Molecular hurdles in polyfectin design and mechanistic background to polycation induced cytotoxicity.
Synthetic polymer based Polyfectins (cationic polymer-DNA complex) have received intensive scientific research as they can potentially circumvent problems associated with viral vectors for gene therapy. These cationic macromolecules can readily condense DNA or RNA into stable nanostructures for use in gene delivery. Recently two commonly used polycations, poly(ethylenimine) (PEI) and poly(L-lysine) have demonstrated their ability to induce apoptosis in a range of human cell lines. This may be the explanation for short-term gene transfection observed with polyfectins. It is the aim of this review to discuss these and other factors behind observed toxicities including the inherent polydisperse nature of polymeric macromolecules and their behaviour in vivo. Strategies for reduction of toxicity are included such as new polymeric synthetic technologies and vector pegylation. There is a clear and immediate need for understanding of the mechanisms which cause polyfectin toxicity which will ultimately facilitate improved vector design and safer gene delivery.
Hunter
A Christy
AC
Molecular Targeting and Polymer Toxicology Group, School of Pharmacy and Biomolecular Sciences, University of Brighton, East Sussex BN2 4GJ, UK. c.hunter@bton.ac.uk
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D018014:Gene Transfer Techniques; D006801:Humans; D011073:Polyamines / Q000633:toxicity*; D000071228:Polyelectrolytes; D011094:Polyethyleneimine / Q000633:toxicity*; D011107:Polylysine / Q000633:toxicity*; D013778:Tetrazolium Salts / Q000378:metabolism / Q000494:pharmacology; D013844:Thiazoles / Q000378:metabolism / Q000494:pharmacology
D011073:Polyamines; D000071228:Polyelectrolytes; D011094:Polyethyleneimine; D011107:Polylysine; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue