Cancer Imaging Agents Research Articles

PEGylated Pemetrexed and PolyNIPAM Decorated Gold Nanoparticles: A Biocompatible and Highly Stable CT Contrast Agent for Cancer Imaging.

This study describes a multifunctional nanoparticle platform for targeted CT imaging and therapy of cancers. Pemetrexed (conjugated with polyethylene glycol, MW 2000 Da) and polyNIPAM (PEGylated) were designed for targeted delivery to folate receptors and thermally ablated tumors, respectively. These moieties were coated on gold nanoparticles (7 and 30 nm), and the prepared compounds were characterized using 1H NMR, FT-IR, CHNS, DLS, TEM, TGA, and UV-vis. The resulting agents exhibited 2-4 times higher X-ray attenuation compared to Visipaque and demonstrated specific accumulation in tumor tissue (4T1 xenograft model) 90 min after injection in mice. The nanoparticles displayed anticancer activity against 4T1 and MDA-MB-231 breast cancer cells (IC50: 182.87 and 206.18 μg/mL) and good biocompatibility. Importantly, the platform showed excellent stability over a year and at pH 2-12 and temperature range of -78 to 40 °C, and a water-dichloromethane extraction method was optimized for efficient purification, facilitating large-scale production.

Development of gelatin nanoparticles for positron emission tomography diagnosis in pancreatic cancer

Abstract Pancreatic cancer remains difficult to diagnose using currently available imaging probes. Thus, this study aimed to develop a novel imaging agent for the diagnosis of pancreatic cancer using positron emission tomography (PET). Specifically, this study explores gelatin-based nanoparticles fabricated via radiation-induced crosslinking, as gelatin is known for its ability to produce biocompatible materials. Aqueous gelatin solutions were irradiated with γ-rays to produce nanoparticles with average diameters of 5–20 nm via a radiation crosslinking technique. The gelatin nanoparticles were labeled with 64Cu, exhibiting negative surface potentials. Furthermore, the nanoparticles were evaluated in vivo by injecting them into pancreatic tumor-bearing mice. Notably, the nanoparticles accumulated in the tumors. Hence, 64Cu-labeled gelatin nanoparticles show promise as a platform for next-generation PET imaging agents for pancreatic cancer.

Time-efficient HPLC Validation Methodology for the Qualitative Analysis of 68Ga PSMA-11 in Routine Clinical Usage under Isocratic Method

Background: Prostate-specific membrane antigen (PSMA) has shown to be a promising agent for prostate cancer imaging under PET-CT. With the automation in radiolabeling with 68Ga, using iTG 68Ge/68Ga generator, it has helped introduce various new diagnostic agents and achieve good manufacturing practices (GMP) simultaneously. However, before any radiopharmaceutical is put into clinical usage, it should always be checked for its radiochemical purity and other quality parameters before injecting in the patient. Chromatography techniques such as Gas Chromatography (GC), High-Performance Liquid Chromatography (HPLC), and Thin-Layer Chromatography (TLC) are the most frequently utilized separation technique for purity analysis. A rapid quality control HPLC based methodology was required for radiopharmaceuticals. Aim & Objective: In our current setting, we conducted quality control analysis and standardized and validated HPLC method for the routine quality check of 68Ga-PSMA-11. Materials and Methods: The QC of 68Ga PSMA-11 was performed under ITLC and HPLC. Results: Linearity, accuracy, precision and specificity were assessed and quantified in accordance with International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use (Q2 (R1) ICH) guidelines, which can be implemented in resource-limited settings to check the quality. Conclusion: The current HPLC based methodology is rapid, with a retention time of 2.24 min, rendering it a favorable analytical standard operating procedure for QC analysis of 68Ga-PSMA-11.

Synthesis and Biological Evaluation of Fluorine-18 and Deuterium Labeled l-Fluoroalanines as Positron Emission Tomography Imaging Agents for Cancer Detection.

