The encapsulation of DNA molecules within biomimetic lipid nanocapsules

Vonarbourg, Arnaud; Passirani, Catherine; Désigaux, Léa; Allard, Émilie; Saulnier, Patrick; Lambert, Olivier; Benoit, Jean‐Pierre; Pitard, Bruno

doi:10.1016/j.biomaterials.2009.03.009

Cited by 64 publications

(45 citation statements)

References 24 publications

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“…Inserted into the particle shell, this polymer protects the drug-delivery system against the complement system of the organism to maintain a prolonged circulation time in the body. 37,38 Furthermore, PEG is used for the covalent binding of FITC.…”

Section: Lnc Drug Delivery For Auditory Neuron Protectionmentioning

confidence: 99%

Lipidic nanocapsule drug delivery: neuronal protection for cochlear implant optimization

Meyer

Stöver²,

Fouchet³

et al. 2012

IJN

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Objective: Sensorineural hearing loss leads to the progressive degeneration of spiral ganglion cells (SGC). Next to postoperative fibrous tissue growth, which should be suppressed to assure a close nerve-electrode interaction, the density of healthy SGC is one factor that influences the efficiency of cochlear implants (CI), the choice of treatment for affected patients. Rolipram, a phosphodiesterase-4 inhibitor, has proven neuroprotective and anti-inflammatory effects and might also reduce SGC degeneration and fibrosis, but it has to pass the cellular membrane to be biologically active. Methods: Lipidic nanocapsules (LNC) can be used as biodegradable drug carriers to increase the efficacy of conventional application methods. We examined the biological effects of rolipram and LNC's core encapsulated rolipram on SGC and dendritic cell (DC) tumor necrosis factor-α (TNF-α) production in vitro and on SGC survival in systemically-deafened guinea pigs in vivo. Results: Our results prove that rolipram does not have a beneficial effect on cultured SGC. Incorporation of rolipram in LNC increased the survival of SGC significantly. In the DC study, rolipram significantly inhibited TNF-α in a dose-dependent manner. The rolipram-loaded LNC provided a significant cytokine inhibition as well. In vivo data do not confirm the in vitro results. Conclusion: By transporting rolipram into the SGC cytoplasm, LNC enabled the neuroprotective effect of rolipram in vitro, but not in vivo. This might be due to dilution of test substances by perilymph or an inadequate release of rolipram based on differing in vivo and in vitro conditions. Nevertheless, based on in vitro results, proving a significantly increased neuronal survival when using LNC-rolipram compared to pure rolipram and pure LNC application, we believe that the combination of rolipram and LNC can potentially reduce neuronal degeneration and fibrosis after CI implantation. We conclude that rolipram is a promising drug that can be used in inner ear therapy and that LNC have potential as an inner ear drug-delivery system. Further experiments with modified conditions might reveal in vivo biological effects.

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Section: Lnc Drug Delivery For Auditory Neuron Protectionmentioning

confidence: 99%

Lipidic nanocapsule drug delivery: neuronal protection for cochlear implant optimization

Meyer

Stöver²,

Fouchet³

et al. 2012

IJN

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“…% of Solutol ® (w/w), 9.9 % of Labrafac ® (w/w), 78.9 % of water (w/w) and 1.4 % of NaCl, were mixed together under magnetic stirring. DNA LNCs were synthesized as already described [6]. Fluorescent lipid nanocapsules (DiI or DiD empty LNCs and DiI or DiD DNA LNCs) were obtained by a previouslydescribed method [13].…”

Section: -Dna-loaded Lipid Nanocapsules (Dna Lncs)mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

“…Heurtault et al[4] developed lipid nanocapsules synthesised by a solvent-free method and covered by PEG 660 at high density, leading to really weak complement activation and low macrophage uptake [3,5]. In a previous work, the formulation of these nanocapsules was adapted to obtain DNA nanocapsules (DNA LNCs) [6]. Thanks to the use of oleic Plurol ® instead of Lipoid ® in their formulation, the lipid core allowed the entrapment of plasmid DNA molecules via the formation of lipoplexes (cationic liposomes of DOTAP:DOPE complexed with plasmid DNA).…”

Section: Introductionmentioning

confidence: 99%

“…Thanks to the use of oleic Plurol ® instead of Lipoid ® in their formulation, the lipid core allowed the entrapment of plasmid DNA molecules via the formation of lipoplexes (cationic liposomes of DOTAP:DOPE complexed with plasmid DNA). DNA LNCs were small (117 ± 10nm), suitable for an intravenous injection, but in vivo stability and blood half-life remained low and were ill-adapted to efficient in vivo transfection [6].To allow an extended circulation time, and consequently a higher tumor selectivity by passive accumulation through the EPR (enhanced permeability and retention) effect [7], we chose to modify the surface of our gene delivery systems, by inserting longer PEG chains at the surface of DNA LNCs between the already-existing, dense PEG 660 chains. This was carried out through the use of two kinds of amphiphilic and flexible polymers.…”

