Tumoral uptake of large-size nanoparticles is mediated by the enhanced permeability and retention (EPR) effect, with variable accumulation and heterogenous tumor tissue penetration depending on the tumor phenotype. The performance of nanocarriers specific targeting has the potential to improve imaging contrast and therapeutic efficacy with increased deep tissue penetration. To address this hypothesis, we designed and synthesized prostate cancer-targeting starPEG nanocarriers (40 kDa, 15 nm), [Zr]PEG-(DFB)(ACUPA) and [Zr]PEG-(DFB)(ACUPA), with one or three prostate-specific membrane antigen (PSMA)-targeting ACUPA ligands. The PSMA binding affinity and pharmacokinetics of the targeted nanocarriers were compared with a nontargeted starPEG, [Zr]PEG-(DFB), in PSMA+ PC3-Pip and PSMA- PC3-Flu cells, and xenografts. Increasing the number of ACUPA ligands improved the binding affinity of PEG-derived polymers to PC3-Pip cells. While both PSMA-targeted nanocarriers significantly improved tissue penetration in PC3-Pip tumors, the multivalent [Zr]PEG-(DFB)(ACUPA) showed a remarkably higher PC3-Pip/blood ratio and background clearance. In contrast, the nontargeted [Zr]PEG-(DFB) showed low EPR-mediated accumulation with poor tumor tissue penetration. Overall, ACUPA conjugated targeted starPEGs significantly improve tumor retention with deep tumor tissue penetration in low EPR PC3-Pip xenografts. These data suggest that PSMA targeting with multivalent ACUPA ligands may be a generally applicable strategy to increase nanocarrier delivery to prostate cancer. These targeted multivalent nanocarriers with high tumor binding and low healthy tissue retention could be employed in imaging and therapeutic applications.