Molecular Imaging Of Cancer Research Articles

Abstract LB-001: Development and evaluation of a fluorescent antibody-drug conjugate for molecular imaging and targeted therapy of pancreatic cancer

Abstract Developing new strategies to effectively diagnose and treat various types of cancer is paramount to increasing patient survival rates. Although chemotherapeutic small molecules are effective for some cancer types, they often have harmful side effects, resulting in significant damage to healthy tissue. Targeted therapy, where anti-cancer drugs are more precisely delivered to specific cells, has the potential to revolutionize chemotherapy, through increased localized effective doses with minimized systemic toxicity. Antibody-drug conjugates (ADCs) are one such class of targeted therapy biopharmaceuticals, employing the inherent specificity of antibodies as a targeting mechanism to yield a potent drug delivery system. In addition to being used as ADCs, antibody-conjugates are also commonly used as a highly effective tool for cancer typing and longitudinal treatment monitoring by immunohistochemistry staining or diagnostic imaging. However, antibody-conjugates used for tumor diagnosis and treatment are different molecules. Fluorescent dye labeling of therapeutic antibodies has been previously demonstrated for cancer imaging. However, therapeutic antibodies dual-labeled with both chemotherapeutic small molecules and fluorescent dyes has not been reported. Here, we demonstrate the development of a directly-labeled, fluorescent antibody-drug conjugate for simultaneous targeted drug delivery and in vivo molecular imaging of cancer. Our novel biopharmaceutical entity is a monoclonal antibody specific for a carcinoembryonic antigen (CEA) biomarker conjugated to an average of one molecule of paclitaxel and two molecules of a near-infrared fluorophore (DyLight 680-4xPEG). Preliminary data show that this fluorescent ADC selectively binds CEA positive cells and is cytotoxic using in vitro model systems. Ongoing studies using an in vivo mouse xenograft cancer model will demonstrate the utility of this fluorescent ADC as a new concurrent pancreatic cancer detection, monitoring and treatment technology. Citation Format: Steve Knutson, Erum Raja, Ryan Bomgarden, Marie Nlend, Aoshuang Chen, Ramaswamy Kalyanasundaram, Surbhi Desai. Development and evaluation of a fluorescent antibody-drug conjugate for molecular imaging and targeted therapy of pancreatic cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-001. doi:10.1158/1538-7445.AM2015-LB-001

Mammalian models of chemically induced primary malignancies exploitable for imaging-based preclinical theragnostic research.

Compared with transplanted tumor models or genetically engineered cancer models, chemically induced primary malignancies in experimental animals can mimic the clinical cancer progress from the early stage on. Cancer caused by chemical carcinogens generally develops through three phases namely initiation, promotion and progression. Based on different mechanisms, chemical carcinogens can be divided into genotoxic and non-genotoxic ones, or complete and incomplete ones, usually with an organ-specific property. Chemical carcinogens can be classified upon their origins such as environmental pollutants, cooked meat derived carcinogens, N-nitroso compounds, food additives, antineoplastic agents, naturally occurring substances and synthetic carcinogens, etc. Carcinogen-induced models of primary cancers can be used to evaluate the diagnostic/therapeutic effects of candidate drugs, investigate the biological influential factors, explore preventive measures for carcinogenicity, and better understand molecular mechanisms involved in tumor initiation, promotion and progression. Among commonly adopted cancer models, chemically induced primary malignancies in mammals have several advantages including the easy procedures, fruitful tumor generation and high analogy to clinical human primary cancers. However, in addition to the time-consuming process, the major drawback of chemical carcinogenesis for translational research is the difficulty in noninvasive tumor burden assessment in small animals. Like human cancers, tumors occur unpredictably also among animals in terms of timing, location and the number of lesions. Thanks to the availability of magnetic resonance imaging (MRI) with various advantages such as ionizing-free scanning, superb soft tissue contrast, multi-parametric information, and utility of diverse contrast agents, now a workable solution to this bottleneck problem is to apply MRI for noninvasive detection, diagnosis and therapeutic monitoring on those otherwise uncontrollable animal models with primary cancers. Moreover, it is foreseeable that the combined use of chemically induced primary cancer models and molecular imaging techniques may help to develop new anticancer diagnostics and therapeutics.

