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Lipid encapsulation enables the effective systemic delivery of polyplex plasmid DNA
James Heyes1, Lorne Palmer, Kitty Chan
1Protiva Biotherapeutics, Burnaby, British Columbia, Canada.
Molecular Therapy : the Journal of the American Society of Gene Therapy
|February 15, 2007
Summary
New pre-condensed stable plasmid lipid particles (pSPLPs) enhance gene delivery. Encapsulating condensed DNA with poly(ethyleneimine) (PEI) in lipid bilayers significantly boosts tumor gene expression, showing promise for systemic delivery.
Area of Science:
- Biotechnology
- Gene Therapy
- Nanomedicine
Background:
- Developing effective non-viral gene delivery vectors is crucial for therapeutic applications.
- Stable plasmid lipid particles (SPLPs) offer a platform for DNA delivery, but their potency can be limited.
- Polyplexes, formed by condensing DNA with cationic polymers like poly(ethyleneimine) (PEI), can enhance transfection efficiency.
Purpose of the Study:
- To develop and characterize pre-condensed stable plasmid lipid particles (pSPLPs) for improved gene delivery.
- To evaluate the in vitro and in vivo performance of pSPLPs compared to traditional SPLPs.
- To assess the impact of including endosomolytic agents like PEI within pSPLPs on gene expression and biodistribution.
Main Methods:
- A controlled mixing process was used to form polyplexes and encapsulate them within lipid bilayers, creating pSPLPs.
- pSPLPs were characterized for size and surface charge.
- In vitro gene expression studies were performed using poly-L-lysine or PEI condensed DNA.
- In vivo studies involved administering pSPLPs and SPLPs to A/J mice with subcutaneous Neuro-2a tumors.
- Plasma clearance and tumor gene expression were quantified.
Main Results:
- pSPLPs exhibited small size (104+/-3 nm) and low surface charge.
- Lipid encapsulation of both poly-L-lysine and PEI condensed DNA was achieved.
- PEI-containing pSPLPs demonstrated enhanced endosomolytic activity in vitro.
- In vivo, pSPLP plasma clearance was comparable to SPLP, with significant tumor accumulation.
- PEI-pSPLP formulations resulted in a sixfold increase in reporter gene expression in tumors compared to SPLP.
- No significant gene expression was observed in off-target organs (liver, lung, spleen).
- Both SPLP and pSPLP formulations were well tolerated.
Conclusions:
- Lipid encapsulation of polyplex plasmid DNA is an effective strategy to modify pharmacologic properties and enable systemic delivery.
- The inclusion of endosomolytic agents like PEI significantly enhances the potency of SPLP formulations.
- pSPLPs represent a promising platform for targeted gene delivery with improved therapeutic efficacy.
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