Gold nanorod-assisted theranostic solution for nonvisible residual disease in bladder cancer.

Residual nonvisible bladder cancer after proper treatment caused by technological and therapeutic limitations is responsible for tumor relapse and progression. This study aimed to demonstrate the feasibility of a solution for simultaneous detection and treatment of bladder cancer lesions smaller than one millimeter. The α5β1 integrin was identified as a specific marker in 81% of human high-grade nonmuscle invasive bladder cancers and used as a target for the delivery of targeted gold nanorods (GNRs).

Contrast enhanced photoacoustic detection of fibrillar collagen in the near infrared region-I.

Fibrillar collagen accumulation emerges as a promising biomarker in several diseases, such as desmoplastic tumors and unstable atherosclerotic plaque. Gold nanorods (GNRs) hold great potential as contrast agents in high-resolution, biomedically safe, and non-invasive photoacoustic imaging (PAI). This study presents the design and characterization of a specialized imaging tool which exploits GNR assisted targeted photoacoustic imaging that is tailored for the identification of fibrillar collagen.

A novel aminopeptidase N/CD13 inhibitor selectively targets an endothelial form of CD13 after coupling to proteins.

Aminopeptidase N/CD13, a membrane-bound enzyme upregulated in tumor vasculature and involved in angiogenesis, can be used as a receptor for the targeted delivery of drugs to tumors through ligand-directed targeting approaches. We describe a novel peptide ligand (VGCARRYCS, called "G4") that recognizes CD13 with high affinity and selectivity. Enzymological and computational studies showed that G4 is a competitive inhibitor that binds to the catalytic pocket of CD13 through its N-terminal region.

A simple and robust nanosystem for photoacoustic imaging of bladder cancer based on α5β1-targeted gold nanorods.

Background: Early detection and removal of bladder cancer in patients is crucial to prevent tumor recurrence and progression. Because current imaging techniques may fail to detect small lesions of in situ carcinomas, patients with bladder cancer often relapse after initial diagnosis, thereby requiring frequent follow-up and treatments.

Results: In an attempt to obtain a sensitive and high-resolution imaging modality for bladder cancer, we have developed a photoacoustic imaging approach based on the use of PEGylated gold nanorods (GNRs) as a contrast agent, functionalized with the peptide cyclic [CphgisoDGRG] (Iso4), a selective ligand of α5β1 integrin expressed by bladder cancer cells.

A stapled chromogranin A-derived peptide homes in on tumors that express αvβ6 or αvβ8 integrins.

: The αvβ6- and αvβ8-integrins, two cell-adhesion receptors upregulated in many tumors and involved in the activation of the latency associated peptide (LAP)/TGFβ complex, represent potential targets for tumor imaging and therapy. We investigated the tumor-homing properties of a chromogranin A-derived peptide containing an RGDL motif followed by a chemically stapled alpha-helix (called "), which selectively recognizes the LAP/TGFβ complex-binding site of αvβ6 and αvβ8. Peptide was labeled with IRDye 800CW (a near-infrared fluorescent dye) or with F-NOTA (a label for positron emission tomography (PET)); the integrin-binding properties of free peptide and conjugates were then investigated using purified αvβ6/αvβ8 integrins and various αvβ6/αvβ8 single - or double-positive cancer cells; tumor-homing, biodistribution and imaging properties of the conjugates were investigated in subcutaneous and orthotopic αvβ6-positive carcinomas of the pancreas, and in mice bearing subcutaneous αvβ8-positive prostate tumors.

Neuropilin-1 and Integrins as Receptors for Chromogranin A-Derived Peptides.

Human chromogranin A (CgA), a 439 residue-long member of the "" secretory protein family, is the precursor of several peptides and polypeptides involved in the regulation of the innate immunity, cardiovascular system, metabolism, angiogenesis, tissue repair, and tumor growth. Despite the many biological activities observed in experimental and preclinical models for CgA and its most investigated fragments (vasostatin-I and catestatin), limited information is available on the receptor mechanisms underlying these effects. The interaction of vasostatin-1 with membrane phospholipids and the binding of catestatin to nicotinic and b2-adrenergic receptors have been proposed as important mechanisms for some of their effects on the cardiovascular and sympathoadrenal systems.

Early diagnosis of bladder cancer by photoacoustic imaging of tumor-targeted gold nanorods.

