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Self-assembling micelle-like nanoparticles for systemic gene delivery

A nanoparticle and carrier technology, applied in the field of self-assembled micelle-like nanoparticles for gene delivery in vivo, can solve the problems of complex and time-consuming preparation steps, low carrying capacity, long circulation time, etc., and achieve a repeatable preparation method, The effect of high load-carrying capacity

Inactive Publication Date: 2011-02-09
NORTHEASTERN UNIV LIAONING
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, despite being stable in vivo and having a long cycle time to reach the target site, the combined system includes complex and time-consuming preparation steps and has low loading capacity

Method used

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  • Self-assembling micelle-like nanoparticles for systemic gene delivery
  • Self-assembling micelle-like nanoparticles for systemic gene delivery
  • Self-assembling micelle-like nanoparticles for systemic gene delivery

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0078] Preparation of micellar nanoparticles (MNPs)

[0079] Preparation of micelle-like nanoparticles (MNP): Plasmid DNA and PLPEI form a complex, and then wrap the prepared complex with a lipid monolayer containing PEG-phosphatidylcholine conjugate (PEG-PE) ( figure 1 ). For complex formation, since complex formation will prevent DNA migration, retaining it in the wells, the optimal ratio of PLPEI to DNA is determined by the amount of amine required to completely inhibit DNA migration on an agarose gel . A certain amount of plasmid DNA was mixed with PLPEI at different amine / phosphorus ratios (N / P), and detected by agarose gel electrophoresis. The ratio of bound DNA increases with the increase of N / P ratio, and when the N / P ratio is higher than 6, most of the DNA is bound. Comparing the composite situation of PLPEI with that of non-modified PEI, it can be seen that conjugation with lipids does not reduce the ability of PEI to bind DNA ( Figure 2a ). An N / P ratio of 10 ...

Embodiment 2

[0083] Physicochemical characteristics of MNP

[0084] Traditional PEI / DNA complexes tend to aggregate rapidly under high-salt physiological conditions [8]. To demonstrate the stabilizing effect of the lipid outer membrane against salt-induced aggregation, NaCl was added to the complex formulation to a final concentration of 0.15M and the hydrodynamic diameter was monitored. As expected, PEI / DNA complexes rapidly aggregated upon addition of NaCl, with a sustained increase in hydrodynamic diameter up to nearly 20-fold within 24 h. The diameter of the PLPEI / DNA complex intermediate without free lipid and PEG-PE rapidly increased by 2-fold upon the addition of NaCl, and then remained relatively constant within 24 hours. In contrast, MNPs remained stable after the addition of salt, with no apparent aggregation within 24 h ( Figure 3a ).

[0085] Zeta potential measurements revealed that MNPs have a favorable neutral surface charge ( ) of −2.1±0.86 mV (mean±s.e.m., n=5), while ...

Embodiment 3

[0089] In vivo biodistribution and gene expression

[0090] In order to show the prolonged circulation time of MNP in the blood and the resulting higher feasibility of delivering it to target organs such as tumors, mice carrying 111 In-DNA MNP was studied for pharmacokinetics and biodistribution. IV bolus carry 111 After In-DNA MNP, radioactivity in major organs was measured and compared with control PEI / 111 In-DNA for comparison. After 10 minutes, as much as 30% ID / ml of MNP was still in the blood, compared to about 10% ID / ml for PEI / DNA. One hour after injection, about 20% ID / ml of MNP was still in the blood, while only about 5% ID / ml of PEI / DNA could be detected in the circulation (Fig. 5A).

[0091] The slower clearance of MNP-encapsulated DNA relative to PEI / DNA and the resulting prolongation of circulation time were also confirmed by pharmacokinetic parameters. The half-life (t 1 / 2β ), the half-life was found to be approximately 239 minutes, compared to 33 minutes...

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Abstract

Nanoparticles containing nucleic acid and suitable for use as in vivo delivery agents for nucleic acids are provided. The nanoparticles use a covalent conjugate of a polycation such as polyethylenimine and phospholipids. The final DNA- containing nanoparticle has a vesicular structure with a polyplex core surrounded by a mixed lipid / PEG- lipid monolayer envelope and offers simple preparation, high loading capacity, and in vivo stability. The nanoparticles have good in vivo stability and a prolonged blood circulation time and can effectively deliver a gene to a biological target such as a tumor.

Description

[0001] Cross References to Related Applications [0002] This application claims priority to US Provisional Application No. 61 / 002,626, filed November 9, 2007, entitled Gene Delivery Nanoparticles, which is incorporated herein by reference in its entirety. [0003] Statement Regarding Federal Funding for Research or Development [0004] Research on the present invention was performed with US Government support using National Institutes of Health grant No. R01HL55519. Accordingly, the US Government has certain rights in this invention. Background of the invention [0005] In vivo gene therapy relies on the delivery of DNA-based drugs, either in the form of oligonucleotides (antisense oligodeoxynucleotide (ODN) siRNA) or entire genes (plasmid DNA) into cells where they function. Location. With few exceptions where it can be administered locally, widespread clinical application of gene therapy will require the development of non-invasive delivery methods. A non-viral system i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/553C12Q1/68G01N33/551
CPCA61K47/488A61K9/1075A61K9/5146C12N15/88A61K47/48192A61K47/59A61K47/6907A61P35/00A61P43/00
Inventor Y·T·高A·凯勒V·P·托奇林
Owner NORTHEASTERN UNIV LIAONING
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