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Theranostics 2022Small Ac-labeled prostate-specific membrane antigen (PSMA)-targeted radioconjugates have been described for targeted alpha therapy of metastatic castration-resistant...
Small Ac-labeled prostate-specific membrane antigen (PSMA)-targeted radioconjugates have been described for targeted alpha therapy of metastatic castration-resistant prostate cancer. Transient binding to serum albumin as a highly abundant, inherent transport protein represents a commonly applied strategy to modulate the tissue distribution profile of such low-molecular-weight radiotherapeutics and to enhance radioactivity uptake into tumor lesions with the ultimate objective of improved therapeutic outcome. Two ligands and were synthesized by combining a macropa-derived chelator with either one or two lysine-ureido-glutamate-based PSMA- and 4-(-iodophenyl)butyrate albumin-binding entities using multistep peptide-coupling chemistry. Both compounds were labeled with [Ac]Ac under mild conditions and their reversible binding to serum albumin was analyzed by an ultrafiltration assay as well as microscale thermophoresis measurements. Saturation binding studies and clonogenic survival assays using PSMA-expressing LNCaP cells were performed to evaluate PSMA-mediated cell binding and to assess the cytotoxic potency of the novel radioconjugates and , respectively. Biodistributions of both Ac-radioconjugates were investigated using LNCaP tumor-bearing SCID mice. Histological examinations of selected organs were performed to analyze the occurrence of necrosis using H&E staining, DNA damage via γH2AX staining and proliferation via Ki67 expression in the tissue samples. Enhanced binding to serum components in general and to human serum albumin in particular was revealed for and , respectively. Moreover, the novel derivatives are highly potent PSMA ligands as their K values in the nanomolar range (23.38 and 11.56 nM) are comparable to the reference radioconjugates (30.83 nM) and (10.20 nM) without albumin binders. The clonogenic activity of LNCaP cells after treatment with the Ac-labeled ligands was affected in a dose- and time-dependent manner, whereas the bivalent radioconjugate has a stronger impact on the clonogenic cell survival than its monovalent counterpart . Biodistribution studies performed in LNCaP tumor xenografts showed prolonged blood circulation times for both albumin-binding radioconjugates and a substantially increased tumor uptake (46.04 ± 7.77 %ID/g for at 128 h p.i. and 153.48 ± 37.76 %ID/g at 168 h p.i. for ) with favorable tumor-to-background ratios. Consequently, a clear histological indication of DNA damage was discovered in the tumor tissues, whereas DNA double-strand break formation in kidney and liver sections was less pronounced. The modification of the PSMA-based Ac-radioconjugates with one or two albumin-binding entities resulted in an improved radiopharmacological behavior including a greatly enhanced tumor accumulation combined with a rather low uptake in most non-targeted organs combined with a high excretion via the kidneys.
Topics: Animals; Male; Mice; Humans; Tissue Distribution; Cell Line, Tumor; Mice, SCID; Radiopharmaceuticals; Ligands; Serum Albumin
PubMed: 36438496
DOI: 10.7150/thno.78043 -
Molecules (Basel, Switzerland) Sep 2020Identified in 1973, somatostatin (SST) is a cyclic hormone peptide with a short biological half-life. Somatostatin receptors (SSTRs) are widely expressed in the whole... (Review)
Review
Identified in 1973, somatostatin (SST) is a cyclic hormone peptide with a short biological half-life. Somatostatin receptors (SSTRs) are widely expressed in the whole body, with five subtypes described. The interaction between SST and its receptors leads to the internalization of the ligand-receptor complex and triggers different cellular signaling pathways. Interestingly, the expression of SSTRs is significantly enhanced in many solid tumors, especially gastro-entero-pancreatic neuroendocrine tumors (GEP-NET). Thus, somatostatin analogs (SSAs) have been developed to improve the stability of the endogenous ligand and so extend its half-life. Radiolabeled analogs have been developed with several radioelements such as indium-111, technetium-99 m, and recently gallium-68, fluorine-18, and copper-64, to visualize the distribution of receptor overexpression in tumors. Internal metabolic radiotherapy is also used as a therapeutic strategy (e.g., using yttrium-90, lutetium-177, and actinium-225). With some radiopharmaceuticals now used in clinical practice, somatostatin analogs developed for imaging and therapy are an example of the concept of personalized medicine with a theranostic approach. Here, we review the development of these analogs, from the well-established and authorized ones to the most recently developed radiotracers, which have better pharmacokinetic properties and demonstrate increased efficacy and safety, as well as the search for new clinical indications.
