Prostate-Specific Membrane Antigen Targeted StarPEG Nanocarrier for Imaging and Therapy of Prostate Cancer.

BACKGROUND:The uptake of large (>10 nm) non-targeted nanocarriers by bulk tumors is thought to be dominated by passive extravasation through porous tumor vessels and limited lymphatic drainage, the enhanced permeability and retention (EPR) effect. Prior studies demonstrated radiolabeled tumor-targeted and non-targeted 4-arm 40 kDa star polyethylene glycol (StarPEG) polymers for cancer imaging. By adding small molecule ligands targeting prostate-specific membrane antigen (PSMA) to the StarPEG polymer, marked increase in tumor uptake, penetration and retention in the tumor core was observed. These prior studies support the application of imaging surrogates for the evaluation of targeted delivery of chemotherapeutic nanomedicines and the potential for therapy using analogous β-emitting radiopharmaceuticals. METHODS:To evaluate the delivery and therapeutic efficacy of PSMA-targeted StarPEG nanocarriers, StarPEG nanodrugs with or without three copies of PSMA-targeting, ACUPA, ligands were designed and synthesized. One copy of the radiometal chelator, DOTA, was conjugated to each nanocarrier for labelling with b-emitting 177Lu, providing non-targeted [177Lu]PEG-(DOTA)1 and PSMA targeting [177Lu]PEG-(DOTA)1(ACUPA)3, for SPECT imaging and therapy. The radiolabeled nanodrugs were evaluated in vitro and in vivo using PSMA+ PC3-Pip and/or PSMA- PC3-Flu cell lines, subcutaneous xenografts and disseminated metastatic models. RESULTS:The nanocarriers PEG-(DOTA)1 and PEG-(DOTA)1(ACUPA)3 were efficiently radiolabeled with 177Lu with molar activities of 10.8-15.8 MBq/nmol. Along with excellent in vitro PSMA binding affinity (kD = 51.7 nM in PC3-Pip cells), the targeted nanocarrier [177Lu]PEG-(DOTA)1(ACUPA)3 demonstrated excellent in vivo single-photon emission computed tomography (SPECT) imaging contrast with 21.3% ID/g uptake in PC3-Pip tumors at 192 h post injection. Single doses of 18.5 MBq [177Lu]PEG-(DOTA)1(ACUPA)3 showed complete resolution of the PC3-Pip xenografts, without any regrowth up to 138 days. CONCLUSIONS AND FUTURE DIRECTIONS:The StarPEG nanocarriers demonstrated high PSMA-targeted delivery of the therapeutic isotope 177Lu with excellent imaging contrast. The targeted nanocarrier eliminated subcutaneous and metastatic PC3-Pip tumors. Overall, these preclinical results demonstrated high treatment efficacy of the PSMA-targeted nanocarrier [177Lu]PEG-(DOTA)1(ACUPA)3 for prostate cancer, with potential for clinical translation. This article is protected by copyright. All rights reserved.