Redox-Sensitive Polymer/SPIO Nanocomplexes for Efficient Magnetofection and MR Imaging of Human Cancer Cells

Magnetofection has received increasing attention for its great potential on gene therapy. To promote its clinical therapeutic applications, development of safe and effective magnetic nanocarriers is in high demand. Herein, we present a redox-sensitive polymer/metal nanocomplex system (PSPIO) for efficient magnetofection and magnet resonance imaging (MRI) on cancer cells. PSPIO was prepared by modifying SPIO with redox-sensitive polyethylenimine (SSPEI) via a ligand exchange process. PSPIO could efficiently condense plasmid DNA (pDNA) into nanoparticles, which exhibited several favorable properties for gene delivery, including protection of nucleic acids from enzymatic degradation, stable colloids in serum, and redox-responsive pDNA release. As a potential MR imaging agent, PSPIO displayed good magnetization (28.3 emu/g) and dose-dependent T2-weighted imaging contrast (R2 = 291.1 s(-1) mM(-1)) in vitro. The use of redox-sensitive SSPEI polymer contributed to much lower cytotoxicity of PSPIO compared to nondegradable bPEI25k. In vitro transfection efficiency of PSPIO was significantly enhanced under an external magnetic field. In the presence of serum, PSPIO exhibited higher transgene expression than SSPEI or bPEI25k polymer on mouse glioma (ALTS1C1) or human prostate cancer (PC3) cell lines. Taken together, it is demonstrated that PSPIO possess great potential for cancer gene therapy and molecular imaging.

Is carbonic anhydrase IX a validated target for molecular imaging of cancer and hypoxia?

The presence of hypoxia is a general feature of most solid malignancies, and hypoxia is considered as one of major factors for anticancer therapy failure. Carbonic anhydrase IX (CAIX) has been reported to be an endogenous hypoxia marker, CAIX monoclonal antibodies, their segments and inhibitors are developed for CAIX imaging. However, growing evidence indicates that CAIX expression under hypoxia condition may be cancer cell lines or cancer-type dependent. Here we review the current literature on CAIX and discuss the advantage and limitation of CAIX as a target for tumor hypoxia imaging. Accordingly, CAIX would be unreliable as a universal target for cancer and tumor hypoxia visualization.

Challenges of Pancreatic Cancer.

The development of novel molecular cancer imaging agents has considerably advanced in recent years. Numerous cancer imaging agents have demonstrated remarkable potential for aiding the diagnosis, staging, and treatment planning at the preclinical stage, which in turn has led to a number of agents being approved for human trials. Pancreatic ductal adenocarcinoma is currently the most deadly common carcinoma with an overall 5-year survival rate of about 6%. As detection technologies progress, the need for molecular imaging tools that will allow the diagnosis at an early stage will be crucial to improving patient outcomes. In this review, we will highlight agents that illuminate various cell populations that comprise the tumor: epithelial, endothelial, and stromal tumor cells.

Near-infrared light-responsive nanomaterials for cancer theranostics.

Early diagnosis and effective cancer therapy are required, to properly treat cancer, which causes more than 8.2 million deaths in a year worldwide. Among various cancer treatments, nanoparticle-based cancer therapies and molecular imaging techniques have been widely exploited over the past decades to overcome current drawbacks of existing cancer treatments. In particular, gold nanoparticles (AuNPs), carbon nanotubes (CNTs), graphene oxide (GO), and upconversion nanocrystals (UNCs) have attracted tremendous attention from researchers due to their near-infrared (NIR) light-responsive behaviors. These nanomaterials are considered new multifunctional platforms for cancer theranostics. They would enable on-demand control of drug release or molecular imaging in response to a remote trigger by NIR light exposure. This approach allows the patient or physician to adjust therapy precisely to a target site, thus greatly improving the efficacy of cancer treatments, while reducing undesirable side effects. In this review, we have summarized the advantages of NIR light-responsive nanomaterials for in vivo cancer treatments, which includes NIR triggered photothermal therapy (PTT) and photodynamic therapy (PDT). Furthermore, recent developments, perspectives, and new challenges of NIR light-responsive nanomaterials are discussed for cancer theranostic applications.

PET imaging of insulin-like growth factor type 1 receptor expression with a 64Cu-labeled Affibody molecule.

