177Lu-DOTA-StarPEG-ACUPA3

The tumor uptake of large non‐targeted nanocarriers primarily occurs through passive extravasation, known as the enhanced permeability and retention (EPR) effect. Prior studies demonstrated improved tumor uptake and retention of 4‐arm 40 kDa star polyethylene glycol (StarPEG) polymers for cancer imaging by adding prostate‐specific membrane antigen (PSMA) targeting small molecule ligands. To test PSMA‐targeted delivery and therapeutic efficacy, StarPEG nanodrugs with/without three copies of PSMA‐targeting ligands, ACUPA, are designed and synthesized. For single‐photon emission computed tomography (SPECT) imaging and therapy, each nanocarrier is labeled with 177Lu using DOTA radiometal chelator. The radiolabeled nanodrugs, [177Lu]PEG‐(DOTA)1 and [177Lu]PEG‐(DOTA)1(ACUPA)3, are evaluated in vitro and in vivo using PSMA+ PC3‐Pip and/or PSMA– PC3‐Flu cell lines, subcutaneous xenografts and disseminated metastatic models. The nanocarriers are efficiently radiolabeled with 177Lu with molar activities 10.8–15.8 MBq/nmol. Besides excellent in vitro PSMA binding affinity (kD = 51.7 nM), the targeted nanocarrier, [177Lu]PEG‐(DOTA)1(ACUPA)3, demonstrated excellent in vivo SPECT imaging contrast with 21.3% ID/g PC3‐Pip tumors uptake at 192 h. Single doses of 18.5 MBq [177Lu]PEG‐(DOTA)1(ACUPA)3 showed complete resolution of the PC3‐Pip xenografts observed up to 138 days. Along with PSMA‐targeted excellent imaging contrast, these results demonstrated high treatment efficacy of [177Lu]PEG‐(DOTA)1(ACUPA)3 for prostate cancer, with potential for clinical translation.