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Targeted decationized polyplexes for cell specific gene delivery.

Luís Novo1, Enrico Mastrobattista, Cornelus F van Nostrum

  • 1Department of Pharmaceutics, Utrecht Institute for Pharmaceutical Sciences, Utrecht University , 3584 CG Utrecht, The Netherlands.

Bioconjugate Chemistry
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Targeted decationized polyplexes with folate demonstrated enhanced cellular uptake and gene delivery efficiency in cancer cells. These novel folate-targeted polyplexes show promise for safe and effective targeted gene therapy applications.

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Area of Science:

  • Biomaterials Science
  • Nanotechnology
  • Gene Therapy

Background:

  • Decationized polyplexes offer excellent cytocompatibility and low nonspecific cellular uptake.
  • Targeted delivery systems are crucial for enhancing therapeutic efficacy and reducing side effects.
  • Folate receptors are overexpressed on various tumor cells, making them attractive targets for drug delivery.

Purpose of the Study:

  • To develop and evaluate targeted disulfide cross-linked decationized polyplexes decorated with folate for enhanced gene delivery.
  • To investigate the cellular uptake and transfection efficiency of folate-targeted polyplexes in folate receptor-expressing and non-expressing cancer cell lines.
  • To assess the cytocompatibility of the folate-targeted polyplexes.

Main Methods:

  • Synthesis of disulfide cross-linked poly(hydroxypropyl methacrylamide) (pHPMA) core polyplexes entrapping plasmid DNA (pDNA).
  • Decoration of poly(ethylene glycol) (PEG) shell with folate molecules as targeting ligands.
  • In vitro evaluation of cellular uptake and gene transfection efficiency using HeLa, OVCAR-3 (folate receptor-positive), and A549 (folate receptor-negative) cell lines.

Main Results:

  • Folate-targeted decationized polyplexes exhibited significantly higher cellular uptake in OVCAR-3 and HeLa cells compared to non-targeted counterparts.
  • Cellular uptake was similar for targeted and non-targeted polyplexes in A549 cells, indicating receptor-specific targeting.
  • Higher gene transfection efficiency was observed in OVCAR-3 cells with folate-targeted polyplexes, correlating with enhanced cellular uptake.
  • The introduction of folate did not compromise the inherent cytocompatibility of the decationized polyplexes.

Conclusions:

  • Coupling folate to decationized polyplexes creates an effective system for targeted gene delivery.
  • Folate-mediated targeting enhances cellular uptake and transfection efficiency in cancer cells overexpressing folate receptors.
  • These targeted polyplexes represent a promising platform for developing safer and more effective gene therapy strategies.