With the ability to noninvasively image and monitor molecular processes within tumors, molecular imaging represents a fundamental tool for cancer scientists. In the current review, we describe ...emergent optical technologies for molecular imaging. We aim to provide the reader with an overview of the fundamental principles on which each imaging strategy is based, to introduce established and future applications, and to provide a rationale for selecting optical technologies for molecular imaging depending on disease location, biology, and anatomy. To accelerate clinical translation of imaging techniques, we also describe examples of practical applications in patients. Elevating these techniques into standard-of-care tools will transform patient stratification, disease monitoring, and response evaluation.
Auger: The future of precision medicine Pirovano, Giacomo; Wilson, Thomas C.; Reiner, Thomas
Nuclear medicine and biology,
05/2021, Letnik:
96-97
Journal Article
Recenzirano
Odprti dostop
First reported by Lise Meitner in 1922 and independently by Pierre Auger in 1923, the Auger effect has been explored as a potential source for targeted radiotherapy. The Auger effect is based on the ...emission of a low energy electron (typically <25 keV) from an atom post electron capture (EC), internal conversion (IC), or incident X-rays excitation. This phenomenon can cause the emission of a primary electron and multiple electron tracks typically in the nearest proximity of the emission site (2–500 nm). The short range of the emitted Auger cascade results in medium/high levels of linear energy transfer (4–26 keV/μm) exerted on the surrounding tissue. This property makes Auger emitters the ideal candidates for delivering high levels of targeted radiation to a specific target with dimensions comparable to, for example, the DNA. By using a targeting vector such as a small molecule, peptide or antibody, one has the potential of delivering high levels of radiation to tumor specific biomarkers while circumventing off-site toxicity in healthy cells; a challenge which is harder to overcome when using other, longer range sources of radiation such as beta and alpha emitting radionuclides. Several reviews on Auger emitters have been published over the years with two recent examples. For these reviews and others, we support their analysis and therefore to avoid simple repetition, this commentary will seek to address additional aspects and viewpoints. Specifically, we will focus on those most promising preclinical and clinical studies using small molecules, peptides, antibodies and how these studies may serve as a template for future studies.
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'Targeted' or 'biological' cancer treatments rely on differential gene expression between normal tissue and cancer, and genetic changes that render tumour cells especially sensitive to the agent ...being applied. Problems exist with the application of many agents as a result of damage to local tissues, tumour evolution and treatment resistance, or through systemic toxicity. Hence, there is a therapeutic need to uncover specific clinical targets which enhance the efficacy of cancer treatment whilst minimising the risk to healthy tissues. T-LAK cell-originated protein kinase (TOPK) is a MAPKK-like kinase which plays a role in cell cycle regulation and mitotic progression. As a consequence, TOPK expression is minimal in differentiated cells, although its overexpression is a pathophysiological feature of many tumours. Hence, TOPK has garnered interest as a cancer-specific biomarker and biochemical target with the potential to enhance cancer therapy whilst causing minimal harm to normal tissues. Small molecule inhibitors of TOPK have produced encouraging results as a stand-alone treatment in vitro and in vivo, and are expected to advance into clinical trials in the near future. In this review, we present the current literature pertaining to TOPK as a potential clinical target and describe the progress made in uncovering its role in tumour development. Firstly, we describe the functional role of TOPK as a pro-oncogenic kinase, followed by a discussion of its potential as a target for the treatment of cancers with high-TOPK expression. Next, we provide an overview of the current preclinical progress in TOPK inhibitor discovery and development, with respect to future adaptation for clinical use.