To fully explore the potential of 18F-labeled l-fluoroalanine for imaging cancer and other chronic diseases, a simple and mild radiosynthesis method has been established to produce optically pure l-3-[18F]fluoroalanine (l-[18F]FAla), using a serine-derivatized, five-membered-ring sulfamidate as the radiofluorination precursor. A deuterated analogue, l-3-[18F]fluoroalanine-d3 (l-[18F]FAla-d3), was also prepared to improve metabolic stability. Both l-[18F]FAla and l-[18F]FAla-d3 were rapidly taken up by 9L/lacZ, MIA PaCa-2, and U87MG cells and were shown to be substrates for the alanine-serine-cysteine (ASC) amino acid transporter. The ability of l-[18F]FAla, l-[18F]FAla-d3, and the d-enantiomer, d-[18F]FAla-d3, to image tumors was evaluated in U87MG tumor-bearing mice. Despite the significant bone uptake was observed for both l-[18F]FAla and l-[18F]FAla-d3, the latter had enhanced tumor uptake compared to l-[18F]FAla, and d-[18F]FAla-d3 was not specifically taken up by the tumors. The enhanced tumor uptake of l-[18F]FAla-d3 compared with its nondeuterated counterpart, l-[18F]FAla, warranted the further biological investigation of this radiotracer as a potential cancer imaging agent.

Preclinical studies and absorbed dose estimation of [89Zr]Zr-DFO-Bevacizumab for PET imaging of VEGF-expressing tumors

This study aimed to carry out the preclinical studies of [89Zr]Zr-DFO-Bevacizumab. The radiolabeled compound was prepared with radiochemical purity >99% (ITLC), and a specific activity of 74 GBq/g. Cellular studies indicated the great capability of [89Zr]Zr-DFO-Bevacizumab for binding to SKOV3 cell lines. High accumulation was observed in the tumor. The liver and spleen received the highest absorbed dose with 1.12 and 0.72 mGy/MBq, respectively. This radiopharmaceutical can be considered as a suitable PET agent for VEGF-expressing ovarian cancer imaging.

Abstract PO2-25-07: PEGylated Functional Upstream Domain (PEG-FUD): an anti-cancer therapy for breast Cancer

Abstract Background: Breast cancer (BC) is the most common cancer diagnosed in women. In breast cancers, the extracellular matrix (ECM) is known to play a key role in disease progression by mediating cell signaling processes that drive cancer cell proliferation, migration and invasion. Work by our group identified that aligned collagen fibers perpendicular to the tumor boundary are prognostic of poor patient prognosis. Further, through matrix targeted proteomics we determined that the ECM protein, Fibronectin (FN), organizes with aligned collagen fibers in BC tissues. FN is known as the master regulator of ECM assembly because FN deposition precedes and regulates the deposition of several other ECM proteins. Clinical evidence shows that high expression of FN levels in BC patients correlates with an increased mortality risk. Due to the abundant expression of FN in the tumor microenvironment, FN has been a useful biomarker for cancer imaging and therapy. Despite multiple efforts in developing therapies that target the ECM, currently there are no effective ECM treatments available due to toxicity and lack of specificity. Methods: To target abnormal FN deposition, we used a FN binding peptide, Functional Upstream Domain (FUD), derived from the F1 adhesin from Streptococcus pyogenes. PEGylated-FUD (PEG-FUD) is a potent inhibitor of FN assembly which binds the 70 kDa N-terminal region of FN with high affinity. We hypothesize that PEG-FUD will localize to the tumor site and that targeted disruption of FN assembly with PEG-FUD will reduce ECM deposition, thus block tumor progression in-vivo. In this study, we used an in vivo imaging system to assess the biodistribution of 20-kDa PEG-FUD following subcutaneous injection of Cy5 labeled peptide in 4T1 mammary tumor bearing mice. Additionally, in a second therapeutic experiment, we treated 4T1 mammary tumor bearing mice with 20-kDa PEG-FUD every 48 hr for a total of 10 treatments and measured tumor volume as an indicator of primary tumor burden. Results: As anticipated, we observed PEG-FUD’s accumulation and localization in 4T1 tumors. Additionally, PEG-FUD treatment significantly reduced tumor growth compared to saline treatment. There were no observed changes in standard toxicity assessments such as body weight and spleen weight among treatment groups. After PEG-FUD’s therapeutic treatment, we observed a significant reduction in the deposition of FN matrix and an increase in cleaved caspase-3, a known marker for apoptosis by western blotting providing a potential mechanism of action of PEG-FUD inducing changes in tumor growth. Conclusions: PEG-FUD’s localization in tumors suggests its utility as a solo cancer imaging agent while providing indications that PEG-FUD can be used to deliver other therapeutics to the tumor site as a conjugate in the future. In addition, therapeutic treatment of PEG-FUD inhibited tumor growth providing preliminary evidence for PEG-FUD’s use as a tumor targeting anti-cancer agent. Citation Format: Metti Gari. PEGylated Functional Upstream Domain (PEG-FUD): an anti-cancer therapy for breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-25-07.