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Long-circulating DNA lipid nanocapsules as new vector for passive tumor targeting

Morille

Montier

Legras³

et al. 2010

Biomaterials

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Systemic gene delivery systems are needed for therapeutic application to organs that are inaccessible by percutaneous injection. Currently, the main objective is the development of a stable and non-toxic vector that can encapsulate and deliver foreign genetic material to target cells. To this end, DNA, complexed with cationic lipids i.e DOTAP/DOPE, was encapsulated into lipid nanocapsules (LNCs) leading to the formation of stable nanocarriers (DNA LNCs) with a size inferior to 130nm. Amphiphilic and flexible poly (ethylene glycol) (PEG) polymer coatings [PEG lipid derivative (DSPE-mPEG 2000 ) orF108 poloxamer] at different concentrations were selected to make DNA LNCs stealthy. Some of these coated lipid nanocapsules were able to inhibit complement activation and were not phagocytised in vitro by macrophagic THP-1 cells whereas uncoated DNA LNCs accumulated in the vacuolar compartment of THP-1 cells. These results correlated with a significant increase of in vivo circulation time in mice especially for DSPE-mPEG 2000 10mM and an early half-life time (t 1/2 of distribution) 5-fold greater than for non-coated DNA LNCs (7.1h vs 1.4h). Finally, a tumor accumulation assessed by in vivo fluorescence imaging system was evidenced for these coated LNCs as a passive targeting without causing any hepatic damage. Furthermore, when injected intravenously, colloidal carriers are rapidly cleared by the mononuclear phagocyte system (MPS) mainly represented by Kupffer cells in the liver and spleen macrophages. The recognition of the carriers by macrophages usually occurs through specific recognition by cellular receptors specific for plasma proteins that have been adsorbed at the vector surface. Among them, the C3 protein of the complement system plays a major role in the immune system's recognition of foreign particles [2]. The concept of modifying the surface of vectors has therefore been applied in order to decrease the opsonisation process and the specific or non-specific recognition by MPS and blood components [3]. Heurtault et al.[4] developed lipid nanocapsules synthesised by a solvent-free method and covered by PEG 660 at high density, leading to really weak complement activation and low macrophage uptake [3,5]. In a previous work, the formulation of these nanocapsules was adapted to obtain DNA nanocapsules (DNA LNCs) [6]. Thanks to the use of oleic Plurol ® instead of Lipoid ® in their formulation, the lipid core allowed the entrapment of plasmid DNA molecules via the formation of lipoplexes (cationic liposomes of DOTAP:DOPE complexed with plasmid DNA). DNA LNCs were small (117 ± 10nm), suitable for an intravenous injection, but in vivo stability and blood half-life remained low and were ill-adapted to efficient in vivo transfection [6].To allow an extended circulation time, and consequently a higher tumor selectivity by passive accumulation through the EPR (enhanced permeability and retention) effect [7], we chose to modify the surface of our gene delivery systems, by inserting longer PEG chains at the sur...

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Efficient in vitro gene therapy with PEG siRNA lipid nanocapsules for passive targeting strategy in melanoma

Resnier

LeQuinio

Lautram

et al. 2014

Biotechnology Journal

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Small interfering RNA (siRNA)-mediated gene therapy is a promising strategy to temporarily inhibit the expression of proteins implicated in carcinogenesis or chemotherapy resistance. Although intra-tumoral administration can be envisaged, studies currently focus on formulating nanomedicines for intravenous injection to target tumor sites as well as metastases. The development of synthetic nanoparticles and liposomes has advanced greatly during the last decade. The objective of this work consists in formulating and optimizing the encapsulation of siRNA into lipid nanocapsules (LNCs) for efficient gene therapy to target melanoma cells. SiRNA LNCs were prepared from DOTAP/DOPE lipoplexes, and the siRNA amount and lipid/siRNA charge ratio were assayed to improve the stability and the encapsulation yield. Cryo-TEM imaging of the siRNA lipoplexes and LNC morphology revealed specific organization of the siRNA DOTAP/DOPE lipoplexes as well as specific lipid microstructures that can be eliminated by purification. No cytotoxicity of the siRNA LNCs against the melanoma SK-Mel28 cell line was observed at concentrations of up to 500 ng/mL siRNA. In vitro siRNA transfection experiments, compared to Oligofectamine™, demonstrated interesting targeted gene silencing effects. Finally, complement activation assays confirmed the feasibility of the PEGylation of siRNA LNCs as part of a passive targeting strategy for future in vivo melanoma- and metastasis-targeting experiments.

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The encapsulation of DNA molecules within biomimetic lipid nanocapsules

Cited by 64 publications

References 24 publications

Lipidic nanocapsule drug delivery: neuronal protection for cochlear implant optimization

Lipidic nanocapsule drug delivery: neuronal protection for cochlear implant optimization

Long-circulating DNA lipid nanocapsules as new vector for passive tumor targeting

Efficient in vitro gene therapy with PEG siRNA lipid nanocapsules for passive targeting strategy in melanoma

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