Cationic gene delivery molecules are relatively cytotoxic [50% cell survival concentrations
(IC50) < 0.05 mg mL-1], limiting their use clinically. We hypothesise that a low
molecular weight polymer with reduced amine content would yield biocompatible gene
therapy nanoparticles with DNA. We synthesised and characterised an amine terminated
poly(ethylene glycol) – (PEG) based polymer - tetra-O,O,O,O-[poly(ethyleneglycol-O-2-
ethyleneimine)-graft-N-(2-ethylamine)-]-pentaerythritol (4-arm-PEG-ethylamine - 4APEA) and subjected 4APEA
to physicochemical and biological testing. 4APEA was relatively non-toxic against the A431 cell line (IC50
of 4.76 ± 0.27 mg mL-1), formed 200 nm positively charged nanoparticles with DNA and transfected the A431
cell line with a similar efficacy to the less biocompatible poly(ethylenimine) (PEI, IC50 = 0.002 mg mL-1).
On intravenous injection of 4APEA – DNA nanoparticles, significantly more DNA was found in the lungs
and liver when compared to the injection of DNA alone. When 4APEA, 4APEA -TNF-alpha DNA nanoparticles
and TNF-alpha DNA alone were intravenously injected to MiaPaCa tumour bearing mice, only the
4APEA - TNF-alpha DNA nanoparticles were tumouricidal, with tumour volumes significantly different from
untreated controls. A new PEG derivative 4APEA is 1000 time less toxic than PEI in the A431 cell line, has
comparable cell transfection capability to PEI in this cell line and produces tumouricidal nanoparticles when
complexed with TNF-alpha.
Keywords: Biocompatibility, cancer, gene delivery, pancreatic cancer, PEG amines, PEG, poly(ethylene
glycol), tumour regression.
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