Bifunctional folic acid targeted biopolymer Ag@NMOF nanocomposite [{Zn2 (1,4-bdc) 2 (DABCO)} n] as a novel theranostic agent for molecular imaging of colon cancer by SERS

Without a doubt, cancer and its negative impact on human health have created many hurdles for people across the world since conventional approaches have not offered a reliable ability in the eradication of cancer. As a result, finding novel approaches, like using bimodal nanoparticles as a potential nanocarrier in molecular imaging and cancer therapy, is remarkably required these days. In the present study, ex-situ (Ge) and in-situ (Gi) green synthesized silver (Ag) nanoparticles entrapped in metal-organic framework nanocomposites (NMOF) coated with folic acid (FA) targeted chitosan (CS) was successfully developed as a novel bifunctional nanocarrier for detection and treatment of colon cancer cells. Then nanocarriers, such as NMOF–CS–FA, Ge–Ag@NMOF–CS–FA, Gi-Ag@NMOF–CS–FA, and C–Ag@NMOF–CS–FA, were characterized via FT-IR, DLS, SERS, TEM, and SEM and results have potentially confirmed the quality and quantity of synthesized nanocomposites. The hydrodynamic diameters of NMOF-CS, Ge–Ag@NMOF-CS, Gi-Ag@NMOF-CS, and C–Ag@NMOF-CS specimens were measured at around 99.7 ± 10 nm, 110 ± 10 nm, 118 ± 10 nm, 115 ± 10 nm, respectively. Also, the PDI values less than 0.2 confirm the reliable distribution of these nanocomposites. Afterward, the cell viability assay was conducted on HCT116 and HGF cell lines for evaluating biocompatibility and targeting efficiency of nanocomposites; FA functionalized nanocomposites have intensively indicated better performance in cancer cells targeting and their inhibition, and IC50 was attained for 10 ng/mL of Ge–Ag@NMOF–CS–FA while non-targeted nanocarriers did not have toxicity more than 20 % on HCT116 colon cancer cells. Moreover, according to the results, the cell viability of HGF normal cells was at least 85 % after being exposed to different concentrations of nanocomposites for 24 h. This indicates that the synthesized nanocomposites do not have significant toxic effects on normal cells. The results indicate that this novel nanocomposite has the potential to effectively deliver drugs to cancer cells.

Cell-Penetrating and Enzyme-Responsive Peptides for Targeted Cancer Therapy: Role of Arginine Residue Length on Cell Penetration and In Vivo Systemic Toxicity.

