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• W2313304731 endingPage "3053" @default.
• W2313304731 startingPage "3043" @default.
• W2313304731 abstract "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." @default.
• W2313304731 created "2016-06-24" @default.
• W2313304731 creator A5037127680 @default.
• W2313304731 creator A5051866931 @default.
• W2313304731 creator A5069727172 @default.
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• W2313304731 date "2015-07-21" @default.
• W2313304731 modified "2023-09-24" @default.
• W2313304731 title "Effect of the Conjugation Density of Triphenylphosphonium Cation on the Mitochondrial Targeting of Poly(amidoamine) Dendrimers" @default.
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• W2313304731 doi "https://doi.org/10.1021/acs.molpharmaceut.5b00320" @default.
• W2313304731 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/26158804" @default.
• W2313304731 hasPublicationYear "2015" @default.
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