Detection and delineation of oral cancer with a PARP1 targeted optical imaging agent.
Ontology highlight
ABSTRACT:
SUBMITTER: Kossatz S
PROVIDER: S-EPMC4761964 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:More sensitive and specific methods for early detection are imperative to improve survival rates in oral cancer. However, oral cancer detection is still largely based on visual examination and histopathology of biopsy material, offering no molecular selectivity or spatial resolution. Intuitively, the addition of optical contrast could improve oral cancer detection and delineation, but so far no molecularly targeted approach has been translated. Our fluorescently labeled small-molecule inhibitor PARPi-FL binds to the DNA repair enzyme poly(ADP-ribose)polymerase 1 (PARP1) and is a potential diagnostic aid for oral cancer delineation. Based on our preclinical work, a clinical phase I/II trial opened in March 2017 to evaluate PARPi-FL as a contrast agent for oral cancer imaging. In this commentary, we discuss why we chose PARP1 as a biomarker for tumor detection and which particular characteristics make PARPi-FL an excellent candidate to image PARP1 in optically guided applications. We also comment on the potential benefits of our molecularly targeted PARPi-FL-guided imaging approach in comparison to existing oral cancer screening adjuncts and mention the adaptability of PARPi-FL imaging to other environments and tumor types.
| S-EPMC5582799 | biostudies-literature
Project description:We designed and synthesized a folate receptor-targeted, water-soluble, and pharmacomodulated photodynamic therapy (PDT) agent that selectively detects and destroys the targeted cancer cells while sparing normal tissue. This was achieved by minimizing the normal organ uptake (e.g., liver and spleen) and by discriminating between tumors with different levels of folate receptor (FR) expression. This construct (Pyro-peptide-Folate, PPF) is composed of three components: (1) pyropheophorbide a (Pyro) as an imaging and therapeutic agent, (2) peptide sequence as a stable linker and modulator improving the delivery efficiency, and (3) Folate as a homing molecule targeting FR-expressing cancer cells. We observed an enhanced accumulation of PPF in KB cancer cells (FR+) compared to HT 1080 cancer cells (FR-), resulting in a more effective post-PDT killing of KB cells over HT 1080 or normal CHO cells. The accumulation of PPF in KB cells can be up to 70% inhibited by an excess of free folic acid. The effect of Folate on preferential accumulation of PPF in KB tumors (KB vs HT 1080 tumors 2.5:1) was also confirmed in vivo. In contrast to that, no significant difference between the KB and HT 1080 tumor was observed in case of the untargeted probe (Pyro-peptide, PP), eliminating the potential influence of Pyro's own nonspecific affinity to cancer cells. More importantly, we found that incorporating a short peptide sequence considerably improved the delivery efficiency of the probe--a process we attributed to a possible peptide-based pharmacomodulation--as was demonstrated by a 50-fold reduction in PPF accumulation in liver and spleen when compared to a peptide-lacking probe (Pyro-K-Folate, PKF). This approach could potentially be generalized to improve the delivery efficiency of other targeted molecular imaging and photodynamic therapy agents.
| S-EPMC2535810 | biostudies-literature
Project description:Early detection and diagnosis of prostate cancer is key to designing effective treatment strategies. Microarrays have resulted in the discovery of hepsin (HPN) as a biomarker for detection of prostate cancer. In this study, we explore the development of HPN imaging probes for detection of prostate cancer. We used phage display to isolate HPN binding peptides with 190 + 2.2 nmol/L affinity in monomeric form and high specificity. The identified peptides were able to detect human prostate cancer on tissue microarrays and in cell-based assays. HPN-targeted imaging agents were synthesized by conjugating multiple peptides to fluorescent nanoparticles to further improve avidity through multivalency and to improve pharmacokinetics. When injected into mouse xenograft models, HPN-targeted nanoparticles bound specifically to HPN-expressing LNCaP xenografts compared with non-HPN-expressing PC3 xenografts. HPN imaging may provide a new method for detection of prostate cancer.
| S-EPMC2709884 | biostudies-literature
Project description:Targeting and inhibiting DNA repair pathways is a powerful strategy of controlling malignant growth. One such strategy includes the inhibition of PARP1, a central element in the intracellular DNA damage response. To determine and visualize the expression and intercellular distribution of PARP1 in vivo, and to monitor the pharmacokinetics of PARP1 targeted therapeutics, fluorescent small probes were developed. To date, however, it is unclear how these probes behave in a more realistic clinical setting, where DNA damage has been induced through one or more prior lines of therapy. Here, we use one such imaging agent, PARPi-FL, in tissues both with and without prior DNA damage, and investigate its value as a probe for PARP1 imaging. We show that PARP1 expression in oral cancer is high, and that the uptake of PARPi-FL is selective, irrespective of whether cells were exposed to irradiation or not. We also show that PARPi-FL uptake increases in response to DNA damage, and that this increase is reflected in higher enzyme expression. Our findings provide a framework for measuring exposure of cells to external beam radiation, and could help to elucidate the effects of such treatments non-invasively in mouse models of cancer.