Topics: Amino Acid Sequence; Animals; Humans; Neoplasms; Peptides; Radiopharmaceuticals; Receptors, Somatostatin; Somatostatin; Tissue Distribution
PubMed: 32887456
DOI: 10.3390/molecules25174012 -
Oncoimmunology 2021Multiple myeloma (MM) is a hematological malignancy characterized by the presence of clonal plasma cells in the bone marrow niche. Despite significant therapeutic...
Multiple myeloma (MM) is a hematological malignancy characterized by the presence of clonal plasma cells in the bone marrow niche. Despite significant therapeutic advances, MM remains incurable for the majority of patients. Targeted radionuclide therapy (TRNT) has emerged as a promising treatment option to eradicate residual cancer cells. In this study, we developed and characterized single-domain antibodies (sdAbs) against the MM-antigen CS1 and evaluated its therapeutic potential in MM using TRNT. We first validated CS1 as potential target for TRNT. CS1 is expressed in normal and malignant plasma cells in different disease stages including progression and relapse. It is expressed in dormant as well as proliferating MM cells, while low expression could be observed in environmental cells. Biodistribution studies demonstrated the specific uptake of anti-CS1 sdAbs in tissues of 5TMM cell infiltration including bone, spleen and liver. TRNT using anti-CS1 sdAbs labeled with actinium-225 significantly prolonged survival of syngeneic, immunocompetent 5T33MM mice. In addition, we observed an increase in CD8 T-cells and more overall PD-L1 expression on immune and non-immune cells, implying an interferon gamma signature using actinium-225 labeled CS1-directed sdAbs. In this proof-of-principle study, we highlight, for the first time, the therapeutic potential and immunomodulating effects of anti-CS1 radionuclide therapy to target residual MM cells.
Topics: Actinium; Animals; B7-H1 Antigen; CD8-Positive T-Lymphocytes; Humans; Mice; Multiple Myeloma; Signaling Lymphocytic Activation Molecule Family; Single-Domain Antibodies; Tissue Distribution; Xenograft Model Antitumor Assays
PubMed: 34777918
DOI: 10.1080/2162402X.2021.2000699 -
Cancer Immunology, Immunotherapy : CII Nov 2023Epithelial ovarian cancer is the most lethal of gynecological cancers. The therapeutic efficacy of chimeric antigen receptor (CAR) T cell directed against single...
Epithelial ovarian cancer is the most lethal of gynecological cancers. The therapeutic efficacy of chimeric antigen receptor (CAR) T cell directed against single antigens is limited by the heterogeneous target antigen expression in epithelial ovarian tumors. To overcome this limitation, we describe an engineered cell with both dual targeting and orthogonal cytotoxic modalities directed against two tumor antigens that are highly expressed on ovarian cancer cells: cell surface Muc16 and intracellular WT1. Muc16-specific CAR T cells (4H11) were engineered to secrete a bispecific T cell engager (BiTE) constructed from a TCR mimic antibody (ESK1) reactive with the WT1-derived epitope RMFPNAPYL (RMF) presented by HLA-A2 molecules. The secreted ESK1 BiTE recruited and redirected other T cells to WT1 on the tumor cells. We show that ESK1 BiTE-secreting 4H11 CAR T cells exhibited enhanced anticancer activity against cancer cells with low Muc16 expression, compared to 4H11 CAR T cells alone, both in vitro and in mouse tumor models. Dual orthogonal cytotoxic modalities with different specificities targeting both surface and intracellular tumor-associated antigens present a promising strategy to overcome resistance to CAR T cell therapy in epithelial ovarian cancer and other cancers.
