An acid-activatable fluorouracil prodrug for colorectal cancer synergistic therapy.

5-Fluorouracil has demonstrated certain efficiency in patients with colorectal cancer. However, significant side effects of use by injection are common. To address this issue defects, a reengineered 5'-deoxy-5-fluorocytidine (DFCR) based drug delivery system (POACa) is developed as a prominent tumor-selective nano-activator. Investigations demonstrate that the constructed nano-activator exhibits good biocompatibility and high therapeutic efficiency in mice with subcutaneous and orthotopic SW-480 colorectal tumors, as its activity is strictly dependent on the tumor-associated acid environment and thymidine phosphorylase. These strategies diminish the off-target toxicity and improve the specificity and sensitivity of human colorectal cancer cells to 5-Fu, obtaining potent efficiency by the combination of H2O2 mediated oxidative stress, calcium overload and 5-Fu-induced chemotherapy (the combination index is 0.11). Overall, the engineered nano-activator exhibits a high therapeutic index in vitro and in vivo. STATEMENT OF SIGNIFICANCE: In this study, we designed and prepared a pH-responsive polymer to synchronously deliver DFCR (5'-deoxy-5-fluorocytidine, a prodrug of 5-Fu), Ca2+ and H2O2. The constructed nano-activator was denoted as POACa. (1) To address the problem of premature leakage of cargo by physical embedding, our research modified the inactive prodrug DFCR through chemical bonding. (2) The activation of the prepared nano-activator was strictly dependent on the tumor-associated acid environment and thymidine phosphorylase, providing the drug delivery system with inherent safety. (3) A distinctly low combination index value (0.11) of CaO2 and DFCR indicated that POACa has a prominent tumor suppression effect by tumor calcium overload sensitized chemotherapy and H2O2 mediated cytotoxicity.

Engineered Antibodies as Cancer Radiotheranostics.

Radiotheranostics is a rapidly growing approach in personalized medicine, merging diagnostic imaging and targeted radiotherapy to allow for the precise detection and treatment of diseases, notably cancer. Radiolabeled antibodies have become indispensable tools in the field of cancer theranostics due to their high specificity and affinity for cancer-associated antigens, which allows for accurate targeting with minimal impact on surrounding healthy tissues, enhancing therapeutic efficacy while reducing side effects, immune-modulating ability, and versatility and flexibility in engineering and conjugation. However, there are inherent limitations in using antibodies as a platform for radiopharmaceuticals due to their natural activities within the immune system, large size preventing effective tumor penetration, and relatively long half-life with concerns for prolonged radioactivity exposure. Antibody engineering can solve these challenges while preserving the many advantages of the immunoglobulin framework. In this review, the goal is to give a general overview of antibody engineering and design for tumor radiotheranostics. Particularly, the four ways that antibody engineering is applied to enhance radioimmunoconjugates: pharmacokinetics optimization, site-specific bioconjugation, modulation of Fc interactions, and bispecific construct creation are discussed. The radionuclide choices for designed antibody radionuclide conjugates and conjugation techniques and future directions for antibody radionuclide conjugate innovation and advancement are also discussed.

Integrated anti-vascular and immune-chemotherapy for colorectal carcinoma using a pH-responsive polymeric delivery system.

Colorectal carcinoma (CRC) has become one of the most prevalent malignant tumors and exploring a potential therapeutic strategy with diminished drug-associated adverse effects to combat CRC is urgent. Herein, we designed a pH-responsive polymer to efficiently encapsulate a stimulator of interferon genes (STING) agonist (5,6- dimethylxanthenone-4-acetic acid, termed ASA404) and a common clinically used chemotherapeutic agent (1-hexylcarbamoyl-5-fluorouracil, termed HCFU). Investigations in vitro demonstrated that polymer encapsulation endowed the system with a pH-dependent disassembly behavior (pHt 6.37), which preferentially selected cancerous cells with a favorable dose reduction (dose reduction index (DRI) of HCFU was 4.09). Moreover, the growth of CRC in tumor-bearing mice was effectively suppressed, with tumor suppression rates up to 94.74%, and a combination index (CI) value of less than one (CI = 0.41 for CT26 cell lines), indicating a significant synergistic therapeutic effect. Histological analysis of the tumor micro-vessel density and enzyme-linked immunosorbent assay (ELISA) tests indicated that the system increased TNF-α and IFN-ß levels in serum. Therefore, this research introduces a pH-responsive polymer-based theranostic platform with great potential for immune-chemotherapeutic and anti-vascular combination therapy of CRC.

