Folate Targeted Nanoparticles for Gene Delivery

The use of folate-targeted nanoparticles for gene delivery has also been studied. In gene delivery, tissue targeting is very important for the efficacy and safety of treatment. To date, the transfection efficiency offered by synthetic gene delivery systems is very low compared to that of viral vectors. This is also true for nanoparticle-based systems. Extensive research is being done in the area to improve transfection efficiencies by designing better delivery systems with improved targeting ability, DNA stabilization, and cellular interaction.

Mansouri reported on the formulation of nanoparticles through the complex coacervation of chitosan-folic acid conjugates with DNA.69 Chitosan is a biocompatible polycation that joins to form a complex with DNA through electrostatic interactions and provides protection against nuclease degradation. Complex coacervation is an optimal preparation technique for the encapsulation of DNA because it avoids the use of organic solvents and high-energy ultrasonication. Results revealed that the integrity of plasmid DNA in the particles was maintained and that conjugation of chitosan to folic acid did not interfere with the electrostatic interaction between chitosan and DNA. As expected, the ratio of chitosan to DNA, and consequent charge ratio, had an effect on particle size and zeta potential. Nanoparticles smaller than 200 nm were obtained with a chitosan amino group to DNA phosphate group ratio of more than 2. The use of these nanoparticles consequently offers a promising alternative for nonviral gene therapy for the treatment of cancer and other diseases in which folate receptors are overexpressed.

Nanoparticles with a poly(l-lactic acid) (PLL) core and a polyethyleneimide (PEI) surface conjugated to folate were utilized for delivery of plasmid DNA.70 Folic acid was conjugated to the N-terminal amino group of PEI. PEI is a polycation that has been used in the past for DNA condensation and delivery because it protects DNA from degradation through an endosomal escape mechanism. Here nanoparticles were prepared through the self-assembly of the amphiphilic folate-PEI-PLL copolymer with DNA in an aqueous medium. Nanoparticles of approximately 100150 nm in diameter and spherical shape were produced. In vitro luciferase transfection studies revealed that this system actually resulted in lower luciferase expression than PEI-DNA complexes.

In a separate report, folate-polyethyleneglycol-distearoylphophatidylethanolamine conjugate (f-PEG-DSPE), 3([N-(N/,N/-dimethylaminoethane)-carbamoyl] cholesterol, and Tween 80 were used to complex with DNA into cationic nanoparticles of 100-200 nm in diameter with a modified ethanol injection method.71 The formulation was carried out by dissolving the lipids in ethanol and then removing the solvent through evaporation in the presence of water. The folate moiety, which is conjugated to the PEG end of one of the lipid conjugates, naturally localizes at the surface of the nanoparticles because of PEG migration toward the water phase. Tween 80, a nonionic surfactant, and PEG were incorporated with the purpose of improving the in vivo stability of the cationic nanoparticles through steric hindrance. The size of the nanoparticles with higher PEG content was maintained in the presence of serum. This suggests that these nanoparticles are better able to maintain their structural integrity in the presence of anionic competitors present in blood. Folate targeting enhanced association and transfection efficacy of nanoparticles complexed with a luci-ferase-encoding plasmid on FR( +) KB cells. The association and efficacy were reduced when folic acid was present in the medium, thus revealing the involvement of the folate receptor in the transport of the plasmid DNA into the cells.

A possible limitation of folate targeting is the noted variability of FR expression levels not only between patients, but also within a single tumor.44 In addition, it has been reported that expression of FR in cancerous cell lines is not representative of those one sees in vivo.44 Consequently, screening protocols for FR expression will need to be utilized clinically in order to determine if folate-targeted therapies are appropriate.

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