Detection and removal of bladder cancer lesions at an early stage is crucial for preventing tumor relapse and progression. This study aimed to develop a new technological platform for the visualization of small and flat urothelial lesions of high-grade bladder carcinoma in situ (CIS). We found that the integrin α5β1, overexpressed in bladder cancer cell lines, murine orthotopic bladder cancer and human bladder CIS, can be exploited as a receptor for targeted delivery of GNRs functionalized with the cyclic CphgisoDGRG peptide ().

Chromogranin A and Its Fragments in the Critically Ill: An Expanding Domain of Interest for Better Care.

Life-threatening diseases challenge immunity with a release of chromogranins. This report focuses on Chromogranin A (CGA) and some of its derived peptides in critically ill patients, with attention paid to their potential to become biomarkers of severity and actors of defense. First, we studied whether circulating CGA may be a biomarker of outcome in non-selected critically ill patients: CGA concentrations were reliably associated with short-term death, systemic inflammation, and multiple organ failure.

Quantification of Chromogranin A and Its Fragments in Biological Fluids.

Human chromogranin A (CgA), a 439-residue long neurosecretory protein, can serve as a circulating biomarker for a wide range of neuroendocrine tumors. Increased levels of immunoreactive CgA are also present in the blood of patients with cardiovascular, gastrointestinal, or inflammatory diseases with, in certain cases, important diagnostic and prognostic implications. A growing body of evidence suggest that CgA and various CgA-derived fragments have complex roles in the regulation of cardiovascular system, metabolism, innate immunity, angiogenesis, and tissue repair, sometime with opposite biological effects.

Targeting the Blood-Brain Tumor Barrier with Tumor Necrosis Factor-α.

The blood-brain tumor barrier represents a major obstacle for anticancer drug delivery to brain tumors. Thus, novel strategies aimed at targeting and breaching this structure are of great experimental and clinical interest. This review is primarily focused on the development and use of a derivative of tumor necrosis factor-α (TNF) that can target and alter the blood-brain-tumor-barrier.

A Novel RGD-4C-Saporin Conjugate Inhibits Tumor Growth in Mouse Models of Bladder Cancer.

Although toxin may have some advantages compared to chemotherapeutic drugs in cancer therapy, e.g. a potent cytotoxic activity and a reduced risk of resistance, their successful application in the treatments to solid tumors still remains to be fully demonstrated.

Chromogranin A plasma levels predict mortality in COVID-19.

Background: Chromogranin A (CgA) and its fragment vasostatin I (VS-I) are secreted in the blood by endocrine/neuroendocrine cells and regulate stress responses. Their involvement in Coronavirus 2019 disease (COVID-19) has not been investigated.

Methods: CgA and VS-I plasma concentrations were measured at hospital admission from March to May 2020 in 190 patients.

Vasostatin-1 as a potential novel circulating biomarker in patients with chronic systolic heart failure: A pilot study.

Background And Aims: Previous studies have shown that circulating chromogranin A (CgA) increases in patients with chronic systolic heart failure (HF). Aim of the present study is to evaluate the potential role of circulating vasostatin-1 (VS-1), a cardioregulatory fragment of CgA, as prognostic marker in patients with chronic HF.

Materials And Methods: The plasma levels of CgA and VS-1 were determined in 80 patients with chronic systolic HF.

CXCL10 levels at hospital admission predict COVID-19 outcome: hierarchical assessment of 53 putative inflammatory biomarkers in an observational study.

Background: Host inflammation contributes to determine whether SARS-CoV-2 infection causes mild or life-threatening disease. Tools are needed for early risk assessment.

Methods: We studied in 111 COVID-19 patients prospectively followed at a single reference Hospital fifty-three potential biomarkers including alarmins, cytokines, adipocytokines and growth factors, humoral innate immune and neuroendocrine molecules and regulators of iron metabolism.

Nanogold Functionalized With Lipoamide-DGR: A Simple, Robust and Versatile Nanosystem for αvβ3-Integrin Targeting.

Gold nanoparticles functionalized with DGR, a tripeptide motif that recognizes αvβ3 integrin overexpressed in tumor vessels, have been used as nano-vectors for the delivery of cytokines to tumors. Functionalization of nanogold with this peptide has been achieved by coating nanoparticles with a peptide-albumin conjugate consisting of heterogeneous molecules with a variable number of linkers and peptides. To reduce nanodrug heterogeneity we have designed, produced and preclinically evaluated a homogeneous and well-defined reagent for nanogold functionalization, consisting of a head-to-tail cyclized CGDGRG peptide () coupled its thiol group to maleimide-PEG-lipoamide (LPA).