Cu2+ -Anchored Carbon Nano-Photocatalysts for Visible Water Splitting to Boost Hydrogen Cuproptosis.

Both hydrogen (H2 ) and copper ions (Cu+ ) can be used as anti-cancer treatments. However, the continuous generation of H2 molecules and Cu+ in specific sites of tumors is challenging. Here we anchored Cu2+ on carbon photocatalyst (Cu@CDCN) to allow the continuous generation of H2 and hydrogen peroxide (H2 O2 ) in tumors using the two-electron process of visible water splitting. The photocatalytic process also generated redox-active Cu-carbon centers. Meanwhile, the Cu2+ residues reacted with H2 O2 (the obstacle to the photocatalytic process) to accelerate the two-electron process of water splitting and cuprous ion (Cu+ ) generation, in which the Cu2+ residue promoted a pro-oxidant effect with glutathione through metal-reducing actions. Both H2 and Cu+ induced mitochondrial dysfunction and intracellular redox homeostasis destruction, which enabled hydrogen therapy and cuproptosis to inhibit cancer cell growth and suppress tumor growth. Our research is the first attempt to integrate hydrogen therapy and cuproptosis using metal-enhanced visible solar water splitting in nanomedicine, which may provide a safe and effective cancer treatment.

Novel GRPR-Targeting Peptide for Pancreatic Cancer Molecular Imaging in Orthotopic and Liver Metastasis Mouse Models.

Despite advancements in pancreatic cancer treatment, it remains one of the most lethal malignancies with extremely poor diagnosis and prognosis. Herein, we demonstrated the efficiency of a novel peptide GB-6 labeled with a near-infrared (NIR) fluorescent dye 3H-indolium, 2-[2-[2-[(2-carboxyethyl)thio]-3-[2-[1,3-dihydro-3,3-dimethyl-5-sulfo-1-(3-sulfopropyl)-2H-indol-2-ylidene]ethylidene]-1-cyclohexen-1-yl]ethenyl]-3,3-dimethyl-5-sulfo-1-(3-sulfopropyl)-, inner salt (MPA) and radionuclide technetium-99m (99mTc) as targeting probes using the gastrin-releasing peptide receptor (GRPR) that is overexpressed in pancreatic cancer as the target. A short linear peptide with excellent in vivo stability was identified, and its radiotracer [99mTc]Tc-HYNIC-PEG4-GB-6 and the NIR probe MPA-PEG4-GB-6 exhibited selective and specific uptake by tumors in an SW1990 pancreatic cancer xenograft mouse model. The favorable biodistribution of the tracer [99mTc]Tc-HYNIC-PEG4-GB-6 in vivo afforded tumor-specific accumulation with high tumor-to-muscle and -bone contrasts and renal body clearance at 1 h after injection. The biodistribution analysis revealed that the tumor-to-pancreas and -intestine fluorescence signal ratios were 5.2 ± 0.3 and 6.3 ± 1.5, respectively, in the SW1990 subcutaneous xenograft model. Furthermore, the high signal accumulation in the orthotopic pancreatic and liver metastasis tumor models with tumor-to-pancreas and -liver fluorescence signal ratios of 7.66 ± 0.48 and 3.94 ± 0.47, respectively, enabled clear tumor visualization for intraoperative navigation. The rapid tumor targeting, precise tumor boundary delineation, chemical versatility, and high potency of the novel GB-6 peptide established it as a high-contrast imaging probe for the clinical detection of GRPR, with compelling additional potential in molecular-targeted therapy.

Nanosensitizer-mediated unique dynamic therapy tactics for effective inhibition of deep tumors.

