Scheme 2.

Synthesis of HPMA copolymer-EPI conjugates and dual-radiolabeling strategy. (A) Synthesis of 2nd-generation conjugate 2P-Tyr-EPI(DTPA) by RAFT copolymerization of MA-GFLG-Abu(N₃)-EPI with HPMA and MA-Tyr-NH₂ using a cleavable diarm RAFT agent CTA-GFLG-CTA. Propargylamine was coupled with N₃ group and chelator DTPA was attached for drug labeling with ¹¹¹In. The polymer precursor was consecutively labeled with ¹²⁵I (polymer backbone) and ¹¹¹In (EPI). (B) Synthesis of 2nd-generation conjugate 2P-DTPA-EPI(Tyr) by copolymerization of MA-GFLG-Abu(N₃)-EPI with HPMA and APMA. Tyrosine residue was incorporated via Cu(I) assisted alkyne-azide click reaction. DTPA was attached to polymer backbone via pendent amino group modification with p-SCN-Bn-DTPA. The polymer precursor was then labeled with ¹²⁵I and ¹¹¹In, consecutively.