Abstract
This review critically examines current understanding of the kinetics and biodistribution of antisense oligonucleotides, both at the cellular level and at the level of the intact organism. The pharmacodynamic relationships between biodistribution and the ultimate biological effects of antisense agents are considered. The problems and advantages inherent in the use of delivery systems are discussed in the light of further enhancing in vivo pharmacological actions of oligonucleotides.
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REFERENCES
P. Wittung-Stafshede. Genetic medicine—when will it come to the drugstore. Science 281:657–658 (1998).
A. M. Gewirtz. Developing oligonucleotide therapeutics for human leukemia. Anti-Cancer Drug Design 12:341–358 (1997).
J. C. Reed. Promise and problems of Blc-2 antisense therapy. J. Natl. Cancer Inst. 89:988–990 (1997).
P. T. Ho and D. R. Parkinson. Antisense oligonucleotides as therapeutics for malignant diseases. Semin. Oncol. 24:187–202 (1997).
D. Robertson. Crohn's trial shows the pros of antisense. Nat. Biotechnol. 15:209 (1997).
J. Summerton and D. Weller. Morpholino antisense oligomers: design, preparation, and properties. Antisense Nucleic Acid Drug Devel. 7:187–195 (1997).
M. Matteucci. Structural modifications toward improved antisense oligonucleotides. Drug Discovery and Design 4:1–16 (1996).
K. L. Fearon, B. L. Hirschbein, C. Y. Chiu, M. R. Quijano, and G. Zon. Phosphorothioate oligodeoxynucleotides: large synthesis and analysis, impurity characterization, and the effects of phosphorus stereochemistry. Ciba Found. Symp. 209:19–31 (1997).
J. F. Milligan, M. D. Matteucci, and J. C. Martin. Current concepts in antisense drug design. Med. Chem. 36:1923–1937 (1993).
C. A. Stein and Y.-C. Cheng. Antisense oligonucleotides as therapeutic agents-is the bullet really magical. Science 261:1004–1012 (1993).
S. T. Crooke. Advances in understanding the pharmacological properties of antisense oligonucleotides. Adv. Pharmacol. 40:1–49 (1997).
S. Agrawal and R. P. Iyer. Perspectives in antisense therapeutics. Pharmacol. Ther. 76:151–160 (1997).
S. Akthar and S. Agrawal. In vivo studies with antisense oligonucleotides. Trends Pharmacol. Sci. 18:12–18 (1997).
C. F. Bennett. Antisense oligonucleotides: Is the glass half full or half empty? Biochem. Pharmacol. 55:9–19 (1998).
A. D. Branch. A good antisense molecule is hard to find. Trends in Biological Sci. 23:45–50 (1998).
J. H. Lin and A. Y. Lu. Role of pharmacokinetics and metabolism in drug discovery and development. Pharmacol. Rev. 49:403–449 (1997).
C. A. Stein and A. M. Krieg. Problems in interpretation of data derived from in vitro and in vivo use of antisense oligodeoxynucleotides. Antisense Res. Dev. 4:67–69 (1994).
C. A. Stein. How to design an antisense oligodeoxynucleotide experiment: a consensus approach. Antisense Nucleic Acid Drug Dev. 8:129–132 (1998).
A. D. Branch. Antisense drug discovery: can cell-free screens speed the process? Antisense Nucleic Acid Drug Dev. 8:249–254 (1998).
A. D. Ellington and J. W. Szostak. Selection in vitro of single-stranded DNA molecules that fold into specific lingand-binding structures. Nature 355:850–852 (1992).
T. L. Burgess, E. F. Fisher, S. L. Ross, J. V. Bready, Y. X. Qian, L. A. Bayewitch, A. M. Cohen, C. J. Herrera, S. S. Hu, and T. B. Kramer. The antiproliferative activity of c-myb and c-myc antisense oligonucleotides in smooth muscle cells is caused by a nonantisense mechanism. Proc. Natl. Acad. Sci. USA 92:4051–4055 (1995).
