The effect of metal-chelating polymers (MCPs) for 111In complexed via the streptavidin-biotin system to trastuzumab Fab fragments on tumor and normal tissue distribution in mice.

PURPOSE: To study the effects of backbone composition and charge of biotin-functionalized metal-chelating polymers (Bi-MCPs) for (111)In complexed to streptavidin (SAv)-trastuzumab Fab fragments on tumor and normal tissue localization.

METHODS

Bi-MCPs were synthesized with a polyacrylamide [Bi-PAm(DTPA)(40)], polyaspartamide [Bi-PAsp(DTPA)(33)] or polyglutamide [Bi-PGlu(DTPA)(28)] backbone and harboured diethylenetriaminepentaacetic acid (DTPA) chelators for (111)In. Bi-PAm(DTPA)(40) had a net negative charge; Bi-PAsp(DTPA)(33) and Bi-PGlu(DTPA)(28) were zwitterionic with a net neutral charge. Binding to HER2+ SKOV-3 human ovarian carcinoma cells was determined. Tissue uptake was studied in Balb/c mice by MicroSPECT/CT imaging and biodistribution studies. Tumor and normal tissue uptake of (111)In-labeled Bi-PAsp(DTPA)(33) or Bi-PGlu(DTPA)(28) complexed to SAv-Fab was evaluated 48 h post-injection in athymic mice with subcutaneous SKOV-3 xenografts.

RESULTS

SAv-Fab complexed to MCPs bound specifically to SKOV-3 cells; but specific binding was decreased 2-fold. Liver uptake was 5-13 fold higher for Bi-PAm(DTPA)(40) than Bi-PAsp(DTPA)(33) and Bi-PGlu(DTPA)(28) but was reduced by decreasing negative charges by saturation with indium. (111)In-Bi-PAsp(DTPA)(33) complexed to SAv-Fab accumulated in SKOV-3 tumors; low tumor uptake was found for (111)In-Bi-PGlu(DTPA)(28)-SAv-Fab.

CONCLUSIONS

Zwitterionic MCPs composed of polyaspartamide with a net neutral charge are most desirable for constructing radioimmunoconjugates.