X-ray and ultrasound waves are widely employed for diagnostic and therapeutic purposes in clinic. Recently, they have been demonstrated to be ideal excitation sources that activate sensitizers for the dynamic therapy of deep-seated tumors due to their excellent tissue penetration. Here, we focused on the recent progress in five years in the unique dynamic therapy strategies for the effective inhibition of deep tumors that activated by X-ray and ultrasound waves. The concepts, mechanisms, and typical nanosensitizers used as energy transducers are described as well as their applications in oncology. The future developments and potential challenges are also discussed. These unique therapeutic methods are expected to be developed as depth-independent, minimally invasive, and multifunctional strategies for the clinic treatment of various deep malignancies.

Composition tunability of semiconductor radiosensitizers for low-dose X-ray induced photodynamic therapy.

Radiation therapy is one of the most commonly used methods in clinical cancer treatment, and radiosensitizers could achieve enhanced therapeutic efficacy by incorporating heavy elements into structures. However, the secondary excitation of these high-Z elements-doped nanosensitizers still imply intrinsic defects of low efficiency. Herein, we designed Bi-doped titanium dioxide nanosensitizers in which high-Z Bi ions with adjustable valence state (Bi3+ or Bi4+) replaced some positions of Ti4+ of anatase TiO2, increasing both X-rays absorption and oxygen vacancies. The as-prepared TiO2:Bi nanosensitizers indicated high ionizing radiation energy-transfer efficiency and photocatalytic activity, resulting in efficient electron-hole pair separation and reactive oxygen species production. After further modification with cancer cell targeting peptide, the obtained nanoplatform demonstrated good performance in U87MG cell uptakes and intracellular radicals-generation, severely damaging the vital subcellular organs of U87MG cells, such as mitochondrion, membrane lipid, and nuclei etc. These combined therapeutic actions mediated by the composition-tunable nanosensitizers significantly inhibited the U87MG tumor growth, providing a refreshing strategy for X-ray induced dynamic therapy of malignant tumors.

In vivo assessing colitis severity by topical administration of fluorescent probe against neutrophils.

Inflammatory bowel disease has become a global burden given its high incidence and refractory to medical treatment. Improved diagnostic strategies to monitor disease activity more accurately are necessary to conduct and evaluate medical treatment. High level of neutrophil infiltration in colon is associated with poor prognosis and enhanced risk of developing colitis-associated cancer. Herein, to accurately monitor neutrophil levels in colitis condition, we designed and constructed a specific probe (CPM), consisting of a neutrophil formyl peptide receptor targeting group (cFLFLFK), a short PEG linker and a near-infrared fluorescent dye. CPM selectively identified neutrophils in vitro and preferentially recognized neutrophils in vivo with enhanced targeting ability and biodistribution property. After verified the ability to target activated neutrophils, CPM was used to detect neutrophils in experimental colitis by systemic and topical administration. Compared to systemic administration, topical administration of CPM allows lower dosage, higher target-to-background ratio and longer duration of effective monitoring. More importantly, we used CPM to assess neutrophil levels in the course of colitis development. The fluorescence intensity of CPM increased along with colitis progression. Additionally, CPM was used to detected neutrophil levels in colitis-associated cancer and enhanced neutrophil infiltration in the tumor sites was detected. In conclusion, the probe CPM is a promising tool for in vivo improved diagnosis of colitis severity by monitoring the extent of neutrophil infiltration.

A novel peptide targeting c-Met for hepatocellular carcinoma diagnosis.

Hepatocellular carcinoma (HCC) is one of the most common malignant tumors with limited diagnosis. Mesenchymal epithelial transition factor (c-Met) has become a hot target for cancer diagnosis and therapy, which is overexpressed in HCC. In this study, we labeled a novel c-Met targeting peptide YQ-M3 with a near-infrared fluorescent dye MPA and a radionuclide technetium-99m for HCC detection. YQ-M3-MPA showed high affinity for c-Met positive HepG2 tumor in vitro and higher tumor uptake and higher T/N ratio than GE137-MPA (a positive tracer for c-Met) in HepG2 tumor-bearing mice in vivo by fluorescence imaging. In addition, 99mTc-HYNIC-YQ-M3 also showed significant tumor uptake in vivo through SPECT imaging. These results indicated that c-Met positive tumors were successfully detected via fluorescence and SPECT imaging using YQ-M3-MPA and 99mTc-HYNIC-YQ-M3, respectively, and further suggested that YQ-M3-MPA and 99mTc-HYNIC-YQ-M3 have some possibly potential clinical applications for HCC diagnosis.

