Tumor-specific Imaging Research Articles

Novel EBV LMP1 C-terminal domain binding affibody molecules as potential agents for in vivo molecular imaging diagnosis of nasopharyngeal carcinoma

Nasopharyngeal carcinoma (NPC) is consistently associated with Epstein-Barr virus (EBV) latent infection and is common in Southern China and Southeast Asia. The viral latent membrane proteins LMP1 and LMP2 are persistently expressed in NPC tissues; the cytoplasmic domain of LMP1 (LMP1 C-terminal) and LMP2A (LMP2A N-terminal) proteins is essential for maintenance of latency and can alter host cell signaling to facilitate tumor growth and progression. Thus, targeting LMP1 or LMP2 oncoprotein has been an increasing interest for diagnosis and targeted therapy of NPC. Affibody molecules, a new class of small-affinity engineered scaffold proteins, have demonstrated high potential for therapeutics, diagnostics, and biotechnological applications. More recently, radiolabelled HER2-specific affibody molecules have demonstrated to be useful in imaging of HER2 expressing tumor. In this study, we report three novel EBV LMP1 C-terminal (EBV LMP1-C) domain affibody molecules (ZLMP1-C15, ZLMP1-C114, and ZLMP1-C277) were selected by biopanning from a random-peptide displayed phage library and used for molecular imaging in tumor-bearing nude mice. Surface plasmon resonance (SPR), indirect immunofluorescence, and immunohistochemistry (IHC) clearly showed that all three selected affibody molecules have high affinity and specificity in binding to EBV LMP1 protein. Moreover, in vivo tumor imaging revealed that Dylight-755-labeled affibody molecules accumulated rapidly in tumor site after injection (1h) and then were continuously maintained for 24h in EBV-positive NPC xenograft mice model. In conclusion, our findings highlight the potential use of ZLMP1-C affibody molecules as tumor-specific molecular imaging agents of EBV-associated NPC.Key points• We screened three novel affibody molecules (ZLMP1-C15, ZLMP1-C114, and ZLMP1-C277) targeting EBV LMP1-C terminal domain• ZLMP1-C recognize the recombinant and native LMP1-C with high affinity and specificity• ZLMP1-C can be used for molecular imaging.

Insulin-Like Growth Factor-1 Receptor Targeted Fluorescent Imaging for Gallbladder Cancer in Orthotopic Mouse Models.

Background/AimsGallbladder cancer is fatal, but fluorescent imaging technology can facilitate timely diagnosis and improve patient outcomes. Fluorophore-conjugated insulin-like growth factor-1 receptor (IGF-1R) targeted antibodies were used to visualize gallbladder cancer in orthotopic tumor mouse models.MethodsWestern blotting, flow cytometric analysis, and confocal microscopy detected the expression of IGF-1R in SNU-308, SNU-478, and SNU-1196 bile duct cancer cells. In vivo imaging of SNU-478 and SNU-1196 subcutaneous tumors and orthotopic gallbladder tumor models of SNU-478 were performed after injection with DyLight 650-conjugated IGF-1R antibody.ResultsWestern blotting and flow cytometric analysis showed that IGF-1R was expressed in bile duct cancer cells, and confocal microscopy demonstrated that IGF-1R antibody was able to bind to IGF-1R on the cell membrane. Fluorescent IGF-1R antibody injected into the mouse tail vein made subcutaneous tumors and orthotopic tumors become fluorescent. The intensity of fluorescence from the tumor was stronger than that from surrounding normal tissues. Histochemical examination confirmed that the tumor was located inside the gallbladder and adjacent liver parenchyma of mice.ConclusionsOur study showed that a fluorescent IGF-1R-targeted antibody could help detect gallbladder tumors. Tumor-specific imaging technology can be applied to endoscopy, laparoscopy, and robotic surgery for better management of gallbladder cancer.

A Cooperatively Activatable, DNA-based Fluorescent Reporter for Imaging of Correlated Enzymatic Activities.

