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ACS Central Science Jun 2023Molecularly targeted radionuclide therapies (TRTs) struggle with balancing efficacy and safety, as current strategies to increase tumor absorption often alter drug...
Molecularly targeted radionuclide therapies (TRTs) struggle with balancing efficacy and safety, as current strategies to increase tumor absorption often alter drug pharmacokinetics to prolong circulation and normal tissue irradiation. Here we report the first covalent protein TRT, which, through reacting with the target irreversibly, increases radioactive dose to the tumor without altering the drug's pharmacokinetic profile or normal tissue biodistribution. Through genetic code expansion, we engineered a latent bioreactive amino acid into a nanobody, which binds to its target protein and forms a covalent linkage via the proximity-enabled reactivity, cross-linking the target irreversibly , on cancer cells, and on tumors . The radiolabeled covalent nanobody markedly increases radioisotope levels in tumors and extends tumor residence time while maintaining rapid systemic clearance. Furthermore, the covalent nanobody conjugated to the α-emitter actinium-225 inhibits tumor growth more effectively than the noncovalent nanobody without causing tissue toxicity. Shifting the protein-based TRT from noncovalent to covalent mode, this chemical strategy improves tumor responses to TRTs and can be readily scaled to diverse protein radiopharmaceuticals engaging broad tumor targets.
PubMed: 37396859
DOI: 10.1021/acscentsci.3c00288 -
Biomolecules Aug 2023Following previously published systematic reviews on the diagnostic use of nanoparticles (NPs), in this manuscript, we report published methods for radiolabeling... (Review)
Review
Following previously published systematic reviews on the diagnostic use of nanoparticles (NPs), in this manuscript, we report published methods for radiolabeling nanoparticles with therapeutic alpha-emitting, beta-emitting, or Auger's electron-emitting isotopes. After analyzing 234 papers, we found that different methods were used with the same isotope and the same type of nanoparticle. The most common type of nanoparticles used are the PLGA and PAMAM nanoparticles, and the most commonly used therapeutic isotope is Lu. Regarding labeling methods, the direct encapsulation of the isotope resulted in the most reliable and reproducible technique. Radiolabeled nanoparticles show promising results in metastatic breast and lung cancer, although this field of research needs more clinical studies, mainly on the comparison of nanoparticles with chemotherapy.
Topics: Dendrimers; Isotope Labeling; Nanomedicine; Nanoparticles; Radioisotopes
PubMed: 37627307
DOI: 10.3390/biom13081241 -
Nature Reviews. Cancer Jun 2015The eradication of cancer remains a vexing problem despite recent advances in our understanding of the molecular basis of neoplasia. One therapeutic approach that has... (Review)
Review
The eradication of cancer remains a vexing problem despite recent advances in our understanding of the molecular basis of neoplasia. One therapeutic approach that has demonstrated potential involves the selective targeting of radionuclides to cancer-associated cell surface antigens using monoclonal antibodies. Such radioimmunotherapy (RIT) permits the delivery of a high dose of therapeutic radiation to cancer cells, while minimizing the exposure of normal cells. Although this approach has been investigated for several decades, the cumulative advances in cancer biology, antibody engineering and radiochemistry in the past decade have markedly enhanced the ability of RIT to produce durable remissions of multiple cancer types.
Topics: Actinium; Alpha Particles; Antibodies, Monoclonal; Clinical Trials as Topic; Hematologic Neoplasms; Humans; Molecular Targeted Therapy; Neoplasms; Radioimmunotherapy
PubMed: 25998714
DOI: 10.1038/nrc3925 -
Journal of Nuclear Medicine : Official... Apr 2023Neuroendocrine tumors (NETs) express somatostatin receptors (SSTRs) 2 and 5. Modified variants of somatostatin, the cognate ligand for SSTR2 and SSTR5, are used in...
