Abstract
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Objectives To investigate the effect of co-administration of tumor-penetrating peptide CRGDKGPDC (iRGD) with a high affinity to integrin αvβ3 on tumor uptake of In-111 labeled B3, a murine IgG1k mAb directed against the Ley antigen, in A431 tumor which expresses Ley, but not integrin αvβ3 on the cell surface.
Methods Groups of nude mice (n=4~5 per time point) were inoculated subcutaneously with 3×106 A431 tumor cells in right hind flank. Ten days after inoculation, the mice received i.v. In-111-MX-B3 (3.0 μCi/60 μg in 0.2 ml of PBS containing 1% BSA; radiochemical purity, >98%; immunoreactivity, >70%) with and without iRGD (4μmol/kg). Mice were euthanized at designated time intervals for biodistribution studies.
Results The biodistribution studies of In-111-MX-B3 with and without the iRGD coinjection showed similar distributions of the radiolabel in blood and organs. However, the iRGD coinjection increased the peak tumor uptake value by 29% (20.24±2.49 vs 15.71±1.33 %ID/g for the control; p<0.01) whereas it did not change the peak tumor uptake time (48 h) nor slowed the tumor clearance rate. The iRGD coinjection produced 23, 31, 29, and 23% higher tumor uptake than the control at 3, 24, 48, and 72 h, respectively. However, the tumor uptake with and without iRGD became identical (4.59±1.21 vs 4.53±0.38 %ID/g for the control) at 120 h.
Conclusions These findings suggest that the iRGD coinjection increased the extravasation of the radiolabel into interstitial space of A431 tumor by 29~31% due to binding of iRGD to αvβ3 on neovasculature and subsequent increase of vascular permeability, but did not improve the tumor retention of In-111-MX-B3, perhaps due to lack of αvβ3 and neuropilin-1 expression on A431 cells that are required for increased tumor-tissue penetration. The system may be further improved by using different tumor models, and optimizing the dose and injection schedules