Physicochemical and biological characterisation of an antisense oligonucleotide targeted against the bcl-2 mRNA complexed with cationic-hydrophilic copolymers
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Physicochemical and biological characterisation of an antisense oligonucleotide targeted against the bcl-2 mRNA complexed with cationic-hydrophilic copolymers. / Read, M L; Dash, P R; Clark, A; Howard, K A; Oupicky, D; Toncheva, V; Alpar, H O; Schacht, E H; Ulbrich, K; Seymour, L W.
In: European Journal of Pharmaceutical Science, Vol. 10, No. 3, 05.2000, p. 169-77.Research output: Contribution to journal › Article › peer-review
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TY - JOUR
T1 - Physicochemical and biological characterisation of an antisense oligonucleotide targeted against the bcl-2 mRNA complexed with cationic-hydrophilic copolymers
AU - Read, M L
AU - Dash, P R
AU - Clark, A
AU - Howard, K A
AU - Oupicky, D
AU - Toncheva, V
AU - Alpar, H O
AU - Schacht, E H
AU - Ulbrich, K
AU - Seymour, L W
PY - 2000/5
Y1 - 2000/5
N2 - 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 microg/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.
AB - 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 microg/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.
KW - Animals
KW - Chemistry, Physical
KW - DNA
KW - Electrophoresis, Agar Gel
KW - Female
KW - Intercalating Agents
KW - Methacrylates
KW - Mice
KW - Mice, Inbred BALB C
KW - Oligonucleotides, Antisense
KW - Particle Size
KW - Pharmaceutical Vehicles
KW - Physicochemical Phenomena
KW - Polyethylene Glycols
KW - Polymers
KW - Propidium
KW - Proto-Oncogene Proteins c-bcl-2
KW - RNA, Messenger
KW - Spectrometry, Fluorescence
KW - Surface Properties
KW - Tissue Distribution
M3 - Article
C2 - 10767594
VL - 10
SP - 169
EP - 177
JO - European Journal of Pharmaceutical Science
JF - European Journal of Pharmaceutical Science
SN - 0928-0987
IS - 3
ER -