For the improved delivery of cancer therapeutics and imaging agents, the conjugation of cell-penetrating peptides (CPPs) increases the cellular uptake and water solubility of agents. Among the various CPPs, arginine-rich peptides have been the most widely used. Combining CPPs with enzyme-responsive peptides presents an innovative strategy to target specific intracellular enzymes in cancer cells and when combined with the appropriate click chemistry can enhance theranostic drug delivery through the formation of intracellular self-assembled nanostructures. However, one drawback of CPPs is their high positive charge which can cause nonspecific binding, leading to off-target accumulation and potential toxicity. Hence, balancing cell-specific penetration, toxicity, and biocompatibility is essential for future clinical efficacy. We synthesized six cancer-specific, legumain-responsive RnAANCK peptides containing one to six arginine residues, with legumain being an asparaginyl endopeptidase that is overexpressed in aggressive prostate tumors. When conjugated to Alexa Fluor 488, R1-R6AANCK peptides exhibited a concentration- and time-dependent cell penetration in prostate cancer cells, which was higher for peptides with higher R values, reaching a plateau after approximately 120 min. Highly aggressive DU145 prostate tumor cells, but not less aggressive LNCaP cells, self-assembled nanoparticles in the cytosol after the cleavage of the legumain-specific peptide. The in vivo biocompatibility was assessed in mice after the intravenous injection of R1-R6AANCK peptides, with concentrations ranging from 0.0125 to 0.4 mmol/kg. The higher arginine content in R4-6 peptides showed blood and urine indicators for the impairment of bone marrow, liver, and kidney function in a dose-dependent manner, with instant hemolysis and morbidity in extreme cases. These findings underscore the importance of designing peptides with the optimal arginine residue length for a proper balance of cell-specific penetration, toxicity, and in vivo biocompatibility.

Preparation of near-infrared photoacoustic imaging and photothermal treatment agent for cancer using a modifiable acid-triggered molecular platform.

Ratiometric near-infrared fluorescent pH probes with various pKa values were innovatively designed and synthesized based on cyanine with a diamine moiety. The photochemical properties of these probes were thoroughly evaluated. Among the series, IR-PHA exhibited an optimal pKa value of approximately 6.40, closely matching the pH of cancerous tissues. This feature is particularly valuable for real-time pH monitoring in both living cells and living mice. Moreover, when administered intravenously to tumor-bearing mice, IR-PHA demonstrated rapid and significant enhancement of near-infrared fluorescence and photoacoustic signals within the tumor region. This outcome underscores the probe's exceptional capability for dual-modal cancer imaging utilizing near-infrared fluorescence (NIRF) and photoacoustic (PA) modalities. Concurrently, the application of a continuous-wave near-infrared laser efficiently ablated cancer cells in vivo, attributed to the photothermal effect induced by IR-PHA. The results strongly indicate that IR-PHA is well-suited for NIRF/PA dual-modality imaging and photothermal therapy of tumors. This makes it a promising candidate for theranostic applications involving small molecules.

Toward Type I/II ROS Generation Photoimmunotherapy by Molecular Engineering of Semiconducting Perylene Diimide.

As prospective phototheranostic agents for cancer imaging and therapy, semiconducting organic molecule-based nanomedicines are developed. However, near-infrared (NIR) emission, and tunable type I (O2 • -) and type II (1O2) photoinduced reactive oxygen species (ROS) generation to boost cancer photoimmunotherapy remains a big challenge. Herein, a series of D-π-A structures, NIR absorbing perylene diimides (PDIs) with heavy atom bromide modification at the bay position of PDIs are prepared for investigating the optimal photoinduced type I/II ROS generation. The heavy atom effect has demonstrated a reduction of molecular ∆EST and promotion of the intersystem crossing processes of PDIs, enhancing the photodynamic therapy (PDT) efficacy. The modification of three bromides and one pyrrolidine at the bay position of PDI (TBDT) has demonstrated the best type I/II PDT performance by batch experiments and theoretical calculations. TBDT based nanoplatforms (TBDT NPs) enable type I/II PDT in the hypoxic tumor microenvironment as a strong immunogenic cell death (ICD) inducer. Moreover, TBDT NPs showing NIR emission allow in vivo bioimaging guided phototherapy of tumor. This work uses novel PDIs with adjustable type I/II ROS production to promote antitumor immune response and accomplish effective tumor eradication, consequently offering molecular guidelines for building high-efficiency ICD inducers.

