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.

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@article{d565b80c1236421cb6e0e6d3338d3580,
title = "Physicochemical and biological characterisation of an antisense oligonucleotide targeted against the bcl-2 mRNA complexed with cationic-hydrophilic copolymers",
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 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.",
keywords = "Animals, Chemistry, Physical, DNA, Electrophoresis, Agar Gel, Female, Intercalating Agents, Methacrylates, Mice, Mice, Inbred BALB C, Oligonucleotides, Antisense, Particle Size, Pharmaceutical Vehicles, Physicochemical Phenomena, Polyethylene Glycols, Polymers, Propidium, Proto-Oncogene Proteins c-bcl-2, RNA, Messenger, Spectrometry, Fluorescence, Surface Properties, Tissue Distribution",
author = "Read, {M L} and Dash, {P R} and A Clark and Howard, {K A} and D Oupicky and V Toncheva and Alpar, {H O} and Schacht, {E H} and K Ulbrich and Seymour, {L W}",
year = "2000",
month = may,
language = "English",
volume = "10",
pages = "169--77",
journal = "European Journal of Pharmaceutical Science",
issn = "0928-0987",
publisher = "Elsevier",
number = "3",

}

RIS

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 -