Efficient Radiolabeling of Proteins and Antibodies via Maleamate-Cysteine Bioconjugation.

The study introduces a novel maleamate-based prosthetic group specifically designed for efficient, site-specific radioiodination of biomolecules that contain or are modified with cysteine residues. This strategy is a compelling alternative to the conventional maleimide-based approach, demonstrating outstanding attributes such as high radiochemical yield, rapid reaction kinetics, applicability in aqueous media at neutral pH, and exceptional stability under a competitive environment.

From molecules to medicine: thiol selective bioconjugation in synthesis of diagnostic and therapeutic radiopharmaceuticals.

Radiolabeling of biomolecules and cells with radiolabeled prosthetic groups has significant implications for nuclear medicine, imaging, and radiotherapy. Achieving site-specific and controlled incorporation of radiolabeled prostheses under mild reaction conditions is crucial for minimizing the impact on the bioactivity of the radiolabeled compounds. The targeting of natural and abundant amino acids during radiolabeling of biomolecules often results in nonspecific and uncontrolled modifications. Cysteine is distinguished by its low natural abundance and unique nucleophilicity. It is therefore an optimal target for site-selective and site-specific radiolabeling of biomolecules under controlled parameters. This review extensively discusses thiol-specific radiolabeled prosthetic groups and provides a critical analysis and comprehensive study of the synthesis of these groups, their in vitro and in vivo stability profiles, reaction kinetics, stability of resulting adducts, and overall impact on the targeting ability of radiolabeled biomolecules. The insights presented here aim to facilitate the development of highly efficient radiopharmaceuticals, initially in preclinical settings and ultimately in clinical applications.

Bioaccumulation and in vivo tracking of radiolabeled 4-nonylphenol in mice.

4-Nonylphenol (4NP) is concerning due to its growing presence and endocrine-disrupting nature, raising concerns about its impact on health. In this study 124I-labeled 4NP was synthesized for in vivo tracing. Positron emission tomography imaging and biodistribution studies showed significant accumulation in various tissues after oral or intraperitoneal administration, emphasizing its intricate distribution and potential long-term effects, crucial for future risk assessments.

64Cu-Labeled Boron-Containing Cyclic RGD Peptides for BNCT and PET Imaging.

The burgeoning interest in developing boron neutron capture therapy (BNCT) tracers and their accompanying diagnostics for the treatment of recalcitrant tumors has prompted this investigation. Our study aims to devise a tumor treatment strategy utilizing BNCT to target the αvß3 integrin. To this end, we propose a pioneering boron-infused cyclic Arg-Gly-Asp (RGD) peptide, cRGD(d-BPA)K, designed as an efficacious BNCT tracer. Additionally, we introduce its diagnostic complement, DOTA-cRGD(d-BPA)K, tailored for positron emission tomography (PET) to visualize αvß3 expressed tumors. Radiolabeling [64Cu]Cu-DOTA-cRGD(d-BPA)K (64Cu-1) resulted in a high radiochemical yield and purity. The radiotracer exhibited exceptional in vitro stability and demonstrated significant uptake in U87MG tumors via PET imaging. Biodistribution analysis using compound 2 showed a 7.0 ppm accumulation of boron in the U87MG tumor 1 h post-intravenous injection. Furthermore, compound 2 displayed superior tumor/blood (2.41) and tumor/muscle (2.46) ratios compared to the clinically approved l-BPA-fructose. Both compound 2 and its diagnostic counterpart 64Cu-1 hold potential for BNCT and cancer diagnosis, respectively, via molecular imaging.

MXene/AgNW composite material for selective and efficient removal of radioactive cesium and iodine from water.