The insulin-like growth factor 1 receptor (IGF-1R) serves as an attractive target for cancer molecular imaging and therapy. Previous single photon emission computerized tomography (SPECT) studies showed that the IGF-1R-targeting Affibody molecules (99m)Tc-ZIGF1R:4551-GGGC, [(99m)Tc(CO)3](+)-(HE)3-ZIGF1R:4551 and (111)In-DOTA-ZIGF1R:4551 can discriminate between high and low IGF-1R-expression tumors and have the potential for patient selection for IGF-1R-targeted therapy. Compared with SPECT, positron emission tomography (PET) may improve imaging of IGF-1R-expression, because of its high sensitivity, high spatial resolution, strong quantification ability. The aim of the present study was to develop the (64)Cu-labeled NOTA-conjugated Affibody molecule ZIGF-1R:4:40 as a PET probe for imaging of IGF-1R-positive tumor. An Affibody analogue (Ac-Cys-ZIGF-1R:4:40) binding to IGF-1R was site-specifically conjugated with NOTA and labeled with (64)Cu. Binding affinity and specificity of (64)Cu-NOTA-ZIGF-1R:4:40 to IGF-1R were evaluated using human glioblastoma U87MG cells. Small-animal PET, biodistribution, and metabolic stability studies were conducted on mice bearing U87MG xenografts after the injection of (64)Cu-NOTA-ZIGF-1R:4:40 with or without co-injection of unlabeled Affibody proteins. The radiosynthesis of (64)Cu-NOTA-ZIGF-1R:4:40 was completed successfully within 60min with a decay-corrected yield of 75%. (64)Cu-NOTA-ZIGF-1R:4:40 bound to IGF-1R with low nanomolar affinity (K D=28.55±3.95nM) in U87MG cells. (64)Cu-NOTA-ZIGF-1R:4:40 also displayed excellent in vitro and in vivo stability. In vivo biodistribution and PET studies demonstrated targeting of U87MG gliomas xenografts was IGF-1R specific. The tumor uptake was 5.08±1.07%ID/g, and the tumor to muscle ratio was 11.89±2.16 at 24h after injection. Small animal PET imaging studies revealed that (64)Cu-NOTA-ZIGF-1R:4:40 could clearly identify U87MG tumors with good contrast at 1-24h after injection. This study demonstrates that (64)Cu-NOTA-ZIGF-1R:4:40 is a promising PET probe for imaging IGF-1R positive tumor.

Cancer stratification by molecular imaging.

The lack of specificity of traditional cytotoxic drugs has triggered the development of anticancer agents that selectively address specific molecular targets. An intrinsic property of these specialized drugs is their limited applicability for specific patient subgroups. Consequently, the generation of information about tumor characteristics is the key to exploit the potential of these drugs. Currently, cancer stratification relies on three approaches: Gene expression analysis and cancer proteomics, immunohistochemistry and molecular imaging. In order to enable the precise localization of functionally expressed targets, molecular imaging combines highly selective biomarkers and intense signal sources. Thus, cancer stratification and localization are performed simultaneously. Many cancer types are characterized by altered receptor expression, such as somatostatin receptors, folate receptors or Her2 (human epidermal growth factor receptor 2). Similar correlations are also known for a multitude of transporters, such as glucose transporters, amino acid transporters or hNIS (human sodium iodide symporter), as well as cell specific proteins, such as the prostate specific membrane antigen, integrins, and CD20. This review provides a comprehensive description of the methods, targets and agents used in molecular imaging, to outline their application for cancer stratification. Emphasis is placed on radiotracers which are used to identify altered expression patterns of cancer associated markers.

