Tat-Conjugated PAMAM Dendrimers as Delivery Agents for Antisense and siRNA Oligonucleotides

Kang, Hong Tae; Delong, Robert K.; Fisher, Michael H.; Juliano, Rudolph L.

doi:10.1007/s11095-005-8330-5

Cited by 192 publications

(152 citation statements)

References 22 publications

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“…Lactoferrin is reported to be weakly cationic (Chasteen and Woodworth, 1990) and target Lf receptors in both the BBB and the neural cells (Huang et al, 2007a;Ji et al, 2006). In addition, PAMAM is cationic itself with primary amino groups on the surface (Kang et al, 2005;Luo et al, 2002;Patil et al, 2008). Thus, the synthesized Lf-modified vectors were also cationic.…”

Section: Discussionmentioning

confidence: 99%

Brain-Targeting Mechanisms of Lactoferrin-Modified DNA-Loaded Nanoparticles

Huang

Han

et al. 2009

J Cereb Blood Flow Metab

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Ligand-mediated brain-targeting drug delivery is one of the focuses at present. Elucidation of exact targeting mechanisms serves to efficiently design these drug delivery systems. In our previous studies, lactoferrin (Lf) was successfully exploited as a brain-targeting ligand to modify cationic dendrimer-based nanoparticles (NPs). The mechanisms of Lf-modified NPs to the brain were systematically investigated in this study for the first time. The uptake of Lf-modified vectors and NPs by brain capillary endothelial cells (BCECs) was related to clathrin-dependent endocytosis, caveolae-mediated endocytosis, and macropinocytosis. The intracellular trafficking results showed that Lf-modified NPs could rapidly enter the acidic endolysosomal compartments within 5 mins and then partly escape within 30 mins. Both Lf-modified vectors and NPs showed higher blood-brain barrier-crossing efficiency than unmodified counterparts. All the results suggest that both receptorand adsorptive-mediated mechanisms contribute to the cellular uptake of Lf-modified vectors and NPs. Enhanced brain-targeting delivery could be achieved through the synergistic effect of the macromolecular polymers and the ligand.

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Section: Discussionmentioning

confidence: 99%

Brain-Targeting Mechanisms of Lactoferrin-Modified DNA-Loaded Nanoparticles

Huang

Han

et al. 2009

J Cereb Blood Flow Metab

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“…These intrinsic characteristics enable dendrimers to have unique properties for various biomedical applications (24)(25)(26). In gene delivery, most studies have used the limited number of commercial dendrimers for further chemical modification (27)(28)(29). However, orthogonal click chemistry has recently made a transformative impact on the synthesis of dendritic materials through protecting group-free methodologies to overcome historical limitations in fidelity and provide a larger toolbox for dendrimer design (30)(31)(32)(33)(34).…”

mentioning

confidence: 99%

Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model

Zhou

Nguyen

Miller

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

137

135

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RNA-based cancer therapies are hindered by the lack of delivery vehicles that avoid cancer-induced organ dysfunction, which exacerbates carrier toxicity. We address this issue by reporting modular degradable dendrimers that achieve the required combination of high potency to tumors and low hepatotoxicity to provide a pronounced survival benefit in an aggressive genetic cancer model. More than 1,500 dendrimers were synthesized using sequential, orthogonal reactions where ester degradability was systematically integrated with chemically diversified cores, peripheries, and generations. A lead dendrimer, 5A2-SC8, provided a broad therapeutic window: identified as potent [EC 50 < 0.02 mg/kg siRNA against FVII (siFVII)] in doseresponse experiments, and well tolerated in separate toxicity studies in chronically ill mice bearing MYC-driven tumors (>75 mg/kg dendrimer repeated dosing). Delivery of let-7g microRNA (miRNA) mimic inhibited tumor growth and dramatically extended survival. Efficacy stemmed from a combination of a small RNA with the dendrimer's own negligible toxicity, therefore illuminating an underappreciated complication in treating cancer with RNA-based drugs.dendrimers | miRNA | cancer

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“…TAT peptide (13.30 µmol) in PBS/50 mM was then added to the intermediate, and the reaction was maintained at a room temperature for 24 h. Finally, the reaction mixture was purified on a G25 column as previously described (16 …”

Section: Methodsmentioning

confidence: 99%

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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Tat-Conjugated PAMAM Dendrimers as Delivery Agents for Antisense and siRNA Oligonucleotides

Abstract: Dendrimer-oligonucleotide complexes were moderately effective for delivery of antisense and only poorly effective for delivery of siRNA. Conjugation of the dendrimer with the Tat cell penetrating peptide failed to further enhance the effectiveness of the dendrimer.

Cited by 192 publications

References 22 publications

Brain-Targeting Mechanisms of Lactoferrin-Modified DNA-Loaded Nanoparticles

Brain-Targeting Mechanisms of Lactoferrin-Modified DNA-Loaded Nanoparticles

Modular degradable dendrimers enable small RNAs to extend survival in an aggressive liver cancer model

Development of Tat-Conjugated Dendrimer for Transdermal DNA Vaccine Delivery

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