Mitochondrial targeting dendrimer allows efficient and safe gene delivery

Wang, Xinyu; Shao, Naimin; Zhang, Qiang; Cheng, Yiyun

doi:10.1039/c3tb21348j

Cited by 62 publications

(60 citation statements)

References 48 publications

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“…TPP is attracted to and tends to cross cellular and mitochondrial membranes to preferentially accumulate in the mitochondria. 1 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 nucleic acids, 23 and photsensitizers 24, 25 towards the mitochondria. These have included TPP conjugated directly to therapeutic of choice 5,17,22 as well as TPP conjugated to a nanocarrier 15, 18-20, 23, 25 for targeted therapeutic delivery.…”

Section: Discussionmentioning

confidence: 99%

Effect of the Conjugation Density of Triphenylphosphonium Cation on the Mitochondrial Targeting of Poly(amidoamine) Dendrimers

et al. 2015

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Many clinically relevant diseases with known poor therapeutic outcomes, including cancer and neurodegenerative disorders, have been directly linked to mitochondrial dysfunction. The ability to efficiently target therapeutics to intracellular organelles such as mitochondria may represent new opportunities for the effective treatment of such ailments. The present study reports the synthesis, cellular uptake, cytotoxicity, and mitochondrial colocalization of conjugates of triphenylphosphonium cation (TPP) to amine-terminated, generation 4, poly(amidoamine) (PAMAM) dendrimer (G4NH2) nanocarriers. The mitochondrial-targeting moiety TPP was either directly conjugated to G4NH2 (G4NH2-TPP) or to the dendrimer through a flexible polyethylene glycol (PEG) linker (G4NH2-PEGTPP). Conjugation was done at various TPP densities to assess their biological activity and potential for mitochondrial-targeted drug delivery. Tests in an in vitro model of the human alveolar carcinoma (A549 cells) showed that even at a low TPP density (∼5 TPP) both the cellular internalization and mitochondrial targeting increase significantly, as determined by fluorescence activated cell sorting (FACS) and confocal microscopy (CM), respectively. At a density of ∼10 TPP per G4NH2, further increase in cellular internalization and mitochondrial targeting was achieved. However, at this higher density, the nanocarriers also showed pronounced cytotoxicity. It was observed that the toxicity of the conjugates is decreased upon the addition of a PEG linker between the dendrimer and TPP (G4NH2-PEGTPP), while the mitochondrial targeting ability of the nanocarriers is not affected as the PEG density increases. The proposed strategies indicate that TPP-conjugated G4NH2 dendrimers represent a potentially viable strategy for the targeting of therapeutic molecules to mitochondria, which may help improve therapeutic outcomes of diseases related to mitochondrial dysfunction.

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Section: Discussionmentioning

confidence: 99%

Effect of the Conjugation Density of Triphenylphosphonium Cation on the Mitochondrial Targeting of Poly(amidoamine) Dendrimers

et al. 2015

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“…[ 9,[37][38][39] Promising polycationic gene vectors should have high gene transfection capability Early View Publication; these are NOT the final page numbers, use DOI for citation !! as well as low cytotoxicity.…”

Section: Cytotoxicity and In Vitro Gene Transfectionmentioning

confidence: 99%

Low Molecular Weight PEI‐Based Vectors via Acid‐Labile Ortho Ester Linkage for Improved Gene Delivery

Zhang

Wang

et al. 2016

Macromolecular Bioscience

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A series of novel pH-sensitive gene delivery vectors (POEI 1, 2, and 3) are synthesized through Michael addition from low molecular weight PEI (LMW PEI) via acid-labile ortho ester linkage with terminal acrylates (OEAc) by various feed molar ratios. The obtained POEI 1 and POEI 2 can efficiently condense plasmid DNA into nanoparticles with size range of 200-300 nm and zeta-potentials of about +15 mV while protecting DNA from enzymatic digestion compared with POEI 3. Significantly, ortho ester groups of POEI main-chains can make an instantaneous degradation-response to acidic endosomal pH (≈5.0), resulting in accelerated disruption of polyplexes and intracellular DNA release. MTT assay reveals that all POEIs exhibit much lower cytotoxicity in different cells than branched PEI (25 KDa). As expected, POEI 1 and POEI 2 perform improved gene transfection in vitro, suggesting that such polycations might be promising gene vectors based on overcoming toxicity-efficiency contradiction.