The dynamic variation of the expression profile and spatial landscape of multiple enzymes are crucial factors influencing tumor progression and drug treatment. However, the comprehensive analysis of these events has been hampered by the limitations of existing imaging technologies. Here we report a cooperatively activatable, DNA-based fluorescent reporter programmed to detect the correlated activity of dual enzymes, telomerase (TE) and apurinic/apyrimidinic endonuclease 1 (APE1), both in vitro and in vivo. The conformational change of the DNA probe can be orthogonally triggered through TE-induced DNA elongation and APE1-mediated specific cleavage, producing a fluorescent signal for imaging the activity of the two enzymes in an AND-gated manner. Furthermore, we demonstrate the capability of the system for specific tumor imaging through "dual lock-and-key" strategy, and visualizing the correlated enzymatic activities during drug treatment of cancer.

A Cooperatively Activatable, DNA‐based Fluorescent Reporter for Imaging of Correlated Enzymatic Activities

AbstractThe dynamic variation of the expression profile and spatial landscape of multiple enzymes are crucial factors influencing tumor progression and drug treatment. However, the comprehensive analysis of these events has been hampered by the limitations of existing imaging technologies. Here we report a cooperatively activatable, DNA‐based fluorescent reporter programmed to detect the correlated activity of dual enzymes, telomerase (TE) and apurinic/apyrimidinic endonuclease 1 (APE1), both in vitro and in vivo. The conformational change of the DNA probe can be orthogonally triggered through TE‐induced DNA elongation and APE1‐mediated specific cleavage, producing a fluorescent signal for imaging the activity of the two enzymes in an AND‐gated manner. Furthermore, we demonstrate the capability of the system for specific tumor imaging through “dual lock‐and‐key” strategy, and visualizing the correlated enzymatic activities during drug treatment of cancer.

A Standardized Framework for Fluorescence-Guided Margin Assessment for Head and Neck Cancer Using a Tumor Acidosis Sensitive Optical Imaging Agent

PurposeIntra-operative management of the surgical margin in patients diagnosed with head and neck squamous cell carcinoma (HNSCC) remains challenging as surgeons still have to rely on visual and tactile information. Fluorescence-guided surgery using tumor-specific imaging agents can assist in clinical decision-making. However, a standardized imaging methodology is lacking. In this study, we determined whether a standardized, specimen-driven, fluorescence imaging framework using ONM-100 could assist in clinical decision-making during surgery.ProceduresThirteen patients with histologically proven HNSCC were included in this clinical study and received ONM-100 24 ± 8 h before surgery. Fluorescence images of the excised surgical specimen and of the surgical cavity were analyzed. A fluorescent lesion with a tumor-to-background ratio (TBR) > 1.5 was considered fluorescence-positive and correlated to standard of care (SOC) histopathology.ResultsAll six tumor-positive surgical margins were detected immediately after excision using fluorescence-guided intra-operative imaging. Postoperative analysis showed a median TBR (±IQR) of the fluorescent lesions on the resection margin of 3.36 ± 1.62. Three fluorescence-positive lesions in the surgical cavity were biopsied and showed occult carcinoma and severe dysplasia, and a false-positive fluorescence lesion.ConclusionOur specimen-driven fluorescence framework using a novel, pH-activatable, fluorescent imaging agent could assist in reliable and real-time adequate clinical decision-making showing that a fluorescent lesion on the surgical specimen with a TBR of 1.5 is correlated to a tumor-positive resection margin. The binary mechanism of ONM-100 allows for a sharp tumor delineation in all patients, giving the surgeon a clinical tool for real-time margin assessment, with a high sensitivity.

EpCAM-Targeting Aptamer Radiotracer for Tumor-Specific PET Imaging.

Noninvasive in vivo imaging to measure the expression of EpCAM, a biomarker overexpressed in the majority of carcinoma tumors and metastatic lesions, is highly desirable for accurate tumor staging and therapy evaluation. Here, we report the use of an aptamer radiotracer to enable tumor-specific EpCAM-targeting PET imaging. Oligonucleotide aptamers are small molecular ligands that specifically bind with high affinity to their target molecules. For specific tumor imaging, an aptamer radiotracer was formulated by chelating a 64Cu isotope and DOTA-PEGylated aptamer sequence to target EpCAM. In vitro cell uptake assays demonstrated that the aptamer radiotracer specifically bound EpCAM-expressing breast cancer cells but did not react with off-target tumor cells. For in vivo tumor imaging, aptamer radiotracer was systemically administered into xenograft mice. MicroPET/CT scans revealed that the aptamer radiotracer rapidly highlighted xenograft tumors derived from MDA-MB-231 breast cancer cells (EpCAM positive) as early as 2 h postadministration with a gradually increasing tumor uptake signal that peaked at 24 h but not in lymphoma 937 tumors (EpCAM negative). In contrast, nonspecific background signals in the liver and kidneys were rapidly decreased postadministration. This proof-of-concept study demonstrates the utility of aptamer radiotracers for tumor-specific PET imaging.

