The advent of click chemistry has had a profound influence on almost all branches of chemical science. This is particularly true of radiochemistry and the synthesis of agents for positron emission ...tomography (PET), single photon emission computed tomography (SPECT), and targeted radiotherapy. The selectivity, ease, rapidity, and modularity of click ligations make them nearly ideally suited for the construction of radiotracers, a process that often involves working with biomolecules in aqueous conditions with inexorably decaying radioisotopes. In the following pages, our goal is to provide a broad overview of the first 10 years of research at the intersection of click chemistry and radiochemistry. The discussion will focus on four areas that we believe underscore the critical advantages provided by click chemistry: (i) the use of prosthetic groups for radiolabeling reactions, (ii) the creation of coordination scaffolds for radiometals, (iii) the site-specific radiolabeling of proteins and peptides, and (iv) the development of strategies for in vivo pretargeting. Particular emphasis will be placed on the four most prevalent click reactionsthe Cu-catalyzed azide-alkyne cycloaddition (CuAAC), the strain-promoted azide-alkyne cycloaddition (SPAAC), the inverse electron demand Diels-Alder reaction (IEDDA), and the Staudinger ligationalthough less well-known click ligations will be discussed as well. Ultimately, it is our hope that this review will not only serve to educate readers but will also act as a springboard, inspiring synthetic chemists and radiochemists alike to harness click chemistry in even more innovative and ambitious ways as we embark upon the second decade of this fruitful collaboration.
In vivo pretargeting stands as a promising approach to harnessing the exquisite tumor-targeting properties of antibodies for nuclear imaging and therapy while simultaneously skirting their ...pharmacokinetic limitations. The core premise of pretargeting lies in administering the targeting vector and radioisotope separately and having the 2 components combine within the body. In this manner, pretargeting strategies decrease the circulation time of the radioactivity, reduce the uptake of the radionuclide in healthy nontarget tissues, and facilitate the use of short-lived radionuclides that would otherwise be incompatible with antibody-based vectors. In this short review, we seek to provide a brief yet informative survey of the 4 preeminent mechanistic approaches to pretargeting, strategies predicated on streptavidin and biotin, bispecific antibodies, complementary oligonucleotides, and bioorthogonal click chemistry.
Maleimide-bearing bifunctional chelators have been used extensively for the site-selective bioconjugation and radiolabeling of peptides and proteins. However, bioconjugates obtained using these ...constructs inevitably suffer from limited stability in vivo, a trait that translates into suboptimal activity concentrations in target tissues and higher uptake levels in healthy, nontarget tissues. To circumvent this issue, phenyloxadiazolyl methylsulfones have previously been reported as alternatives to maleimides for thiol-based ligations, but these constructs have scarcely been used in the field of radiochemistry. In this report, we describe the synthesis of two thiol-reactive bifunctional chelators for 89Zr and 177Lu based on a new, easy-to-make phenyloxadiazolyl methylsulfone reagent, PODS. Radioimmunoconjugates created using these novel bifunctional chelators displayed in vitro stability that was higher than that of their maleimide-derived cousins. More importantly, positron emission tomography imaging in murine models of cancer revealed that a 89Zr-labeled radioimmunoconjugate created using a PODS-bearing bifunctional chelator produced a rate of uptake in nontarget tissues that is significantly lower than that of its analogous maleimide-based counterpart.
Glioblastoma multiforme is a highly aggressive form of brain cancer whose location, tendency to infiltrate healthy surrounding tissue, and heterogeneity significantly limit survival, with scant ...progress having been made in recent decades.
I-MAPi (Iodine-123 Meitner-Auger PARP1 inhibitor) is a precise therapeutic tool composed of a PARP1 inhibitor radiolabeled with an Auger- and gamma-emitting iodine isotope. Here, the PARP inhibitor, which binds to the DNA repair enzyme PARP1, specifically targets cancer cells, sparing healthy tissue, and carries a radioactive payload within reach of the cancer cells' DNA.
The high relative biological efficacy of Auger electrons within their short range of action is leveraged to inflict DNA damage and cell death with high precision. The gamma ray emission of
I-MAPi allows for the imaging of tumor progression and therapy response, and for patient dosimetry calculation. Here we demonstrated the efficacy and specificity of this small-molecule radiotheranostic in a complex preclinical model.
and
studies demonstrate high tumor uptake and a prolonged survival in mice treated with
I-MAPi when compared with vehicle controls. Different methods of drug delivery were investigated to develop this technology for clinical applications, including convection enhanced delivery and intrathecal injection.
Taken together, these results represent the first full characterization of an Auger-emitting PARP inhibitor which demonstrate a survival benefit in mouse models of GBM and confirm the high potential of
I-MAPi for clinical translation.
Due to their remarkable selectivity and specificity for cancer biomarkers, immunoconjugates have emerged as extremely promising vectors for the delivery of diagnostic radioisotopes and fluorophores ...to malignant tissues. Paradoxically, however, these tools for precision medicine are synthesized in a remarkably imprecise way. Indeed, the vast majority of immunoconjugates are created
via
the random conjugation of bifunctional probes (
e.g.
, DOTA-NCS) to amino acids within the antibody (
e.g.