Synthesis of novel nano-radiotracer for in-vivo molecular SPECT imaging: Nanosize chitosan and its conjugation with glutamine

This study presents the synthesis and characterization of chitosan-glutamine-based biocompatible nanoparticles (nano-conjugate) as a platform for developing an efficient nano-radiopharmaceutical agent for liver imaging. The nanoparticles were labeled with technetium-99 m, resulting in the formation of 99mTc-chitosan-glutamine. Various characterization techniques, including furrier transform infrared spectroscopy (FT-IR) and proton nuclear magnetic resonance (1H NMR) were performed for confirmation of synthesized nano-conjugate. Scanning electron microscopy (SEM), dynamic light scattering (DLS), and static light scattering (SLS) spectroscopies were employed to investigate the particle properties such as size, zeta potential, and molecular weight. MTT assay was conducted to study the toxicity of chitosan-glutamine showing that nano-conjugate had a toxicity on cancer cell in-vitro. In-vivo studies were conducted by administering 99mTc-chitosan-glutamine to mice, followed by whole body SPECT imaging. The imaging process was performed at three different time points post-injection: 15, 60, and 120 min. The SPECT results revealed a significantly accumulation in the liver. Also, biodistribution study showed that accumulation in liver (% ID/g = 23.15%) was significantly higher than other organs. Our in-vitro and in-vivo findings suggest that 99mTc-chitosan-glutamine could serve as a theranostic agent for cancer imaging using SPECT technology.

Over 20% Carbon-13 Polarization of Perdeuterated Pyruvate Using Reversible Exchange with Parahydrogen and Spin-Lock Induced Crossing at 50 μT.

Carbon-13 hyperpolarized pyruvate is about to become the next-generation contrast agent for molecular magnetic resonance imaging of cancer and other diseases. Here, efficient and rapid pyruvate hyperpolarization is achieved via signal amplification by reversible exchange (SABRE) with parahydrogen through synergistic use of substrate deuteration, alternating, and static microtesla magnetic fields. Up to 22 and 6% long-lasting 13C polarization (T1 = 3.7 ± 0.25 and 1.7 ± 0.1 min) is demonstrated for the C1 and C2 nuclear sites, respectively. The remarkable polarization levels become possible as a result of favorable relaxation dynamics at the microtesla fields. The ultralong polarization lifetimes will be conducive to yielding high polarization after purification, quality assurance, and injection of the hyperpolarized molecular imaging probes. These results pave the way to future in vivo translation of carbon-13 hyperpolarized molecular imaging probes prepared by this approach.

Radiolabeled gemcitabine hydrochloride as an imaging agent for lung cancer: Radiolabeling, quality control and cell incorporation studies

The development of new drugs that can specifically screen tumors is a global need. When it comes to lung cancer, which is the second main cause of cancer-related deaths, early detection of lung tumors using appropriate imaging is very important. In this study, gemcitabine hydrochloride (GCH) was radiolabeled with [99mTc]Tc under different conditions (changing reducing agent, antioxidant agent, incubation time, pH, [99mTc]Tc activity) and radiolabeling activity (quality control) using Radio Thin Layer Chromatography and paper electrophoresis. The results showed that the most stable complex ([99mTc]Tc-GCH) was prepared using 0.015 mg of stannous chloride as a reducing agent, 0.01 mg of ascorbic acid as an antioxidant and 37 MBq activity at pH 7.4 after 15 min of incubation time. The complex remained stable for 6 h. Cell incorporation studies showed a six-fold higher uptake of [99mTc]Tc-GCH in cancer (A-549) cells (38.42 ± 1.53) than healthy (L-929) cells (6.11 ± 0.17) have shown that it can. In addition, the different behaviors of R/H-[99mTc]Tc confirmed the specificity of this newly developed radiopharmaceutical. Although these studies are preliminary, it has been concluded that [99mTc]Tc-GCH may be a candidate drug for use in nuclear medicine, particularly in the diagnosis of lung cancer.

