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Preferential Binding of Radiolabeled Poly-L-lysines to C6 and U87 MG Glioblastomas Compared with Endothelial Cells in Vitro¹

Departments of Neurology [S. E. K., T. K., H. I. R.], Physiological Chemistry [S. E. K.], Medicine [H. I. R., J. C.], Human Oncology [H. I. R., J. C.], and Radiology [P. T.], University of Wisconsin Medical Center, Madison, Wisconsin

This report describes the preparation of polylysine-diethylene triamine pentaacetic acid (DTPA)-metal ion complexes and of iodinated polylysine derivatives and the preferential binding of these polymers to glioblastomas in culture. Synthetic polylysines (DP88 and DP299) were modified covalently either with the chelator DTPA or with ¹²⁵I-Bolton Hunter reagent. The polylysine (DP88) was modified initially with fluorescein to permit fluorescence cytological studies and quantitative measurements of polylysine concentrations. The polylysines contained an average of one DTPA per 16 lysyl moieties. The polylysine-DTPA derivatives were then modified with a mixture of ¹⁵³Gd and stable Gd. A copolymer (DP120) of lysine and tyrosine (4:1) was modified with ¹²⁵I using chloramine T as catalyst. C6 (rat) and U87 MG (human) glioblastoma cells, in culture, bound six to seven times more polylysine-DTPA-Gd than endothelial cells from either aorta or brain. Each of the tumor cell types bound 10⁸ molecules of the modified polylysine per cell when 2.5 x 10⁵ cells were reacted with 50 µg or greater of the polylysine-DTPA-nuclide complex. The higher molecular weight polylysines delivered more radionuclide to the cells in culture. Although the tumor cells bound more [¹²⁵I]polylysine and [¹²⁵I]poly(lysine HBr,tyrosine) than they bound polylysyl-DTPA-Gd, the endothelial cells and the plastic culture dish also bound more of the iodinated polymers. The stoichiometry of polylysine bound per cell suggests that the sialic acid moieties on the cell surface are the primary binding sites for polylysine derivatives. Fluorescence microscopy studies revealed that the fluorescein polylysine (DP88) and the fluorescein polylysine-DTPA nuclide complex bound the tumor cells primarily at branch points along the neuritic processes, at the edge of the perikaryon and at the terminal regions of the outgrowth processes. The polylysyl-DTPA-Gd can be used, with magnetic resonance imaging, to provide measurable contrast of the margin between C6 glioblastomas and normal brain in vivo in Wistar Furth rats.

¹ Supported by a grant from the American Cancer Society, RD-298 to S. E. K., and by grants from the Graduate School of the University of Wisconsin-Madison, the Departments of Neurology and Radiology, and the Thornton Fund for Neurooncology Research, University of Wisconsin, Madison, Wisconsin.

² To whom requests for reprints should be addressed, at Waisman Center, Room 659, University of Wisconsin, Madison, WI 53706.

³ Supported by NIH Physician Scientist Training Grant T32 CA09614.

Received 2/ 8/89. Revised 5/ 1/89. Revised 8/ 7/89. Accepted 8/18/89.

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