Journal: Theranostics

Abbreviation

Publisher

Ivyspring

Journal Volumes

ISSN

1838-7640

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2020 - 20256
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Publications 1 - 6 of 6
  • Large-scale super-resolution optoacoustic imaging facilitated by FeNP/ICG-loaded coreless polyelectrolyte microcapsules
    Item type: Journal Article
    Nozdriukhin, Daniil; Lyu, Shuxin; Razansky, Daniel; et al. (2025)
    Theranostics
    Rationale: Localization optoacoustic tomography (LOT) enhances imaging of deep-tissue microvasculature by leveraging flowing contrast particles. However, achieving high-resolution, large-scale imaging requires contrast agents with strong per-particle signal, good biocompatibility, and prolonged circulation time. This study introduces coreless polyelectrolyte microcapsules (MCs) encapsulating indocyanine green (ICG) and iron oxide nanoparticles (FeNP) to overcome current limitations in LOT imaging. Methods: MCs were engineered using a layer-by-layer technique by depositing polyelectrolytes, FeNP and ICG on a CaCO3 core, which was eventually dissolved. Their optical, morphological, and biocompatibility properties were characterized via UV-Vis-NIR spectroscopy, SEM, and toxicity assays In vitro and In vivo. Optoacoustic tomography (OAT), motion contrast optoacoustic imaging (MC-OA), directional motion contrast optoacoustic imaging (DMC-OA), localization optoacoustic tomography (LOT), and velocity mapping were conducted in mice to evaluate cerebral, testicular, and tumor vasculature. A raster scanning approach enabled large-scale brain imaging with 9-position coverage. Results: MCs displayed strong optoacoustic contrast, low cytotoxicity, and long circulation times (>45 min). In vivo LOT imaging revealed super-resolved microvascular networks in brain, testis, and tumor, with up to 2.5-fold enhancement in vessel visualization parameters. Velocity maps enabled quantification of cerebral blood flow, and oxygenation maps were further rendered by integrating LOT with spectral unmixing. Extended imaging was enabled by persistent MC signal, facilitating full-cortex vascular imaging.
  • Non-invasive longitudinal imaging of VEGF-induced microvascular alterations in skin wounds
    Item type: Journal Article
    Liu, Yu-Hang; Brunner, Lorenz; Rebling, Johannes; et al. (2022)
    Theranostics
    Background: Microcirculation is essential for skin homeostasis and repair. A variety of growth factors have been identified as important regulators of wound healing. However, direct observation and longitudinal monitoring of skin remodeling in an unperturbed in vivo environment remains challenging. Methods: We report on non-invasive longitudinal imaging of the wound healing process in transgenic mice overexpressing vascular endothelial growth factor A (VEGF-A) in keratinocytes by means of large-scale optoacoustic microscopy (LSOM). This rapid, label-free, high throughput intravital microscopy method averts the use of dorsal skin-fold chambers, allowing for fully non-invasive repeated imaging of intact wounds with capillary resolution over field-of-view spanning several centimeters. Results: We observed VEGF-driven enhancement of dermal vascularization in ears, dorsal skin and healing wounds and quantified the hemoglobin content, fill fraction, vessel diameter and tortuosity. The in vivo findings were further corroborated by detailed side-by-side classical histological whole-mount vascular stainings and pan-endothelial CD31 immunofluorescence. Conclusion: The new approach is suitable for supplementing or replacing the cumbersome histological procedures in a broad range of skin regeneration and tissue engineering applications.
  • Pharmacological inhibition of mTORC1 increases CCKBR-specific tumor uptake of radiolabeled minigastrin analogue [177Lu]Lu-PP-F11N
    Item type: Journal Article
    Grzmil, Michal; Qin, Yun; Schleuniger, Carina; et al. (2020)
    Theranostics