Y. Castier, E. Chemla, J. Nieerat, D. Heudes, M. A. Vasseur, C. Rajnoch, P. Bruneval, A. Carpentier, and J. N. Fabiani. The activity of c-myb antisense oligonucleotide to prevent intimal hyperplasia is nonspecific. J. Cardiovasc. Surg. 39:1–7 (1998).
A. M. Krieg, A. K. Yi, S. Matson, T. J. Waldschmidt, G. A. Bishop, R. Teasdale, G. A. Koretzky, and D. M. Klinman. CpG motifs in bacterial DNA trigger direct B-cell activation. Nature 374:546–549 (1995).
W. M. Galbraith, W. C. Hobson, P. C. Giclas, P. J. Schechter, and S. Agrawal. Complement activation and hemodynamic changes following intravenous administration of phosphorothioate oligonucleotides in the monkey. Antisense Res. Dev. 4:201–206 (1994).
J. L. Vaerman, P. Moureau, F. Deldime, P. Lewalle, C. Lammineur, F. Morschhauser, and P. Martiat. Antisense oligonucleotide deoxyribonucleotides suppress hematologic cell growth through stepwise release of deoxyribonucleotides. Blood 90:331–339 (1997).
S. T. Crooke and C. F. Bennett. Progress in antisense oligonucleotide therapeutics. Ann. Rev. Pharmacol. Toxicol. 36:107–129 (1996).
J. M. Kean, S. A. Kipp, P. S. Miller, M. Kulka, and L. Aurelian. Inhibition of herpes simplex virus replication by antisense oligo-2′-O-methylribonucleoside methylphosphonates. Biochemistry 34:14617–14620 (1995).
H. Sierakowska, M. J. Sambade, S. Agrawal, and R. Kole. Repair of thalassemic human beta-globin mRNA in mammalian cells by antisense oligonucleotides. Proc. Natl. Acad. Sci. USA 93:12840–12844 (1996).
B. F. Baker, S. S. Lot, T. P. Condon, S. Cheng-Flournoy, E. A. Lesnik, H. M. Sasmor, and C. F. Bennett. 2′-O-(2-Methoxy)ethyl-modified anti-intercellular adhesion molecule (ICAM-1) oligonucleotides selectively increase the ICAM-1 mRNA level and inhibit formation of the ICAM-1 translation initiation complex in human umbilical vein endothelial cells. J. Biol. Chem. 272:11994–12000 (1997).
S. Akhtar and R. L. Juliano. Cellular uptake and intracellular fate of antisense oligonucleotides. Trends in Cell Biology 2:139–143 (1992).
G. D. Gray, S. Basu, and E. Wickstrom. Transformed and immortalized cellular uptake of oligodeoxynucleoside phosphorothioates, 3′-alkylamino oligodeoxynucleotides, 2′-O-methyl oligoribonucleotides, oligodeoxynucleoside and methylphosphonates, and peptide nucleic acids. Biochem. Pharmacol. 53:1465–1476 (1997).
Y. Shoji, S. Akhtar, A. Periasamy, B. Herman, and R. L. Juliano. Mechanism of cellular uptake of modified oligodeoxynucleotides containing methylphosphonate linkages. Nucleic Acids Res. 19:5543–5550 (1991).
J. P. Leonetti, N. Mechti, G. Degols, C. Gagnor, and B. LeBleu. Intracellular distribution of microinjected antisense oligonucleotides. Proc. Natl. Acad. Sci. USA 88:2702–2706 (1991).
T. L. Fisher, T. Terhorst, X. Cao, and R. W. Wagner. Intracellular disposition and metabolism of fluorescently-labeled unmodified oligonucleotides microinjected into mammalian cells. Nucleic Acids Res. 21:3857–3865 (1993).
J. A. Hughes, A. V. Avrutska, A. Aronson, and R. L. Juliano. Evaluation of adjuvants that enhance the effectiveness of antisense oligonucleotides. Pharm. Res. 13:404–410 (1996).