Topics: Humans; Mice; Female; Animals; Carcinoma, Ovarian Epithelial; Receptors, Chimeric Antigen; Ovarian Neoplasms; Antigens, Neoplasm; T-Lymphocytes; WT1 Proteins
PubMed: 37635172
DOI: 10.1007/s00262-023-03529-w -
Leukemia Research Nov 2023Numerous recent advances have been made in therapeutic approaches toward acute myeloid leukemia (AML). Since 2017, we have seen eleven novel Food & Drug Administration... (Review)
Review
Numerous recent advances have been made in therapeutic approaches toward acute myeloid leukemia (AML). Since 2017, we have seen eleven novel Food & Drug Administration (FDA)-approved medications for AML, all of which extend beyond the classical cytarabine-based cytostatic chemotherapy. In the recent two decades, the role of immune surveillance in AML has been intensively investigated. The power of one's own innate and adaptive immunity has been harnessed pharmacologically toward the goal of clearance of AML cells. Specifically, pre-clinical studies have shown great promise for antibodies that disinhibit T cells and macrophages by blocking checkpoint receptors within the immunologic synapse, thereby resulting in the elimination of AML cells. Anti-CD33 CAR-T therapies and anti-CD3/CD123 bispecific antibodies have also exhibited encouraging results in pre-clinical and early clinical studies. However, despite these translational efforts, we currently have no immune-based therapies for AML on the market, with the exception of gemtuzumab ozogamicin. In this focused review, we discuss molecular target validation and the most relevant clinical updates for immune-based experimental therapeutics including anti-CD47 monoclonal antibodies, CAR-T therapies, and bispecific T cell engagers. We highlight barriers to the clinical translation of these therapies in AML, and we propose solutions to optimize the manufacturing and delivery of the most novel immune-based therapies in the pipeline.
Topics: Humans; Receptors, Chimeric Antigen; Antibodies, Monoclonal; Gemtuzumab; Antibodies, Bispecific; Leukemia, Myeloid, Acute
PubMed: 37729719
DOI: 10.1016/j.leukres.2023.107388 -
ACS Central Science Mar 2017Metal aquo ions occupy central roles in all equilibria that define metal complexation in natural environments. These complexes are used to establish thermodynamic...
Metal aquo ions occupy central roles in all equilibria that define metal complexation in natural environments. These complexes are used to establish thermodynamic metrics (i.e., stability constants) for predicting metal binding, which are essential for defining critical parameters associated with aqueous speciation, metal chelation, transport, and so on. As such, establishing the fundamental chemistry of the actinium(III) aquo ion (Ac-aquo ion, Ac(HO) ) is critical for current efforts to develop Ac [ = 10.0(1) d] as a targeted anticancer therapeutic agent. However, given the limited amount of actinium available for study and its high radioactivity, many aspects of actinium chemistry remain poorly defined. We overcame these challenges using the longer-lived Ac [ = 21.772(3) y] isotope and report the first characterization of this fundamentally important Ac-aquo coordination complex. Our X-ray absorption fine structure study revealed 10.9 ± 0.5 water molecules directly coordinated to the Ac cation with an Ac-O distance of 2.63(1) Å. This experimentally determined distance was consistent with molecular dynamics density functional theory results that showed (over the course of 8 ps) that Ac was coordinated by 9 water molecules with Ac-O distances ranging from 2.61 to 2.76 Å. The data is presented in the context of other actinide(III) and lanthanide(III) aquo ions characterized by XAFS and highlights the uniqueness of the large Ac coordination numbers and long Ac-O bond distances.
PubMed: 28386595
DOI: 10.1021/acscentsci.6b00356 -
Molecules (Basel, Switzerland) Mar 2018This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha-particle... (Review)
Review
This review summarizes recent progress and developments as well as the most important pitfalls in targeted alpha-particle therapy, covering single alpha-particle emitters as well as alpha-particle generators. It discusses the production of radionuclides like At, Ra, Ac/Bi, labelling and delivery employing various targeting vectors (small molecules, chelators for alpha-emitting nuclides and their biomolecular targets as well as nanocarriers), general radiopharmaceutical issues, preclinical studies, and clinical trials including the possibilities of therapy prognosis and follow-up imaging. Special attention is given to the nuclear recoil effect and its impacts on the possible use of alpha emitters for cancer treatment, proper dose estimation, and labelling chemistry. The most recent and important achievements in the development of alpha emitters carrying vectors for preclinical and clinical use are highlighted along with an outlook for future developments.