Neuroendocrine tumors (NETs) express somatostatin receptors (SSTRs) 2 and 5. Modified variants of somatostatin, the cognate ligand for SSTR2 and SSTR5, are used in treatment for metastatic and locoregional disease. Peptide receptor radionuclide therapy with Lu-DOTATATE (DOTA-octreotate), a β-particle-emitting somatostatin derivative, has demonstrated survival benefit in patients with SSTR-positive NETs. Despite excellent results, a subset of patients has tumors that are resistant to treatment, and alternative agents are needed. Targeted α-particle therapy has been shown to kill tumors that are resistant to targeted β-particle therapy, suggesting that targeted α-particle therapy may offer a promising treatment option for patients with Lu-DOTATATE-resistant disease. Although DOTATATE can chelate the clinically relevant α-particle-emitting radionuclide Ac, the labeling reaction requires high temperatures, and the resulting radioconjugate has suboptimal stability. We designed and synthesized MACROPATATE (MACROPA-octreotate), a novel radioconjugate capable of chelating Ac at room temperature, and assessed its in vitro and in vivo performance. MACROPATATE demonstrated comparable affinity to DOTATATE (dissociation constant, 21 nM) in U2-OS-SSTR2, a SSTR2-positive transfected cell line. Ac-MACROPATATE demonstrated superior serum stability at 37°C over time compared with Ac-DOTATATE. Biodistribution studies demonstrated higher tumor uptake of Ac-MACROPATATE than of Ac-DOTATATE in mice engrafted with subcutaneous H69 NETs. Therapy studies showed that Ac-MACROPATATE exhibits significant antitumor and survival benefit compared with saline control in mice engrafted with SSTR-positive tumors. However, the increased accumulation of Ac-MACROPATATE in liver and kidneys and subsequent toxicity to these organs decreased its therapeutic index compared with Ac-DOTATATE. Ac-MACROPATATE and Ac-DOTATATE exhibit favorable therapeutic efficacy in animal models. Because of elevated liver and kidney accumulation and lower administered activity for dose-limiting toxicity of Ac-MACROPATATE, Ac-DOTATATE was deemed the superior agent for targeted α-particle peptide receptor radionuclide therapy.
Topics: Mice; Animals; Octreotide; Neuroendocrine Tumors; Organometallic Compounds; Tissue Distribution; Somatostatin; Receptors, Somatostatin; Radioisotopes; Radiopharmaceuticals
PubMed: 36396453
DOI: 10.2967/jnumed.122.264707 -
Hellenic Journal of Nuclear Medicine 2023The first description of the in vivo visualization of somatostatin receptor-positive tumors in patients was based on the use of a radioiodine (I) labelled somatostatin...
The first description of the in vivo visualization of somatostatin receptor-positive tumors in patients was based on the use of a radioiodine (I) labelled somatostatin analogue (Krenning et al. 1989). In the years that followed an Indium-111 (In) labelled somatostatin analogue, chelated with diethylenetriaminepentaacetic acid (DTPA), was successfully developed. Subsequently, In-OctreoScan was introduced worldwide. In the years to come Tc-Tektrotyde became commercially available with easy access. In the last decade, with the increasing use of positron emission tomography (PET) imaging, somatostatin analogues have been labelled with various positron-emitting isotopes, such as Gallium-68 (Ga) and Copper-64 (Cu) (Lewis et al. 1999, Schottelius et al. 2004, Gabriel et al. 2007) e.g Ga-DOTATOC, Ga-DOTATATE Ga-DOTANOC and Cu-DOTATATE. Scintigraphy with these investigational compounds display encouraging good imaging quality amd improved sensitivity in tumor site detection compared with SPECT scintigraphy. Also, other PET radiopharmaceuticals were developed, such as F-dihydroxy-phenyl-alanine (F-DOPA) and C-labelled 5-hydroxytryptophan (C-5-HTP) with encouraging results in terms of visualization of GEP-NETs (Koopmans et al. 2008). After the successful introduction of SRS in the diagnosis and staging of NETs, the next logical step was to increase the administered activity so that the radiopharmaceutical can induce tumor shrinkage in patients who had inoperable and/or metastasized NENs. Therefore, the first peptide receptor radionuclide therapy (PRRT) was performed with high administered activity of [In-DTPA0] octreotide (Krenning et al. 1994a). To make significant advancements in the treatment of somatostatin receptor-positive metastatic disease, more efficient radiolabelled somatostatin analogues were developed with higher affinity to the somatostatin receptor. Treatment with radiolabelled peptides or PRRT is a promising new therapeutic option in the management of inoperable or metastasized NETs. Symptomatic control can be achieved with all In-, Y- and Lu-labelled somatostatin analogue-based PRRT. For objective response and long-lasting duration of