Abstract 4926: Molecular imaging of colorectal cancer in the setting of colitis

Abstract Introduction: Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is defined by chronic inflammation of the gastrointestinal tract. In the colon, persistent colitis is a major risk factor in IBD-associated colorectal cancer (CRC). While primary and metastatic CRC can often be visualized using radiotracers such as 18F-FDG for PET imaging, the sensitivity for detection of primary CRC is decreased in the setting of IBD due to increased glucose metabolism at sites of inflammation. EGFR overexpression is reported in up to 97% of CRCs. The lower expression in inflammatory cells makes it a valuable imaging target to identify CRC in the setting of colitis. Objective: The goal of this effort is to develop and test in murine models an EGFR targeted PET imaging probe for the detection of CRC, with the ability to differentiate neoplasia from colonic inflammation. Methods: The F(ab')2 fragment of cetuximab was generated by enzymatic digestion. After the integrity and purity of the F(ab')2 was evaluated with SDS-PAGE and FPLC, the F(ab')2 fragment was conjugated with the p-SCN-Bn-DOTA chelate, and then radiolabeled with 64Cu. The receptor binding affinity and specificity of the 64Cu-DOTA-F(ab')2 was evaluated using EGFR expressing CT26 murine colon cancer cells. Tumor to bowel ratio of the EGFR PET imaging probe was compared with 18F-FDG using DSS-treated CT26 tumor-bearing BALB/c mice at 24 h. The in vivo behavior of the probe was demonstrated with PET-CT in two different mouse models of CRC (ApcCKOp53flox/flox and ApcLoxP/ LoxPMsh2null/LoxP). Histochemical examination were also performed. Results: F(ab')2 fragments of cetuximab can be generated efficiently and with high purity. The radioligand binding assay revealed that 64Cu labeled EGFR-DOTA-F(ab')2 conjugate bound specifically to EGFR on CT26 xenografts, with KD and Bmax values in vitro of 6.6 0.7 nM and 3.3 0.1 x 106 receptors/cell respectively. DSS-induced colitis was confirmed with relative change in body weight, 18F-FDG PET imaging, and histological examination. 64Cu-DOTA-F(ab')2 showed a significantly higher (p < 0.001) tumor to bowel ratio (TBR = 3.8 0.10) in comparison with 18F-FDG (TBR =1.5 0.05) during inflammation in the colon. Colon tumors in GEMM were successfully visualized and showed high correlation with ex-vivo PET imaging results and IHC examination. Conclusions: The developed EGFR targeted PET imaging probe demonstrated high target specificity for colonic tumors in the setting of colitis as compared to 18F-FDG. Future clinical translation of this paradigm is promising for the detection of CRC in IBD. Citation Format: N. Selcan Turker, Umar Mahmood, Melani H. Kucherlapati, Raju Kucherlapati. Molecular imaging of colorectal cancer in the setting of colitis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4926. doi:10.1158/1538-7445.AM2014-4926

Abstract 3005: Vascular endothelial growth factor A - a systematic review and meta-analysis of expression patterns in breast cancer

Abstract Background Vascular Endothelial Growth Factor-A (VEGF-A), pivotal for neo-angiogenesis, is an interesting target for breast cancer molecular imaging. To assess its potential clinical value, we performed a systematic review and meta-analysis of VEGF-A expression rates in normal breast tissue, benign and (pre-)invasive breast disease, and investigated associations with clinicopathological characteristics. Methods We systematically searched EMBASE and MEDLINE for articles describing VEGF-A expression in breast disease assessed by immunohistochemistry (IHC) or Enzyme-Linked Immunosorbent Assay (ELISA). We pooled IHC expression rates with random-effects models and applied meta-regression to identify associations with clinicopathological characteristics. We summarized findings for ELISA results. Results Of 2,711 unique articles retrieved, 157 studies described IHC results (16,046 tissue samples). Pooled expression rates were lower in studies applying antibody clone VG1 (-21%, p=0.018) or C-1 (-24%, p=0.016), compared to A-20. Expression compared to invasive carcinoma was lower in normal tissue (-51%, p<0.001) and benign breast diseases (-34%, p<0.001), but comparable for carcinoma in situ (+5%, p=0.289). Expression rates increased with tumour grade (II: +14%, p<0.001; III: +25%, p<0.001), stage (II: +11%, p<0.001; III: +22%, p<0.001), size (T3/4: +11%, p=0.004), HER2-positivity (+14%, p<0.001), lymph node positivity(+11%, p<0.001), and decreased in hormone receptor positive (PR-positive: -7%, p<0.001; ER-positive:-8%, p<0.001) and lobular cancers (-14%, p<0.001). Substantial heterogeneity was observed in study results. Furthermore, expression rates strongly depended on VEGF-A positivity threshold. VEGF-A levels assessed by ELISA (42 studies, 8,498 samples) were highly variable. Conclusion Although reported VEGF-A expression rates in breast cancer were variable, we found significant correlations with clinicopathological characteristics indicating aggressive disease. Also, expression rates were low in normal breast tissue and benign breast disease. As expression rates strongly depended on VEGF-A positivity - arguing against an on/off phenomenon - applicability of VEGF-A for molecular imaging purposes will depend on sensitivity of the molecular imaging modality, target population, and envisioned applications. Acknowledgment This research was supported by the Center for Translational Molecular Medicine (MAMMOTH). Citation Format: Arthur Adams, Jeroen Vermeulen, Peter Zuithoff, Elsken Van der Wall, Laetitia Lamberts, Elisabeth de Vries, Johannes de Jong, Gooitzen Van Dam, Paul J. van Diest, Willem P.Th.M. Mali, Sjoerd G. Elias. Vascular endothelial growth factor A - a systematic review and meta-analysis of expression patterns in breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3005. doi:10.1158/1538-7445.AM2014-3005

Synthesis of AS1411-aptamer-conjugated CdTe quantum dots with high fluorescence strength for probe labeling tumor cells.