Toxic fission products, such as cesium (137Cs) and iodine (129I) are of great concern because of their long half-lives and high solubility in water. The simultaneous removal of Cs and I using a single adsorbent is an area of increasing interest. In this study, MXene/silver nanowire (AgNW) composite was synthesized through physical mixing and employed for simultaneous removal of iodide (I-) and cesium (Cs+) ions from contaminated water. The MXene/AgNW composite demonstrated excellent adsorption capacities of 84.70 and 26.22 mg/g for I- and Cs+, respectively. The experimental data supported the hypothesis of multilayer adsorption of Cs+ owing to the inter-lamellar structures and the presence of heterogeneous adsorption sites in MXene. The interaction between I- and the AgNW involved chemisorption followed by monolayer adsorption. MXene/AgNW composite material exhibited promising results in the presence of competitive ions under extreme pH conditions. Thus, synthesized composite materials holds promising potential as an adsorbent for the remediation of radioactive liquid waste.

The role of radiolabeling in BNCT tracers for enhanced dosimetry and treatment planning.

Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are potent technologies for non-invasive imaging of pharmacological and biochemical processes in both preclinical and advanced clinical research settings. In the field of radiation therapy, boron neutron capture therapy (BNCT) stands out because it harnesses biological mechanisms to precisely target tumor cells while preserving the neighboring healthy tissues. To achieve the most favorable therapeutic outcomes, the delivery of boron-enriched tracers to tumors must be selective and efficient, with a substantial concentration of boron atoms meticulously arranged in and around the tumor cells. Although several BNCT tracers have been developed to facilitate the targeted and efficient delivery of boron to tumors, only a few have been labeled with PET or SPECT radionuclides. Such radiolabeling enables comprehensive in vivo examination, encompassing crucial aspects such as pharmacodynamics, pharmacokinetics, tumor selectivity, and accumulation and retention of the tracer within the tumor. This review provides a comprehensive summary of the essential aspects of BNCT tracers, focusing on their radiolabeling with PET or SPECT radioisotopes. This leads to more effective and targeted treatment approaches which ultimately enhance the quality of patient care with respect to cancer treatment.

Porphyrin-Based Brain Tumor-Targeting Agents: [64Cu]Cu-porphyrin and [64Cu]Cu-TDAP.

The aim of this study is to evaluate a radioactive metal complex platform for brain tumor targeting. Herein, we introduce a new porphyrin derivative, 5,10,15,20-(tetra-N,N-dimethyl-4-aminophenyl)porphyrin (TDAP), in which four N,N-dimethyl-4-p-phenylenediamine (DMPD) moieties are conjugated to the porphyrin labeled with the radiometal 64Cu. DMPD affected the pharmacokinetics of porphyrin in terms of retention time in vivo and tumor-targeting ability relative to those of unmodified porphyrin. [64Cu]Cu-TDAP showed stronger enhancement than [64Cu]Cu-porphyrin in U87MG glioblastoma cells, especially in the cytoplasm and nucleus, indicating its tumor-targeting properties and potential use as a therapeutic agent. In the subcutaneous and orthotopic models of brain-tumor-bearing mice, [64Cu]Cu-TDAP was clearly visualized in the tumor site via positron emission tomography imaging and showed a tumor-to-brain ratio as high as 13. [64Cu]Cu-TDAP deserves attention as a new diagnostic agent that is suitable for the early diagnosis and treatment of brain tumors.

Early Prediction of Radiation-Induced Pulmonary Fibrosis Using Gastrin-Releasing Peptide Receptor-Targeted PET Imaging.