Dual-Stimulus Responsive Near-Infrared Reversible Ratiometric Fluorescent and Photoacoustic Probe for In Vivo Tumor Imaging.

Tumor-specific imaging is a major challenge in clinical tumor resection. To overcome this problem, several activatable probes have been developed for use in tumor imaging. However, most of these probes are activated based on a single-factor stimulation and are irreversible. Therefore, false signals that make tumor-specific imaging difficult are easily generated. We have developed a new dual-stimulus responsive near-infrared (NIR) reversible adenosine 5'-triphosphate (ATP)-pH probe for fluorescence and photoacoustic ratiometric imaging of tumors. Since the H+ and ATP content is significantly higher in the tumor microenvironment than that in normal tissues, the Förster resonance energy transfer-based probe ATP-pH was constructed with silicon rhodamine as the donor, CS dye as the acceptor, and ATP/H+ recognition units that could only be activated when both H+ and ATP were connected to the acceptor. The ATP-pH probe is reversibly activated by both the H+ and ATP, which effectively reduces the cumulative response of the probe in circulation after intravenous injection. Further, the NIR ratiometric property of the probe makes it suitable for in vivo imaging. Finally, our probe was successfully utilized in ratiometric photoacoustic and fluorescence tumor imaging and ratiometric fluorescence imaging-guided tumor resection.

Development of biotin-tagged near-infrared fluorescence probes for tumor-specific imaging

Near-infrared (NIR) probes are applicable for tumor imaging due to deep tissue penetration and low background signal. And cyanine dyes with long emission wavelength are excellent fluorophores to develop NIR probes. However, the aggregation of cyanine dyes in aqueous solution reduces the utilization of light. To solve this problem, polyethylene glycol (PEG) was introduced into the probes to reduce their aggregation. In our work, two new NIR probes G1 and G2 were designed and prepared by conjugating the cyanine dye G0 with Biotin-PEG5-Azide. The conjugated biotin could enhance the target specificity of probes. And the photophysical and photochemical parameters demonstrated that G1 and G2 had a reduced aggregation tendency. In vitro fluorescence imaging proved that these two probes could be specifically taken up by HeLa cells, and in vivo imaging demonstrated that these two probes could specifically target tumors with large tumor-to-muscle (T/M) ratios. All these results indicated that G1 and G2 are promising NIR fluorescent contrast agents for tumor-specific imaging.

Recent Advances in Nanotechnology-Based Diagnosis and Treatments of Human Osteosarcoma.

Osteosarcoma (OSA) is a type of bone cancer that begins in the cells that form bones.OSA is a rare mesenchymal bone neoplasm derived from mesenchymal stem cells. Genome disorganization, chromosomal modifications, deregulation of tumor suppressor genes, and DNA repair defects are the factors most responsible for OSA development. Despite significant advances in the diagnosing and treatment of OSA, patients’ overall survival has not improved within the last twenty years. Lately, advances in modern nanotechnology have spurred development in OSA management and offered several advantages to overcome the drawbacks of conventional therapies. This technology has allowed the practical design of nanoscale devices combined with numerous functional molecules, including tumor-specific ligands, antibodies, anti-cancer drugs, and imaging probes. Thanks to their small sizes, desirable drug encapsulation efficiency, and good bioavailability, functionalized nanomaterials have found wide-spread applications for combating OSA progression. This review invokes the possible utility of engineered nanomaterials in OSA diagnosis and treatment, motivating the researchers to seek new strategies for tackling the challenges associated with it.

Candidate Biomarkers for Specific Intraoperative Near-Infrared Imaging of Soft Tissue Sarcomas: A Systematic Review.