response, Y-DOTATOC and Lu-DOTATATE are the most promising radiopharmaceuticals. Side effects of PRRT are few and mild, if adequate kidney protective measures are taken and dose-limits are respected. In a minority of patients, when SRS fails to identify neuroendocrine disease, MIBG scintigraphy and subsequent I-MBG therapy might be an alternative treatment option. Targeted alpha-particle therapy (TAT) has emerged as an alternative treatment option to beta emitters in PRRT. The use of alpha emitters for cancer therapy has two advantages over beta emitter PRRT. The short range of alpha particles of only a few cell diameters (<0.1mm) allows for selective ablation of the target cancer cells, while sparing the surrounding healthy tissue. In addition, the higher linear energy transfer (LET), when compared to conventional beta emitters, results in the formation of complex DNA double-strand and DNA cluster breaks, which ultimately lead to cell death.(Lassmann M et al. Ann ICRP. 2018) Putative radiopharmaceuticals that can be considered for metastatic NEN treatment include Actinium-225 (Ac)-DOTATATE and Bismuth-213 (Bi)-DOTATOC. There was evidence of partial response using both radiopharmaceutical agents without significant hematological, renal, or hepatotoxicity. Future studies should consider longer term, randomized controlled trials investigating the role of TAT, in particular, c-DOTATATE, in the treatment of metastatic NENs. Nuclear medicine plays a pivotal role in the imaging and treatment of neuroendocrine tumors (NETs). New techniques in somatostatin receptor imaging include the use of different radiolabelled somatostatin analogues with higher affinity and different affinity profiles to the somatostatin receptor subtypes. Considerable advances have been made in the imaging of NETs, but to find the ideal imaging method with increased sensitivity and better topographic localization of the primary and metastatic disease remains the ultimate goal of research.
Topics: Humans; Radiopharmaceuticals; Receptors, Somatostatin; Gallium Radioisotopes; Iodine Radioisotopes; Copper; Somatostatin; Pancreatic Neoplasms; Neuroendocrine Tumors; DNA; Organometallic Compounds
PubMed: 37658556
DOI: No ID Found -
Current Radiopharmaceuticals Oct 2011Alpha particle-emitting isotopes are being investigated in radioimmunotherapeutic applications because of their unparalleled cytotoxicity when targeted to cancer and... (Review)
Review
Alpha particle-emitting isotopes are being investigated in radioimmunotherapeutic applications because of their unparalleled cytotoxicity when targeted to cancer and their relative lack of toxicity towards untargeted normal tissue. Actinium- 225 has been developed into potent targeting drug constructs and is in clinical use against acute myelogenous leukemia. The key properties of the alpha particles generated by 225Ac are the following: i) limited range in tissue of a few cell diameters; ii) high linear energy transfer leading to dense radiation damage along each alpha track; iii) a 10 day halflife; and iv) four net alpha particles emitted per decay. Targeting 225Ac-drug constructs have potential in the treatment of cancer.
Topics: Actinium; Alpha Particles; Animals; Antibodies, Monoclonal; Clinical Trials as Topic; Humans; Liposomes; Models, Animal; Neoplasms; Radioimmunotherapy; Radiopharmaceuticals; Radiotherapy Dosage
PubMed: 22202153
DOI: 10.2174/1874471011104040306 -
Blood Oct 2022There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under...
There is a growing body of evidence that therapy-related myeloid neoplasms (t-MNs) with driver gene mutations arise in the background of clonal hematopoiesis (CH) under the positive selective pressure of chemo- and radiation therapies. Uncovering the exposure relationships that provide selective advantage to specific CH mutations is critical to understanding the pathogenesis and etiology of t-MNs. In a systematic analysis of 416 patients with t-MN and detailed prior exposure history, we found that TP53 mutations were significantly associated with prior treatment with thalidomide analogs, specifically lenalidomide. We demonstrated experimentally that lenalidomide treatment provides a selective advantage to Trp53-mutant hematopoietic stem and progenitor cells (HSPCs) in vitro and in vivo, the effect of which was specific to Trp53-mutant HSPCs and was not observed in HSPCs with other CH mutations. Because of the differences in CK1α degradation, pomalidomide treatment did not provide an equivalent level of selective advantage to Trp53-mutant HSPCs, providing a biological rationale for its use in patients at high risk for t-MN. These findings highlight the role of lenalidomide treatment in promoting TP53-mutated t-MNs and offer a potential alternative strategy to mitigate the risk of t-MN development.
