In vitro myotoxicity of selected cationic macromolecules used in non- viral gene delivery

Gayle A. Brazeau, Steven Attia, Scott Poxon, Jeffrey A. Hughes

Research output: Contribution to journalArticle

95 Citations (Scopus)

Abstract

Purpose. Cationic lipid/DNA complexes have been proposed as a method of in vivo gene delivery via intravenous or intramuscular injection. A concern with using these polycationic molecules is whether they are associated with tissue toxicity at the injection site. Therefore, the objective of these studies was to investigate the myotoxic potential of selected non-viral gone delivery macromolecules (e.g., cationic lipids and polymers) with and without plasmid DNA (pDNA) in vitro. Methods. Myotoxicity was assessed by the cumulative release of creatine kinase (CK) over 90 minutes from the isolated rodent extensor digitorum longus muscle into a carbogenated balanced salt solution (BBS, pH 7.4, 37°C) following a 15 μL injection of the test formulation. Phenytoin (Dilantin®) and normal saline served as positive and negative controls, respectively. Results. The myotoxicity of plasmid DNA (pDNA, ~5000bp, 1 mg/ml) was not statistically different from normal saline. However, the myotoxicity of Dilantin® was 16-times higher than either normal saline or pDNA (p < 0.05). Cationic liposomes were found to be less myotoxic than polylysine and PAMAM dendrimers. Polylysine's myotoxicity was found to be dependent upon concentration and molecular weight. The myotoxicity of formulations of cationic liposomes(s), lower molecular weight polylysine (25,000) and higher concentration of PAMAM dendrimers with pDNA were found to be statistically less significant than those formulations without pDNA. Conclusions. The cationic liposomes were less myotoxic compared to the dendrimers and polylysine. Myotoxicity was dependent upon the type of cationic lipid macromolecule, concentration, molecular weight and the presence of pDNA. A possible explanation for this reduced tissue damage in cationic lipids complexed with pDNA is that the formation of complex reduces the overall positive charge of the injectable system resulting in less damage.

Original languageEnglish (US)
Pages (from-to)680-684
Number of pages5
JournalPharmaceutical Research
Volume15
Issue number5
DOIs
StatePublished - 1998
Externally publishedYes

Fingerprint

Viral Genes
Macromolecules
Genes
Plasmids
DNA
Polylysine
Phenytoin
Liposomes
Lipids
Molecular Weight
Molecular weight
Injections
Tissue
Bulletin boards
In Vitro Techniques
Dendrimers
Intramuscular Injections
Creatine Kinase
Intravenous Injections
Toxicity

Keywords

  • Dendrimers
  • Gene delivery
  • Liposomes
  • Myotoxicity
  • Plasmid DNA
  • Polylysine

ASJC Scopus subject areas

  • Chemistry(all)
  • Pharmaceutical Science
  • Pharmacology

Cite this

In vitro myotoxicity of selected cationic macromolecules used in non- viral gene delivery. / Brazeau, Gayle A.; Attia, Steven; Poxon, Scott; Hughes, Jeffrey A.

In: Pharmaceutical Research, Vol. 15, No. 5, 1998, p. 680-684.

Research output: Contribution to journalArticle

Brazeau, Gayle A. ; Attia, Steven ; Poxon, Scott ; Hughes, Jeffrey A. / In vitro myotoxicity of selected cationic macromolecules used in non- viral gene delivery. In: Pharmaceutical Research. 1998 ; Vol. 15, No. 5. pp. 680-684.
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AU - Attia, Steven

AU - Poxon, Scott

AU - Hughes, Jeffrey A.

PY - 1998

Y1 - 1998

N2 - Purpose. Cationic lipid/DNA complexes have been proposed as a method of in vivo gene delivery via intravenous or intramuscular injection. A concern with using these polycationic molecules is whether they are associated with tissue toxicity at the injection site. Therefore, the objective of these studies was to investigate the myotoxic potential of selected non-viral gone delivery macromolecules (e.g., cationic lipids and polymers) with and without plasmid DNA (pDNA) in vitro. Methods. Myotoxicity was assessed by the cumulative release of creatine kinase (CK) over 90 minutes from the isolated rodent extensor digitorum longus muscle into a carbogenated balanced salt solution (BBS, pH 7.4, 37°C) following a 15 μL injection of the test formulation. Phenytoin (Dilantin®) and normal saline served as positive and negative controls, respectively. Results. The myotoxicity of plasmid DNA (pDNA, ~5000bp, 1 mg/ml) was not statistically different from normal saline. However, the myotoxicity of Dilantin® was 16-times higher than either normal saline or pDNA (p < 0.05). Cationic liposomes were found to be less myotoxic than polylysine and PAMAM dendrimers. Polylysine's myotoxicity was found to be dependent upon concentration and molecular weight. The myotoxicity of formulations of cationic liposomes(s), lower molecular weight polylysine (25,000) and higher concentration of PAMAM dendrimers with pDNA were found to be statistically less significant than those formulations without pDNA. Conclusions. The cationic liposomes were less myotoxic compared to the dendrimers and polylysine. Myotoxicity was dependent upon the type of cationic lipid macromolecule, concentration, molecular weight and the presence of pDNA. A possible explanation for this reduced tissue damage in cationic lipids complexed with pDNA is that the formation of complex reduces the overall positive charge of the injectable system resulting in less damage.

AB - Purpose. Cationic lipid/DNA complexes have been proposed as a method of in vivo gene delivery via intravenous or intramuscular injection. A concern with using these polycationic molecules is whether they are associated with tissue toxicity at the injection site. Therefore, the objective of these studies was to investigate the myotoxic potential of selected non-viral gone delivery macromolecules (e.g., cationic lipids and polymers) with and without plasmid DNA (pDNA) in vitro. Methods. Myotoxicity was assessed by the cumulative release of creatine kinase (CK) over 90 minutes from the isolated rodent extensor digitorum longus muscle into a carbogenated balanced salt solution (BBS, pH 7.4, 37°C) following a 15 μL injection of the test formulation. Phenytoin (Dilantin®) and normal saline served as positive and negative controls, respectively. Results. The myotoxicity of plasmid DNA (pDNA, ~5000bp, 1 mg/ml) was not statistically different from normal saline. However, the myotoxicity of Dilantin® was 16-times higher than either normal saline or pDNA (p < 0.05). Cationic liposomes were found to be less myotoxic than polylysine and PAMAM dendrimers. Polylysine's myotoxicity was found to be dependent upon concentration and molecular weight. The myotoxicity of formulations of cationic liposomes(s), lower molecular weight polylysine (25,000) and higher concentration of PAMAM dendrimers with pDNA were found to be statistically less significant than those formulations without pDNA. Conclusions. The cationic liposomes were less myotoxic compared to the dendrimers and polylysine. Myotoxicity was dependent upon the type of cationic lipid macromolecule, concentration, molecular weight and the presence of pDNA. A possible explanation for this reduced tissue damage in cationic lipids complexed with pDNA is that the formation of complex reduces the overall positive charge of the injectable system resulting in less damage.

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KW - Plasmid DNA

KW - Polylysine

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