In vitro and in vivo gene transfer with poly(amino acid) vesicles.
Non-viral gene delivery systems utilise either amine lipids or polyamines and although non-viral gene delivery systems are said to have a superior safety profile to viruses, the polyamines such as poly(L-lysine) are toxic when used without derivatisation and usually require specific receptor mediated uptake and/or endosomolytic agents to be effective. However, the conversion of poly(L-lysine) and poly(L-ornithine) polyamino acids into amphiphilic vesicle forming polymers reduces the toxicity of the polyamino acids and enables the resulting polyamino acid vesicles to deliver genes both in vitro and in vivo in the absence of receptor specific ligands and endosomolytic agents. The incorporation of a distearoylphosphatidylethanolamine poly(ethylene glycol)-galactosamine conjugate (with the galactosamine unit at the distal end of the poly(ethylene glycol) moiety) into the polyamino acid formulations improved in vitro gene transfer in the case of the amphiphilic poly(L-ornithine) (POP) although no in vivo targeting was detected with the galactosamine formulations. We conclude that the conversion of poly(L-lysine) and poly(L-ornithine) into amphiphilic colloid forming molecules reduces their toxicity, thus allowing these systems to be used for gene transfer in vivo. It is possible that this approach may be extended to other polyamines.
Brown
Maureen D
MD
Department of Pharmaceutical Sciences, University of Strathclyde, Strachclyde Inst. For Bio. Scis., 22 Taylor Street G4 0NR, Glasgow, UK
Gray
Alexander I
AI
Tetley
Laurence
L
Santovena
Ana
A
Rene
Judith
J
Schätzlein
Andreas G
AG
Uchegbu
Ijeoma F
IF
D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D022162:Cytoplasmic Vesicles; D016503:Drug Delivery Systems; D004353:Drug Evaluation, Preclinical / Q000379:methods; D005260:Female; D005688:Galactosamine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000138:chemical synthesis; D018014:Gene Transfer Techniques; D008099:Liver / Q000187:drug effects / Q000648:ultrastructure; D008168:Lung / Q000187:drug effects / Q000648:ultrastructure; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009952:Ornithine / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D011073:Polyamines / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D011092:Polyethylene Glycols / Q000138:chemical synthesis; D011107:Polylysine / Q000008:administration & dosage / Q000737:chemistry / Q000627:therapeutic use; D011108:Polymers / Q000008:administration & dosage / Q000737:chemistry; D013501:Surface-Active Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D022161:Transport Vesicles / Q000737:chemistry / Q000502:physiology*
C493636:DSPE-PEG-galactosamine; D011073:Polyamines; D011108:Polymers; D013501:Surface-Active Agents; D011107:Polylysine; D011092:Polyethylene Glycols; D005688:Galactosamine; D009952:Ornithine