Early diagnosis of radiation-induced pulmonary fibrosis (RIPF) in lung cancer patients after radiation therapy is important. A gastrin-releasing peptide receptor (GRPR) mediates the inflammation and fibrosis after irradiation in mice lungs. Previously, our group synthesized a GRPR-targeted positron emission tomography (PET) imaging probe, [64Cu]Cu-NODAGA-galacto-bombesin (BBN), an analogue peptide of GRP. In this study, we evaluated the usefulness of [64Cu]Cu-NODAGA-galacto-BBN for the early prediction of RIPF. We prepared RIPF mice and acquired PET/CT images of [18F]F-FDG and [64Cu]Cu-NODAGA-galacto-BBN at 0, 2, 5, and 11 weeks after irradiation (n = 3-10). We confirmed that [64Cu]Cu-NODAGA-galacto-BBN targets GRPR in irradiated RAW 264.7 cells. In addition, we examined whether [64Cu]Cu-NODAGA-galacto-BBN monitors the therapeutic efficacy in RIPF mice (n = 4). As a result, the lung uptake ratio (irradiated-to-normal) of [64Cu]Cu-NODAGA-galacto-BBN was the highest at 2 weeks, followed by its decrease at 5 and 11 weeks after irradiation, which matched with the expression of GRPR and was more accurately predicted than [18F]F-FDG. These uptake results were also confirmed by the cell uptake assay. Furthermore, [64Cu]Cu-NODAGA-galacto-BBN could monitor the therapeutic efficacy of pirfenidone in RIPF mice. We conclude that [64Cu]Cu-NODAGA-galacto-BBN is a novel PET imaging probe for the early prediction of RIPF-targeting GRPR expressed during the inflammatory response.

Optimizing and determining the click chemistry mediated Cu-64 radiolabeling and physiochemical characteristics of trastuzumab conjugates.

Over the last decade, 64Cu-labeling of monoclonal antibody (mAb) via inverse electron demand Diels-Alder click chemistry (IEDDA) have received much attention. Despite the tetrazine-transcyclooctene (Tz-TCO) click chemistry's convenience and efficiency in mAb labeling, there is limited information about the ideal parameters in the development of click chemistry mediated (radio)immunoconjugates. This encourages us to conduct a systematic optimization while concurrently determining the physiochemical characteristics of the model mAb, trastuzumab, and TCO conjugates. To accomplish this, we investigated a few critical parameters, first, we determined the degree of conjugations with varying molar equivalents (eq.) of TCO (3, 5, 10, and 15 eq.). Through analytical techniques like size exclusion chromatography, dynamic light scattering, and zeta potential, qualitative analysis were performed to determine the purity, degree of aggregation and net charge of the conjugates. We found that as the degree of conjugation increased the purity of intact mAb fraction is compromised and net charge of conjugates became less positive. Next, all trastuzumab-PEG4-TCO conjugates with varying molar ratio and quantity (30, 50, 100, 200, 250 µg) were radiolabeled with 64Cu-NOTA-PEG4-Tz via IEDDA click chemistry and radiochemical yields were determined by radio-thin layer chromatography. The radiochemical yields of trastuzumab conjugates improved with increased amount and molar ratio. Next, we investigated the effect of the radioprotectant ascorbic acid (AA) of varied concentrations (0.25, 0.5, 0.75, 1 mM) on radiochemical yields and subsequent pharmacokinetics. A concentration of 0.25 mM of AA was found to be optimal for click reaction and in vivo biodistribution. Finally, we investigated the indirect influence of bioconjugation buffers on radiochemical yields and biodistribution in NIH3T6.7 tumor models that resulted approximately ∼11 %ID/g tumor uptake.

Cancer therapy by antibody-targeted Cerenkov light and metabolism-selective photosensitization.

Photodynamic therapy (PDT) is an effective cancer treatment option, but it suffers from penetration limit of light, making it available only for superficial and endoscopically accessible cancers. Recently, there have been reports that Cerenkov luminescence originated from radioisotopes can be utilized as an excitation source for PDT without external light illumination. Here, cancer-selective agents, i.e., (1) clinically available 5-aminolevulinic acid (5-ALA), which promotes cancer metabolism-specific accumulation of protoporphyrin IX (PpIX), and (2) 64Cu-DOTA-trastuzumab, which has HER2-expressing cancer selective uptake, are separately applied as a photosensitizer and an in situ radiator, respectively, to potentiate tumor-specific Cerenkov luminescence energy transfer (CLET) from 64Cu to PpIX for high-precision PDT of cancer. It is shown that the combinational administration and tumor colocalization of 5-ALA and 64Cu-DOTA-trastuzumab exert significant in vitro cytotoxicity (cell viability <9%) as well as in vivo antitumor effects (tumor volume ratio of 0.50 on 14 days post-injection) on HER2-expressing breast and gastric cancer models. This study proves that high-precision treatment regimen using dual-targeted CLET-based PDT is feasible for HER2-expressing cancers. Furthermore, the results offer great potential for clinical translation to the dual-targeted CLET-based PDT because the treatment regimen uses components, 5-ALA and 64Cu-DOTA-trastuzumab, which are already in clinical uses.