Topics: Actinium; Alpha Particles; Astatine; Bismuth; Chelating Agents; Dose-Response Relationship, Radiation; Drug Carriers; Heterocyclic Compounds; Heterocyclic Compounds, 1-Ring; Humans; Neoplasms; Radiation Dosage; Radioisotopes; Radiopharmaceuticals; Radium; Small Molecule Libraries
PubMed: 29510568
DOI: 10.3390/molecules23030581 -
Pharmaceutics Dec 2020This review outlines the accomplishments and potential developments of targeted alpha (α) particle therapy (TAT). It discusses the therapeutic advantages of the short... (Review)
Review
This review outlines the accomplishments and potential developments of targeted alpha (α) particle therapy (TAT). It discusses the therapeutic advantages of the short and highly ionizing path of α-particle emissions; the ability of TAT to complement and provide superior efficacy over existing forms of radiotherapy; the physical decay properties and radiochemistry of common α-emitters, including Ac, Bi, Ra, Pb, Th, Ra, At, and Tb; the production techniques and proper handling of α-emitters in a radiopharmacy; recent preclinical developments; ongoing and completed clinical trials; and an outlook on the future of TAT.
PubMed: 33396374
DOI: 10.3390/pharmaceutics13010049 -
Pharmaceuticals (Basel, Switzerland) Apr 2020Atomic in vivo nanogenerators such as actinium-225, thorium-227, and radium-223 are of increasing interest and importance in the treatment of patients with metastatic... (Review)
Review
Atomic in vivo nanogenerators such as actinium-225, thorium-227, and radium-223 are of increasing interest and importance in the treatment of patients with metastatic cancer diseases. This is due to their peculiar physical, chemical, and biological characteristics, leading to astonishing responses in otherwise resistant patients. Nevertheless, there are still a few obstacles and hurdles to be overcome that hamper the broader utilization in the clinical setting. Next to the limited supply and relatively high costs, the in vivo complex stability and the fate of the recoiling daughter radionuclides are substantial problems that need to be solved. In radiobiology, the mechanisms underlying treatment efficiency, possible resistance mechanisms, and late side effect occurrence are still far from being understood and need to be unraveled. In this review, the current knowledge on the scientific and clinical background of targeted alpha therapies is summarized. Furthermore, open issues and novel approaches with a focus on the future perspective are discussed. Once these are unraveled, targeted alpha therapies with atomic in vivo nanogenerators can be tailored to suit the needs of each patient when applying careful risk stratification and combination therapies. They have the potential to become one of the major treatment pillars in modern cancer management.
PubMed: 32340103
DOI: 10.3390/ph13040076 -
Blood Advances Sep 2023Accurate classification and risk stratification are critical for clinical decision making in patients with acute myeloid leukemia (AML). In the newly proposed World...
Accurate classification and risk stratification are critical for clinical decision making in patients with acute myeloid leukemia (AML). In the newly proposed World Health Organization and International Consensus classifications of hematolymphoid neoplasms, the presence of myelodysplasia-related (MR) gene mutations is included as 1 of the diagnostic criteria for AML, AML-MR, based largely on the assumption that these mutations are specific for AML with an antecedent myelodysplastic syndrome. ICC also prioritizes MR gene mutations over ontogeny (as defined in the clinical history). Furthermore, European LeukemiaNet (ELN) 2022 stratifies these MR gene mutations into the adverse-risk group. By thoroughly annotating a cohort of 344 newly diagnosed patients with AML treated at the Memorial Sloan Kettering Cancer Center, we show that ontogeny assignments based on the database registry lack accuracy. MR gene mutations are frequently observed in de novo AML. Among the MR gene mutations, only EZH2 and SF3B1 were associated with an inferior outcome in the univariate analysis. In a multivariate analysis, AML ontogeny had independent prognostic values even after adjusting for age, treatment, allo-transplant and genomic classes or ELN risks. Ontogeny also helped stratify the outcome of AML with MR gene mutations. Finally, de novo AML with MR gene mutations did not show an adverse outcome. In summary, our study emphasizes the importance of accurate ontogeny designation in clinical studies, demonstrates the independent prognostic value of AML ontogeny, and questions the current classification and risk stratification of AML with MR gene mutations.
Topics: Humans; Leukemia, Myeloid, Acute; Mutation; Myelodysplastic Syndromes; Prognosis; Risk Factors
PubMed: 37142255
DOI: 10.1182/bloodadvances.2023009675