Detection of colorectal cancer using a small molecular fluorescent probe targeted against c-Met.

Colorectal cancer (CRC), a highly heterogeneous genetic disease, is currently the second leading cause of cancer-related deaths worldwide. This malignant cancer is typically preceded by the development of precancerous lesions, which are challenging to distinguish their subtle morphologic changes. Molecular-based fluorescence imaging can effectively identify lesion targets to enhance image contrast and improve the detection of early neoplasia comparing to conventional wide-light screening endoscopy. C-Met has been identified as overexpressed in CRC advanced stage and has been suggested as a validated potential theranostic target. Herein, we developed a new small molecular fluorescence probe, namely Crizotinib-PEG4-MPA, specifically binds to c-Met in CRC cells and colitis-associated cancer adenoma. In vitro binding studies confirmed the specificity and selectively of Crizotinib-PEG4-MPA against c-Met, the corresponding apparent equilibrium dissociation constants (Kd) was 3.86 µM for Crizotinib-PEG4-MPA. Additionally, the probe was carried out to c-Met positive tumor-bearing mice in vivo to explore the diagnostic potential clinical value, the method used a randomized block design to cluster mice into groups and found the tumor/normal signal ratio value up to 4.23 (95% confidence interval (CI) 4.07-4.39) at 6 h. More importantly, Crizotinib-PEG4-MPA was used to detect the occurrence of the colon adenoma and the in vivo imaging results showed the mean fluorescence intensity of the CAC colon is significantly higher than that in the normal group (P < 0.001). Furthermore, the immunofluorescence signals of biopsies samples demonstrated the probe indeed targets the c-Met and possesses the property to distinguish colon adenoma from normal colon tissue. Altogether, this novel fluorescence probe, with excellent C-met-targeting ability, has a substantial potential to serve as a widely available in vivo tracer for the early diagnosis and monitoring of colorectal cancer.

AT1R-Specific Ligand Angiotensin II as a Novel SPECT Agent for Hepatocellular Carcinoma Diagnosis.

Hepatocellular carcinoma (HCC) is characterized by a high mortality and early diagnosis and treatment are critically needed. Ang II type 1 receptor (AT1R) has recently emerged as a potential molecular target for cancer diagnosis and intervention. Here, we labeled angiotensin II (Ang II), an AT1R ligand that is overexpressed in various solid cancers, with the near-infrared fluorescent dye, MPA, and radionuclide technetium-99m, and evaluated its capacity for HCC detection. These analyses were done in vitro using HepG2 (AT1R-positive) and BxPC3 (AT1R-negative) cell lines, and in vivo using a subcutaneous and orthotopic xenograft mouse model by fluorescence and SPECT imaging. Both Ang II-PEG4-MPA- and [99mTc]Tc-HYNIC-PEG4-Ang II-bound AT1R exhibited a high affinity in vitro and [99mTc]Tc-HYNIC-PEG4-Ang II displayed an acceptable level of in vitro stability in rat plasma and whole blood. In vivo imaging revealed excellent specific tumor-targeting in HepG2 mouse xenografts models. In vitro and in vivo competition experiments revealed specific Ang II-PEG4-MPA and [99mTc]Tc-HYNIC-PEG4-Ang II uptake by HepG2 cells and tumors. Altogether, AT1R-positive tumors were successfully detected via fluorescence and SPECT imaging using Ang II-PEG4-MPA and [99mTc]Tc-HYNIC-PEG4-Ang II, respectively. Given their superior targeting capacity, Ang II-PEG4-MPA and [99mTc]Tc-HYNIC-PEG4-Ang II are promising tools for HCC detection and warrant clinical translation.

GRPR-targeted SPECT imaging using a novel bombesin-based peptide for colorectal cancer detection.