Development of Brain-Tumor-Targeted Benzothiazole-Based Boron Complex for Boron Neutron Capture Therapy.

Boron neutron capture therapy (BNCT) is a precision treatment technology that ideally damages only boron-accumulating cells. The effectiveness of BNCT depends on the amount of boron in the tumor cells and the concentration ratio between normal and tumor tissues. Therefore, for successful brain-tumor treatment using BNCT, it is essential to develop a drug with high blood-brain barrier (BBB) permeability and high tumor accumulation. The benzothiazole-based boron complex 4-(benzo[d]thiazol-2-yl)phenylboronic acid (BTPB) is a hydrophobic, low-molecular-weight compound that has shown high BBB permeability and brain accumulation. The highest boron concentration of BTPB is 36.11 ± 2.73 µg/g (at 1 h post-injection) in the brain, and the highest brain/blood ratio is 3.94 ± 0.46 (at 2 h post-injection), which is sufficient for the BNCT drug condition. In addition, BTPB showed good tumor-targeting ability in vivo in a U87MG glioma tumor model. In this study, we conducted a biological evaluation of BTPB compared to boronophenylalanine as a novel drug for BNCT.

A High-Affinity 64Cu-Labeled Ligand for PET Imaging of Hepsin: Design, Synthesis, and Characterization.

Hepsin, a cell surface serine protease, is a potential biomarker for the detection of prostate cancer due to its high expression in prostate cancer but not in normal prostate. This study aimed to develop a radioligand for positron emission tomography (PET) imaging of hepsin. Six leucine-arginine (Leu-Arg) dipeptide derivatives (two diastereomers for each of three ligands) were synthesized and evaluated for their binding affinities and selectivity for hepsin. Based on the binding assay, a natCu-1,4,7,10-tetraazacyclododecane-N,N',N″,N‴-tetraacetic acid (DOTA)-conjugated ligand (3B) was selected for the development of a PET radioligand. [64Cu]3B was synthesized by labeling the DOTA-conjugated compound 11B with [64Cu]CuCl2 at 80 °C for 20 min. The radioligand was evaluated for prostate cancer cell binding and PET imaging in a prostate tumor mouse model. The results demonstrated that [64Cu]3B exhibited high binding to LNCaP cells, intermediate binding to 22Rv1 cells, and low binding to PC3 cells. PET studies of [64Cu]3B in mice, implanted with 22Rv1 and PC3 cells on each flank, revealed that the radioligand uptake was high and persistent in the 22Rv1 tumors over time, whereas it was low in PC3 tumors. The results of this study suggest that [64Cu]3B is a promising PET radioligand for hepsin imaging.

Preclinical Evaluation of hnRNPA2B1 Antibody in Human Triple-Negative Breast Cancer MDA-MB-231 Cells via PET Imaging.