Simple SummaryNear-infrared imaging of tumors during surgery facilitates the oncologic surgeon to distinguish malignant from healthy tissue. The technique is based on fluorescent tracers binding to tumor biomarkers on malignant cells. Currently, there are no clinically available fluorescent tracers that specifically target soft tissue sarcomas. This review searched the literature to find candidate biomarkers for soft tissue sarcomas, based on clinically used therapeutic antibodies. The search revealed 7 biomarkers: TEM1, VEGFR-1, EGFR, VEGFR-2, IGF-1R, PDGFRα, and CD40. These biomarkers are abundantly present on soft tissue sarcoma tumor cells and are already being targeted with humanized monoclonal antibodies. The conjugation of these antibodies with a fluorescent dye will yield in specific tracers for image-guided surgery of soft tissue sarcomas to improve the success rates of tumor resections.Surgery is the mainstay of treatment for localized soft tissue sarcomas (STS). The curative treatment highly depends on complete tumor resection, as positive margins are associated with local recurrence (LR) and prognosis. However, determining the tumor margin during surgery is challenging. Real-time tumor-specific imaging can facilitate complete resection by visualizing tumor tissue during surgery. Unfortunately, STS specific tracers are presently not clinically available. In this review, STS-associated cell surface-expressed biomarkers, which are currently already clinically targeted with monoclonal antibodies for therapeutic purposes, are evaluated for their use in near-infrared fluorescence (NIRF) imaging of STS. Clinically targeted biomarkers in STS were extracted from clinical trial registers and a PubMed search was performed. Data on biomarker characteristics, sample size, percentage of biomarker-positive STS samples, pattern of biomarker expression, biomarker internalization features, and previous applications of the biomarker in imaging were extracted. The biomarkers were ranked utilizing a previously described scoring system. Eleven cell surface-expressed biomarkers were identified from which 7 were selected as potential biomarkers for NIRF imaging: TEM1, VEGFR-1, EGFR, VEGFR-2, IGF-1R, PDGFRα, and CD40. Promising biomarkers in common and aggressive STS subtypes are TEM1 for myxofibrosarcoma, TEM1, and PDGFRα for undifferentiated soft tissue sarcoma and EGFR for synovial sarcoma.

Nanobody-A versatile tool for cancer diagnosis and therapeutics.

In spite of the successful use of monoclonal antibodies (mAbs) in clinic for tumor treatment, their applications are still hampered in therapeutic development due to limitations, such as tumor penetration and high cost of manufacture. Nanobody, a single domain antibody that holds the strong antigen targeting and binding capacity, has demonstrated various advantages relative to antibody. Nanobody is considered as a next-generation of antibody-derived tool in the antigen related recognition and modulation. A number of nanobodies have been developed and evaluated in different stages of clinical trials for cancer treatment. Here we summarized the current progress of nanobody in tumor diagnosis and therapeutics, particularly on the conjugation of nanobody with functional moieties. The nanobody conjugation of diagnostic agents, such as radionuclide and optical tracers, can achieve specific tumor imaging. The nanobody-drug conjugates can enhance the therapeutic efficacy of anti-tumor drugs and reduce the adverse effects. The decoration of nanobody on nanodrug delivery systems can further improve the drug targeting to specific tumors. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

All-in-one mitochondria-targeted NIR-II fluorophores for cancer therapy and imaging.

Small-molecule subcellular organelle-targeting theranostic probes are crucial for early disease diagnosis and treatment. The imaging window of these molecules is mainly focused on the visible and near-infrared region (below ∼900 nm) which limits the tissue penetration depth and therapeutic effects. Herein, a novel NIR-II small-molecule probe H4–PEG-Glu with a thiopyrylium cation was synthesized. H4–PEG-Glu not only can quickly and effectively image mitochondria in acute myeloid leukemia (AML) cells, and induce G0/G1 phase arrest by the intrinsic mitochondrial apoptosis pathway w/o irradiation, but also exhibit moderate cytotoxicity against AML cancer cells in a dose dependent-manner without laser irradiation. The THP-1 cells treated with H4–PEG-Glu upon NIR laser irradiation showed enhanced chemo- and photothermal therapy (CPTT) with 93.07% ± 6.43 apoptosis by Annexin V staining. Meanwhile, H4–PEG-Glu displayed high synergistic CPTT effects in vivo, as well as specific NIR-II tumor imaging in AML patient derived PDX mouse models for the first time. Our work lays down a solid foundation for designing small-molecule NIR-II mitochondria-selective theranostic probes.