In this paper, we report microwave-assisted, one-stage synthesis of high-quality functionalized water-soluble cadmium telluride (CdTe) quantum dots (QDs). By selecting sodium tellurite as the Te source, cadmium chloride as the Cd source, mercaptosuccinic acid (MSA) as the capping agent, and a borate-acetic acid buffer solution with a pH range of 5-8, CdTe nanocrystals with four colors (blue to orange) were conveniently prepared at 100 °C under microwave irradiation in less than one hour (reaction time: 10-60 min). The influence of parameters such as the pH, Cd:Te molar ratio, and reaction time on the emission range and quantum yield percentage (QY%) was investigated. The structures and compositions of the prepared CdTe QDs were characterized by transmission electron microscopy, energy-dispersive X-ray spectroscopy, selective area electron diffraction, and X-ray powder diffraction experiments. The formation mechanism of the QDs is discussed in this paper. Furthermore, AS1141-aptamer-conjugated CdTe QDs in the U87MG glioblastoma cell line were assessed with a fluorescence microscope. The obtained results showed that the best conditions for obtaining a high QY of approximately 87% are a pH of 6, a Cd:Te molar ratio of 5:1, and a 30-min reaction time at 100 °C under microwave irradiation. The results showed that AS1141-aptamer-conjugated CdTe QDs could enter tumor cells efficiently. It could be concluded that a facile high-fluorescence-strength QD conjugated with a DNA aptamer, AS1411, which can recognize the extracellular matrix protein nucleolin, can specifically target U87MG human glioblastoma cells. The qualified AS1411-aptamer-conjugated QDs prepared in this study showed excellent capabilities as nanoprobes for cancer targeting and molecular imaging.

SPECT and near-infrared fluorescence imaging of breast cancer with a neuropilin-1-targeting peptide.

Breast cancer is the most common malignant cancer and is the leading cause of cancer death among females. Molecular imaging is a promising approach for the early detection and staging of breast cancer as well as for assessing therapeutic responses. Tumor-targeting peptides are effective targeting vehicles for molecular imaging. Here, we identified a breast cancer-targeting peptide CLKADKAKC (CK3) contains a cryptic C-end rule motif that may mediate its binding to neuropilin-1 (NRP-1), an attractive therapeutic target which expression was associated with poor outcome of the patients with breast cancer. Phage CK3 bound to NRP-1-positive breast cancer cells, which could be inhibited by peptide CK3 in a dose-dependent manner or by knock-down NRP-1 expression. Consistently, NRP-1 overexpression in cells increased the binding of phage CK3. Furthermore, peptide CK3 co-localized with NRP-1. Importantly, unlike previously reported NRP-1-targeting peptides with exposed C-end rule motifs, peptide CK3 did not penetrate into lungs and heart in vivo, which could make it more clinically applicable. Single-photon emission CT (SPECT) and near-infrared fluorescence (NIRF) imaging showed enrichment of peptide CK3 to the xenograft tumors in nude mice. In conclusion, as a novel NRP-1-targeting peptide, peptide CK3 could be used for breast cancer molecular imaging, which may represent a new avenue for breast cancer diagnostics, staging and assessments of therapeutic response.

Synthesis and evaluation of 2-amino-5-(4-[(18)F]fluorophenyl)pent-4-ynoic acid ([(18)F]FPhPA): a novel (18)F-labeled amino acid for oncologic PET imaging.