Triple-negative breast cancer (TNBC) does not express estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Because TNBC lacks the expression of commonly targeted receptors, it is challenging to develop a new imaging agent for this cancer subtype. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA-protein complexes that have been linked to tumor development and progression. Considering the high expression of hnRNPA2B1, an hnRNP subtype, in TNBC MDA-MB-231 cells, this study aimed to develop a novel hnRNPA2B1 antibody-based nuclear imaging agent. The hnRNPA2B1-specific antibody was radiolabeled with 64Cu and evaluated in vitro and in vivo. The trans-cyclooctene (TCO) was functionalized on the antibody to obtain hnRNP-PEG4-TCO and reactive tetrazine (Tz) on the ultrastable bifunctional chelator PCB-TE2A-alkyne to yield PCB-TE2A-Tz for the inverse electron demand Diels-Alder reaction. The 64Cu-radiolabeled antibody was administered and imaged at 1-18 h time points for conventional imaging. Alternatively, the unlabeled antibody conjugate was administered, and 48 h later radiolabeled 64Cu-PCB-TE2A-Tz was administered to the same mice for the pretargeting strategy and imaged at the same time intervals for direct comparison. The tumor was successfully visualized in both strategies, and comparatively, pretargeting showed superior results. The 64Cu-PCB-TE2A-Tz was successfully clicked at the tumor site with hnRNP-PEG4-TCO and the non-clicked were concurrently eliminated. This led to increase the tumor uptake with extremely high tumor-to-background ratio manifested by positron emission tomography (PET) imaging and biodistribution studies.

In vivo evaluation of the effects of combined boron and gadolinium neutron capture therapy in mouse models.

While boron neutron capture therapy (BNCT) depends primarily on the short flight range of the alpha particles emitted by the boron neutron capture reaction, gadolinium neutron capture therapy (GdNCT) mainly relies on gamma rays and Auger electrons released by the gadolinium neutron capture reaction. BNCT and GdNCT can be complementary in tumor therapy. Here, we studied the combined effects of BNCT and GdNCT when boron and gadolinium compounds were co-injected, followed by thermal neutron irradiation, and compared these effects with those of the single therapies. In cytotoxicity studies, some additive effects (32‒43%) were observed when CT26 cells were treated with both boron- and gadolinium-encapsulated PEGylated liposomes (B- and Gd-liposomes) compared to the single treatments. The tumor-suppressive effect was greater when BNCT was followed by GdNCT at an interval of 10 days rather than vice versa. However, tumor suppression with co-injection of B- and Gd-liposomes into tumor-bearing mice followed by neutron beam irradiation was comparable to that observed with Gd-liposome-only treatment but lower than B-liposome-only injection. No additive effect was observed with the combination of BNCT and GdNCT, which could be due to the shielding effect of gadolinium against thermal neutrons because of its overwhelmingly large thermal neutron cross section.

Therapeutic Response Monitoring with 89Zr-DFO-Pertuzumab in HER2-Positive and Trastuzumab-Resistant Breast Cancer Models.

Immuno-positron emission tomography (PET) has great potential to evaluate the target expression level and therapeutic response for targeted cancer therapy. Immuno-PET imaging with pertuzumab, due to specific recognition in different binding sites of HER2, could be useful for the determination of the therapeutic efficacy of HER2-targeted therapy, trastuzumab, and heat shock protein 90 (HSP90) inhibitor, in HER2-expressing breast cancer. The aim of this study is to evaluate the feasibility of monitoring therapeutic response with 89Zr-DFO-pertuzumab for the treatment of HER2-targeted therapeutics, trastuzumab, or the HSP90 inhibitor 17-DMAG, in trastuzumab-resistant JIMT-1 breast cancer models. We prepared an immuno-PET imaging agent using desferoxamine (DFO)-pertuzumab labeled with 89Zr and performed the biodistribution and PET imaging in breast cancer xenograft models for monitoring therapeutic response to HER2-targeted therapy. 89Zr-DFO-pertuzumab was successfully prepared and showed specific binding to HER2 in vitro and clearly visualized HER2 expressing JIMT-1 tumors. 89Zr-DFO-pertuzumab had prominent tumor uptake in HER2 expressing JIMT-1 tumors. JIMT-1 tumors showed trastuzumab-resistant and HSP90 inhibitor sensitive characterization. In immuno-PET imaging, isotype antibody-treated JIMT-1 tumors had similar uptake in trastuzumab-treated JIMT-1 tumors, but 17-DMAG-treated JIMT-1 tumors showed greatly reduced uptake compared to vehicle-treated tumors. Additionally, HER2 downregulation evaluated by immuno-PET imaging was verified by western blot analysis and immunofluorescence staining which resulted in a significant reduction in the tumor's HER2 level in 17-DMAG-treated JIMT-1 tumors. 89Zr-DFO-pertuzumab immuno-PET may be clinically translated to select pertinent patients for HER2-targeted therapy and to monitor the therapeutic response in HER2-positive cancer patients under various HER2-targeted therapeutics treatments.