P. J. Gonzalez-Cabrera, P. L. Iversen, M. F. Liu, M. A. Scofield, and W. B. Jeffries. Selective inhibition of alpha1B-adrenergic receptor expression and function using a phosphorothioate antisense oligodeoxynucleotide. Mol. Pharmacol. 53:1034–1039 (1998).
R. I. Mahato, Y. Takakura, and M. Hashida. Development of targeted delivery systems for nucleic acid drugs. J. Drug Target 4:337–357 (1997).
C. F. Bennett, M. Y. Chiang, H. Chan, J. E. Shoemaker, and C. K. Mirabelli. Cationic lipids enhance cellular uptake and activity of phosphorothioate antisense oligonucleotides. Mol. Pharmacol. 41:1023–1033 (1992).
M. J. Hope, B. Mui, S. Ansell, and Q. F. Ahkong. Cationic lipids, phosphatidylethanolamine and the intracellular delivery of polymeric, nucleic acid-based drugs. Mol. Membr. Biol. 15:1–14 (1998).
I. Koltover, T. Salditt, J. O. Rädler, and C. R. Safinya. An inverted hexagonal phase of cationic liposome — DNA complexes related to DNA release and delivery. Science 281:78–81 (1998).
O. Zelphati and F. C. Szoka, Jr. Mechanism of oligonucleotide release from cationic liposomes. Proc. Natl. Acad. Sci. USA 93:11493–11498 (1996).
E. G. Marcusson, B. Bhat, M. Manoharan, C. F. Bennett, and N. M. Dean. Phosphorothioate oligodeoxyribonucleotides dissociate from cationic lipids before entering the nucleus. Nucleic Acids Res. 26:2016–2023 (1998).
P. C. Gokhale, V. Soldatenkov, F. H. Wang, A. Rahman, A. Dritschilo, and U. Kasid. Antisense raf oligodeoxyribonucleotide is protected by liposomal encapsulation and inhibits Raf-1 protein expression in vitro and in vivo: implication for gene therapy of radioresistant cancer. Gene Ther. 4:1289–1299 (1997).
O. Meyer, D. Kirpotin, K. Hong, B. Sternberg, J. W. Park, M. C. Woodle, and D. Papahajopoulos. Cationic liposomes coated with polyethylene glycol as carriers for oligonucleotides. J. Biol. Chem. 273:15621–15627 (1998).
J. Zabner, A. J. Fasbender, T. Moninger, K. A. Poellinger, and M. J. Welsh. Cellular and molecular barriers to gene transfer by a cationic lipid. J. Biol. Chem. 270:18997–19007 (1995).
S. Basu and E. Wickstrom. Synthesis and characterization of a peptide nucleic acid conjugated to a D-peptide analog of insulin-like growth factor 1 for increased cellular uptake. Bioconjug. Chem. 8:481–488 (1997).
A. S. Bachmann, A. Surovoy, G. Jung, and K. Moelling. Integrin receptor-targeted transfer peptides for efficient delivery of antisense oligodeoxynucleotides. J. Mol. Med. 76:126–132 (1998).
J.-P. Bongartz, A.-M. Aubertin, P. G. Milhaud, and B. Lebleu. Improved biological activity of antisense oligonucleotides conjugated to a fusogenic peptide. Nucleic Acids Res. 22:4681–4688 (1994).
T. B. Wyman, F. Nicol, O. Zelphati, P. V. Scaria, C. Plank, and J. Szoka, F.C. Design, synthesis, and characterization of a cationic peptide that binds to nucleic acids and permeabilizes bilayers. Biochemistry 36:3008–3017 (1997).
C. Picheon, K. Arar, A. J. Stewart, M. D. Dodon, L. Gazzolo, P. J. Courtoy, R. Mayer, M. Monsigny, and A. C. Roche. Intracellular routing and inhibitory activity of oligonucleopeptides containing a KDEL motif. Mol. Pharmacol. 51:431–438 (1997).
Y.-Z. Lin, S. Y. Yao, R. A. Veach, T. R. Torgerson, and J. Hawiger. Inhibition of nuclear translocation of transcription factor NF-κB by a synthetic peptide containing a cell membrane-permeable motif and nuclear localization sequence. J. Biol. Chem. 270:14255–14258 (1995).
