Antigen targeting and anti-tumor activity of a novel anti-CD146 Pb internalizing alpha-radioimmunoconjugate against malignant peritoneal mesothelioma.

Malignant mesothelioma, a highly aggressive cancer that primarily affects the serosal membranes, has limited therapeutic options, particularly for cavitary tumors, such as peritoneal and pleural malignant mesothelioma. Intracavitary administration of a radioimmunoconjugate to locally target mesothelioma cancer cells has been proposed as a treatment. CD146, upregulated in mesothelioma but not in healthy tissues, is a promising therapeutic target.

Exploring the Impact of mRNA Modifications on Translation Efficiency and Immune Tolerance to Self-Antigens.

Therapeutic modified mRNAs are being developed for a broad range of human diseases. However, the impact of potential miscoding of modified mRNAs on self-tolerance remains unknown. Additionally, more studies are needed to explore the effects of nucleoside alkylation on translation.

Imaging of Pb in mice with a clinical SPECT/CT.

Introduction: Pb is a promising radionuclide for targeted alpha therapy. Here, the feasibility of visualising the tumour uptake and biodistribution of Pb-NG001 in mice with a clinical SPECT/CT scanner was investigated.

Methods: A mouse phantom with Pb was imaged with a clinical- and a preclinical SPECT/CT scanner.

ALPL-1 is a target for chimeric antigen receptor therapy in osteosarcoma.

Osteosarcoma (OS) remains a dismal malignancy in children and young adults, with poor outcome for metastatic and recurrent disease. Immunotherapies in OS are not as promising as in some other cancer types due to intra-tumor heterogeneity and considerable off-target expression of the potentially targetable proteins. Here we show that chimeric antigen receptor (CAR) T cells could successfully target an isoform of alkaline phosphatase, ALPL-1, which is highly and specifically expressed in primary and metastatic OS.

Dual targeting with Ra/Pb-conjugates for targeted alpha therapy of disseminated cancers: A conceptual approach.

Metastases are the primary cause of death among cancer patients and efficacious new treatments are sorely needed. Targeted alpha-emitting radiopharmaceuticals that are highly cytotoxic may fulfill this critical need. The focus of this paper is to describe and explore a novel technology that may improve the therapeutic effect of targeted alpha therapy by combining two radionuclides from the same decay chain in the same solution.

Targeted alpha therapy with the Ra/Pb-TCMC-TP-3 dual alpha solution in a multicellular tumor spheroid model of osteosarcoma.

Osteosarcoma patients with overt metastases at primary diagnosis have a 5-year survival rate of less than 20%. TP-3 is a murine IgG2b monoclonal antibody with high affinity for an epitope residing on the p80 osteosarcoma cell surface membrane antigen. The tumor-associated antigen p80 is overexpressed in osteosarcomas, and has very low normal tissue expression.

Use of antihypertensive drugs and risk of cutaneous melanoma: a nationwide nested case-control study.

Background: Most antihypertensives can induce dermal photosensitivity, which may increase melanoma risk. However, corroborating evidence is limited. We examined the associations between use of antihypertensives and melanoma risk.

Factors Influencing the Therapeutic Efficacy of the PSMA Targeting Radioligand Pb-NG001.

This study aimed to determine the influence of cellular PSMA expression, radioligand binding and internalization, and repeated administrations on the therapeutic effects of the PSMA-targeting radioligand Pb-NG001. Cellular binding and internalization, cytotoxicity, biodistribution, and the therapeutic efficacy of Pb-NG001 were investigated in two human prostate cancer cell lines with different PSMA levels: C4-2 (PSMA+) and PC-3 PIP (PSMA+++). Despite 10-fold higher PSMA expression on PC-3 PIP cells, cytotoxicity and therapeutic efficacy of the radioligand was only 1.

Evaluation of the PSMA-Binding Ligand Pb-NG001 in Multicellular Tumour Spheroid and Mouse Models of Prostate Cancer.

