Reference - Detail
| RRC ID | 58086 |
|---|---|
| Author | Hayashi Y, Higashi T, Motoyama K, Jono H, Ando Y, Onodera R, Arima H. |
| Title | Hepatocyte-Targeted Delivery of siRNA Polyplex with PEG-Modified Lactosylated Dendrimer/Cyclodextrin Conjugates for Transthyretin-Related Amyloidosis Therapy. |
| Journal | Biol Pharm Bull |
| Abstract |
Targeted drug delivery system (DDS) is required for RNA interference (RNAi) therapy to increase the therapeutic effect and to reduce the adverse effect. Especially in transthyretin (TTR)-related amyloidosis, hepatocyte specific delivery is desired because TTR mainly expresses in hepatocyte. Herein, we report on a hepatocyte-specific small interfering RNA (siRNA) delivery system using polyethylene glycol (PEG)-modified lactosylated dendrimer (generation 3; G3) conjugates with α-cyclodextrin (PEG-LαCs (G3)) for TTR-related amyloidosis therapy, and investigated the in vitro and in vivo gene silencing effect of PEG-LαCs (G3)/siRNA polyplexes. PEG-LαC (G3, average degree of substitution of PEG (DSP) 2)/TTR siRNA (siTTR) polyplex exhibited the asialoglycoprotein receptor (ASGPR)-mediated cellular uptake, high endosomal escaping ability and localization of the siRNA in cytoplasm, resulting in significant TTR silencing in HepG2 cells. In vivo studies showed that PEG-LαC (G3, DSP2)/siTTR polyplex led to a significant TTR silencing effect in liver after systemic administration to mice. Furthermore, safety evaluation revealed that PEG-LαC (G3, DSP2)/siTTR polyplex had no significant toxicity both in vitro and in vivo. These findings suggest the utility of PEG-LαC (G3, DSP2) as a promising hepatocyte-specific siRNA delivery system both in vitro and in vivo, and as a therapeutic approach for TTR-related amyloidosis. |
| Volume | 42(10) |
| Pages | 1679-1688 |
| Published | 2019-1-1 |
| DOI | 10.1248/bpb.b19-00278 |
| PMID | 31582656 |
| MeSH | Amyloid Neuropathies, Familial / drug therapy* Amyloid Neuropathies, Familial / genetics Amyloid Neuropathies, Familial / metabolism Animals Cyclodextrins / administration & dosage* Dendrimers / administration & dosage* Dendrimers / pharmacokinetics Hep G2 Cells Hepatocytes / metabolism* Humans Male Mice, Inbred BALB C Polyethylene Glycols / administration & dosage* Polyethylene Glycols / pharmacokinetics Prealbumin / genetics* Prealbumin / metabolism RNA, Small Interfering / administration & dosage* RNA, Small Interfering / pharmacokinetics |
| IF | 1.863 |
| Times Cited | 0 |
| Altmetric score |
オルトメトリクス指標項目
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| The most frequently cited source | X(Twitter) |
| Total number of mentions | 2 |
| Altmetric score changes over past 6months | 0.0 |
| Resource | |
| Human and Animal Cells | Hep G2 |