G. Elliott and P. O'Hare. Intercellular trafficking and protein delivery by a herpesvirus structural protein. Cell 88:223–233 (1997).
D. Derossi, A. H. Joliot, G. Chassaing, and A. Prochiantz. The third helix of the Antennapedia homeodomain translocates through biological membranes. J. Biol. Chem. 269:10444–10450 (1994).
J. Haensler and F. C. Szoka, Jr. Polyamidoamine cascade polymers mediate efficient transfection of cells in culture. Bioconjugate Chem. 4:372–379 (1993).
R. DeLong, K. Stephenson, T. Loftus, S. K. Alahari, M. H. Fisher, and R. L. Juliano. Characterization of complexes of oligonucleotides with polyamidoamine starburst dendrimers and effects on intracellular delivery. J. Pharm. Sci. 86:762–764 (1997).
S. K. Alahari, R. K. DeLong, M. Fisher, N. M. Dean, P. Viliet, and R. J. Juliano. Novel chemically modified oligonucleotides provide potent inhibition of P-glycoprotein expression. J. Pharmacol. Exp. Ther. 286:419–428 (1998).
S. K. Alahari, N. M. Dean, M. H. Fisher, R. DeLong, M. Manoharan, K. L. Tivel, and R. L. Juliano. Inhibition of expression of the multi-drug resistance associated P-glycoprotein by phosphorothioate and 5′ cholesterol-phosphorothioate antisense oligonucleotides. Mol. Pharmacol. 50:808–819 (1996).
D. G. Spiller, R. V. Giles, J. Grzybowski, D. M. Tidd, and R. E. Clark. Improving the intracellular delivery and molecular efficacy of antisense oligonucleotides in chronic myeloid leukemia cells: a comparison of streptolysin-O permeabilization, electroporation, and lipophilic conjugation. Blood 91:4738–4746 (1998).
G. Schwab, C. Chavany, I. Duroux, G. Goubin, J. Lebeau, C. Helene, and T. Saison-Behmoaras. Antisense oligonucleotides adsorbed to polyalkylcyanoacrylate nanoparticles specifically inhibit mutated Ha-ras-mediated cell proliferation and tumorigenicity in nude mice. Proc. Natl. Acad. Sci. USA 91:10460–10464 (1994).
H. P. Zobel, J. Kreuter, D. Werner, C. R. Noe, G. Kumel, and A. Zimmer. Cationic polyhexylcyanoacrylate nanoparticles as carriers for antisense oligonucleotides. Antisense Nucleic Acid Drug Dev. 7:483–493 (1997).
E. Fattal, C. Vauthier, I. Aynie, Y. Nakada, G. Lambert, C. Malvy, and P. Couvreur. Biodegradable polyalkylcyanoacrylate nanoparticles for the delivery of oligonucleotides. J. Contr. Rel. 53:137–143 (1998).
R. Kole. Modification of pre-mRNA splicing by antisense oligonucleotides. In Applied Antisense Oligonucleotide Technology, ed. by C. A. Stein and A. M. Krieg, Willey-Liss, Inc., pp. 451–469 (1998).
G. Hartmann, A. Krug, M. Bidlingmaier, U. Hacker, A. Eigler, R. Albrecht, C. J. Strasburger, and S. Endres. Spontaneous and cationic lipid-mediated uptake of antisense oligonucleotides in human monocytes and lymphocytes. J. Pharmacol. Exp. Ther. 285:920–928 (1998).
R. Kronenwett, U. Steidl, M. Kirsch, G. Sczakiel, and R. Haas. Oligodeoxyribonucleotide uptake in primary human hematopoietic cells is enhanced by cationic lipids and depends on the hematopoietic cell subset. Blood 91:852–862 (1998).
