disulfide-functional poly(amido amine)s with tunable degradability for gene delivery",
abstract = "Controlled degradability in response to the local environment is one of the most effective strategies to achieve spatiotemporal release of genes from a polymeric carrier. Exploiting the differences in reduction potential between the extracellular and intracellular environment, disulfides are frequently incorporated into the backbone of polymeric drug delivery agents to ensure efficient intracellular release of the payload. However, although to a lesser extent, reduction of disulfides may also occur in the extracellular environment and should be prevented to avoid premature release. Accurate control over the stability of disulfide linkages enables the optimization of polymeric carriers for efficient drug delivery. Bioreducible poly(amido amine)s (PAAs) with varying degrees of steric hindrance adjacent to the disulfide bonds (0, 2 or 4 methyl groups) were prepared in order to obtain carriers with controlled stability. The degradation behavior of these PAA-polymers was evaluated under different reducing conditions and their in vitro toxicities and transfection efficiencies were assessed. Degradation of the PAA-based polyplexes consistently required higher reducing strengths as the steric hindrance near the disulfide bonds increased. Polyplexes based on 2-methyl cystamine disulfide based PAA polymer (PAA2m) remained stable under extracellular glutathione concentrations (0.001–0.01 mM), while degrading within 1 h under reducing conditions similar to those in the intracellular environment (1–10 mM glutathione). This polymer exhibited excellent transfection capabilities, with efficiencies up to 90{\%} of transfected cells. PAA0m showed slightly reduced transfection properties compared to PAA2m, likely due to premature degradation. The severely hindered PAA4m, however, displayed increased toxicity, accompanied by reduced transfection efficiency, as a result of its exceptional stability. These results demonstrate the feasibility of introducing steric hindrance near the disulfide moiety to tune polyplex stability against bioreduction, and show that PAA2m is a promising polymer to be further developed for gene therapy.",
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author = "Elzes, {Marie-Louise Rachel} and N. Akeroyd and Engbersen, {Johannes F.J.} and Paulusse, {Jos Marie Johannes}",
note = "The 14th edition of the European Symposium on Controlled Drug Delivery, Egmond aan Zee, The Netherlands on April 13-15, 2016- Chair: Dr. J.M.J. Paulusse",
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Disulfide-functional poly(amido amine)s with tunable degradability for gene delivery. / Elzes, Marie-Louise Rachel; Akeroyd, N.; Engbersen, Johannes F.J.; Paulusse, Jos Marie Johannes.

In: Journal of controlled release, Vol. 244, 2016, p. 357-365.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Disulfide-functional poly(amido amine)s with tunable degradability for gene delivery

AU - Elzes, Marie-Louise Rachel

AU - Akeroyd, N.

AU - Engbersen, Johannes F.J.

AU - Paulusse, Jos Marie Johannes

N1 - The 14th edition of the European Symposium on Controlled Drug Delivery, Egmond aan Zee, The Netherlands on April 13-15, 2016- Chair: Dr. J.M.J. Paulusse

PY - 2016

Y1 - 2016

N2 - Controlled degradability in response to the local environment is one of the most effective strategies to achieve spatiotemporal release of genes from a polymeric carrier. Exploiting the differences in reduction potential between the extracellular and intracellular environment, disulfides are frequently incorporated into the backbone of polymeric drug delivery agents to ensure efficient intracellular release of the payload. However, although to a lesser extent, reduction of disulfides may also occur in the extracellular environment and should be prevented to avoid premature release. Accurate control over the stability of disulfide linkages enables the optimization of polymeric carriers for efficient drug delivery. Bioreducible poly(amido amine)s (PAAs) with varying degrees of steric hindrance adjacent to the disulfide bonds (0, 2 or 4 methyl groups) were prepared in order to obtain carriers with controlled stability. The degradation behavior of these PAA-polymers was evaluated under different reducing conditions and their in vitro toxicities and transfection efficiencies were assessed. Degradation of the PAA-based polyplexes consistently required higher reducing strengths as the steric hindrance near the disulfide bonds increased. Polyplexes based on 2-methyl cystamine disulfide based PAA polymer (PAA2m) remained stable under extracellular glutathione concentrations (0.001–0.01 mM), while degrading within 1 h under reducing conditions similar to those in the intracellular environment (1–10 mM glutathione). This polymer exhibited excellent transfection capabilities, with efficiencies up to 90% of transfected cells. PAA0m showed slightly reduced transfection properties compared to PAA2m, likely due to premature degradation. The severely hindered PAA4m, however, displayed increased toxicity, accompanied by reduced transfection efficiency, as a result of its exceptional stability. These results demonstrate the feasibility of introducing steric hindrance near the disulfide moiety to tune polyplex stability against bioreduction, and show that PAA2m is a promising polymer to be further developed for gene therapy.

AB - Controlled degradability in response to the local environment is one of the most effective strategies to achieve spatiotemporal release of genes from a polymeric carrier. Exploiting the differences in reduction potential between the extracellular and intracellular environment, disulfides are frequently incorporated into the backbone of polymeric drug delivery agents to ensure efficient intracellular release of the payload. However, although to a lesser extent, reduction of disulfides may also occur in the extracellular environment and should be prevented to avoid premature release. Accurate control over the stability of disulfide linkages enables the optimization of polymeric carriers for efficient drug delivery. Bioreducible poly(amido amine)s (PAAs) with varying degrees of steric hindrance adjacent to the disulfide bonds (0, 2 or 4 methyl groups) were prepared in order to obtain carriers with controlled stability. The degradation behavior of these PAA-polymers was evaluated under different reducing conditions and their in vitro toxicities and transfection efficiencies were assessed. Degradation of the PAA-based polyplexes consistently required higher reducing strengths as the steric hindrance near the disulfide bonds increased. Polyplexes based on 2-methyl cystamine disulfide based PAA polymer (PAA2m) remained stable under extracellular glutathione concentrations (0.001–0.01 mM), while degrading within 1 h under reducing conditions similar to those in the intracellular environment (1–10 mM glutathione). This polymer exhibited excellent transfection capabilities, with efficiencies up to 90% of transfected cells. PAA0m showed slightly reduced transfection properties compared to PAA2m, likely due to premature degradation. The severely hindered PAA4m, however, displayed increased toxicity, accompanied by reduced transfection efficiency, as a result of its exceptional stability. These results demonstrate the feasibility of introducing steric hindrance near the disulfide moiety to tune polyplex stability against bioreduction, and show that PAA2m is a promising polymer to be further developed for gene therapy.

KW - IR-101063

KW - METIS-317659

U2 - 10.1016/j.jconrel.2016.08.021

DO - 10.1016/j.jconrel.2016.08.021

M3 - Article

VL - 244

SP - 357

EP - 365

JO - Journal of controlled release

JF - Journal of controlled release

SN - 0168-3659

ER -