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Methods and compositions for the delivery of bioactive compounds

a bioactive compound and composition technology, applied in the direction of drug compositions, tissue culture, dna/rna fragmentation, etc., can solve the problems of undesirable pharmacokinetic properties and toxic side effects, and achieve the effect of reducing the immunogenic

Inactive Publication Date: 2011-05-19
THE UNIV OF NORTH CAROLINA AT CHAPEL HILL
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0004]Compositions also include delivery systems comprising a lipid vehicle and a bioactive compound, wherein the lipid vehicle encapsulates the bioactive compound, and wherein the lipid vehicle comprises a covalent bilayer or a core supported bilayer comprising polycationic lipids. In some of the embodiments wherein the lipid vehicle comprises a covalent bilayer, the covalent bilayer comprises a covalent leaflet supported bilayer. Covalent bilayers and supported bilayers provide stabilize the delivery system, allowing the surface charge of the lipid vehicle of the delivery system to be shielded fully or partially through the association of polyethylene glycol molecules with the surface of the lipid vehicle, thus reducing the clearance of the delivery system when administered to a subject and enhancing the bioavailability.

Problems solved by technology

However, many of these vehicles exhibit undesirable pharmacokinetic properties and are associated with toxic side effects due to the stimulation of an inflammatory response when administered in vivo.

Method used

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  • Methods and compositions for the delivery of bioactive compounds
  • Methods and compositions for the delivery of bioactive compounds
  • Methods and compositions for the delivery of bioactive compounds

Examples

Experimental program
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Effect test

example 1

Development of the LPH-NP Formulation

[0342]We prepared the complex of siRNA / hyaluronic acid (HA) and protamine in different ratios and measured their particle size and zeta potential. As shown in FIG. 2, particle size and zeta potential changed according to the ratio of siRNA / HA to protamine. Large aggregates were found at the approximate ratio of 0.9 (siRNA / HA:protamine, weight ratio). At this ratio, a neutral complex was formed (zeta potential ˜0 mV), which tended to aggregate. An increase in the amount of protamine in the complex resulted in an increase in the zeta potential with a dramatic change between ratios 0.865-0.9625 (from −35 mV to 20 mV). We chose 1.0 as the optimal ratio, as the complex stayed negatively charged and had a relatively small size (˜150 nm).

[0343]Next, we mixed the siRNA / HA / protamine complex with different amounts of cationic lipid to prepare the naked LPH-NP and analyzed the size and zeta potential of the resulting particle. As mentioned earlier, a slight...

example 2

In Vitro Intracellular siRNA Delivery and Gene Silencing with Different Formulations

[0346]In vitro intracellular siRNA delivery studies were performed in B16F10 cells (FIG. 6). The fluorescence intensity of cells treated with free siRNA was indistinguishable from background fluorescence levels. This indicates that free siRNA inefficiently penetrates the cell membrane due to its highly hydrophilic nucleic acid backbone. The siRNA delivery efficiency of the targeted LPH-NP (PEGylated with ligand) was significantly higher than that of the non-targeted LPH-NP (PEGylated without ligand), and was inhibited by co-incubation with haloperidol, a known ligand for sigma receptor. This indicates that targeted LPH-NP can deliver siRNA to the B16F10 cells through sigma receptor mediated endocytosis, similar to the targeted LPD-NP (Li et al. (2008) J. Control. Rel. 126:77-84). Interestingly, the delivery efficiency of targeted LPH-NP was significantly higher than that of the targeted LPD-NP. The r...

example 3

In Vivo Luciferase Gene Silencing and Associated Immunotoxicity of Different Formulations

[0348]In vivo gene silencing studies were performed in the B16F10 lung metastasis model (FIG. 6). Anti-luciferase siRNA formulated in targeted LPH-NPs silenced 80% of the luciferase activity (FIG. 8A). This effect was similar to that of anti-luciferase siRNA formulated in targeted LPD-NPs (FIG. 8A). The other control treatments, including free siRNA, siRNA in non-targeted LPD-NPs or non-targeted LPH-NPs and control siRNA in targeted LPD-NPs or LPH-NPs, showed no RNAi effect. The data shown in FIGS. 5 and 7 suggest that the enhanced gene silencing activity of the targeted LPH-NP is mainly due to the significantly improved tumor uptake. The ED50 of targeted LPH-NP was 0.075 mg / kg (FIG. 8B), the same as the targeted LPD-NP formulation. The optimal dose for maximal gene silencing (80%) was 0.15 mg / kg, and further increases in dosage did not result in greater activity (FIG. 8B). Both the in vitro and...

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Abstract

The present invention provides compositions comprising delivery systems comprising a lipid vehicle, a bioactive compound, and a polyanionic carrier macromolecule that is not a carrier polynucleotide, wherein the lipid vehicle encapsulates the polynucleotide of interest and the polyanionic carrier macromolecule, and wherein the delivery system is essentially free of carrier polynucleotides. Compositions also include delivery systems comprising a lipid vehicle and a bioactive agent, wherein the lipid vehicle encapsulates the bioactive agent, and wherein the lipid vehicle comprises a covalent bilayer or a core supported bilayer comprising polycationic lipids. Other compositions provided herein comprise a delivery system comprising a polypeptide of interest and a means for delivering the polypeptide into a cell. Also provided herein are methods for making the delivery systems, methods for delivering bioactive compounds, methods for treating a disease or unwanted condition in a subject with the delivery systems, and methods for detecting apoptosis in a cell.

Description

FIELD OF THE INVENTION[0001]The present invention relates to lipid vehicles for the delivery of bioactive compounds into cells.BACKGROUND OF THE INVENTION[0002]The development of new forms of therapeutics which use macromolecules such as proteins or nucleic acids as therapeutic agents has created a need to develop new and effective means of delivering such macromolecules to their appropriate cellular targets. Lipid-comprising vehicles have been developed to aid in the delivery of polynucleotides and other macromolecules. However, many of these vehicles exhibit undesirable pharmacokinetic properties and are associated with toxic side effects due to the stimulation of an inflammatory response when administered in vivo. Considering the great potential of novel macromolecular therapeutics in the treatment of various disorders, the need exists for the development of stable, bioavailable vehicles that are able to effectively deliver these therapeutics with minimal immunogenic effect.BRIEF...

Claims

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Application Information

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IPC IPC(8): A61K9/127C12Q1/02C12N5/071A61K31/713A61K49/00A61P35/00
CPCA61K9/1271A61K9/1272C12N15/88C07C279/10C07C279/20A61K47/48815A61K47/6911A61P35/00A61P35/02A61P43/00
Inventor TSENG, YU-CHENKIM, SANG KYOONHACKETT, MICHAELCHONO, SUMIOHUANG, LEAFLI, SHYH-DAR
Owner THE UNIV OF NORTH CAROLINA AT CHAPEL HILL
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