N. Dean, R. McKay, L. Miraglia, R. Howard, S. Cooper, J. Giddings, P. Nicklin, L. Meister, R. Ziel, T. Geiger, M. Muller, and D. Fabbro. Inhibition of growth of human tumor cell lines in nude mice by an antisense oligonucleotide inhibitor of protein kinase C-expression. Cancer Res. 56:3499–3507 (1996).
Y. S. Cho-Chung, M. Nesterova, A. Kondrashin, K. Noguchi, R. Srivastava, and S. Pepe. Antisense-protein kinase A: a singlegene based therapeutic approach. Antisense Nucleic Acid Drug Dev. 7:217–223 (1997).
T. Skorski, D. Perrotti, M. Nieborowska-Skorska, S. Grayaznov, and B. Calabretta. Antileukemia effect of c-myc N3′ → P5′ phosphoramidate antisense oligonucleotides in vivo. Proc. Natl. Acad. Sci. USA 94:3966–3971 (1997).
B. Jansen, H. Schlagbauer-Wadl, B. D. Brown, R. N. Bryan, A. van Elsas, M. Muller, K. Wolff, H. G. Eichler, and H. Pehamberger. bcl-2 Antisense therapy chemosensitizes human melanoma in SCID mice. Nat. Med. 4:232–234 (1998).
C. F. Bennett, D. Kornbrust, S. Henry, K. Stecker, R. Howard, S. Cooper, S. Dutson, W. Hall, and H. I. Jacoby. An ICAM-1 antisense oligonucleotide prevents and reverses dextran sulfate sodium-induced colitis in mice. J. Pharmacol. Exp. Ther. 280:988–1000 (1997).
J. W. Nyce and W. J. Metzger. DNA antisense therapy for asthma in an animal model. Nature 385:721–725 (1997).
M. Sugano, N. Makino, S. Sawada, S. Otsuka, M. Watanabe, H. Okamoto, M. Kamada, and A. Mizushima. Effect of antisense oligonucleotides against cholesteryl ester transfer protein on the development of atherosclerosis in cholesterol-fed rabbits. J. Biol. Chem. 273:5033–5036 (1998).
J. Gunn, C. M. Holt, S. E. Francis, L. Shepherd, M. Grohmann, C. M. Newman, D. C. Crossman, and D. C. Cumberland. The effect of oligonucleotides to c-myb on vascular smooth muscle cell proliferation and neointima formation after porcine coronary angioplasty. Circ. Res. 80:520–531 (1997).
N. Galeottia, C. L. Ghelardini, S. Capaccioli, A. Quattrone, and A. Bartolini. An antisense oligonucleotide on the mouse Shaker-like potassium channel Kv1.1 gene prevents antinociception induced by morphine and baclofen. J. Pharmacol. Exp. Ther. 281:941–949 (1997).
N. M. Dean and R. McKay. Inhibition of protein kinase C-alpha expression in mice after systemic administration of phosphorothioate antisense oligodeoxynucleotides. Proc. Natl. Acad. Sci. USA 91:11762–11766 (1994).
M. Nesterova and Y. S. Cho-Chung. A single-injection protein kinase A-directed antisense treatment to inhibit tumour growth. Nature Med. 1:528–533 (1995).
C. Hagios, A. Lochter, and M. J. Bissell. Tissue architecture: the ultimate regulator of epithelial function? Philos. Trans. R. Soc. Lond. B. Biol. Sci. 353:857–870 (1998).
C. D. Roskelley, P. Y. Desprez, and M. J. Bissell. Extracellular matrix-dependent tissue-specific gene expression in mammary epithelial cells requires both physical and biochemical signal transduction. Proc. Natl. Acad. Sci. USA 91:12378–12382 (1994).
B. St. Croix and R. S. Kerbel. Cell adhesion and drug resistance in cancer. Curr. Opin. Oncol. 6:549–556 (1997).
R. B. Diasio and R. Zhang. Pharmacology of therapeutic oligonucleotides. Antisense Nucleic Acid Drug Dev. 7:239–243 (1997).
J. Temsamani, A. Roskey, C. Chaix, and S. Agrawal. In vivo metabolic profile of a phosphorothioate oligodeoxyribonucleotide. Antisense Nucleic Acid Drug Dev. 7:159–165 (1997).