(18)F-labeled amino acids are important PET radiotracers for molecular imaging of cancer. This study describes synthesis and radiopharmacological evaluation of 2-amino-5-(4-[(18)F]fluorophenyl)pent-4-ynoic acid ([(18)F]FPhPA) as a novel amino acid radiotracer for oncologic imaging. (18)F]FPhPA was prepared using Pd-mediated Sonogashira cross-coupling reaction between 4-[(18)F]fluoroiodobenzene ([(18)F]FIB) and propargylglycine. The radiopharmacological profile of [(18)F]FPhPA was evaluated in comparison with O-(2-[(18)F]fluoroethyl)-L-tyrosine ([(18)F]FET) using the murine breast cancer cell line EMT6 involving cellular uptake studies, radiotracer uptake competitive inhibition experiments and small animal PET imaging. (18)F]FPhPA was prepared in 42±10% decay-corrected radiochemical yield with high radiochemical purity >95% after semi-preparative HPLC purification. Cellular uptake of L-[(18)F]FPhPA reached a maximum of 58±14 % radioactivity/mg protein at 90 min. Lower uptake was observed for racemic and D-[(18)F]FPhPA. Radiotracer uptake inhibition studies by synthetic and naturally occurring amino acids suggested that Na(+)-dependent system ASC, especially ASCT2, and Na(+)-independent system L are important amino acid transporters for [(18)F]FPhPA uptake into EMT6 cells. Small animal PET studies demonstrated similar high tumor uptake of [(18)F]FPhPA in EMT6 tumor-bearing mice compared to [(18)F]FET reaching a maximum standardized uptake value (SUV) of 1.35 after 60 min p.i.. Muscle uptake of [(18)F]FPhPA was higher (SUV30min=0.65) compared to [(18)F]FET (SUV30min=0.40), whereas [(18)F]FPhPA showed a more rapid uptake and clearance from the brain compared to [(18)F]FET. L-[(18)F]FPhPA is the first (18)F-labeled amino acid prepared through Pd-mediated cross-coupling reaction. L-[(18)F]FPhPA displayed promising properties as a novel amino acid radiotracer for molecular imaging of system ASC and system L amino acid transporters in cancer.

MO‐C‐BRE‐01: The WMIS‐AAPM Joint Symposium: Advances in Molecular Imaging

This joint symposium of the World Molecular Imaging Society (WMIS) and the AAPM includes three luminary speakers discussing work in new paradigms of molecular imaging in cancer (Contag), applications of optical imaging technologies to radiation therapy (Pogue) and an update on PET imaging as a surrogate biomarker for cancer progression and response to therapy.Learning Objectives: Appreciate the current trends in molecular and systems imaging. Understand how optical imaging technologies, and particularly Cerenkov detectors, can be used in advancing radiation oncology. Stay current on new PET tracers – and targets – of interest in cancer treatment.

DNA‐Templated Assembly of a Heterobivalent Quantum Dot Nanoprobe For Extra‐ and Intracellular Dual‐Targeting and Imaging of Live Cancer Cells

AbstractQuantum dots (QDs) hold great promise for the molecular imaging of cancer because of their superior optical properties. Although cell‐surface biomarkers can be readily imaged with QDs, non‐invasive live‐cell imaging of critical intracellular cancer markers with QDs is a great challenge because of the difficulties in the automatic delivery of QD probes to the cytosol and the ambiguity of intracellular targeting signals. Herein, we report a new type of DNA‐templated heterobivalent QD nanoprobes with the ability to target and image two spatially isolated cancer markers (nucleolin and mRNA) present on the cell surface and in the cell cytosol. Bypassing endolysosomal sequestration, this type of QD nanoprobes undergo macropinocytosis following the nucleolin targeting and then translocate to the cytosol for mRNA targeting. Fluorescence resonance energy transfer (FRET) based confocal microscopy enables unambiguous signal deconvolution of mRNA‐targeted QD nanoprobes inside cancer cells.

DNA-templated assembly of a heterobivalent quantum dot nanoprobe for extra- and intracellular dual-targeting and imaging of live cancer cells.

Quantum dots (QDs) hold great promise for the molecular imaging of cancer because of their superior optical properties. Although cell-surface biomarkers can be readily imaged with QDs, non-invasive live-cell imaging of critical intracellular cancer markers with QDs is a great challenge because of the difficulties in the automatic delivery of QD probes to the cytosol and the ambiguity of intracellular targeting signals. Herein, we report a new type of DNA-templated heterobivalent QD nanoprobes with the ability to target and image two spatially isolated cancer markers (nucleolin and mRNA) present on the cell surface and in the cell cytosol. Bypassing endolysosomal sequestration, this type of QD nanoprobes undergo macropinocytosis following the nucleolin targeting and then translocate to the cytosol for mRNA targeting. Fluorescence resonance energy transfer (FRET) based confocal microscopy enables unambiguous signal deconvolution of mRNA-targeted QD nanoprobes inside cancer cells.