Colorectal cancer (CRC) is the third most common cancer worldwide, and the prognosis of CRC is better with an earlier diagnosis. The presence of the gastrin-releasing peptide receptor (GRPR) has been documented in very high numbers on colorectal cancer cells, which makes it an ideal biomarker for the diagnosis of CRC. Bombesin (BBN) peptide analogs have been extensively investigated for the imaging of human cancers with GRPR overexpression. Recently, we have reported a novel GRPR-targeted peptide named the GB-6 peptide. The GB-6 peptide based on BBN7-14 was designed to improve in vivo metabolic stability and decrease intestinal uptake. Meanwhile, GB-6 greatly retained the original GRPR-binding affinity of BBN7-14. In this study, the GB-6 peptide was labeled with radionuclide 99mTc or fluorescent dye for colorectal cancer imaging. In vitro receptor binding was studied in Caco-2 cells, and the GRPR targeting capacity and kinetics in vivo were evaluated using Caco-2 tumor xenografted mice models. In addition, cells and mice were also subjected to the corresponding BBN7-14 conjugations for comparison. The GB-6 peptide exhibited specific GRPR binding in vitro with a high affinity similar to that of BBN7-14. Furthermore, we observed that GB-6 showed higher tumor uptake and displayed lower intestinal activity than corresponding unmodified probe BBN7-14 in Caco-2 tumor-bearing mice. Overall, our studies demonstrated that GB-6 has the potential for early detection of CRC patients, and it may also serve as a valuable tool for non-invasive monitoring of colorectal tumor growth.

A novel peptide targeting gastrin releasing peptide receptor for pancreatic neoplasm detection.

Pancreatic cancer has a high mortality rate and efforts towards diagnosis and therapy at an early stage are particularly appealing. Recently, a small peptide, BBN7-14, has attracted much attention for its specific binding ability to gastrin releasing peptide receptor (GRPR), which is highly overexpressed in various types of cancer, including pancreatic cancer. However, its poor stability in vivo restricts its direct clinical application. Herein, by rational design and transformation of BBN7-14, a novel six-amino acid peptide, GB-6, which maintains a specific GRPR-binding feature and exhibits enhanced stability in vitro and in vivo, was designed. Competitive binding with BBN7-14 and cellular uptake related to GRPR expression levels verified the specific affinity of GB-6 to GRPR. Additionally, this novel peptide was conjugated with near-infrared dye and the radionuclide 99mTc for pancreatic cancer diagnosis in cells and in vivo. Surprisingly, despite having the same cellular affinity as BBN7-14, GB-6 showed much higher pancreatic cancer-targeting ability than BBN7-14 by both fluorescence imaging and radionuclide imaging. It was proven that this strange phenomenon was attributed to the distinct in vivo stability of GB-6 and its more favorable pharmacokinetic properties and metabolic stability relative to BBN7-14. Altogether, this novel peptide GB-6, with GRPR-targeting ability and enhanced stability, is a more promising candidate for the clinical diagnosis of pancreatic cancer.

Experimental and theoretical studies on the NLO properties of two quaternary non-centrosymmetric chalcogenides: BaAg2GeS4 and BaAg2SnS4.

New middle and far-infrared (MFIR) nonlinear optical (NLO) chalcogenides have been receiving increasing attention for their great importance in military and civil fields. In addition, the current challenge in the efforts for identifying a promising MFIR NLO material lies in achieving simultaneously large second-harmonic generation (SHG) intensity and high laser-induced damage threshold (LIDT) in the same material. In this study, two quaternary non-centrosymmetric (NCS) sulfides, BaAg2GeS4 (1) and BaAg2SnS4 (2), were synthesized from a high-temperature solid-state reaction using BaCl2 flux in evacuated closed silica tubes. Although 1 and 2 show identical stoichiometry, they crystallize in different NCS space groups, tetragonal I4[combining macron]2m (no. 121) and orthorhombic I222 (no. 23), respectively, based on the results of crystal structure solution. In their structures, highly distorted AgS4 tetrahedra interconnect together via corner-sharing to form two-dimensional (2D) layers, which are further bridged with isolated GeS4 or SnS4 units to produce a three-dimensional (3D) framework structure with Ba cations lying in the tunnels. Remarkably, they not only possess phase-matchable (PM) abilities but also exhibit a good balance between strong SHG responses (1.7× and 0.4× AgGaS2) and high LIDTs (3.2× and 1.5× AgGaS2). Moreover, theoretical calculations based on density functional theory (DFT) methods have aided the understanding of energy bands, electronic structures, and linear and NLO properties.