Enzymatical biomineralization of DNA nanoflowers mediated by manganese ions for tumor site activated magnetic resonance imaging

DNA nanoflower has been demonstrated as a promising DNA nanostructure for therapeutics and bioimaging primarily because of the programmable DNA sequence and unique structure. Herein, we report manganese ions mediated enzymatic biomineralization to prepare DNA-Mn hybrid nanoflower (DMNF). Paramagnetic Mn2+ was explored as the co-factor of DNA polymerase for the extension of long strand DNA. The biomimetic synthesis of DMNF was performed using the long strand DNA as template via nucleation and growth of Mn2PPi. The morphology and size of DMNF were controllable by tuning reaction time and Mn2+ concentration. The aptamer sequence was encoded into circle template to achieve tumor-targeted DMNF, and cellular uptake assay demonstrated obvious aptamer-mediated internalization. DMNF showed enhanced T1-weighted magnetic resonance (MR) imaging effect in acid environment for high tumor-specific MR imaging, and high spatial resolution imaging of kidneys and liver. Our work provides a facile enzymatically biomineral strategy to integrate multifunctional modules into one DNA structure and promotes the development of DNA nanostructure for precision medicine.

NIMG-01. MRI VIRTUAL BIOPSY AND TREATMENT OF PRIMARY OR BRAIN METASTATIC TUMORS WITH TARGETED NANOBIOCONJUGATES

Abstract Differential diagnosis of brain magnetic resonance imaging (MRI) enhancement(s) remains a significant problem, which may be difficult to resolve without biopsy that can be often dangerous or even impossible. Such MRI enhancement(s) can result from metastasis of primary tumors such as lung or breast, radiation necrosis, infections or a new primary brain tumor (glioma, meningioma). Neurological symptoms are often the same on initial presentation. METHODS: We present a noninvasive tumor-specific imaging approach “MRI virtual biopsy” by engineering new nano imaging agents (NIA) on polymalic acid polymer (PMLA) scaffold containing linear-Gd-DOTA or star-Gd-DOTA moieties for differential diagnosis of brain tumors. The strategy is that after non-invasive MRI diagnosis recognizing the brain lesion on the basis of its molecular signatures, the primary cancer or brain metastasis (BM) is suppressed by tumor-specific molecular inhibitor(s), which is structurally similar to the used NIA. Anti-TfR antibody or Angiopep-2 (AP-2) peptide used to cross blood-brain barrier (BBB) by receptor-mediated transcytosis, and targeting antibody against EFGR- or HER2-overexpressing tumors were covalently attached to PMLA to recognize the tissues of interest. Delivery of contrast agents across BBB was studied by optical imaging. MRI signals in healthy brain and tumors were quantified using 9.4-Tesla MRI system. RESULTS: High specific signal values prevailed for 3 hours for NIA, in comparison with clinical Gd (MultiHance) that declined rapidly. In newly developed double tumor xenogeneic mouse models of brain metastasis this method allowed differential diagnosis of HER2- and EGFR-expressing brain tumors. After MRI diagnosis, breast and lung cancer brain metastases were successfully treated with similar tumor-targeted nanoconjugates carrying molecular inhibitors of EGFR or HER2 instead of imaging contrast agent. The treatment resulted in significant increase of animal survival and markedly reduced immunostaining for several cancer stem cell markers. Support: NIH grants: R01 CA188743, R01 CA206220, R01 CA209921

Intraoperative detection of colorectal and pancreatic liver metastases using SGM-101, a fluorescent antibody targeting CEA

