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.
OBJECTIVE
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.
Department of Pharmaceutical Sciences, University of Toronto, Toronto, Ontario M5S 3M2, Canada.
Amanda J
AJ
Boyle
Peng
P
Liu
Yijie
Y
Lu
Dirk
D
Weinrich
Deborah A
DA
Scollard
Ghislaine
G
Ngo Njock Mbong
Mitchell A
MA
Winnik
Raymond M
RM
Reilly
D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D001710:Biotin / Q000737:chemistry; D045744:Cell Line, Tumor; D002614:Chelating Agents / Q000737:chemistry*; D005260:Female; D006801:Humans; D018796:Immunoconjugates / Q000737:chemistry / Q000493:pharmacokinetics*; D007140:Immunoglobulin Fab Fragments / Q000737:chemistry; D007205:Indium Radioisotopes / Q000737:chemistry / Q000493:pharmacokinetics*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010051:Ovarian Neoplasms / Q000175:diagnosis / Q000188:drug therapy; D004369:Pentetic Acid / Q000031:analogs & derivatives; D011108:Polymers / Q000737:chemistry*; D019809:Streptavidin / Q000737:chemistry; D000068878:Trastuzumab
D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D002614:Chelating Agents; D018796:Immunoconjugates; D007140:Immunoglobulin Fab Fragments; D007205:Indium Radioisotopes; D011108:Polymers; D001710:Biotin; D004369:Pentetic Acid; D019809:Streptavidin; D000068878:Trastuzumab