A Gold Nanocage Probe Targeting Survivin for the Diagnosis of Pancreatic Cancer.

In this paper, Au nanocages (AuNCs) loaded with the MRI contrast agent gadolinium (Gd) and capped with the tumor-targeting gene survivin (Sur-AuNC•Gd-Cy7 nanoprobes) were designed and applied as a targeted imaging agent for pancreatic cancer. With its capacity to transport fluorescent dyes and MR imaging agents, the gold cage is an outstanding platform. Furthermore, it has the potential to transport different drugs in the future, making it a unique carrier platform. The utilization of Sur-AuNC•Gd-Cy7 nanoprobes has proven to be an effective means of targeting and localizing survivin-positive BxPC-3 cells within their cytoplasm. By targeting survivin, an antiapoptotic gene, the Sur-AuNC•Gd-Cy7 nanoprobe was able to induce pro-apoptotic effects in BxPC-3 pancreatic cancer cells. The biocompatibility of AuNCs•Gd, AuNCs•Gd-Cy7 nanoparticles, and Sur-AuNC•Gd-Cy7 nanoprobes is evaluated through the hemolysis rate assay. The stability of AuNCs•Gd, AuNCs•Gd-Cy7 nanoparticles, and Sur-AuNC•Gd-Cy7 nanoprobes was evaluated by determining their hydrodynamic dimensions following storage in different pH solutions for a corresponding duration. Excellent biocompatibility and stability of the Sur-AuNC•Gd-Cy7 nanoprobes will facilitate their further utilization in vivo and in vitro. The surface-bound survivin plays a role in facilitating the Sur-AuNC•Gd-Cy7 nanoprobes' ability to locate the BxPC-3 tumor. The probe was modified to incorporate Gd and Cy7, thereby enabling the simultaneous utilization of magnetic resonance imaging (MRI) and fluorescence imaging (FI) techniques. In vivo, the Sur-AuNC•Gd-Cy7 nanoprobes were found to effectively target and localize survivin-positive BxPC-3 tumors through the use of MRI and FI. After being injected via the caudal vein, the Sur-AuNC•Gd-Cy7 nanoprobes were found to accumulate effectively in an in situ pancreatic cancer model within 24 h. Furthermore, these nanoprobes were observed to be eliminated from the body through the kidneys within 72 h after a single injection. This characteristic is crucial for a diagnostic agent. Based on the aforementioned outcomes, the Sur-AuNC•Gd-Cy7 nanoprobes have significant potential advantages for the theranostic treatment of pancreatic cancer. This nanoprobe possesses distinctive characteristics, such as advanced imaging abilities and specific drug delivery, which offer the possibility of enhancing the precision of diagnosis and efficacy of treatment for this destructive illness.

Evaluation of 134Ce/134La as a PET Imaging Theranostic Pair for 225Ac α-Radiotherapeutics.

