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The biodistribution of radiotracers used in diagnostic imaging is grossly and recognizably altered by a wide variety of drugs and other treatment modalities, such as surgery and radiotherapy. Knowledge of such altered biodistribution is important both in making diagnostic inferences from scans and in dosimetric considerations.
PURPOSE: To conduct a phase I and biodistribution study of the EphA3 antibody ifabotuzumab and zirconium-89-labeled ifabotuzumab (89Zr-ifabotuzumab) in patients with glioblastoma (GBM). PATIENTS AND METHODS: This multisite study was conducted in adults with recurrent GBM whose tumors were measurable according to Response Assessment in Neuro-Oncology (RANO) criteria and whose Eastern Cooperative Oncology Group performance status was 0 to 1. Patients underwent a biodistribution study with PET scans with 89Zr-ifabotuzumab, followed by three infusions of ifabotuzumab at either 3.5 or 5.25 mg/kg before undergoing a second study with 89Zr-ifabotuzumab PET scans. Resected patient diagnostic tumor samples were collected for multiplex immunofluorescence and spatial transcriptomics analyses. RESULTS: Twelve patients were recruited, of which six were treated with 3.5 mg/kg and six with 5.25 mg/kg of ifabotuzumab. 89Zr-ifabotuzumab and associated PET scanning were well tolerated, as was ifabotuzumab. There were no objective responses, but one patient had prolonged stable disease. In addition, two patients showed changes in peritumor edema that were suggestive of modulation of tumor vasculature. 89Zr-ifabotuzumab scans showed highly specific tumor uptake in all patients concordant with disease sites on MRI and PET imaging, without evidence of nonspecific binding. Spatial transcriptomics and immunofluorescence analyses of the patient's archival tissue specimens showed that EphA3 was expressed in the tumor microenvironment in all patients and tumor cells with different transcriptional states. CONCLUSIONS: Targeting EphA3 with ifabotuzumab in patients with GBM is safe and attractive, showing chronologic stable expression across both tumor compartments (particularly in cells with a mesenchymal phenotype) and nontumor compartments (particularly the vascular compartment) with evidence of target modulation.
Food-derived carbon dots (CDs) are a new class of carbon-based nanoparticles generated during the thermal processing of food matrices. These nanomaterials have been extensively studied for their unique fluorescence, good biocompatibility, and tunable surface chemistry in food detection, intelligent packaging, and biomedical applications. However, their nanoscale size and high surface activity have raised safety concerns regarding biological interactions, in vivo biodistribution, and potential long-term health hazards. Although CDs have traditionally been regarded as low-toxicity materials due to their favorable biocompatibility, the potential hidden risks of CDs have not received sufficient attention. CDs exhibit dose-dependent toxicity, not only accumulating in various tissues and organs but also potentially inducing oxidative stress and interfering with cellular metabolic functions. Therefore, this review summarizes the advances in sources, synthetic strategies, and core properties of CDs, with a special focus on in vivo biological interactions, fates, and potential safety challenges. In addition, it is proposed that the standardized detection and risk assessment system should be established to further explore the long-term health effects of CDs under real dietary exposure, thereby ensuring their safety and sustainable application.
According to our concept that biodistribution of salicylates (SA) might be an important factor of their mode of action the distribution of sodiumsalicylate (NaSA) and acetylsalicylic acid (ASA) was investigated in vivo and in vitro. It was shown that particular high concentrations of both compounds were found in vivo in the glandular stomach region and the kidney tubules of rats as well as in inflamed tissue. Quantitative studies showed that in chicken, in inflamed joints, higher concentrations as in plasma and about three times higher concentrations as in control joints were observed. In vitro studies using human erythrocytes suspended in buffer of different pH showed that added NaSA accumulated in these cells when the environmental pH was lowered from 7.4 to 6.8. From these results it is speculated that SA being weak acids accumulate within cells which are surrounded or bordering acidic fluids. This is the case in the stomach, the kidney and the inflamed tissue. This is where SA exert their effects and side effects.
The biodistribution of a lipid-soluble brominated female sex hormone, Br-77-labeled estrone, has been determined in dogs and rabbits. Following i.v. or intragastric administration, Br-77-labeled estrone localized in the gallbladder bile within 20-25 min. Fifty-six percent of the injected activity was found in the bile at 90 min. Breast tissue was imaged by scintillation camera in three female dogs with postpartum breast enlargement at 24 hr following i.v. injection. Analysis of digitized images revealed 50% more counts per pixel in stimulated female breast tissue than was in surrounding tissue. Increased Br-77 activity in the breast was associated with the presence of increased concentrations of estrogen receptors.
Technetium-99m phytate has been suggested as a bone-marrow imaging agent. This article compares the biodistribution of Tc-99m labeled "bone marrow" phytate, sulfur colloid, and diphosphonate in young rats and rabbits. Autoclaved bone marrow phytate revealed significant long-base depositon, but 96% of this activity was associated with compact bone and only 4% with bone marrow. This distribution is similar to that of diphosphonate, but significantly different from that of sulfur colloid. Technetium-99m-phytate is not recommended as a bone-marrow imaging agent.