Compressed sensing based virtual-detector photoacoustic microscopyin vivo

Photoacoustic microscopy (PAM) is becoming a vital tool for various biomedical studies, including functional and molecular imaging of cancer. However, due to the use of a focused ultrasonic transducer for photoacoustic detection, the image quality of conventional PAM degrades rapidly away from the ultrasonic focal zone. To improve the image quality of PAM for out-of-focus regions, we have developed compressed sensing based virtual-detector photoacoustic microscopy (CS-PAM). Through phantom and in vivo experiments, it has been demonstrated that CS-PAM can effectively extend the depth of focus of PAM, and thus may greatly expand its potential biomedical applications.

Nanoparticle-Based Tumor Theranostics with Molecular Imaging

The past few decades have brought on a dramatic change in the treatment of cancer; however, routine treatments fail to specifically clear tumorigenic cells and may be followed by cancer recurrence. Recent advances in developing multifunctional nanoparticles provide exciting new possibilities for drug delivery used in tumor-targeted therapy. Moreover, molecular imaging is an invaluable tool in evaluating new molecular targets, cancer diagnosis, predicting of tumor response to available therapies and monitoring response to therapy as well as developing new drugs prior to clinical translation. Combining of targeted cancer therapy and molecular imaging, termed as image-guided drug delivery, can achieve objectives of noninvasive assessment of drug biodistribution and real-time monitoring of therapeutic responses. Image-guided drug delivery has become an upcoming field with extensive prospect in cancer therapy and may provide an effective platform for personalized cancer care. This review will focus on the significance and recent advances in targeted and traceable therapeutic strategy for cancer therapy.

Biological Carrier Molecules of Radiopharmaceuticals for Molecular Cancer Imaging and Targeted Cancer Therapy

Many tumors express one or more proteins that are either absent or hardly present in normal tissues, and which can be targeted by radiopharmaceuticals for either visualization of tumor cells or for targeted therapy. Radiopharmaceuticals can consist of a radionuclide and a carrier molecule that interacts with the tumor target and as such guides the attached radionuclide to the right spot. Radiopharmaceuticals hold great promise for the future of oncology by providing early, precise diagnosis and better, personalized treatment. Most advanced developments with marketed products are based on whole antibodies or antibody fragments as carrier molecules. However, a substantial number of (pre)clinical studies indicate that radiopharmaceuticals based on other carrier molecules, such as peptides, nonimmunoglobulin scaffolds, or nucleic acids may be valuable alternatives. In this review, we discuss the biological molecules that can deliver radionuclide payloads to tumor cells in terms of their structure, the selection procedure, their (pre)clinical status, and advantages or obstacles to their use in a radiopharmaceutical design. We also consider the plethora of molecular targets existing on cancer cells that can be targeted by radiopharmaceuticals, as well as how to select a radionuclide for a given diagnostic or therapeutic product.

Echographic imaging of tumoral cells through novel nanosystems for image diagnosis.

Since the recognition of disease molecular basis, it has become clear that the keystone moments of medical practice, namely early diagnosis, appropriate therapeutic treatment and patient follow-up, must be approached at a molecular level. These objectives will be in the near future more effectively achievable thanks to the impressive developments in nanotechnologies and their applications to the biomedical field, starting-up the nanomedicine era. The continuous advances in the development of biocompatible smart nanomaterials, in particular, will be crucial in several aspects of medicine. In fact, the possibility of manufacturing nanoparticle contrast agents that can be selectively targeted to specific pathological cells has extended molecular imaging applications to non-ionizing techniques and, at the same time, has made reachable the perspective of combining highly accurate diagnoses and personalized therapies in a single theranostic intervention. Main developing applications of nanosized theranostic agents include targeted molecular imaging, controlled drug release, therapeutic monitoring, guidance of radiation-based treatments and surgical interventions. Here we will review the most recent findings in nanoparticles contrast agents and their applications in the field of cancer molecular imaging employing non-ionizing techniques and disease-specific contrast agents, with special focus on recent findings on those nanomaterials particularly promising for ultrasound molecular imaging and simultaneous treatment of cancer.