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Antisense precision polymer micelles require less poly(ethylenimine) for efficient gene knockdown. | LitMetric

Antisense precision polymer micelles require less poly(ethylenimine) for efficient gene knockdown.

Nanoscale

Department of Chemistry and Center for Self-Assembled Chemical Structures, McGill University, 801 Sherbrooke St. W., Montreal, Quebec H3A 0B8, Canada.

Published: December 2015

AI Article Synopsis

  • Therapeutic nucleic acids are valuable for reducing protein expression but struggle with poor cellular uptake, necessitating the use of transport vectors like cationic polymers.
  • Poly(ethylenimine) (PEI) can effectively transport nucleic acids into cells, but its high cytotoxicity poses challenges for clinical application.
  • The authors developed antisense-polymer conjugates that can self-assemble into micelles, which significantly improve both cellular uptake and gene silencing effects of antisense while minimizing cytotoxicity, allowing for effective gene delivery using lower amounts of PEI.

Article Abstract

Therapeutic nucleic acids are powerful molecules for shutting down protein expression. However, their cellular uptake is poor and requires transport vectors, such as cationic polymers. Of these, poly(ethylenimine) (PEI) has been shown to be an efficient vehicle for nucleic acid transport into cells. However, cytotoxicity has been a major hurdle in the development of PEI-DNA complexes as clinically viable therapeutics. We have synthesized antisense-polymer conjugates, where the polymeric block is completely monodisperse and sequence-controlled. Depending on the polymer sequence, these can self-assemble to produce micelles of very low polydispersity. The introduction of linear poly(ethylenimine) to these micelles leads to aggregation into size-defined PEI-mediated superstructures. Subsequently, both cellular uptake and gene silencing are greatly enhanced over extended periods compared to antisense alone, while at the same time cellular cytotoxicity remains very low. In contrast, gene silencing is not enhanced with antisense polymer conjugates that are not able to self-assemble into micelles. Thus, using antisense precision micelles, we are able to achieve significant transfection and knockdown with minimal cytotoxicity at much lower concentrations of linear PEI then previously reported. Consequently, a conceptual solution to the problem of antisense or siRNA delivery is to self-assemble these molecules into 'gene-like' micelles with high local charge and increased stability, thus reducing the amount of transfection agent needed for effective gene silencing.

Download full-text PDF

Source
http://dx.doi.org/10.1039/c5nr05157fDOI Listing

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