Prostate-Specific Membrane Antigen Targeted Deep Tumor Penetration of Polymer Nanocarriers

Abstract

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 via specific targeting has the potential to improve imaging contrast and therapeutic efficacy in vivo with increased deep tissue penetration. To address this hypothesis, we designed and synthesized prostate cancer-targeting starPEG nanocarriers (40 kDa, 15 nm), [ 89 Zr]PEG-(DFB) 3 (ACUPA) 1 and [ 89 Zr]PEG-(DFB) 1 (ACUPA) 3 , with one or three prostate-specific membrane antigen (PSMA)-targeting ACUPA ligands. The in vitro PSMA binding affinity and in vivo pharmacokinetics of the targeted nanocarriers were compared with a nontargeted starPEG, [ 89 Zr]PEG-(DFB) 4 , in PSMA+ PC3-Pip and PSMA− PC3-Flu cells, and xenografts. Increasing the number of ACUPA ligands improved the in vitro binding affinity of PEGderived polymers to PC3-Pip cells. While both PSMA-targeted nanocarriers significantly improved tissue penetration in PC3-Pip tumors, the multivalent [ 89 Zr]PEG-(DFB) 1 (ACUPA) 3 showed a remarkably higher PC3-Pip/blood ratio and background clearance. In contrast, the nontargeted [ 89 Zr]PEG-(DFB) 4 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.

PSMA-Targeted Nanotheranostics for Imaging and Radiotherapy of Prostate Cancer

“…Considering the threshold size for renal clearance ( Figure 3 A), Beckford-Vera and colleagues evaluated a series of non-targeted 4-armed starPEG nanocarriers of 40 kDa. The 89 Zr-labelled PET tracer demonstrated EPR-mediated high tumor uptake and retention in HT-29 and MX-1 tumor models [ 58 ], whereas they showed low uptake in PC3-Pip PCa xenograft [ 58 , 69 ]. Notably, various other macromolecules and NPs have shown low EPR-mediated tumor uptake in preclinical human PCa models such as PC3, DU-145, and CWR22rv1 [ 5 , 6 , 7 ].…”

“…Notably, various other macromolecules and NPs have shown low EPR-mediated tumor uptake in preclinical human PCa models such as PC3, DU-145, and CWR22rv1 [ 5 , 6 , 7 ]. Meher et al hypothesized and demonstrated that conjugation of ACUPA ligands to those starPEG nanocarriers can improve tumor uptake of EPR-low PCa models with enhanced tissue penetration and retention [ 69 ]. Three 4-arm StarPEG nanocarriers with or without distinctive numbers of PSMA-targeting ACUPA ligands were designed and synthesized ( Figure 14 A).…”

“…Depending on the tumor phenotype, it may result in low, peripheral accumulation ( Figure 14 C). Unfortunately, most of the PCa xenografts possess less permeable vasculature resulting in EPR-mediated low tumor accumulation, which is inadequate for optimum therapeutic response [ 6 , 7 , 69 ]. As observed by Simanek and co-worker, increasing PSMA-targeting ligands from 4 to 64 copies in a dendrimer-based macromolecular system resulted in similar low non-penetrating accumulation in both PSMA- PC3-Flu and PSMA+ PC3-Pip tumors due to an increase in the dendrimer size from 5 kDa to 76 kDa [ 5 ].…”

“…( C ) Autoradiography images of tumor slices were collected after 216 h post-injection of the 89 Zr-labelled nanocarriers. Reprinted with permission from Ref [ 69 ]. Copyright 2022, American Chemical Society.…”

Glutathione and Esterase Dual-Responsive Smart Nano-drug Delivery System Capable of Breaking the Redox Balance for Enhanced Tumor Therapy

“…Globally, cancer has become the leading cause of death for people under 70, which reduces quality of life and life expectancy. , Chemotherapy is one of three main treatments for cancer that can effectively prolong the overall survival in patients with many types of metastatic cancer and even cure some metastatic cancers . However, most chemotherapy drugs such as docetaxel, paclitaxel, camptothecin, 5-fluorouracil, and cisplatin present shortcomings of poor water solubility, poor selectivity to tumor cells, low accumulation in tumor sites, and a short blood circulation half-life, which cause a series of adverse side effects and failure to achieve the ideal antitumor effect. − In order to overcome the above drawbacks of chemotherapy drugs, a new drug delivery strategy is urgently needed. , In recent years, the rapid development of nanomedicine has provided a novel way for delivering chemotherapy agents. − Since nanoparticles can penetrate into tumor tissue more easily and remain there through an enhanced permeability and retention (EPR) effect, numerous nano-drug delivery systems have been carefully designed for the purpose of delivering chemotherapy agents to the tumor site specifically. − …”