Molecular dendritic transporter nanoparticle vectors provide efficient intracellular delivery of peptides.
We present the synthesis of a modular delivery system that is composed of two main macromolecular building blocks, dendritic molecular transporter molecules and a polymeric scaffold in a size dimension of 5-10 nm. The conjugated dendritic molecular transporter units proved to be critical for the delivery of the polymer nanoparticle into 3T3 cells and illustrates the dendritic molecular transporter promoted intracellular uptake of polymer particles derived from intramolecular chain collapse processes. In a sequence of modification steps, pyridinyldithio linker was introduced to undergo thiol-disulfide exchange reactions with peptide sequences containing cysteine amino acid units to furnish peptide-nanoparticle conjugates with cleavable disulfide linkers. The intracellular uptake of the nanoparticle conjugates and the delivery of the peptidic cargo were studied via dual labeling of the nanoparticle with Alexa Fluor 568 dye and fluorescein (FITC) markers on the peptide in mammalian cell lines such as NIH 3T3 cells via confocal microscopy. In this work, we have demonstrated the assembly of a novel nanoscopic delivery system in which the conjugated dendritic molecular transporter molecules facilitated the rapid cellular uptake of a nanoparticle-peptide conjugate with up to 25 copies of peptidic cargo to establish new venues for the implementation of protein and oligonucleotide drugs.
Hamilton
Sharon K
SK
Department of Chemistry, Vanderbilt Institute of Nanoscale Science and Engineering, Vanderbilt University, 7619 Stevenson Center, Nashville, Tennessee 37235, USA.
Harth
Eva
E
D000818:Animals; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D004220:Disulfides / Q000737:chemistry; D042541:Intracellular Space / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D041681:NIH 3T3 Cells; D053758:Nanoparticles / Q000737:chemistry*; D010455:Peptides / Q000378:metabolism* / Q000627:therapeutic use; D021381:Protein Transport; D034741:RNA, Small Interfering / Q000378:metabolism
D050091:Dendrimers; D004220:Disulfides; D010455:Peptides; D034741:RNA, Small Interfering