J. M. Glover, J. M. Leeds, T. G. K. Mant, D. Amin, D. L. Kisner, J. E. Zuckerman, R. S. Geary, A. A. Levin, and J. Shanahan, W.R. Phase I safety and pharmacokinetic profile of an intercellular adhesion molecule-1 antisense oligodeoxynucleotide (ISIS 2302). J. Pharmacol. Exp. Ther. 282:1173–1180 (1997).
M. K. Bijsterbosch, M. Manoharan, E. T. Rump, R. L. De Vrueh, R. van Veghel, K. L. Tivel, E. A. Biessen, C. F. Bennett, P. D. Cook, and T. J. vann Berkel. In vivo fate of phosphorothioate antisense oligodeoxynucleotides: predominant uptake by scavenger receptors on endothelial liver cells. Nucleic Acids Res. 25:3290–3296 (1997).
E. A. Biessen, H. Vietsch, J. Kuiper, M. K. Bijsterbosch, and T. J. Berkel. Liver uptake of phosphodiester oligodeoxynucleotides is mediated by scavenger receptors. Mol. Pharmacol. 53:262–269 (1998).
R. K. DeLong, A. Nolting, M. Fisher, Q. Chen, E. Wickstrom, M. Klingshteyn, S. Demirdji, M. Caruthers, and R. L. Juliano. Comparative pharmacokinetics, tissue distribution and tumor accumulation, of phosphorothioate, phosphorodithioate and methylphosphonate deoxyoligonucleotide analogues in nude mice. Antisense Nucleic Acid Drug Dev. 7:71–77 (1997).
S. Agrawal, Z. Jiang, Q. Zhao, D. Shaw, D. Cai, A. Roskay, L. Channavajjala, C. Saxinger, and R. Zhang. Mixed-backbone oligonucleotides as second generation antisense oligonucleotides: in vitro and in vivo studies. Proc. Natl. Acad. Sci. USA 94:2620–2625 (1997).
S. T. Crooke, M. J. Graham, J. E. Zuckerman, D. Brooks, B. S. Conklin, L. L. Cummins, M. J. Greig, C. J. Guinosso, D. Kornbrust, M. Manoharan, H. M. Sasmor, T. Schleich, K. L. Tivel, and R. H. Griffey. Pharmacokinetic properties of several novel oligonucleotide analogs in mice. J. Pharmacol. Exp. Ther. 277:923–937 (1996).
S. Agrawal and R. Zhang. Pharmacokinetics of oligonucleotides. Ciba Found. Symp. 209:60–78 (1997).
A. Nolting, R. K. DeLong, M. H. Fisher, E. Wickstrom, G. M. Pollack, R. L. Juliano, and K. L. Brouwer. Hepatic distribution and clearance of antisense oligonucleotides in the isolated perfused rat liver. Pharm. Res. 14:516–521 (1997).
J. A. Hughes, A. V. Avrutskaya, K. L. Brouwer, E. Wickstrom, and R. L. Juliano. Radiolabeling of methylphosphonate and phosphorothioate oligonucleotides and evaluation of their transport in everted rat jejunum sacs. Pharm. Res. 12:817–824 (1995).
M. J. Graham, S. T. Crooke, D. K. Monteith, S. R. Cooper, K. M. Lemonidis, K. K. Stecker, M. J. Martin, and R. M. Crooke. In vivo distribution and metabolism of a phosphorothioate oligonucleotide within rat liver after intravenous administration. J. Pharmacol. Exp. Ther. 286:447–458 (1998).
M. Butler, K. Stecker, and C. F. Bennett. Cellular distribution of phosphorothioate oligodeoxynucleotides in normal rodent tissues. Lab. Invest. 77:379–388 (1997).
A. Rifai, W. Brysch, K. Fadden, J. Clark, and K. H. Schlingensiepen. Clearance kinetics, biodistribution, and organ saturability of phosphorothioate oligodeoxynucleotides in mice. Am. J. Pathol. 2:717–725 (1996).