Radioligand therapy targeting the prostate-specific membrane antigen (PSMA) is rapidly evolving as a promising treatment for metastatic castration-resistant prostate cancer. The PSMA-targeting ligand p-SCN-Bn-TCMC-PSMA (NG001) labelled with Pb efficiently targets PSMA-positive cells in vitro and in vivo. The aim of this preclinical study was to evaluate the therapeutic potential of Pb-NG001 in multicellular tumour spheroid and mouse models of prostate cancer.

Improved Formulation of Ra-Labeled Calcium Carbonate Microparticles by Surface Layer Encapsulation and Addition of EDTMP.

Radium-224-labeled CaCO microparticles have been developed to treat peritoneal carcinomatosis. The microparticles function as carriers of Ra, facilitating intraperitoneal retention of the alpha-emitting radionuclide. It was necessary to control the size of microparticles in suspension over time and introduce a sterilization process for the clinical use of the radiopharmaceutical.

Preclinical and Clinical Status of PSMA-Targeted Alpha Therapy for Metastatic Castration-Resistant Prostate Cancer.

Bone, lymph node, and visceral metastases are frequent in castrate-resistant prostate cancer patients. Since such patients have only a few months' survival benefit from standard therapies, there is an urgent need for new personalized therapies. The prostate-specific membrane antigen (PSMA) is overexpressed in prostate cancer and is a molecular target for imaging diagnostics and targeted radionuclide therapy (theragnostics).

Use of Immunomodulating Drugs and Risk of Cutaneous Melanoma: A Nationwide Nested Case-Control Study.

Purpose: Cutaneous melanoma is among the fastest growing malignancies in Norway and ultraviolet radiation (UVR) exposure is the primary environmental risk factor. Immunomodulating drugs can increase skin photosensitivity and suppress immune responses, and by such mechanisms influence melanoma risk. We, therefore, aimed to examine the associations between use of immunomodulating drugs and melanoma risk, at a nationwide population level.

Calcium Carbonate Microparticles as Carriers of Ra: Impact of Specific Activity in Mice with Intraperitoneal Ovarian Cancer.

Background: Patients with advanced-stage ovarian cancer face a poor prognosis because of recurrent peritoneal cavity metastases following surgery and chemotherapy. Alpha-emitters may enable the efficient treatment of such disseminated diseases because of their short range and highly energetic radiation. Radium-224 is a candidate α-emitter due to its convenient 3.

Combinatorial CAR design improves target restriction.

CAR T cells targeting the B lymphocyte antigen CD19 have led to remarkable clinical results in B cell leukemia and lymphoma but eliminate all B lineage cells, leading to increased susceptibility to severe infections. As malignant B cells will express either immunoglobulin (Ig) light chain κ or λ, we designed a second-generation CAR targeting Igκ, IGK CAR. This construct demonstrated high target specificity but displayed reduced efficacy in the presence of serum IgG.

Calibration of sodium iodide detectors and reentrant ionization chambers for Pb activity in different geometries by HPGe activity determined samples.

Lead-212 is a promising radionuclide for cancer therapy, but no primary Pb activity standardization has been published. A need therefore exists for accurate estimation of injected doses of Pb activity in equilibrium with progeny, when it comes to preclinical and clinical trials. In this study, Pb activity was determined using a high purity germanium (HPGe) detector, which allowed the determination of geometry-specific calibration factors for commercially available reentrant ionization chambers (ICs) and sodium iodide (NaI) detectors.

In situ Generated Pb-PSMA Ligand in a Ra-Solution for Dual Targeting of Prostate Cancer Sclerotic Stroma and PSMA-positive Cells.

Background: New treatments combating bone and extraskeletal metastases are needed for patients with metastatic castration-resistant prostate cancer. The majority of metastases overexpress prostate-specific membrane antigen (PSMA), making it an ideal candidate for targeted radionuclide therapy.

Objective: The aim of this study was to test a novel liquid 224Ra/212Pb-generator for the rapid preparation of a dual-alpha targeting solution.

Photodynamic Efficacy of Cercosporin in 3D Tumor Cell Cultures.

In the present work, we study the photodynamic action of cercosporin (cerco), a naturally occurring photosensitizer, on human cancer multicellular spheroids. U87 spheroids exhibit double the uptake of cerco than T47D and T98G spheroids as shown by flow cytometry on the single cell level. Moreover, cerco is efficiently internalized by cells throughout the spheroid as shown by confocal microscopy, for all three cell lines.

