PSMA-Targeted Theranostic Nanocarrier for Prostate Cancer

Abstract

Herein, we report the use of a theranostic nanocarrier (Folate-HBPE(CT20p)) to deliver a therapeutic peptide to prostate cancer tumors that express PSMA (folate hydrolase 1). The therapeutic peptide (CT20p) targets and inhibits the chaperonin-containing TCP-1 (CCT) protein-folding complex, is selectively cytotoxic to cancer cells, and is non-toxic to normal tissue. With the delivery of CT20p to prostate cancer cells via PSMA, a dual level of cancer specificity is achieved: (1) selective targeting to PSMA-expressing prostate tumors, and (2) specific cytotoxicity to cancer cells with minimal toxicity to normal cells. The PSMA-targeting theranostic nanocarrier can image PSMA-expressing cells and tumors when a near infrared dye is used as cargo. Meanwhile, it can be used to treat PSMA-expressing tumors when a therapeutic, such as the CT20p peptide, is encapsulated within the nanocarrier. Even when these PSMA-targeting nanocarriers are taken up by macrophages, minimal cell death is observed in these cells, in contrast with doxorubicin-based therapeutics that result in significant macrophage death. Incubation of PSMA-expressing prostate cancer cells with the Folate-HBPE(CT20p) nanocarriers induces considerable changes in cell morphology, reduction in the levels of integrin β1, and lower cell adhesion, eventually resulting in cell death. These results are relevant as integrin β1 plays a key role in prostate cancer invasion and metastatic potential. In addition, the use of the developed PSMA-targeting nanocarrier facilitates the selective in vivo delivery of CT20p to PSMA-positive tumor, inducing significant reduction in tumor size.

Investigating Chaperonin-Containing TCP-1 subunit 2 as an essential component of the chaperonin complex for tumorigenesis

“…another class of protein-folding complexes, called chaperonins, gained interest with the recognition that cancer cells highly express these mediators of protein-folding [14][15][16][17][18][19][20][21][22][23] . The cytosolic, eukaryotic chaperonin-containing TCP-1 (CCT) is an emerging player in neoplastic transformation with potential for development as a novel diagnostic marker and therapeutic target.…”

“…Genomic amplification of CCT or upregulation of gene expression suggests that CCT could be a marker for oncogenesis 34 . Previous studies reported that the expression levels of different CCT subunits are upregulated in various cancers, such as CCT8 and CCT3 in hepatocellular carcinoma 18,22 or glioblastoma 35 , and CCT2 in prostate, breast, and lung cancers 14,15,21 . Our lab discovered a CCT inhibitor called CT20p that kills cancer cells in a CCT-dependent manner.…”

Targeting prostate cancer: Prostate‐specific membrane antigen based diagnosis and therapy

“…Subsequent in vivo studies in LNCaP tumor-bearing mice indicated tumor regression of up to 90% with no direct toxicity observed. The most recent inhibitor-toxin conjugate was developed by Flores et al 82 They prepared a HBPE polymer nanoparticle and modified it with folate to target PSMA. To exert a cytotoxic effect on PSMA-positive cancer cells, they encapsulated a peptide called CT20p inside the nanoparticle.…”

PEG‐PLA nanoparticles decorated with small‐molecule PSMA ligand for targeted delivery of galbanic acid and docetaxel to prostate cancer cells

“…It is an attractive molecular marker for the detection and therapeutic target of primary and metastatic PCa (Maresca et al, 2009). In contrast, targeting of this ligand can be considered as an approach to fight against drug resistance in PCa by improving of the tumor localization and uptake (Flores et al, 2017;Ganju et al, 2014;Kroon, Kooijman, Cho, Storm, & van der Pluijm, 2016).…”