TY - JOUR
T1 - Cationic porphyrins
T2 - Novel delivery vehicles for antisense oligodeoxynucleotides
AU - Benimetskaya, Lyuba
AU - Takle, Garry B.
AU - Vilenchik, Maria
AU - Lebedeva, Irina
AU - Miller, Paul
AU - Stein, C. A.
PY - 1998/12/1
Y1 - 1998/12/1
N2 - Cationic porphyrins form stable complexes with oligodeoxynucleotides. To evaluate delivery, we used a 20mer phosphorothioate oligomer (Isis 3521) targeted to the 3'-untranslated region of the PKC-α mRNA, and complexed it with porphyrin. The expression of PKC-α protein and mRNA in T24 bladder carcinoma cells was reduced by ~ 80 ± 10% at a concentration of oligomer of 3 μM, and 9 μM porphyrin. The expression of PKC-β1, -δ and -ε isoforms was unaffected by this treatment, but elimination of PKC-ζ protein and mRNA were observed. However, treatment with the porphyrin complex of Isis 3522, an oligomer which is directed at the 5' coding region of the PKC-α mRNA, was equally effective as Isis 3521 with respect to PKC-α, but did not affect PKC-ζ protein or mRNA levels. Since Isis 3521 has an 11-base region of complementarity with the PKC-ζ mRNA, wheras Isis 3522 has only a 4-base region, the effect of Isis 3521 on PKC-ζ protein and mRNA expression may be due to irrelevant cleavage. Depending upon the desired application, this new strategy may offer several advantages over other methods of antisense oligodeoxynucleotide delivery including efficiency, stability, solubility, relatively low toxicity and serum compatibility. Porphyrins may thus be a potentially useful delivery vehicle for antisense therapeutics and/or target validation.
AB - Cationic porphyrins form stable complexes with oligodeoxynucleotides. To evaluate delivery, we used a 20mer phosphorothioate oligomer (Isis 3521) targeted to the 3'-untranslated region of the PKC-α mRNA, and complexed it with porphyrin. The expression of PKC-α protein and mRNA in T24 bladder carcinoma cells was reduced by ~ 80 ± 10% at a concentration of oligomer of 3 μM, and 9 μM porphyrin. The expression of PKC-β1, -δ and -ε isoforms was unaffected by this treatment, but elimination of PKC-ζ protein and mRNA were observed. However, treatment with the porphyrin complex of Isis 3522, an oligomer which is directed at the 5' coding region of the PKC-α mRNA, was equally effective as Isis 3521 with respect to PKC-α, but did not affect PKC-ζ protein or mRNA levels. Since Isis 3521 has an 11-base region of complementarity with the PKC-ζ mRNA, wheras Isis 3522 has only a 4-base region, the effect of Isis 3521 on PKC-ζ protein and mRNA expression may be due to irrelevant cleavage. Depending upon the desired application, this new strategy may offer several advantages over other methods of antisense oligodeoxynucleotide delivery including efficiency, stability, solubility, relatively low toxicity and serum compatibility. Porphyrins may thus be a potentially useful delivery vehicle for antisense therapeutics and/or target validation.
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U2 - 10.1093/nar/26.23.5310
DO - 10.1093/nar/26.23.5310
M3 - Article
C2 - 9826753
AN - SCOPUS:0032404159
SN - 0305-1048
VL - 26
SP - 5310
EP - 5317
JO - Nucleic acids research
JF - Nucleic acids research
IS - 23
ER -