225Ac-targeted α-radiotherapy is a promising approach to treating malignancies, including prostate cancer. However, α-emitting isotopes are difficult to image because of low administered activities and a low fraction of suitable γ-emissions. The invivo generator 134Ce/134La has been proposed as a potential PET imaging surrogate for the therapeutic nuclides 225Ac and 227Th. In this report, we detail efficient radiolabeling methods using the 225Ac-chelators DOTA and MACROPA. These methods were applied to radiolabeling of prostate cancer imaging agents, including PSMA-617 and MACROPA-PEG4-YS5, for evaluation of their invivo pharmacokinetic characteristics and comparison to the corresponding 225Ac analogs. Methods: Radiolabeling was performed by mixing DOTA/MACROPA chelates with 134Ce/134La in NH4OAc, pH 8.0, at room temperature, and radiochemical yields were monitored by radio-thin-layer chromatography. In vivo biodistributions of 134Ce-DOTA/MACROPA.NH2 complexes were assayed through dynamic small-animal PET/CT imaging and ex vivo biodistribution studies over 1 h in healthy C57BL/6 mice, compared with free 134CeCl3 In vivo, preclinical imaging of 134Ce-PSMA-617 and 134Ce-MACROPA-PEG4-YS5 was performed on 22Rv1 tumor-bearing male nu/nu-mice. Ex vivo biodistribution was performed for 134Ce/225Ac-MACROPA-PEG4-YS5 conjugates. Results: 134Ce-MACROPA.NH2 demonstrated near-quantitative labeling with 1:1 ligand-to-metal ratios at room temperature, whereas a 10:1 ligand-to-metal ratio and elevated temperatures were required for DOTA. Rapid urinary excretion and low liver and bone uptake were seen for 134Ce/225Ac-DOTA/MACROPA. NH2 conjugates in comparison to free 134CeCl3 confirmed high invivo stability. An interesting observation during the radiolabeling of tumor-targeting vectors PSMA-617 and MACROPA-PEG4-YS5-that the daughter 134La was expelled from the chelate after the decay of parent 134Ce-was confirmed through radio-thin-layer chromatography and reverse-phase high-performance liquid chromatography. Both conjugates, 134Ce-PSMA-617 and 134Ce-MACROPA-PEG4-YS5, displayed tumor uptake in 22Rv1 tumor-bearing mice. The ex vivo biodistribution of 134Ce-MACROPA.NH2, 134Ce-DOTA and 134Ce-MACROPA-PEG4-YS5 corroborated well with the respective 225Ac-conjugates. Conclusion: These results demonstrate the PET imaging potential for 134Ce/134La-labeled small-molecule and antibody agents. The similar 225Ac and 134Ce/134La-chemical and pharmacokinetic characteristics suggest that the 134Ce/134La pair may act as a PET imaging surrogate for 225Ac-based radioligand therapies.

In vivo evaluation of integrin αvβ6-targeting peptide in NSCLC and brain metastasis.

Integrin αvβ6, which is upregulated in malignancies and remains absent or weak in normal tissue, is a promising target in molecular imaging therapeutics. In vivo imaging of integrin αvβ6 could therefore be valuable for early tumor detection and intraoperative guidance. In this study, integrin αvβ6-targeting probe G2-SFLAP3 was labeled with near-infrared (NIR) dye Cy5.5 or radioisotope 68Ga. The resulting probes were evaluated in integrin αvβ6-positive A549 and αvβ6-negative H1703 xenograft mice models. The cellar uptake of G2-SFLAP3-Cy5.5 was consistent with the expression of integrin αvβ6. Both subcutaneous and brain metastatic A549 tumors could be clearly visualized by NIR fluorescent imaging of G2-SFLAP3-Cy5.5. A549 tumors demonstrated the highest G2-SFLAP3-Cy5.5 accumulation at 4h post-injection (p.i.) and remain detectable at 84h p.i. The fluorescent signal of G2-SFLAP3-Cy5.5 was significantly reduced in H1703 and A549-blocking groups. Consistently, small-animal PET imaging showed tumor-specific accumulation of 68Ga-DOTA-G2-SFLAP3. G2-SFLAP3 represents a promising agent for noninvasive imaging of non-small cell lung cancer (NSCLC) and brain metastases.

Potential of uPAR, αvβ6 Integrin, and Tissue Factor as Targets for Molecular Imaging of Oral Squamous Cell Carcinoma: Evaluation of Nine Targets in Primary Tumors and Metastases by Immunohistochemistry.