Use of Antidepressants and Risk of Cutaneous Melanoma: A Prospective Registry-Based Case-Control Study.

Purpose: Melanoma is the cancer with the most rapidly rising incidence rate in Norway. Although exposure to ultraviolet radiation (UVR) is the major environmental risk factor, other factors may also contribute. Antidepressants have cancer inhibiting and promoting side effects, and their prescription rates have increased in parallel with melanoma incidence.

Preparation of the alpha-emitting prostate-specific membrane antigen targeted radioligand [ Pb]Pb-NG001 for prostate cancer.

Prostate-specific membrane antigen (PSMA) is the most promising target for radioligand therapy of prostate cancer. The aim of this study was to prepare a small molecular ligand p-SCN-Bn-TCMC-PSMA (NG001) and compare it with the commonly used DOTA-based PSMA-617. The PSMA-targeting ability of the Pb-labelled ligands was evaluated using PSMA-positive C4-2 human prostate cancer cells.

Cardiovascular, antidepressant and immunosuppressive drug use in relation to risk of cutaneous melanoma: a protocol for a prospective case-control study.

Introduction: The incidence of cutaneous melanoma (hereafter melanoma) has increased dramatically among fair-skinned populations worldwide. In Norway, melanoma is the most rapidly growing type of cancer, with a 47% increase among women and 57% among men in 2000-2016. Intermittent ultraviolet exposure early in life and phenotypic characteristics like a fair complexion, freckles and nevi are established risk factors, yet the aetiology of melanoma is multifactorial.

Antitumor Activity of Novel Bone-seeking, α-emitting Ra-solution in a Breast Cancer Skeletal Metastases Model.

Background/aim: Bone metastases are associated with increased morbidity and poor prognosis in a variety of cancers. The present study investigated the effects of targeted radionuclide therapy with α-emitting, bone-seeking radium-224 (Ra) on osteolytic bone metastasis of MDA-MB-231(SA)-GFP human breast cancer cells injected intracardially into nude mice.

Materials And Methods: Vehicle, ethylenediamine tetra (methylene phosphonic acid) (EDTMP) and Ra-solution (45, 91 or 179 kBq/kg) with EDTMP were intravenously administered to mice two days after cell injection.

Molecular Mechanisms of UVA-Induced Melanoma.

Cutaneous melanoma is a deadly skin cancer, resulting from malignant transformation of melanocytes. Long-wave ultraviolet radiation (315-400 nm) is able to damage DNA, cause mutations, and induce melanoma. However, the exact mechanisms of UVA-induced cutaneous melanoma remain a matter of debate.

Endosome Targeting meso-Tetraphenylchlorin-Chitosan Nanoconjugates for Photochemical Internalization.

Four amphiphilic covalently linked meso-tetraphenylchlorin-chitosan nanoconjugates were synthesized and evaluated for use in photochemical internalization (PCI) in vitro and in vivo. The synthetic protocol for the preparation of two different hydrophobic chlorin photosensitizers, 5-(4-aminophenyl)-10,15,20-triphenylchlorin and 5-(4-carboxyphenyl)-10,15,20-triphenylchlorin, was optimized. These monofunctional photosensitizers were covalently attached to carrier chitosan via silyl-protected 3,6-di-O-tert-butyldimethylsilyl-chitosan (Di-TBDMS-chitosan) with 0.

The influence of photodynamic therapy with 5-aminolevulinic acid on senescent skin cancer cells.

Background: Senescent cells, which are resistant to apoptosis, accumulate with age and after ultraviolet (UV) radiation, chemotherapy and radiation therapy. Preventing or eliminating senescent cells may be crucial for protection against skin cancer development and improving tumour treatment. The aim of the present study was to investigate the potential of photodynamic therapy (PDT) with 5-aminolevulinic acid (ALA) to induce senescence in skin cancer cells and to eliminate senescent cells induced by chemotherapy (bleomycin) or UVA (315-400nm) exposure.