Topics: Humans; Lenalidomide; Thalidomide; Hematopoietic Stem Cells; Genes, p53; Mutation; Neoplasms, Second Primary; Tumor Suppressor Protein p53
PubMed: 35512188
DOI: 10.1182/blood.2021014956 -
Frontiers in Medicine 2022Targeted alpha therapy (TAT) is a promising approach for addressing unmet needs in oncology. Inherent properties make α-emitting radionuclides well suited to cancer... (Review)
Review
Targeted alpha therapy (TAT) is a promising approach for addressing unmet needs in oncology. Inherent properties make α-emitting radionuclides well suited to cancer therapy, including high linear energy transfer (LET), penetration range of 2-10 cell layers, induction of complex double-stranded DNA breaks, and immune-stimulatory effects. Several alpha radionuclides, including radium-223 (Ra), actinium-225 (Ac), and thorium-227 (Th), have been investigated. Conjugation of tumor targeting modalities, such as antibodies and small molecules, with a chelator moiety and subsequent radiolabeling with α-emitters enables specific delivery of cytotoxic payloads to different tumor types. Ra dichloride, approved for the treatment of patients with metastatic castration-resistant prostate cancer (mCRPC) with bone-metastatic disease and no visceral metastasis, is the only approved and commercialized alpha therapy. However, Ra dichloride cannot currently be complexed to targeting moieties. In contrast to Ra, Th may be readily chelated, which allows radiolabeling of tumor targeting moieties to produce targeted thorium conjugates (TTCs), facilitating delivery to a broad range of tumors. TTCs have shown promise in pre-clinical studies across a range of tumor-cell expressing antigens. A clinical study in hematological malignancy targeting CD22 has demonstrated early signs of activity. Furthermore, pre-clinical studies show additive or synergistic effects when TTCs are combined with established anti-cancer therapies, for example androgen receptor inhibitors (ARI), DNA damage response inhibitors such as poly (ADP)-ribose polymerase inhibitors or ataxia telangiectasia and Rad3-related kinase inhibitors, as well as immune checkpoint inhibitors.
PubMed: 36726355
DOI: 10.3389/fmed.2022.1071086 -
Diagnostics (Basel, Switzerland) Feb 2018Over 90% of prostate cancers over-express prostate specific membrane antigen (PSMA) and these tumor cells may be accurately targeted for diagnosis by Ga-PSMA-positron... (Review)
Review
Over 90% of prostate cancers over-express prostate specific membrane antigen (PSMA) and these tumor cells may be accurately targeted for diagnosis by Ga-PSMA-positron emission tomography/computed tomography (Ga-PSMA-PET/CT) imaging. This novel molecular imaging modality appears clinically to have superseded CT, and appears superior to MR imaging, for the detection of metastatic disease. Ga-PSMA PET/CT has the ability to reliably stage prostate cancer at presentation and can help inform an optimal treatment approach. Novel diagnostic applications of Ga-PSMA PET/CT include guiding biopsy to improve sampling accuracy, and guiding surgery and radiotherapy. In addition to facilitating the management of metastatic castrate resistant prostate cancer (mCRPC), Ga-PSMA can select patients who may benefit from targeted systemic radionuclide therapy. Ga-PSMA is the diagnostic positron-emitting theranostic pair with the beta emitter Lutetium-177 PSMA (Lu-PSMA) and alpha-emitter Actinium-225 PSMA (Ac-PSMA) which can both be used to treat PSMA-avid metastases of prostate cancer in the molecular tumor-targeted approach of theranostic nuclear oncology.
PubMed: 29439481
DOI: 10.3390/diagnostics8010016 -
Current Radiopharmaceuticals 2018The development of radiopharmaceuticals containing 225Ac for targeted alpha therapy is an active area of academic and commercial research worldwide. (Review)
Review
BACKGROUND
The development of radiopharmaceuticals containing 225Ac for targeted alpha therapy is an active area of academic and commercial research worldwide.
OBJECTIVES
Despite promising results from recent clinical trials, 225Ac-radiopharmaceutical development still faces significant challenges that must be overcome to realize the widespread clinical use of 225Ac. Some of these challenges include the limited availability of the isotope, the challenging chemistry required to isolate 225Ac from any co-produced isotopes, and the need for stable targeting systems with high radiolabeling yields.
RESULTS
Here we provide a review of available literature pertaining to these challenges in the 225Acradiopharmaceutical field and also provide insight into how performed and planned efforts at TRIUMF - Canada's particle accelerator centre - aim to address these issues.
Topics: Actinium; Alpha Particles; Humans; Neoplasms; Radiochemistry; Radionuclide Generators; Radiopharmaceuticals
PubMed: 29658444
DOI: 10.2174/1874471011666180416161908