B. P. Monia. First-and second-generation antisense inhibitors targeted to human c-raf kinase: in vitro and in vivo studies. Anticancer Drug Des. 12:327–339 (1997).
H. Wu, A. R. MacLoed, W. F. Lima, and S. T. Crooke. Identification and partial purification of human double strand RNase activity. A novel terminating mechanism for oligoribonucleotide antisense drugs. J. Biol. Chem. 273:2532–2542 (1998).
N. Milner, K. U. Mir, and E. M. Southern. Selecting effective antisense reagents on combinatorial oligonucleotide arrays. Nat. Biotechnol. 15:537–541 (1997).
S. P. Ho, Y. Bao, T. Lesher, R. Malhotra, L. Y. Ma, S. J. Fluharty, and R. R. Sakai. Mapping of RNA accessible sites for antisense experiments with oligonucleotide libraries. Nat. Biotechnol. 16:59–63 (1998).
G. Dreyfuss, M. J. Matunis, S. Pinol-Roma, and C. G. Burd. hnRNP proteins and the biogenesis of mRNA. Ann. Rev. Biochem. 62:289–321 (1993).
S. A. McLuckey. Focus on oligonucleotides. J. Am. Soc. Mass Spectrometry 9:659 (1998).
R. H. Griffey, M. J. Greig, H. J. Gaus, K. Liu, D. Montheith, M. Winniman, and L. L. Gummins. Characterization of oligonucleotide metabolism in vivo via liquid chromatography/electrospray tandem mass spectrometry with a quadrupole ion trap mass spectrometer. J. Mass. Spectrom. 32:305–313 (1997).
H. J. Gaus, S. R. Owens, M. Winniman, S. Cooper, and L. L. Cummins. Online HPLC electrospray mass spectrometry of phosphorothioate oligonucleotide metabolites. Anal. Chem. 69:313–319 (1997).
J. A. Phillips, S. J. Craig, D. Bayley, R. A. Christian, R. Geary, and P. L. Nicklin. Pharmacokinetics, metabolism, and elimination of a 20-mer phosphorothioate oligodeoxynucleotide (CGP 69846A) after intravenous and subcutaneous administration. Biochem. Pharmacol. 54:657–668 (1997).
R. W. Ball and L. C. Packman. Matrix-assisted laser desorption ionization time-of-flight mass spectrometry as a rapid quality control method in oligonucleotide synthesis. Anal. Biochem. 246:185–194 (1997).
R. L. Rill, B. R. Locke, Y. Liu, and D. H. Van Einkle. Electrophoresis in lyotropic polymer liquid crystals. Proc. Natl. Acad. Sci. USA 95:1534–1539 (1998).
J. M. Leeds, S. P. Henry, S. Bistner, S. Scherrill, K. Williams, and A. A. Levin. Pharmacokinetics of an antisense oligonucleotide injected intravitreally in monkeys. Drug Metab. Dispos. 26:670–675 (1998).
L. Reyderman and S. Stavchansky. Pharmacokinetics and biodistribution of a nucleotide-based thrombin inhibitor in rats. Pharm. Res. 15:904–910 (1998).
C. Gelfi, M. Perego, S. Morelli, A. Nicolin, and P. G. Righetti. Analysis of antisense oligonucleotides by capillary electrophoresis, gel-slab electrophoresis, and HPLC: a comparison. Antisense Nucleic Acid Drug Dev. 6:47–53 (1996).
S. H. Kang, M. J. Cho, and R. Kole. Upregulation of the luciferase gene expression: a novel asay for intracellular activity of antisense oligonucleotides. Biochemistry 37:6235–6239 (1998).
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Juliano, R.L., Alahari, S., Yoo, H. et al. Antisense Pharmacodynamics: Critical Issues in the Transport and Delivery of Antisense Oligonucleotides. Pharm Res 16, 494–502 (1999). https://doi.org/10.1023/A:1011958726518
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DOI: https://doi.org/10.1023/A:1011958726518