BackgroundFluorescence-guided surgery can provide surgeons with an imaging tool for real-time intraoperative tumor detection. SGM-101, an anti-CEA antibody labelled with a fluorescent dye, is a tumor-specific imaging agent that can aid in improving detection and complete resection for CEA-positive tumors. In this study, the performance of SGM-101 for the detection of colorectal and pancreatic liver metastases was investigated. MethodsIn this open-label, non-randomized, single-arm pilot study, patients were included with liver metastases from colorectal origin and intraoperatively detected liver metastases from pancreatic origin (during planned pancreatic surgery). SGM-101 was administered two to four days before the scheduled surgery as a single intravenous injection. Intraoperative fluorescence imaging was performed using the Quest Spectrum® imaging system. The performance of SGM-101 was assessed by measuring the intraoperative fluorescence signal and comparing this to histopathology. ResultsA total of 19 lesions were found in 11 patients, which were all suspected as malignant in white light and subsequent fluorescence inspection. Seventeen lesions were malignant with a mean tumor-to-background ratio of 1.7. The remaining two lesions were false-positives as proven by histology. ConclusionCEA-targeted fluorescence-guided intraoperative tumor detection with SGM-101 is feasible for the detection of colorectal and pancreatic liver metastases.

Expression of integrin ανβ6 differentiates perihilar cholangiocarcinoma (PHC) from benign disease mimicking PHC

BackgroundApproximately 15% of patients undergoing resection for presumed perihilar cholangiocarcinoma (PHC) have benign disease at final pathological assessment. Molecular imaging targeting tumor-specific biomarkers could serve as a novel diagnostic tool to reduce these futile surgeries. Imaging agents have been developed, selectively binding integrin ανβ6, a cell receptor upregulated in pancreatobiliary malignancies, for both (preoperative) PET and (intraoperative) fluorescent imaging. Here, expression of integrin ανβ6 is evaluated in PHC, intrahepatic cholangiocarcinoma (ICC), hepatocellular carcinoma (HCC) and benign disease mimicking PHC using immunohistochemistry. Materials & methodsThree tissue microarrays (TMA) including 103 PHC tumor cores and sixty tissue samples were selected from resection specimens of pathologically proven PHC (n = 20), ICC (n = 10), HCC (n = 10), metastatic PHC lymph nodes (n = 10) and benign disease (presumed PHC with benign disease at pathological assessment, n = 10). These samples were stained for integrin ανβ6 and quantified using the H-score. ResultsImmunohistochemical staining for integrin ανβ6 showed membranous expression in all twenty PHC whole mount slides (100%) and 93 out of 103 (92%) PHC tumor cores. Mean H-score of PHC samples was 195 ± 71, compared to a mean H-score of 126 ± 57 in benign samples (p = 0.013). In both benign and PHC samples, inflammatory infiltrates and pre-existent peribiliary glands showed integrin ανβ6 expression. The mean H-score across ten ICC was 33 ± 53, which was significantly lower compared to PHC (p < 0.001) but too weak to consistently discriminate ICC from HCC (H-score 0)(p = 0.062). ConclusionIntegrin ανβ6 is abundantly expressed in PHC and associated metastatic lymph nodes. Expression is significantly higher in PHC as compared to benign disease mimicking PHC, ICC and HCC, emphasizing its potential as a target for tumor-specific molecular imaging.

Abstract 1652: Tumor-specific PET imaging with an 18F-labeled tryptophan analogue in a transgenic medulloblastoma mouse model

Abstract In vivo positron emission tomography (PET) imaging is a key modality to evaluate disease status of brain tumors. In recent years, tremendous efforts have been made in developing PET imaging methods for pediatric brain tumors. Carbon-11 labelled tryptophan derivatives are feasible as PET imaging probes in brain tumor patients with activation of the kynurenine pathway, but the short half-life of carbon-11 limits its application. Using a transgenic mouse model for the sonic hedgehog (Shh) subgroup of medulloblastoma, here we evaluated the potential of the newly developed 1-(2-[18F]fluoroethyl)-L-tryptophan (1-L-[18F]FETrp) as a PET imaging probe for this common malignant pediatric brain tumor. 1-L-[18F]FETrp was synthesized on a PETCHEM automatic synthesizer with good chemical and radiochemical purities and enantiomeric excess values. Imaging was performed in tumor-bearing Smo/Smo medulloblastoma mice using a Perkin-Elmer G4 PET-X-Ray scanner. Medulloblastoma tumors showed significant and specific accumulation of 1-L-[18F]FETrp. 1-L-[18F]FETrp also showed significantly higher tumor uptake than its D-enantiomer 1-D-[18F]FETrp. The uptake of 1-L-[18F]FETrp in normal brain tissue was low, suggesting that 1-L-[18F]FETrp may prove a valuable PET imaging probe for the Shh subgroup of medulloblastoma and possibly other pediatric and adult brain tumors. Citation Format: Xuyi Yue, Yangchun Xin, Hua Li, Zhiqin Li, Hancheng Cai, Sigrid A. Langhans. Tumor-specific PET imaging with an 18F-labeled tryptophan analogue in a transgenic medulloblastoma mouse model [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1652.

