Abstract：
BACKGROUND:We report pharmacokinetic (PK) data, evaluation of modifications for increased stability, evaluation for cellular uptake, and mediation of regression of breast cancer for the aptamer OPN-R3. METHODS:The OPN-R3 aptamer was assessed for PK data in vivo with additional comparison of IV and subcutaneous dosing. Five aptamer variants were generated by differential 2'-O-methylation for comparison with parent. OPN-R3-Cy3 was incubated with MDA-MB231 cells and cellular uptake evaluated under confocal microscopy. Mice were treated with OPN-R3, mutant, or saline 3 weeks after inoculation with MDA-MB231 cells and tumor size was evaluated. RESULTS:OPN-R3 PK data were: t(1/2) 7.76 hours, T(max) 3 hours, C(max) 13.2 mmol/L, mean residence time 9 hours, AUC (0-t) 161.9 mmol/hr/L, and K(d) 57.2 nmol/L. The half-life was higher when given intravenously versus subcutaneously (E(1/2) 7.93 vs 0.74 hours). The 2' methylation of all available bases increased unmodified aptamer stability and affinity (t(1/2) 6.2 hours; K(d) 520 nmol/L), but this did not improve on parent aptamer (t(1/2) 7.78 hours, K(d) 18 nmol/L). The aptamer remained extracellular. OPN-R3 caused regression of tumor to levels seen at 1 week after tumor inoculation. CONCLUSION:We show the efficacy of OPN-R3 for reversing growth of breast cancer cells with adequate PK stability for clinical application.
journal_name
Surgeryjournal_title
Surgeryauthors
Talbot LJ,Mi Z,Bhattacharya SD,Kim V,Guo H,Kuo PCdoi
10.1016/j.surg.2011.05.015subject
Has Abstractpub_date
2011-08-01 00:00:00pages
224-30issue
2eissn
0039-6060issn
1532-7361pii
S0039-6060(11)00215-7journal_volume
150pub_type
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