Despite Auger electrons being highly appealing due to their short-range and high linear energy transfer to surrounding tissues, the progress in the field has been limited due to the challenge in ...delivering a therapeutic dose within the close proximity of cancer cell’s DNA. Here, we demonstrate that the PARP inhibitor 123I-MAPi is a viable agent for the systemic administration and treatment of p53 mutant cancers. Significantly, minimal off-site toxicity was observed in mice administered with up to 74 MBq of 127I-PARPi. Taken together, these results lay the foundation for future clinical evaluation and broader preclinical investigations. By harnessing the scaffold of the PARP inhibitor Olaparib, we were able to deliver therapeutic levels of Auger radiation to the site of human colorectal cancer xenograft tumors after systemic administration. In-depth toxicity studies analyzed blood chemistry levels and markers associated with specific organ toxicity. Finally, p53+/+ and p53–/– human colorectal cancer cell lines were evaluated for the ability of 123I-MAPi to induce tumor growth delay. Toxicity studies demonstrate that both 123I-MAPi and its stable isotopologue, 127I-PARPi, have no significant off-site toxicity when administered systemically. Analysis following 123I-MAPi treatment confirmed its ability to induce DNA damage at the site of xenograft tumors when administered systemically. Finally, we demonstrate that 123I-MAPi generates a therapeutic response in p53–/–, but not p53+/+, subcutaneous xenograft tumors in mouse models. Taken together, these results represent the first example of a PARP Auger theranostic agent capable of delivering a therapeutic dose to xenograft human colorectal cancer tumors upon systemic administration without causing significant toxicity to surrounding mouse organs. Moreover, it suggests that a PARP Auger theranostic can act as a targeted therapeutic for cancers with mutated p53 pathways. This landmark goal paves the way for clinical evaluation of 123I-MAPi for pan cancer therapeutics.
123
I-MAPi, a novel PARP1-targeted Auger radiotherapeutic has shown promising results in pre-clinical glioma model. Currently,
123
I-MAPi is synthesized using multistep synthesis that results in ...modest yields and low molar activities (MA) that limits the ability to translate this technology for human studies where high doses are administered. Therefore, new methods are needed to synthesize
123
I-MAPi in high activity yields (AY) and improved MA to facilitate clinical translation and multicenter trials.
123
I-MAPi was prepared in a single step via
123
I-iododetannylation of the corresponding tributylstannane precursor. In vitro internalization assay, subcellular fractionation and confocal microscopy where used to evaluate the performance of
123
I-MAPi in a small cell lung cancer model.
123
I-MAPi was synthesized in a single step from the corresponding stannane precursor in AY of 45 ± 2% and MA of 11.8 ± 4.8 GBq µmol
−1
. In vitro in LX22 cells showed rapid internalization (5 min) with accumulation found predominantly in the membrane, nucleus and chromatin of the cell as determined by subcellular fractionation.
Here, we have developed an improved radiosynthesis of
123
I-MAPi, an Auger theranostic agent. This process was achieved using a single step,
123
I-iododestannylation reaction from the corresponding stannane precursor in good AY and MA.
123
I-MAPi was evaluated in vitro in a small cell lung cancer model with high PARP expression, rapid internalization and high nuclear uptake shown.
I-MAPi, a novel PARP1-targeted Auger radiotherapeutic has shown promising results in pre-clinical glioma model. Currently,
I-MAPi is synthesized using multistep synthesis that results in modest ...yields and low molar activities (MA) that limits the ability to translate this technology for human studies where high doses are administered. Therefore, new methods are needed to synthesize
I-MAPi in high activity yields (AY) and improved MA to facilitate clinical translation and multicenter trials.
I-MAPi was prepared in a single step via
I-iododetannylation of the corresponding tributylstannane precursor. In vitro internalization assay, subcellular fractionation and confocal microscopy where used to evaluate the performance of
I-MAPi in a small cell lung cancer model.
I-MAPi was synthesized in a single step from the corresponding stannane precursor in AY of 45 ± 2% and MA of 11.8 ± 4.8 GBq
mol
. In vitro in LX22 cells showed rapid internalization (5 min) with accumulation found predominantly in the membrane, nucleus and chromatin of the cell as determined by subcellular fractionation.
