Physicochemical and biological characterisation of an antisense oligonucleotide targeted against the bcl-2 mRNA complexed with cationic-hydrophilic copolymers

Martin L. Read, Philip R. Dash, Anya Clark, Kenneth A. Howard, David Oupicky, Veska Toncheva, H. Oya Alpar, Etienne H. Schacht, Karel Ulbrich, Leonard W. Seymour

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

The aim of this study was to evaluate the use of cationic-hydrophilic copolymers for self-assembly with antisense oligonucleotides targeted to the bcl-2 mRNA in order to improve their biocompatibility and modulation of their pharmacokinetics for greater therapeutic usefulness. Examination of the ability of poly(trimethylammonioethyl methacrylate chloride)-poly[N-(2-hydroxypropyl)methacrylamide] (pHPMA-b-pTMAEM) block copolymers to condense the oligonucleotide by fluorescence and electrophoresis techniques showed that complexes were formed more efficiently than with copolymers containing poly(ethylene glycol) blocks grafted onto the backbone of poly(L-lysine) (pLL-g-pEG). In addition, the copolymer pTMAEM-b-pHPMA produced oligonucleotide complexes with the most favourable physicochemical properties appropriate for in vivo applications. The complexes were small (approximately 36 nm in diameter), with low surface charge as measured by zeta potential, relatively stable to physiological salt conditions and could be formed at a DNA concentration of 500 μg/ml. Complex formation with the copolymer pTMAEM-b-pHPMA or pLL-g-pEG reduced the urinary clearance of the oligonucleotide after intravenous injection into mice. However after 30 min, the oligonucleotide complexes were cleared from the bloodstream. These results indicate that for the systemic delivery of oligonucleotides the polymer-derived complexes are not stable enough for prolonged circulation. Instead, these complexes may be more suitable for localised in vivo applications. Copyright (C) 2000 Elsevier Science B.V.

Original languageEnglish (US)
Pages (from-to)169-177
Number of pages9
JournalEuropean Journal of Pharmaceutical Sciences
Volume10
Issue number3
DOIs
StatePublished - May 1 2000

Fingerprint

Antisense Oligonucleotides
Oligonucleotides
Messenger RNA
Ethylene Glycol
Methacrylates
Intravenous Injections
Lysine
Electrophoresis
Chlorides
Polymers
Pharmacokinetics
Salts
Fluorescence
DNA

Keywords

  • Antisense
  • Cationic polymers
  • Gene therapy
  • Oligonucleotide

ASJC Scopus subject areas

  • Pharmaceutical Science

Cite this

Physicochemical and biological characterisation of an antisense oligonucleotide targeted against the bcl-2 mRNA complexed with cationic-hydrophilic copolymers. / Read, Martin L.; Dash, Philip R.; Clark, Anya; Howard, Kenneth A.; Oupicky, David; Toncheva, Veska; Alpar, H. Oya; Schacht, Etienne H.; Ulbrich, Karel; Seymour, Leonard W.

In: European Journal of Pharmaceutical Sciences, Vol. 10, No. 3, 01.05.2000, p. 169-177.

Research output: Contribution to journalArticle

Read, Martin L. ; Dash, Philip R. ; Clark, Anya ; Howard, Kenneth A. ; Oupicky, David ; Toncheva, Veska ; Alpar, H. Oya ; Schacht, Etienne H. ; Ulbrich, Karel ; Seymour, Leonard W. / Physicochemical and biological characterisation of an antisense oligonucleotide targeted against the bcl-2 mRNA complexed with cationic-hydrophilic copolymers. In: European Journal of Pharmaceutical Sciences. 2000 ; Vol. 10, No. 3. pp. 169-177.
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