Multifunctional Smart Yolk-Shell Nanostructure with Mesoporous MnO2 Shell for Enhanced Cancer Therapy.

Manganese dioxide (MnO2) nanostructures have aroused great interest among analytical and biological medicine researchers as a unique type of tumor microenvironment (TME)-responsive nanomaterial. However, reliable approaches for synthesizing yolk-shell nanostructures (YSNs) with mesoporous MnO2 shell still remain exciting challenges. Herein, a YSN (size, ∼75 nm) containing a mesoporous MnO2 shell and Er3+-doped upconversion/downconversion nanoparticle (UCNP) core with a large cavity is demonstrated for the first time. This nanostructure not only integrates diverse functional components including MnO2, UCNPs, and YSNs into one system but also endows a size-controllable hollow cavity and thickness-tunable MnO2 layers, which can load various guest molecules like photosensitizers, methylene blue (MB), and the anticancer drugs doxorubicin (DOX). NIR-II fluorescence and photoacoustic (PA) imaging from UCNP and MB, respectively, can monitor the enrichment of the nanomaterials in the tumors for guiding chemo-photodynamic therapy (PDT) in vivo. In the TME, degradation of the mMnO2 shell by H2O2 and GSH not only generates Mn2+ for tumor-specific T1-MR imaging but also releases O2 and drugs for tumor-specific treatment. The result confirmed that imaging-guided enhanced chemo-PDT combination therapy that benefited from the unique structural features of YSNs could substantially improve the therapeutic effectiveness toward malignant tumors compared to monotherapy.

Microenvironment-triggered dual-activation of a photosensitizer- fluorophore conjugate for tumor specific imaging and photodynamic therapy

Photodynamic therapy is attracting increasing attention, but how to increase its tumor-specificity remains a daunting challenge. Herein we report a theranostic probe (azo-PDT) that integrates pyropheophorbide α as a photosensitizer and a NIR fluorophore for tumor imaging. The two functionalities are linked with a hypoxic-sensitive azo group. Under normal conditions, both the phototoxicity of the photosensitizer and the fluorescence of the fluorophore are inhibited. While under hypoxic condition, the reductive cleavage of the azo group will restore both functions, leading to tumor specific fluorescence imaging and phototoxicity. The results showed that azo-PDT selectively images BEL-7402 cells under hypoxia, and simultaneously inhibits BEL-7402 cell proliferation after near-infrared irradiation under hypoxia, while little effect on BEL-7402 cell viability was observed under normoxia. These results confirm the feasibility of our design strategy to improve the tumor-targeting ability of photodynamic therapy, and presents azo-PDT probe as a promising dual functional agent.

Biosynthetic molecular imaging probe for tumor-targeted dual-modal fluorescence/magnetic resonance imaging

Molecular imaging enables noninvasive visualization of cancer-related biological processes for tumor diagnostics; engineering molecular probes for accurate and efficient tumor imaging remains challenge. Herein, by using a biosynthetic strategy, we prepared a tumor-targeted fluorescence/magnetic resonance protein-based probe for dual-modal imaging. The probe was biosynthesized by the fusion of targeting peptide (RGD) with fluorescence protein (RFP) and a small peptide (LBT) that had strong affinity with Gd3+. The probe showed excellent RGD-mediated tumor targeting and stable infrared emission, enabling sensitive tumor-specific imaging. Moreover, efficient T1-weighted magnetic resonance imaging was observed both in vitro and at tumor sites, facilitating high spatial resolution tumor imaging. The simultaneous dual-modal imaging provided more complementary information than each imaging modality. Our work demonstrates the capability of biosynthetic strategy to engineer molecular imaging probes for tumor-targeted multimodal bioimaging, and the probes can be customized to precisely localize and monitor other types of diseases.