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“…In vitro expression study Vero cells were seeded at a density of 5x10 4 cells/well, in a 6-well plate in DMEM medium supplemented with 10% FBS and grown at 37 o C in a CO 2 incubator to reach 70-80% confluence prior to transfection. The medium was exchanged with a fresh serum-free medium, and the cells were treated with polyplex for 4 h. The medium was then exchanged with serum-containing DMEM, and the cells were incubated at 37ºC for 24 to 48 h. Finally, expression of the reporter protein, GFP and the transgene AIV H5 was evaluated as follow.…”

Section: Cytotoxic Assay Against Eukaryotic Cellsmentioning

confidence: 99%

“…In addition, they are non-immunogenic and thus are able to prevent DNA degradation (1)(2)(3). Dendrimers are monodisperse three-dimensional and hyperbranched molecules that have received extensive interest as non-viral vectors for gene delivery because they are capable of forming a compact complex with genetic materials and protect them from degradation (4,5). Among the different types of dendrimers, the polyamidoamine (PAMAM) dendrimers have the ability to efficiently transfect DNA into the different types of cell in vitro and the inherent ability to transfect the genes in vivo (6).…”

Section: Introductionmentioning

confidence: 99%

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Development of Tat-Conjugated Dendrimer for Transdermal DNA Vaccine Delivery

et al. 2016

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-PURPOSE:In order to enhance cellular uptake and to facilitate transdermal delivery of DNA vaccine, polyamidoamine (PAMAM) dendrimers conjugated with HIV transactivator of transcription (TAT) was developed. METHODS: First, the plasmid DNA (pIRES-H5/GFP) nanoparticle was formulated using PAMAM dendrimer and TAT peptide and then characterized for surface charge, particle size, DNA encapsulation and protection of the pIRES-H5/GFP DNA plasmid to enzymatic digestion. Subsequently, the potency of the TATconjugated dendrimer for gene delivery was evaluated through in vitro transfection into Vero cells followed by gene expression analysis including western blotting, fluorescent microscopy and PCR. The effect of the TAT peptide on cellular uptake of DNA vaccine was studied by qRT-PCR and flow cytometry. Finally, the ability of TAT-conjugated PAMAM dendrimer for transdermal delivery of the DNA plasmid was assessed through artificial membranes followed by qRT-PCR and flow cytometry. RESULTS: TAT-conjugated PAMAM dendrimer showed the ability to form a compact and nanometre-sized polyplexes with the plasmid DNA, having the size range of 105 to 115 nm and a positive charge of +42 to +45 mV over the N/P ratio of 6:1(+/-). In vitro transfection analysis into Vero cells confirms the high potency of TAT-conjugated PAMAM dendrimer to enhance the cellular uptake of DNA vaccine. The permeability value assay through artificial membranes reveals that TAT-conjugated PAMAM has more capacity for transdermal delivery of the DNA compared to unmodified PAMAM dendrimer (P<0.05). CONCLUSIONS: The findings of this study suggest that TAT-conjugated PAMAM dendrimer is a promising non-viral vector for transdermal use.

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Mitochondrial targeting dendrimer allows efficient and safe gene delivery

Cited by 62 publications

References 48 publications

Effect of the Conjugation Density of Triphenylphosphonium Cation on the Mitochondrial Targeting of Poly(amidoamine) Dendrimers

Effect of the Conjugation Density of Triphenylphosphonium Cation on the Mitochondrial Targeting of Poly(amidoamine) Dendrimers

Low Molecular Weight PEI‐Based Vectors via Acid‐Labile Ortho Ester Linkage for Improved Gene Delivery

Development of Tat-Conjugated Dendrimer for Transdermal DNA Vaccine Delivery

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