title: Dendrimer Conjugates for Light-activated Delivery of Antisense Oligonucleotides.
abstract: Therapeutic oligonucleotides, such as splice switching ONs (SSOs), provide opportunities for treating serious, life-threatening diseases. However, the development of ONs as therapeutic agents has progressed slowly, because difficult cytosolic delivery of SSOs into the cytosol and nucleus remains a major barrier. Photochemical internalization (PCI), a promising strategy for endosomal escape, was introduced to disrupt the endosomal membrane using light and a photosensitizer. Here we constructed Poly(amido amine) (PAMAM) dendrimer conjugates to simultaneously deliver SSOs and photosensitizers into endo/lysosomal compartments. After photo-irradiation, considerable ONs were observed to diffuse into the cytosol and accumulate in the nucleus. Furthermore, the PCI mediated cytosolic delivery of SSOs effectively enhanced their nuclear splice switching activity.
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA ; State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China.
authors.forename: Ahu
authors.initials: A
authors.lastname: Yuan
authors.affiliation: State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China.
authors.forename: Yiqiao
authors.initials: Y
authors.lastname: Hu
authors.affiliation: Division of Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC 27599, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Ming
keywords: Splice switching oligonucleotides; cytosolic delivery; dendrimers; photochemical internalization; photosensitizer