    Rationale: A high tumor-to-healthy-tissue uptake ratio of radiolabeled ligands is an essential prerequisite for safe and effective peptide receptor radionuclide therapy (PRRT). In the present study, we searched for novel opportunities to increase tumor-specific uptake of the radiolabeled minigastrin analogue [177Lu]Lu-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Nle-Asp-Phe-NH2 ([177Lu]Lu-PP-F11N), that targets the cholecystokinin B receptor (CCKBR) in human cancers. Methods: A kinase inhibitor library screen followed by proliferation and internalization assays were employed to identify compounds which can increase uptake of [177Lu]Lu-PP-F11N in CCKBR-transfected human epidermoid carcinoma A431 cells and natural CCKBR-expressing rat pancreatic acinar AR42J cells. Western blot (WB) analysis verified the inhibition of the signaling pathways and the CCKBR level, whereas the cell-based assay analyzed arrestin recruitment. Biodistribution and SPECT imaging of the A431/CCKBR xenograft mouse model as well as histological analysis of the dissected tumors were used for in vivo validation. Results: Our screen identified the inhibitors of mammalian target of rapamycin complex 1 (mTORC1), which increased cell uptake of [177Lu]Lu-PP-F11N. Pharmacological mTORC1 inhibition by RAD001 and metformin increased internalization of [177Lu]Lu-PP-F11N in A431/CCKBR and in AR42J cells. Analysis of protein lysates from RAD001-treated cells revealed increased levels of CCKBR (2.2-fold) and inhibition of S6 phosphorylation. PP-F11N induced recruitment of β-arrestin1/2 and ERK1/2 phosphorylation. In A431/CCKBR-tumor bearing nude mice, 3 or 5 days of RAD001 pretreatment significantly enhanced tumor-specific uptake of [177Lu]Lu-PP-F11N (ratio [RAD001/Control] of 1.56 or 1.79, respectively), whereas metformin treatment did not show a significant difference. Quantification of SPECT/CT images confirmed higher uptake of [177Lu]Lu-PP-F11N in RAD001-treated tumors with ratios [RAD001/Control] of average and maximum concentration reaching 3.11 and 3.17, respectively. HE staining and IHC of RAD001-treated tumors showed a significant increase in necrosis (1.4% control vs.10.6% of necrotic area) and the reduction of proliferative (80% control vs. 61% of Ki67 positive cells) and mitotically active cells (1.08% control vs. 0.75% of mitotic figures). No significant difference in the tumor vascularization was observed after five-day RAD001 or metformin treatment. Conclusions: Our data demonstrates, that increased CCKBR protein level by RAD001 pretreatment has the potential to improve tumor uptake of [177Lu]Lu-PP-F11N and provides proof-of-concept for the development of molecular strategies aimed at enhancing the level of the targeted receptor, to increase the efficacy of PRRT and nuclear imaging.
  • Multimodal assessment of non-alcoholic fatty liver disease with transmission-reflection optoacoustic ultrasound
    Item type: Journal Article
    Lafci, Berkan; Hadjihambi, Anna; Determann, Madita; et al. (2023)
    Theranostics
    Non-alcoholic fatty liver disease (NAFLD) is an umbrella term referring to a group of conditions associated to fat deposition and damage of liver tissue. Early detection of fat accumulation is essential to avoid progression of NAFLD to serious pathological stages such as liver cirrhosis and hepatocellular carcinoma. Methods: We exploited the unique capabilities of transmission-reflection optoacoustic ultrasound (TROPUS), which combines the advantages of optical and acoustic contrasts, for an early-stage multi-parametric assessment of NAFLD in mice. Results: The multispectral optoacoustic imaging allowed for spectroscopic differentiation of lipid content, as well as the bio-distributions of oxygenated and deoxygenated hemoglobin in liver tissues in vivo. The pulse-echo (reflection) ultrasound (US) imaging further provided a valuable anatomical reference whilst transmission US facilitated the mapping of speed of sound changes in lipid-rich regions, which was consistent with the presence of macrovesicular hepatic steatosis in the NAFLD livers examined with ex vivo histological staining. Conclusion: The proposed multimodal approach facilitates quantification of liver abnormalities at early stages using a variety of optical and acoustic contrasts, laying the ground for translating the TROPUS approach toward diagnosis and monitoring NAFLD in patients.