In vivo detection of hydrogen sulfide in the brain of live mouse: application in neuroinflammation models.

PURPOSE: Hydrogen sulfide (H2S) plays important roles in brain pathophysiology. However, nuclear imaging probes for the in vivo detection of brain H2S in living animals have not been developed. Here, we report the first nuclear imaging probe that enables in vivo imaging of endogenous H2S in the brain of live mice. METHODS: Utilizing a bis(thiosemicarbazone) backbone, a fluorescent ATSM-FITC conjugate was synthesized. Its copper complex, Cu(ATSM-FITC) was thoroughly tested as a biosensor for H2S. The same ATSM-FITC ligand was quantitatively labeled with [64Cu]CuCl2 to obtain a radioactive [64Cu][Cu(ATSM-FITC)] imaging probe. Biodistribution and positron emission tomography (PET) imaging studies were performed in healthy mice and neuroinflammation models. RESULTS: The Cu(ATSM-FITC) complex reacts instantly with H2S to release CuS and becomes fluorescent. It showed excellent reactivity, sensitivity, and selectivity to H2S. Endogenous H2S levels in living cells were successfully detected by fluorescence microscopy. Exceptionally high brain uptake of [64Cu][Cu(ATSM-FITC)] (> 9% ID/g) was observed in biodistribution and PET imaging studies. Subtle changes in brain H2S concentrations in live mice were accurately detected by quantitative PET imaging. Due to its dual modality feature, increased H2S levels in neuroinflammation models were characterized at the subcellular level by fluorescence imaging and at the whole-body scale by PET imaging. CONCLUSION: Our biosensor can be readily utilized to study brain H2S function in live animal models and shows great potential as a novel imaging agent for diagnosing brain diseases.

"The surprise questions" using variable time frames in hospitalized patients with advanced cancer.

OBJECTIVE: Several studies supported the usefulness of "the surprise question" in terms of 1-year mortality of patients. "The surprise question" requires a "Yes" or "No" answer to the question "Would I be surprised if this patient died in [specific time frame]." However, the 1-year time frame is often too long for advanced cancer patients seen by palliative care personnel. "The surprise question" with shorter time frames is needed for decision making. We examined the accuracy of "the surprise question" for 7-day, 21-day, and 42-day survival in hospitalized patients admitted to palliative care units (PCUs). METHOD: This was a prospective multicenter cohort study of 130 adult patients with advanced cancer admitted to 7 hospital-based PCUs in South Korea. The accuracy of "the surprise question" was compared with that of the temporal question for clinician's prediction of survival. RESULTS: We analyzed 130 inpatients who died in PCUs during the study period. The median survival was 21.0 days. The sensitivity, specificity, and overall accuracy for the 7-day "the surprise question" were 46.7, 88.7, and 83.9%, respectively. The sensitivity, specificity, and overall accuracy for the 7-day temporal question were 6.7, 98.3, and 87.7%, respectively. The c-indices of the 7-day "the surprise question" and 7-day temporal question were 0.662 (95% CI: 0.539-0.785) and 0.521 (95% CI: 0.464-0.579), respectively. The c-indices of the 42-day "the surprise question" and 42-day temporal question were 0.554 (95% CI: 0.509-0.599) and 0.616 (95% CI: 0.569-0.663), respectively. SIGNIFICANCE OF RESULTS: Surprisingly, "the surprise questions" and temporal questions had similar accuracies. The high specificities for the 7-day "the surprise question" and 7- and 21-day temporal question suggest they may be useful to rule in death if positive.

PET Tracing of Biodistribution for Orally Administered 64Cu-Labeled Polystyrene in Mice.