The in vivo organ distributions of dl- and l-[side 3-14C]-tryptophan and dl-(75Se)-selenomethionine were studied in normal Long-Evans rats to determine which tryptophan isomer had the best pancreas/liver ratio. The commercially available radiochemical agents were injected into the tails of adult rats, and three animals were sacrificed for each compound at 15, 30, 45, 60, and 90 minutes. Samples of blood, pancreas, liver, kidney, spleen, and flank muscles were excised, weighed wet, digested, and counted by standard liquid scintillation technics. A standard fraction of the injected dose was also counted so that results could be reported as per cent injected dose per gram tissue (per cent ID/gm) and per whole organ. The spleen and muscle concentrations (per cent ID/gm) were indistinguishable for the three compounds at all times studied. The kidney concentration of dl-tryptophan was higher than that of l-tryptophan at 60 and 90 minutes, reflecting the renal excretion of the nonmetabolic isomer. The concentration of l-tryptophan was two to three times higher than that of dl-tryptophan and selenomethionine in the pancreas at the earlier times, but after 1 hour they became equivalent. All three compounds had equivalent concentrations in the liver, except for l-tryptophan at 15 minutes. We conclude that pancreas/liver ratios are much higher for tryptophan than for selenomethionine and that for l-tryptophan they are at least tenfold higher. Since the rat is able to partially metabolize d-tryptophan via an inversion step, differences between l- and dl-tryptophan might be even larger for humans. L-tryptophan labeled with a short-lived gamma-emitting nuclide (13N or 11C) should, therefore, be a much better radiopharmaceutical agent for pancreatic scintigraphy.
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A cyclotron target system for the production of anhydrous [18F] fluoride ion has been developed and used for the synthesis of carrier-free [18F]-3-deoxy-3fluoro-D-glucose (3-FDG). The synthesis is sufficiently rapid and efficient to allow production of usable amounts of 3-FDG with a 6-MeV cyclotron. Preliminary animal studies show that 3-FDG is in fact a glucose analog.
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5-thio-D-glucose (5-TDG) exerts profound effects on rapidly metabolizing tissues. We have used liquid scintillation counting to study the tissue distribution and pharmacokinetics of S-35-labeled 5-TDG in hamster models of pancreatic tumors. In the normal hamster, initial uptake of S-35 activity into kidney, liver, and blood was high, but rapidly decreased with time. The pancreatic uptake (% dose/g) never exceeded 0.75%. This level occurred only at the earliest times after administration. Uptake in all three tumor models exceeded that in pancreatic tissue within 15 min of injection. The highest tumor-to-pancreas ratio was seen in the duct-tumor model, which also exhibited the most favorable tumor-to-tissue ratio when compared with kidney, liver and muscle. Favorable ratios were most pronounced at 6 and 24 hr after injection. These studies provide impetus for the use of 5-TDG as a model compound for the synthesis of potentially useful agents for clinical detection of pancreatic tumors.
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[14C] doxorubicin (adriamycin) and [14C] daunorubicin (daunomycin) are cardiotoxic antibodies used in cancer therapy. These drugs were examined as possible agents for the measurement of regional myocardial blood flow. The antibiotics were injected intravenously into mice, which were then killed after various intervals. At a chemical dosage of 0.5 mg per kilogram, the content of the heart never exceeded 0.60% of the administered dose for doxorubicin and 0.55% for daunorubicin. The cardiotoxic effect of these drugs, therefore, is probably related to a specific sensitivity of the heart, rather than to an avid uptake of the drugs by the cardiac muscle. Further studies seem warranted, using a lower chemical dosage and higher specific activity.
Five new HIDA-compounds were synthesized, labelled with 99mTc and compared with 99mTc-(2,6-dimethyl)HIDA viz. (N-2,6-dimethylphenylcarbamoylmethyl)iminodiacetic acid by means of TLC and biodistribution studies on rabbits. The computerized method used by Britton and Brown during renal studies was successfully adapted to study the biodistribution of these agents.
Chronic pain remains a global health challenge, often resistant to available treatments with socioeconomic and psychological burdens. All chronic pain is believed due to neuronal signaling imbalances, resulting in increased excitability. Gene therapy represents a promising molecular therapy targeting molecular pain processing pathways, by offering precise, localized, long-lasting neuromodulation while minimizing systemic exposure and side effects. In model systems, replication-defective, disease-free, herpes simplex virus (rdHSV) gene therapy expressing an analgesic carbonic anhydrase-8 (CA8∗) peptide variant corrects somatosensory hyperexcitability by activating Kv7 voltage-gated potassium channels, produces profound, long-lasting analgesia and treats chronic pain from knee osteoarthritis (OA). In these studies, we provide the first non-glucagon-like peptide (GLP) biosafety, efficacy, biodistribution, shedding, and histopathology examination of this rdHSV-CA8∗. Naive mice were examined for clinical safety, biodistribution across all major tissues, knee histopathology, and analgesic efficacy via the intra-articular knee route of administration. We observed no signs of persistent toxicity, viral genomes remained where they were injected, and there was no evidence of shedding. Profound analgesia persisted for 6 months without functional impairments. These initial biosafety and efficacy data support further development of rdHSV-CA8∗ for treating chronic knee pain due to moderate to severe OA.
PURPOSE OF REVIEW: This review summarizes nonviral genome-editing delivery platforms for hereditary hearing loss, focusing on lipid nanoparticles (LNPs) and engineered virus-like particles (eVLPs), and discusses their advantages over adeno-associated virus-based delivery, as well as the barriers to clinical translation. RECENT FINDINGS: Recent advances have established LNPs as a clinically advanced nonviral platform, although challenges related to inner ear biodistribution, cell type specificity, endosomal escape, and immunogenicity remain to be addressed. In parallel, eVLPs have undergone substantial technical evolution, progressing from early low efficiency systems to advanced base editor- and prime editor-eVLP architectures that enhance cargo loading and editing efficiency. Extracellular vesicle-based genome editing has also emerged as an additional platform, although issues related to reproducibility, loading efficiency, and scalability remain major hurdles. SUMMARY: Nonviral genome editing platforms expand the therapeutic toolkit for hereditary hearing loss by enabling transient delivery of genome editors with potential safety advantages. Future efforts should focus on characterizing biodistribution and immunogenicity, refining cell type-specific tropism, and establishing scalable manufacturing processes to enable successful clinical translation.