  • Development of a new class of PSMA radioligands comprising ibuprofen as an albumin-binding entity
    Item type: Journal Article
    Deberle, Luisa M.; Benešová, Martina; Umbricht, Christoph A.; et al. (2020)
    Theranostics
    Prostate-specific membrane antigen (PSMA)-targeted radioligands have been used for the treatment of metastatic castration-resistant prostate cancer (mCRPC). Recently, albumin-binding PSMA radioligands with enhanced blood circulation were developed to increase the tumor accumulation of activity. The present study aimed at the design, synthesis and preclinical evaluation of a novel class of PSMA-targeting radioligands equipped with ibuprofen as a weak albumin-binding entity in order to improve the pharmacokinetic properties. Methods: Four novel glutamate-urea-based PSMA ligands were synthesized with ibuprofen, conjugated via variable amino acid-based linker entities. The albumin-binding properties of the 177Lu-labeled PSMA ligands were tested in vitro using mouse and human plasma. Affinity of the radioligands to PSMA and cellular uptake and internalization was investigated using PSMA-positive PC-3 PIP and PSMA-negative PC-3 flu tumor cells. The tissue distribution profile of the radioligands was assessed in biodistribution and imaging studies using PC-3 PIP/flu tumor-bearing nude mice. Results: The PSMA ligands were obtained in moderate yields at high purity (>99%). 177Lu-labeling of the ligands was achieved at up to 100 MBq/nmol with >96% radiochemical purity. In vitro assays confirmed high binding of all radioligands to mouse and human plasma proteins and specific uptake and internalization into PSMA-positive PC-3 PIP tumor cells. Biodistribution studies and SPECT/CT scans revealed high accumulation in PC-3 PIP tumors but negligible uptake in PC-3 flu tumor xenografts as well as rapid clearance of activity from background organs and tissues. 177Lu-Ibu-DAB-PSMA, in which ibuprofen was conjugated via a positively-charged diaminobutyric acid (DAB) entity, showed distinguished tumor uptake and the most favorable tumor-to-blood and tumor-to-kidney ratios. Conclusion: The high accumulation of activity in the tumor and fast clearance from background organs was a common favorable characteristic of PSMA radioligands modified with ibuprofen as albumin-binding entity. 177Lu-Ibu-DAB-PSMA emerged as the most promising candidate; hence, more detailed preclinical investigations with this radioligand are warranted in view of a clinical translation.
  • Theranostics - a sure cure for cancer after 100 years?
    Item type: Journal Article
    Song, Yangmeihui; Zou, Jianhua; Castellanos, E. Alejandro; et al. (2024)
    Theranostics
    Cancer has remained a formidable challenge in medicine and has claimed an enormous number of lives worldwide. Theranostics, combining diagnostic methods with personalized therapeutic approaches, shows huge potential to advance the battle against cancer. This review aims to provide an overview of theranostics in oncology: exploring its history, current advances, challenges, and prospects. We present the fundamental evolution of theranostics from radiotherapeutics, cellular therapeutics, and nanotherapeutics, showcasing critical milestones in the last decade. From the early concept of targeted drug delivery to the emergence of personalized medicine, theranostics has benefited from advances in imaging technologies, molecular biology, and nanomedicine. Furthermore, we emphasize pertinent illustrations showcasing that revolutionary strategies in cancer management enhance diagnostic accuracy and provide targeted therapies customized for individual patients, thereby facilitating the implementation of personalized medicine. Finally, we describe future perspectives on current challenges, emerging topics, and advances in the field.
Publications 1 - 6 of 6