| S-EPMC4726809 | biostudies-literature
Project description:Several imaging techniques have been advocated as clinical adjuncts to improve identification of suspicious oral lesions. However, these have not yet shown superior sensitivity or specificity over conventional oral examination techniques. We developed a multimodal, multi-scale optical imaging system that combines macroscopic biochemical imaging of fluorescence lifetime imaging with subcellular morphologic imaging of reflectance confocal microscopy for early detection of oral cancer. We tested our system on excised human oral tissues.In total, 4 tissue specimens were imaged. These specimens were diagnosed as either clinically normal, oral lichen planus, gingival hyperplasia, or superficially invasive squamous cell carcinoma. The optical and fluorescence lifetime properties of each specimen were recorded.Both quantitative and qualitative differences among normal, benign, and squamous cell carcinoma lesions can be resolved with fluorescence lifetime imaging reflectance confocal microscopy. The results demonstrate that an integrated approach based on these two methods can potentially enable rapid screening and evaluation of large areas of oral epithelial tissue.Early results from ongoing studies of imaging human oral cavity illustrate the synergistic combination of the 2 modalities. An adjunct device based on such optical characterization of oral mucosa can potentially be used to detect oral carcinogenesis in early stages.
| S-EPMC4752880 | biostudies-literature
Project description:Reliable methods of imaging myelin are essential to investigate the causes of demyelination and to study drugs that promote remyelination. Myelin-specific compounds can be developed into imaging probes to detect myelin with various imaging techniques. The development of multimodal myelin-specific imaging probes enables the use of orthogonal imaging techniques to accurately visualize myelin content and validate experimental results. Here, we describe the synthesis and application of multimodal myelin-specific imaging agents for light microscopy and magnetic resonance imaging. The imaging agents were synthesized by incorporating the structural features of luxol fast blue MBS, a myelin-specific histological stain, into texaphyrins coordinated to GdIII . These new complexes demonstrated absorption of visible light, emission of near-IR light, and relaxivity values greater than clinically approved contrast agents for magnetic resonance imaging. These properties enable the use of optical imaging and magnetic resonance imaging for visualization of myelin. We performed section- and en block-staining of ex vivo mouse brains to investigate the specificity for myelin of the new compounds. Images obtained from light microscopy and magnetic resonance imaging demonstrate that our complexes are retained in white matter structures and enable detection of myelin. Copyright © 2016 John Wiley & Sons, Ltd.
| S-EPMC5247309 | biostudies-literature
Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy worldwide, and the precise detection is challenging currently. Magnetic particle imaging (MPI) is suitable for imaging deep and internal PDAC tumours because of its high sensitivity and unlimited imaging depth. The purpose of this study was to utilize the MPI, in combination with fluorescence molecular imaging (FMI) and magnetic resonance imaging (MRI), to advance the in vivo precise detection of PDAC xenografts.MethodsThe PDAC targeted plectin-1 peptide and IRDye800CW were conjugated to the superparamagnetic iron oxide nanoparticles (PTP-Fe3O4-IRDye800CW) for the PDAC-targeting triple-modality imaging. Subcutaneous and orthotopic PDAC mouse models were established. FMI, MPI, and MRI were performed for dynamic and quantitative observation of PDAC tumours. Histological staining analyses were used for ex vivo validation.FindingsPTP-Fe3O4-IRDye800CW nanoparticles possessed great triple-modality imaging performance and specific targeting to plectin-1 expressed on PDAC cells. For in vivo multi-modality imaging of orthotopic PDAC models, the PTP-Fe3O4-IRDye800CW nanoparticles demonstrated higher specificity, even distribution, and longer retention effects in tumours for over 7 d compared with Con-Fe3O4-IRDye800CW nanoparticles. (MPI, 2d post-injection: PTP-Fe3O4-IRDye800CW: 85.72% ± 1.53% vs. Con-Fe3O4-IRDye800CW: 74.41% ± 1.91%, **P < 0.01 (Student's t test)). Ex vivo histological and Prussian blue stainings were performed to validate the distribution of probes.InterpretationThese data demonstrate the feasibility of utilizing MPI for in vivo PDAC imaging and complement with FMI/MRI for a precise and comprehensive in vivo characterization of PDAC. This may benefit PDAC patients for precise diagnosis and guidance of therapy.FundingThis study was funded by the National Natural Science Foundation of China (Grant No. 62027901, 82071896, 81871422, 81871514, 81227901), Ministry of Science and Technology of China under Grant No. 2017YFA0205200, 2017YFA0700401, Beijing Natural Science Foundation (Grant No. 7212207), Elite Program of Dong Cheng District of Beijing (2020-dchrcpyzz-28), and Peking University Third Hospital (BYSYZD2019018, and jyzc2018-02).