No clinically approved tumor-specific imaging agents for head and neck cancer are currently available. The identification of biomarkers with a high and homogenous expression in tumor tissue and minimal expression in normal tissue is essential for the development of new molecular imaging targets in head and neck cancer. We investigated the expression of nine imaging targets in both primary tumor and matched metastatic tissue of 41 patients with oral squamous cell carcinoma (OSCC) to assess their potential as targets for molecular imaging. The intensity, proportion, and homogeneity in the tumor and the reaction in neighboring non-cancerous tissue was scored. The intensity and proportion were multiplied to obtain a total immunohistochemical (IHC) score ranging from 0-12. The mean intensity in the tumor tissue and normal epithelium were compared. The expression rate was high for the urokinase-type plasminogen activator receptor (uPAR) (97%), integrin αvβ6 (97%), and tissue factor (86%) with a median total immunostaining score (interquartile range) for primary tumors of 6 (6-9), 12 (12-12), and 6 (2.5-7.5), respectively. For the uPAR and tissue factor, the mean staining intensity score was significantly higher in tumors compared to normal epithelium. The uPAR, integrin αvβ6, and tissue factor are promising imaging targets for OSCC primary tumors, lymph node metastases, and recurrences.

Photophysical and biological assessment of coumarin-6 loaded polymeric nanoparticles as a cancer imaging agent

Coumarin-6 is used as a model hydrophobic drug to investigate delivery to tumors via polymeric micelles. Photophysical characterization, as well as in vitro and in vivo experiments showcase this platform for cancer diagnosis and imaging.

Review on Metal-Based Theranostic Nanoparticles for Cancer Therapy and Imaging.

Theranostic agents are promising due to their ability to diagnose, treat and monitor different types of cancer using a variety of imaging modalities. The advantage specifically of nanoparticles is that they can accumulate easily at the tumor site due to the large gaps in blood vessels near tumors. Such high concentration of theranostic agents at the target site can lead to enhancement in both imaging and therapy. This article provides an overview of nanoparticles that have been used for cancer theranostics, and the different imaging, treatment options and signaling pathways that are important when using nanoparticles for cancer theranostics. In particular, nanoparticles made of metal elements are emphasized due to their wide applications in cancer theranostics. One important aspect discussed is the ability to combine different types of metals in one nanoplatform for use as multimodal imaging and therapeutic agents for cancer.

Lactose-modified enzyme-sensitive branched polymers as a nanoscale liver cancer-targeting MRI contrast agent.

Signal enhancement of magnetic resonance imaging (MRI) in the diseased region is dependent on the molecular structure of the MRI contrast agent. In this study, a macromolecular contrast agent, Branched-LAMA-DOTA-Cy5.5-Gd (BLDCGd), was prepared to target liver cancer. Due to the affinity of lactose to the Asialoglycoprotein receptor (ASGPR) over-expressed on the surface of liver cancer cells, lactose was selected as the targeting moiety in the contrast agent. A cathepsin B-sensitive tetrapeptide, GFLG, was used as a linkage moiety to construct a cross-linked macromolecular structure of the contrast agent, and the contrast agent could be degraded into fragments for clearance. A small-molecular-weight molecule, DOTA-Gd, and a fluorescent dye, Cy5.5, were conjugated to the macromolecular structure via a thiol-ene click reaction. The contrast agent, BLDCGd, had a high molecular weight (81 kDa) and a small particle size (59 ± 12 nm). Its longitudinal relaxivity (12.62 mM-1 s-1) was 4-fold that of the clinical agent DTPA-Gd (3.42 mM-1 s-1). Signal enhancement of up to 184% was observed at the tumor site in an H22 cell-based mouse model. A high accumulation level of BLDCGd in the liver tumor observed from MRI was confirmed from the fluorescence images obtained from the same contrast agent. BLDCGd showed no toxicity to HUVECs and H22 cells in vitro, and low blood chemistry indexes and no distinct histopathological abnormalities were also observed in vivo after injection of BLDCGd since it could be metabolized through the kidneys according to the in vivo MRI results of major organs. Therefore, the branched macromolecule BLDCGd could have great potential as an efficacious and bio-safe nanoscale MRI contrast agent for clinical diagnosis of liver cancer.