, lysines). Yet antibodies have multiple copies of these residues throughout their macromolecular structure, making control over the location of the conjugation reaction impossible. This lack of site specificity can lead to the formation of poorly defined, heterogeneous immunoconjugates with suboptimal
in vivo
behavior. Over the past decade, interest in the synthesis and development of site-specifically labeled immunoconjugates—both antibody-drug conjugates as well as constructs for
in vivo
imaging—has increased dramatically, and a number of reports have suggested that these better defined, more homogeneous constructs exhibit improved performance
in vivo
compared to their randomly modified cousins. In this two-part review, we seek to provide an overview of the various methods that have been developed to create site-specifically modified immunoconjugates for positron emission tomography, single photon emission computed tomography, and fluorescence imaging. We will begin with an introduction to the structure of antibodies and antibody fragments. This is followed by the core of the work: sections detailing the four different approaches to site-specific modification strategies based on cysteine residues, glycans, peptide tags, and unnatural amino acids. These discussions will be divided into two installments: cysteine residues and glycans will be detailed in Part 1 of the review, while peptide tags and unnatural amino acids will be addressed in Part 2. Ultimately, we sincerely hope that this review fosters interest and enthusiasm for site-specific immunoconjugates within the nuclear medicine and molecular imaging communities.
Molecular imaging agents for preoperative positron emission tomography (PET) and near-infrared fluorescent (NIRF)-guided delineation of surgical margins could greatly enhance the diagnosis, staging, ...and resection of pancreatic cancer. PET and NIRF optical imaging offer complementary clinical applications, enabling the noninvasive whole-body imaging to localize disease and identification of tumor margins during surgery, respectively. We report the development of PET, NIRF, and dual-modal (PET/NIRF) imaging agents, using 5B1, a fully human monoclonal antibody that targets CA19.9, a well-established pancreatic cancer biomarker. Desferrioxamine (DFO) and/or a NIRF dye (FL) were conjugated to the heavy-chain glycans of 5B1, using a robust and reproducible site-specific (ss) labeling methodology to generate three constructs (ssDFO-5B1,ssFL-5B1, andssdual-5B1) in which the immunoreactivity was not affected by the conjugation of either label. Each construct was evaluated in a s.c. xenograft model, using CA19.9-positive (BxPC3) and -negative (MIAPaCa-2) human pancreatic cancer cell lines. Each construct showed exceptional uptake and contrast in antigen-positive tumors with negligible nonspecific uptake in antigen-negative tumors. Additionally, the dual-modal construct was evaluated in an orthotopic murine pancreatic cancer model, using the human pancreatic cancer cell line, Suit-2. Thessdual-5B1 demonstrated a remarkable capacity to delineate metastases and to map the sentinel lymph nodes via tandem PET-computed tomography (PET/CT) and NIRF imaging. Fluorescence microscopy, histopathology, and autoradiography were performed on representative sections of excised tumors to visualize the distribution of the constructs within the tumors. These imaging tools have tremendous potential for further preclinical research and for clinical translation.
Poly(ADP-ribose)polymerase-1 (PARP1) is a DNA repair enzyme highly expressed in the nuclei of mammalian cells, with a structure and function that have attracted interest since its discovery. PARP ...inhibitors, moreover, can be used to induce synthetic lethality in cells where the homologous recombination (HR) pathway is deficient. Several small molecule PARP inhibitors have been approved by the FDA for multiple cancers bearing this deficiency These PARP inhibitors also act as radiosensitizing agents by delaying single strand break (SSB) repair and causing subsequent double strand break (DSB) generation, a concept that has been leveraged in various preclinical models of combination therapy with PARP inhibitors and ionizing radiation. Researchers have determined the efficacy of various PARP inhibitors at sub-cytotoxic concentrations in radiosensitizing multiple human cancer cell lines to ionizing radiation. Furthermore, several groups have begun evaluating combination therapy strategies in mouse models of cancer, and a fluorescent imaging agent that allows for subcellular imaging in real time has been developed from a PARP inhibitor scaffold. Other PARP inhibitor scaffolds have been radiolabeled to create PET imaging agents, some of which have also entered clinical trials. Most recently, these highly targeted small molecules have been radiolabeled with therapeutic isotopes to create radiotherapeutics and radiotheranostics in cancers whose primary interventions are surgical resection and whole-body radiotherapy. In this review we discuss the utilization of these small molecules in combination therapies and in scaffolds for imaging agents, radiotherapeutics, and radiotheranostics. Development of these radiolabeled PARP inhibitors has presented promising results for new interventions in the fight against some of the most intractable cancers.
Click Here for Better Chemistry Zeglis, Brian M.; Lewis, Jason S.
The New England journal of medicine,
12/2022, Letnik:
387, Številka:
24
Journal Article
Recenzirano
Odprti dostop
The 2022 Nobel Prize in Chemistry was awarded to Bertozzi, Meldal, and Sharpless for the development of click and bioorthogonal chemistry. This article explains how these techniques are generating ...tools for clinical application.
The 2022 Nobel Prize in Chemistry was awarded to Professors K. Barry Sharpless, Morten Meldal and Carolyn Bertozzi for their pioneering roles in the advent of click chemistry. Sharpless and Meldal ...worked to develop the canonical click reaction-the copper-catalyzed azide-alkyne cycloaddition-while Bertozzi opened new frontiers with the creation of the bioorthogonal strain-promoted azide-alkyne cycloaddition. These two reactions have revolutionized chemical and biological science by facilitating selective, high yielding, rapid and clean ligations and by providing unprecedented ways to manipulate living systems. Click chemistry has affected every aspect of chemistry and chemical biology, but few disciplines have been impacted as much as radiopharmaceutical chemistry. The importance of speed and selectivity in radiochemistry make it an almost tailor-made application of click chemistry. In this Perspective, we discuss the ways in which the copper-catalyzed azide-alkyne cycloaddition, the strain-promoted azide-alkyne cycloaddition and a handful of 'next-generation' click reactions have transformed radiopharmaceutical chemistry, both as tools for more efficient radiosyntheses and as linchpins of technologies that have the potential to improve nuclear medicine.
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