| S-EPMC9079778 | biostudies-literature
Project description:Intraperitoneal metastases commonly recur after surgery because small tumor foci escape detection within the complex anatomy of the peritoneal cavity and mesentery. Accurate localization of peritoneal implants during surgery could improve the resection of ovarian cancer and other malignancies, but few practical techniques to enhance detectability are currently available. Here, we describe a targeted molecular imaging method that employs fluorescently labeled avidin to detect submillimeter peritoneal implants of ovarian cancer in mice. After binding to surface lectins on the tumor, fluorescein-conjugated avidin enabled the spectral fluorescence imaging of disseminated peritoneal implants. High spatial resolution and high tumor-to-background ratio allowed the visualization of implants as small as 0.3 mm (with 100% sensitivity and specificity; n = 150) and the identification of even smaller lesions ex vivo. These results suggest that targeted molecular imaging with a fluorescence-labeled lectin-ligand system is a promising technique for the detection of disseminated submillimeter foci of cancer.
| S-EPMC1601930 | biostudies-literature
Project description:OBJECTIVES:Surgical margin status is a significant determinant of treatment outcome in oral cancer. Negative surgical margins can decrease the loco-regional recurrence by five-fold. The current standard of care of intraoperative clinical examination supplemented by histological frozen section, can result in a risk of positive margins from 5 to 17 percent. In this study, we attempted to assess the utility of intraoperative optical coherence tomography (OCT) imaging with automated diagnostic algorithm to improve on the current method of clinical evaluation of surgical margin in oral cancer. MATERIALS AND METHODS:We have used a modified handheld OCT device with automated algorithm based diagnostic platform for imaging. Intraoperatively, images of 125 sites were captured from multiple zones around the tumor of oral cancer patients (n?=?14) and compared with the clinical and pathologic diagnosis. RESULTS:OCT showed sensitivity and specificity of 100%, equivalent to histological diagnosis (kappa, ??=?0.922), in detection of malignancy within tumor and tumor margin areas. In comparison, for dysplastic lesions, OCT-based detection showed a sensitivity of 92.5% and specificity of 68.8% and a moderate concordance with histopathology diagnosis (??=?0.59). Additionally, the OCT scores could significantly differentiate squamous cell carcinoma (SCC) from dysplastic lesions (mild/moderate/severe; p???0.005) as well as the latter from the non-dysplastic lesions (p???0.05). CONCLUSION:The current challenges associated with clinical examination-based margin assessment could be improved with intra-operative OCT imaging. OCT is capable of identifying microscopic tumor at the surgical margins and demonstrated the feasibility of mapping of field cancerization around the tumor.
| S-EPMC6954689 | biostudies-literature
Project description:PurposeThe current study presents [(18)F]PARPi-FL as a bimodal fluorescent/positron emission tomography (PET) agent for PARP1 imaging.Procedures[(18)F]PARPi-FL was obtained by (19)F/(18)F isotopic exchange and PET experiments, biodistribution studies, surface fluorescence imaging, and autoradiography carried out in a U87 MG glioblastoma mouse model.Results[(18)F]PARPi-FL showed high tumor uptake in vivo and ex vivo in small xenografts (< 2 mm) with both PET and optical imaging technologies. Uptake of [(18)F]PARPi-FL in blocked U87 MG tumors was reduced by 84 % (0.12 ± 0.02 %injected dose/gram (%ID/g)), showing high specificity of the binding. PET imaging showed accumulation in the tumor (1 h p.i.), which was confirmed by ex vivo phosphor autoradiography.ConclusionsThe fluorescent component of [(18)F]PARPi-FL enables cellular resolution optical imaging, while the radiolabeled component of [(18)F]PARPi-FL allows whole-body deep-tissue imaging of malignant growth.
| S-EPMC4609241 | biostudies-literature