Here, we have developed an improved radiosynthesis of
I-MAPi, an Auger theranostic agent. This process was achieved using a single step,
I-iododestannylation reaction from the corresponding stannane precursor in good AY and MA.
I-MAPi was evaluated in vitro in a small cell lung cancer model with high PARP expression, rapid internalization and high nuclear uptake shown.
Human papillomavirus- (HPV-) associated oropharyngeal squamous cell carcinomas (OPSCCs) are clinically and pathologically distinct from HPV-negative tumors. Here, we explore whether HPV affects ...functional biomarkers, including γH2AX, RAD51, and PARP1. Moreover, the role of 18FPARPi as a broadly applicable imaging tool for head and neck carcinomas is investigated.BackgroundHuman papillomavirus- (HPV-) associated oropharyngeal squamous cell carcinomas (OPSCCs) are clinically and pathologically distinct from HPV-negative tumors. Here, we explore whether HPV affects functional biomarkers, including γH2AX, RAD51, and PARP1. Moreover, the role of 18FPARPi as a broadly applicable imaging tool for head and neck carcinomas is investigated.HPV-positive and HPV-negative cell lines were used to evaluate the γH2AX, RAD51, and PARP1 expression with immunoblotting and immunofluorescence. Effects of external beam ionizing radiation were investigated in vitro, and survival was investigated via colony-formation assay. 18FPARPi uptake experiments were performed on HPV-negative and HPV-positive cell lines to quantify PARP1 expression. PARP1 IHC and γH2AX foci were quantified using patient-derived oropharyngeal tumor specimens.MethodsHPV-positive and HPV-negative cell lines were used to evaluate the γH2AX, RAD51, and PARP1 expression with immunoblotting and immunofluorescence. Effects of external beam ionizing radiation were investigated in vitro, and survival was investigated via colony-formation assay. 18FPARPi uptake experiments were performed on HPV-negative and HPV-positive cell lines to quantify PARP1 expression. PARP1 IHC and γH2AX foci were quantified using patient-derived oropharyngeal tumor specimens.Differences in DNA repair were detected, showing higher RAD51 and γH2AX expression in HPV-positive cell lines. Clonogenic assays confirm HPV-positive cell lines to be significantly more radiosensitive. PARP1 expression levels were similar, irrespective of HPV status. Consequently, 18FPARPi uptake assays demonstrated that this tracer is internalized in cell lines independently from their HPV status.ResultsDifferences in DNA repair were detected, showing higher RAD51 and γH2AX expression in HPV-positive cell lines. Clonogenic assays confirm HPV-positive cell lines to be significantly more radiosensitive. PARP1 expression levels were similar, irrespective of HPV status. Consequently, 18FPARPi uptake assays demonstrated that this tracer is internalized in cell lines independently from their HPV status.The HPV status, often used clinically to stratify patients, did not affect PARP1 levels, suggesting that PARP imaging can be performed in both HPV-positive and HPV-negative patients. This study confirms that the PET imaging agent 18FPARPi could serve as a general clinical tool for oropharyngeal cancer patients.ConclusionThe HPV status, often used clinically to stratify patients, did not affect PARP1 levels, suggesting that PARP imaging can be performed in both HPV-positive and HPV-negative patients. This study confirms that the PET imaging agent 18FPARPi could serve as a general clinical tool for oropharyngeal cancer patients.
The immune function within the tumor microenvironment has become a prominent therapeutic target, with tumor-associated macrophages (TAMs) playing a critical role in immune suppression. We propose an ...89Zr-labeled high-density lipoprotein (89Zr-HDL) nanotracer as a means of monitoring response to immunotherapy. Methods: Female MMTV-PyMT mice were treated with pexidartinib, a colony-stimulating factor 1 receptor (CSF1R) inhibitor, to reduce TAM density. The accumulation of 89Zr-HDL within the tumor was assessed using PET/CT imaging and autoradiography, whereas TAM burden was determined using immunofluorescence. Results: A significant reduction in 89Zr-HDL accumulation was observed in PET/CT images, with 2.9% ± 0.3% and 3.7% ± 0.2% injected dose/g for the pexidartinib- and vehicle-treated mice, respectively. This reduction was corroborated ex vivo and correlated with decreased TAM density. Conclusion: These results support the potential use of 89Zr-HDL nanoparticles as a PET tracer to quickly monitor the response to CSF1R inhibitors and other therapeutic strategies targeting TAMs.
Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus 2019 disease (COVID-19), poses a serious risk to humanity and represents a huge challenge for ...healthcare systems worldwide. Since the early days of the COVID-19 pandemic, it has been evident that adequate testing is an essential step in limiting and controlling the spread of SARS-CoV-2. Here, we present an accurate, inexpensive, scalable, portable, and rapid detection kit to directly detect SARS-CoV-2 in biological samples that could even be translated for population testing. We have demonstrated that our method can reliably identify viral load and could be used to reach those fractions of the population with limited access to more sophisticated and expensive tests.
The proposed SARS-CoV-2 detection kit is based on the combination of a SARS-CoV-2-targeted antibody (CR3022) that targets spike protein S1 domain on the viral surface. This antibody was radiolabeled with a long-lived isotope (Iodine-125) to allow us to detect bound antibody in samples with SARS-CoV-2. We used a series of in vitro assays to determine sensitivity and specificity and facilitate automation of the testing kit. Bound antibody was extracted from saliva samples via a centrifugation step and a semi-permeable membrane. Our kit was further validated using SARS-CoV-2 virions.
We were able to accomplish radiosynthesis of 125II-CR3022 reliably without loss of binding. The SARS-CoV-2-sensing antibody was shown to maintain its spike S1 affinity and to bind to as low as 2.5–5 ng of spike protein. We then used beads-bound spike S1 to develop a separation kit which proved to be both easy to use and inexpensive. The kit made it possible to extract bound antibody from the saliva-like sample. We were able to validate the separation kit using intact SARS-CoV-2 virions and showed that our kit can detect a viral concentration as low as 19,700 PFU/mL (~ 9.22%TBF) and as high as 1,970,000 PFU/mL (45.04%TBF).
Here we report the development and validation of a SARS-CoV-2 detection system based on the combination of a specific radiolabeled antibody and a separation membrane. We demonstrate our system to be comparable to other SARS-CoV-2 detection kits already approved by the FDA and believe this technology could be easily deployed to countries with limited resources for the diagnosis of COVID-19. Furthermore, workflows could be easily adapted to target other antigens and therefore other types of diseases.
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Twenty million Americans suffer from peripheral nerve injury caused by trauma and medical disorders, resulting in a broad spectrum of potentially debilitating side effects. In one out of four cases, ...patients identify surgery as the root cause of their nerve injury. Particularly during tumor resections or after traumatic injuries, tissue distortion and poor visibility can challenge a surgeon’s ability to precisely locate and preserve peripheral nerves. Intuitively, surgical outcomes would improve tremendously if nerves could be highlighted using an exogeneous contrast agent. In clinical practice, however, the current standard of carevisual examination and palpationremains unchanged. To address this unmet clinical need, we explored the expression of voltage-gated sodium channel Nav1.7 as an intraoperative marker for the peripheral nervous system. We show that expression of Nav1.7 is high in peripheral nerves harvested from both human and mouse tissue. We further show that modification of a Nav1.7-selective peptide, Hsp1a, can serve as a targeted vector for delivering a fluorescent sensor to the peripheral nervous system. Ex vivo, we observe a high signal-to-noise ratio for fluorescently labeled Hsp1a in both histologically prepared and fresh tissue. Using a surgical fluorescent microscope, we show in a simulated clinical scenario that the identification of mouse sciatic nerves is possible, suggesting that fluorescently labeled Hsp1a tracers could be used to discriminate nerves from their surrounding tissues in a routine clinical setting.
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