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Brain-Targeting Delivery of Two Peptidylic Inhibitors for Their Combination Therapy in Transgenic Polyglutamine Disease Mice via Intranasal Administration

Authors :
Mengbi Yang
Sum Yi Ma
Kin Ming Kwan
Ho Yin Edwin Chan
Knud J. Jensen
Jacky Chi Ki Ngo
Qianwen Wang
Kasper K. Sørensen
Josephine T. Boesen
Zhong Zuo
Qian Zhang
Source :
Molecular Pharmaceutics. 15:5781-5792
Publication Year :
2018
Publisher :
American Chemical Society (ACS), 2018.

Abstract

Polyglutamine diseases are a set of progressive neurodegenerative disorders caused by misfolding and aggregation of mutant CAG RNA and polyglutamin protein. To date, there is a lack of effective therapeutics that can counteract the polyglutamine neurotoxicity. Two peptidylic inhibitors, QBP1 and P3, targeting the protein and RNA toxicities, respectively, have been previously demonstrated by us with combinational therapeutic effects on the Drosophila polyglutamine disease model. However, their therapeutic efficacy has never been investigated in vivo in mammals. The current study aims to (a) develop a brain-targeting delivery system for both QBP1 and L1P3V8 (a lipidated variant of P3 with improved stability) and (b) evaluate their therapeutic effects on the R6/2 transgenic mouse model of polyglutamine disease. Compared with intravenous administration, intranasal administration of QBP1 significantly increased its brain-to-plasma ratio. In addition, employment of a chitosan-containing in situ gel for the intranasal administration of QBP1 notably improved its brain concentration for up to 10-fold. Further study on intranasal cotreatment with the optimized formulation of QBP1 and L1P3V8 in mice found no interference on the brain uptake of each other. Subsequent efficacy evaluation of 4-week daily QBP1 (16 μmol/kg) and L1P3V8 (6 μmol/kg) intranasal cotreatment in the R6/2 mice demonstrated a significant improvement on the motor coordination and explorative behavior of the disease mice, together with a full suppression on the RNA- and protein-toxicity markers in their brains. In summary, the current study developed an efficient intranasal cotreatment of the two peptidylic inhibitors, QBP1 and L1P3V8, for their brain-targeting, and such a novel therapeutic strategy was found to be effective on a transgenic polyglutamine disease mouse model.

Details

ISSN :
15438392 and 15438384
Volume :
15
Database :
OpenAIRE
Journal :
Molecular Pharmaceutics
Accession number :
edsair.doi.dedup.....8898ca9afe69ee5bff21d0f68bb017ce
Full Text :
https://doi.org/10.1021/acs.molpharmaceut.8b00938