Breaching the Blood-Brain Tumor Barrier for Tumor Therapy.

Tumors affecting the central nervous system (CNS), either primary or secondary, are highly prevalent and represent an unmet medical need. Prognosis of these tumors remains poor, mostly due to the low intrinsic chemo/radio-sensitivity of tumor cells, a meagerly known role of the microenvironment and the poor CNS bioavailability of most used anti-cancer agents. The BBTB is the main obstacle for anticancer drugs to achieve therapeutic concentrations in the tumor tissues.

Enhancement of doxorubicin anti-cancer activity by vascular targeting using IsoDGR/cytokine-coated nanogold.

Background: Gold nanospheres tagged with peptides containing isoDGR (isoAsp-Gly-Arg), an αvβ3 integrin binding motif, represent efficient carriers for delivering pro-inflammatory cytokines to the tumor vasculature. We prepared bi- or trifunctional nanoparticles bearing tumor necrosis factor-α (TNF) and/or interleukin-12 (IL12) plus a peptide containing isoDGR, and we tested their anti-cancer effects, alone or in combination with doxorubicin, in tumor-bearing mice.

Results: In vitro biochemical studies showed that both nanodrugs were monodispersed and functional in terms of binding to TNF and IL12 receptors and to αvβ3.

Circulating Chromogranin A Is Cleaved Into Vasoregulatory Fragments in Patients With Pancreatic Ductal Adenocarcinoma.

Chromogranin A (CgA), a secretory protein released in the blood by the neuroendocrine system, consists of a mixture of full-length molecules and fragments endowed of vasoregulatory activity. The extent and the role of CgA fragmentation were investigated in patients with locally advanced or metastatic pancreatic ductal adenocarcinoma (PDAC, n=172). Multivariate analysis showed that full-length CgA was associated with better progression free and overall survival, whereas CgA C-terminal fragmentation was associated with worse prognosis.

The chromogranin A fragment reveals how a single change in the protein sequence exerts strong cardioregulatory effects by engaging neuropilin-1.

Aim: Chromogranin A (CgA), a 439-residue long protein, is an important cardiovascular regulator and a precursor of various bioactive fragments. Under stressful/pathological conditions, CgA cleavage generates the CgA proangiogenic fragment. The present work investigated the possibility that human CgA influences the mammalian cardiac performance, evaluating the role of its C-terminal sequence.

NGR-TNF Engineering with an N-Terminal Serine Reduces Degradation and Post-Translational Modifications and Improves Its Tumor-Targeting Activity.

The therapeutic index of cytokines in cancer therapy can be increased by targeting strategies based on protein engineering with peptides containing the CNGRC (NGR) motif, a ligand that recognizes CD13-positive tumor vessels. We show here that the targeting domain of recombinant CNGRC-cytokine fusion proteins, such as NGR-TNF (a CNGRC-tumor necrosis factor-α (TNF) conjugate used in clinical studies) and NGR-EMAP-II, undergoes various post-translational modification and degradation reactions that lead to the formation of markedly heterogeneous products. These modifications include N-terminal cysteine acetylation or the formation of various asparagine degradation products, the latter owing to intramolecular interactions of the cysteine α-amino group with asparagine and/or its succinimide derivative.

A stapled chromogranin A-derived peptide is a potent dual ligand for integrins αvβ6 and αvβ8.

Combining 2D STD-NMR, computation, biochemical assays and click-chemistry, we have identified a chromogranin-A derived compound (5) that has high affinity and bi-selectivity for αvβ6 and αvβ8 integrins and is stable in microsomal preparations. 5 is suitable for nanoparticle functionalization and delivery to cancer cells, holding promise for diagnostic and/or therapeutic applications.

Chromogranin A and its fragments in cardiovascular, immunometabolic, and cancer regulation.

Chromogranin A (CgA)-the index member of the chromogranin/secretogranin secretory protein family-is ubiquitously distributed in endocrine, neuroendocrine, and immune cells. Elevated levels of CgA-related polypeptides, consisting of full-length molecules and fragments, are detected in the blood of patients suffering from neuroendocrine tumors, heart failure, renal failure, hypertension, rheumatoid arthritis, and inflammatory bowel disease. Full-length CgA and various CgA-derived peptides, including vasostatin-1, pancreastatin, catestatin, and serpinin, are expressed at different relative levels in normal and pathological conditions and exert diverse, and sometime opposite, biological functions.