Plastics are used commonly in the world because of their convenience and cost effectiveness. Microplastics, an environmental threat and human health risk, are widely detected in food and consequently ingested. However, degraded plastics are found everywhere, creating an environmental threat and human health risk. Therefore, real-time monitoring of orally administered microplastics to trace them in the body is tremendously important. Methods: In this study, to visualize their absorption path, we labeled polystyrene with [64Cu]Cu-DOTA. We prepared radiolabeled polystyrene with 64Cu. Afterward, [64Cu]Cu-DOTA-polystyrene was orally administered to mice, and we evaluated its transit and absorption using PET imaging. The absorption path and distribution of [64Cu]Cu-DOTA-polystyrene were determined using PET over 48 h. Ex vivo tissue radio-thin-layer chromatography (TLC) was used to demonstrate the existence of [64Cu]Cu-DOTA-polystyrene in tissue. Results: PET images demonstrated that [64Cu]Cu-DOTA-polystyrene began to transit to the intestine within 1 h. Accumulation of [64Cu]Cu-DOTA-polystyrene in the liver was also observed. The biodistribution of [64Cu]Cu-DOTA-polystyrene confirmed the distribution of [64Cu]Cu-DOTA-polystyrene observed on the PET images. Ex vivo radio-TLC demonstrated that the detected γ-rays originated from [64Cu]Cu-DOTA-polystyrene. Conclusion: This study provided PET evidence of the existence and accumulation of microplastics in tissue and cross-confirmed the PET findings by ex vivo radio-TLC. This information may be used as the basis for future studies on the toxicity of microplastics.

Porphyrin-Based Tumor-Targeting Theranostic Agent: Gd-TDAP.

The aim of this work was to evaluate a tumor-targeting porphyrin-based gadolinium complex (Gd-TDAP) for use as an MR/optical imaging agent and potential therapeutic agent. Gd-TDAP had higher longitudinal relaxivity (11.8 mM-1 s-1) than a commercial MRI contrast agent (Omniscan; 3.7 mM-1 s-1) in HSA solution (0.67 mM) at 3 T. The tumor-targeting characteristics were confirmed by T1-weighted MR imaging and optical imaging using an orthotopic brain tumor mouse model, which showed 1.3-fold higher uptake in tumor compared to normal brain tissues. The cell fraction data using U87MG glioblastoma cells indicated the potential for gadolinium neutron capture therapy (Gd-NCT), which requires gadolinium to be inside the cell nucleus. In addition, porphyrin derivatives can be used for photodynamic therapy (PDT), and the results demonstrated that Gd-TDAP has great potential not only as a bimodal imaging agent but also for treatment.

Imaging Strategy that Achieves Ultrahigh Contrast by Utilizing Differential Esterase Activity in Organs: Application in Early Detection of Pancreatic Cancer.

Most nanoparticles show much higher uptake in mononuclear phagocyte system (MPS) organs than in tumors, which has been a long-lasting dilemma in nanomedicine. Here, we report an imaging strategy that selectively decreases MPS organ uptakes by utilizing the differential esterase activity in tumors and other organs. When an esterase-labile radiotracer loaded liposome was injected into the body, radioactivity was rapidly excreted from the liver and spleen after breakage of the ester bond by esterase. However, the lipophilic radiotracer delivered to the tumor remained in the tumor with minimal bond cleavage. The underlying mechanism was fully characterized in vitro and in vivo in colon tumor models. As a proof of concept, the liposomal radiotracer was further optimized for the early detection of pancreatic cancer. The folate-coated liposomal radiotracer showed highly selective tumor uptake. At 4 h postinjection, a pancreatic tumor a few millimeters in size was unambiguously visualized in orthotopic tumor models by PET imaging. At 24 h, an exceptionally high tumor-to-background ratio was achieved, enabling the visualization of tumors alone with minimal background noise. More than 9% of the total radioactivity was found in the tumor. Utilizing our imaging strategy, various tumor imaging agents can be developed for sensitive detection with ultrahigh contrast.