TY - JOUR
T1 - Synthesis, pharmacokinetics, efficacy, and rat retinal toxicity of a novel mitomycin C-triamcinolone acetonide conjugate
AU - Macky, Tamer A.
AU - Oelkers, Carsten
AU - Rix, Uwe
AU - Heredia, Martin L.
AU - Künzel, Eva
AU - Wimberly, Mark
AU - Rohrer, Baerbel
AU - Crosson, Craig E.
AU - Rohr, Jürgen
PY - 2002/2/28
Y1 - 2002/2/28
N2 - A novel conjugate of mitomycin C (MMC) and triamcinolone acetonide (TA) was synthesized using glutaric acid as a linker molecule. To determine the rate of hydrolysis, the conjugate was dissolved in aqueous solution and the rate of appearance of free MMC and TA was determined by high-performance liquid chromatography analysis. Antiproliferative activity of the MMC-TA conjugate and parent compounds was assessed using an NIH 3T3 fibroblast cell line. Cell growth was quantified using the MTT assay. Kinetic analysis of the hydrolysis rate demonstrated that the conjugate had a half-life of 23.6 h in aqueous solutions. The antiproliferative activities of the MMC-TA conjugate and MMC were both concentration dependent, with similar IC50 values of 2.4 and 1.7 μM, respectively. However, individual responses at concentrations above 3 μM showed that the conjugate was less active than MMC alone. TA alone showed only limited inhibition of cell growth. Studies evaluating intravitreal injection of the conjugate demonstrate that this agent produced no measurable toxicity. Our data provide evidence that the MMC-TA conjugate could be used as a slow-release drug delivery system. This could in turn be used to modulate a posttreatment wound healing process or to treat various proliferative diseases.
AB - A novel conjugate of mitomycin C (MMC) and triamcinolone acetonide (TA) was synthesized using glutaric acid as a linker molecule. To determine the rate of hydrolysis, the conjugate was dissolved in aqueous solution and the rate of appearance of free MMC and TA was determined by high-performance liquid chromatography analysis. Antiproliferative activity of the MMC-TA conjugate and parent compounds was assessed using an NIH 3T3 fibroblast cell line. Cell growth was quantified using the MTT assay. Kinetic analysis of the hydrolysis rate demonstrated that the conjugate had a half-life of 23.6 h in aqueous solutions. The antiproliferative activities of the MMC-TA conjugate and MMC were both concentration dependent, with similar IC50 values of 2.4 and 1.7 μM, respectively. However, individual responses at concentrations above 3 μM showed that the conjugate was less active than MMC alone. TA alone showed only limited inhibition of cell growth. Studies evaluating intravitreal injection of the conjugate demonstrate that this agent produced no measurable toxicity. Our data provide evidence that the MMC-TA conjugate could be used as a slow-release drug delivery system. This could in turn be used to modulate a posttreatment wound healing process or to treat various proliferative diseases.
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U2 - 10.1021/jm010511b
DO - 10.1021/jm010511b
M3 - Article
C2 - 11855992
AN - SCOPUS:0037186483
SN - 0022-2623
VL - 45
SP - 1122
EP - 1127
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 5
ER -