Molecular Imaging of Viable Cancer Cells
Shoogo Ueno in Bioimaging, 2020
In order to expand the range of target cancers, we next focused on cancer-associated carboxypeptidases. Especially, we focused on the glutamate carboxypeptidase activity of prostate-specific membrane antigen (PSMA), which is a type II transmembrane glycoprotein that is overexpressed in prostate cancer.53–55 Based on our finding that aryl glutamate conjugates with an azoformyl linker are recognized by PSMA and have a sufficiently low LUMO energy level to quench the fluorophore through photoinduced electron transfer, we established a new design strategy for activatable fluorescence probes to visualize carboxypeptidase activity, and developed a first-in-class activatable fluorescence probe for detecting the carboxypeptidase activity of PSMA (Figure 2.11).56 We confirmed that the developed probe allowed us to visualize the CP activity of PSMA in living cells and in clinical specimens from prostate cancer patients. This probe is expected to be useful for rapid intraoperative detection and diagnosis of prostate cancer.
Antibody-Based Therapies
David E. Thurston, Ilona Pysz in Chemistry and Pharmacology of Anticancer Drugs, 2021
Variations of this approach (e.g., Gene Directed Enzyme Prodrug Therapy [or GDEPT] and Virus Directed Enzyme Prodrug Therapy [or VDEPT]) were later established in which the activating enzyme is introduced through organ-specific gene therapy or other means rather than through an antibody-enzyme conjugate. GDEPT is one of the most successful prodrug delivery approaches that utilize transgenes to encode enzymes that can convert prodrugs into active therapeutic metabolites. Systems that use viral vectors to deliver the gene are known as VDEPT (i.e., Viral-Directed Enzyme-Produg Therapy). The most well-known carboxypeptidase G2-based ADEPT system that reached clinical trials is described in more detail below.
Selective Drug Delivery Using Targeted Enzymes For Prodrug Activation
Siegfried Matzku, Rolf A. Stahel in Antibodies in Diagnosis and Therapy, 2019
A number of in vivo experiments have been reported using bacterial carboxypeptidase G2 (CPG2) for prodrug activation. ICR12, a mAb that recognizes the HER-2 antigen on some breast carcinomas was covalently linked to CPG2, and tested for in vivo antitumor activity (Eccles et al., 1994). In this case, conjugate cleared very slowly from the blood, requiring a 12-14 day delay before a nitrogen mustard prodrug could be administered. Even after such a delay, the conjugate tumor: blood ratio was only 2:1. Despite this poor localization, a single dose of a glutamic acid mustard prodrug resulted in long term regressions in the animals treated with the anti HER-2-CPG2 conjugate (Figure 3D).
Prostate-specific membrane antigen-directed imaging and radioguided surgery with single-photon emission computed tomography: state of the art and future outlook
Published in Expert Review of Medical Devices, 2022
Luca Filippi, Barbara Palumbo, Viviana Frantellizzi, Susanna Nuvoli, Giuseppe De Vincentis, Angela Spanu, Orazio Schillaci
PSMA is a zinc-containing metal-enzyme transmembrane glycoprotein of type II, that is intensely up-regulated in PC cells with a grade of expression strictly correlated with tumor stage and biological aggressiveness. PSMA’s exact role in prostate normal tissue is still unclear, although it has been hypothesized it might have a trophic function. In past years 111In-capromab pendetide, a monoclonal antibody targeting PSMA, was used for the imaging of PC recurrence and metastases, but it showed limited sensitivity and specificity [32], since this radiocompound recognizes the PSMA-intracytoplasmatic domain that is available only in necrotic or dying tumor cells. Worthy of note, glutamate carboxypeptidase activity is localized in PSMA extracellular domain, thus being exposed to the extracellular space and particularly suitable for theranostic approaches [33].
Prodrugs for targeted cancer therapy
Published in Expert Review of Anticancer Therapy, 2019
Carla Souza, Diogo Silva Pellosi, Antonio Claudio Tedesco
The majority of enzyme ADEPT systems only reach the preclinical stage, and only the carboxypeptidase G2 (CPG2) system has progressed to clinical trial [123]. The ADEPT strategy using CPG2 and a bis-iodo phenol mustard prodrug was evaluated in a phase I study. The system was formed by the conjugation of the antibody-enzyme fusion protein MFECP1 and 4[di(2-iodoethyl)amino]phenyloxy-carbonyl-L-glutaminate as a prodrug (ZD2767P). MFECP1 is a recombinant fusion protein of CPG2, a bacterial enzyme isolated from Pseudomonas sp. that has no known human analog and converts the bis-iodo phenol mustard prodrug into an active drug by the cleavage of the glutamate moiety. But this system showed short half-life with quick elimination and limited normal tissue toxicity [130,131].
Cardiovascular and respiratory safety evaluation of Musca Domestica larvae low molecular weight peptide in beagle dogs
Published in Toxicology Mechanisms and Methods, 2019
Fujiang Chu, Hongyan Ma, Xiaobao Jin
In our previous study, we evaluated the effects of the M. domestica larvae total protein extracts on mice and rats using the acute toxicity test, bone marrow cell micronucleus test, mouse sperm test, and subchronic toxicity test. Results from that study showed that when the oral maximum tolerated dose (MTD) of M. domestica larvae total protein extracts was greater than 33 g/kg body weight of mice and rats, no adverse effect was observed (Li et al. 2010, 2013). In recent studies, the M. domestica larvae LMWP was shown to exhibit more significant biological activity (Ai et al. 2012). And identification of M. domestica larvae LMWP have been carried out which indicated antibacterial and antifungal peptides probably were one of the main components (Fu et al. 2009). In our previous research, the identification test showed that LMWP had four main components (10-30KD, S1, S2, and S3), and there were 5, 7, and 4 peaks in S1, S2, and S3, respectively. And S3-3 was determined as Chain A, carboxypeptidase G2 (data were not shown). Also the antioxidant, anti-inflammatory, and antiatherosclerosis effects of M. domestica larvae LMWP were observed in vivo after oral administration (Pei et al. 2014). However, there was no relevant report on how it works after oral administration. Although there were many reports about M. domestica larvae LMWP activity, the safety evaluation of this peptide has not been sufficiently investigated. Unlike toxicology, safety pharmacology includes a regulatory requirement to predict the risk of rare lethal events (Pugsley et al. 2008). Thus, in this study, cardiovascular and respiratory safety pharmacology was evaluated in conscious telemetered beagle dogs following a single-dose oral administration of M. domestica larvae LMWP. Such evaluation using the telemetry device allowed for collection of ECG, arterial pressure, and respiratory data.
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