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Titolo:
Site-specific administration of antisense oligonucleotides using biodegradable polymer microspheres provides sustained delivery and improved subcellular biodistribution in the neostriatum of the rat brain
Autore:
Khan, A; Sommer, W; Fuxe, K; Akhtar, S;
Indirizzi:
Aston Univ, Pharmaceut Sci Res Inst, Birmingham B4 7ET, W Midlands, England Aston Univ Birmingham W Midlands England B4 7ET 7ET, W Midlands, England Karolinska Inst, Dept Neurosci, S-10401 Stockholm, Sweden Karolinska InstStockholm Sweden S-10401 osci, S-10401 Stockholm, Sweden
Titolo Testata:
JOURNAL OF DRUG TARGETING
fascicolo: 5, volume: 8, anno: 2000,
pagine: 319 - 334
SICI:
1061-186X(2000)8:5<319:SAOAOU>2.0.ZU;2-P
Fonte:
ISI
Lingua:
ENG
Soggetto:
DRUG-DELIVERY; IN-VITRO; PHOSPHOROTHIOATE OLIGODEOXYNUCLEOTIDE; LEUPROLIDE ACETATE; RECEPTOR; ACID; ANALOGS; BARRIER; VIVO; MICROCAPSULES;
Keywords:
oligonucleotides; antisense; poly(lactic acid-co-glycolic acid); brain delivery; biodegradable; controlled release; drug delivery;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
44
Recensione:
Indirizzi per estratti:
Indirizzo: Akhtar, S Aston Univ, Pharmaceut Sci Res Inst, Aston Triangle, Birmingham B4 7ET, W Midlands, England Aston Univ Aston Triangle Birmingham W MidlandsEngland B4 7ET d
Citazione:
A. Khan et al., "Site-specific administration of antisense oligonucleotides using biodegradable polymer microspheres provides sustained delivery and improved subcellular biodistribution in the neostriatum of the rat brain", J DRUG TAR, 8(5), 2000, pp. 319-334

Abstract

Antisense oligonucleotides (ODNs) are being increasingly used in the central nervous system as biological tools, as drug-target validation agents andas potential therapeutic agents. Although the local delivery of naked ODNsto the brain can result in the desired biological effects, the duration ofefficacy is relatively short lived due to the combined effects of rapid ODN degradation and elimination half-lives in vivo. In this study, we have examined the use of biodegradable polymer microspheres as a site-specific delivery system for targeting ODNs to the neostriatum of the rat brain. Model phosphorothioate backbone-modified ODNs were entrapped within poly(D,L-lactide-co-glycolide) (PLAGA) microspheres using a double emulsion-deposition method and the formulations characterised in terms of particle size, surfacemorphology, percent encapsulation efficiency, ODN loading and in vitro release profiles. For in vivo evaluation, PLAGA microspheres containing fluorescently-labelled ODNs were stereo-taxically administered to the neostriatumof the rat brain and biodistribution of ODNs monitored after 48 h. Administration of free fluorescently-labelled ODNs to the neostriatum resulted in a punctate cellular distribution of ODNs after 24 h with little or no ODN remaining in the neostriatum after 48 h. In comparison, fluorescently-labelled ODNs delivered using polymer microspheres were intensely visible in cells after 48 h post-administration and the fluorescence appeared to be diffuse covering both cytosolic and nuclear regions. Dual-label immunohistochemical analyses suggested that ODNs were mainly distributed to neuronal cells. These data indicate that site-specific administration of of ODNs using biodegradable polymer micropheres will not only provide sustained delivery of nucleic acids but can also improve the cellular distribution of ODNs to brain cells. Sustained or controlled-release biodegradable polymer formulations, therefore, represent an attractive strategy fur improved local delivery of ODNs to the CNS.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 19/09/20 alle ore 23:32:27