Black chokeberry (Aronia melanocarpa L.) polyphenols attenuate obesity-induced colonic inflammation by regulating gut microbiota and the TLR4/NF-κB signaling pathway in high fat diet-fed rats.

This study investigated the potential benefits of black chokeberry polyphenol (BCP) supplementation on lipopolysaccharide (LPS)-stimulated inflammatory response in RAW264.7 cells and obesity-induced colonic inflammation in a high fat diet (HFD)-fed rat model. Our findings demonstrated that BCP treatment effectively reduced the production of nitric oxide (NO) and pro-inflammatory cytokines (TNF-α, IL-1ß, IL-6, and MCP-1) in LPS-induced RAW264.7 cells and concurrently mitigated oxidative stress by modulating the levels of malondialdehyde (MDA), catalase (CAT), and glutathione peroxidase (GSH-Px) in a dose-dependent manner. Furthermore, BCP supplementation significantly ameliorated HFD-induced obesity, improved glucose tolerance, and reduced systemic inflammation in HFD-fed rats. Notably, BCP treatment suppressed the mRNA expression of pro-inflammatory cytokines and alleviated intestinal barrier dysfunction by regulating the mRNA and protein expression of key tight junction proteins (ZO-1, occludin, and claudin-1), thereby inhibiting colonic inflammation caused by the TLR4/NF-κB signaling pathway. Additionally, BCP treatment altered the composition and function of the gut microbiota, leading to an increase in the total content of short-chain fatty acids (SCFAs), particularly acetic acid, propionic acid, isobutyric acid, and butyric acid. Collectively, our results highlighted the potential of BCP supplementation as a promising prebiotic strategy for treating obesity-induced colonic inflammation.

Modulation of the gut microbiota and lipidomic profiles by black chokeberry (Aronia melanocarpa L.) polyphenols via the glycerophospholipid metabolism signaling pathway.

Black chokeberry (Aronia melanocarpa L.) is rich in polyphenols with various physiological and pharmacological activities. However, the relationship between the modulation effect of black chokeberry polyphenols on obesity and the alteration of lipid metabolism is not clearly understood. This study aimed to investigate the beneficial effects of the black chokeberry polyphenols (BCPs) treatment on the structure of gut microbiota, lipid metabolism, and associated mechanisms in high-fat diet (HFD)-induced obese rats. Here, we found that a high-fat diet promoted body weight gain and lipid accumulation in rats, while oral BCPs supplementation reduced body weight, liver, and white adipose tissue weight and alleviated dyslipidemia and hepatic steatosis in HFD-induced obese rats. In addition, BCPs supplementation prevented gut microbiota dysbiosis by increasing the relative abundance of Bacteroides, Prevotella, Romboutsia, and Akkermansia and decreasing the relative abundance of Desulfovibrio and Clostridium. Furthermore, 64 lipids were identified as potential lipid biomarkers through lipidomics analysis after BCPs supplementation, especially PE (16:0/22:6), PE (18:0/22:6), PC (20:3/19:0), LysoPE (24:0), LysoPE (24:1), and LysoPC (20:0). Moreover, our studies provided new evidence that composition of gut microbiota was closely related to the alteration of lipid profiles after BCPs supplementation. Additionally, BCPs treatment could ameliorate the disorder of lipid metabolism by regulating the mRNA and protein expression of genes related to the glycerophospholipid metabolism signaling pathway in HFD-induced obese rats. The mRNA and protein expression of PPARα, CPT1α, EPT1, and LCAT were significantly altered after BCPs treatment. In conclusion, the results of this study indicated that BCPs treatment alleviated HFD-induced obesity by modulating the composition and function of gut microbiota and improving the lipid metabolism disorder via the glycerophospholipid metabolism signaling pathway.

Inhibitory effects of polyphenols from black chokeberry on advanced glycation end-products (AGEs) formation.

Plant-based polyphenols are known to exert mitigating effects on the harmful consequences of advanced glycation. In this study, the antioxidant and antiglycation properties of purified black chokeberry polyphenol and its dominant monomers were studied. The phenolics of black chokeberry had a significant inhibitory effect on glycation products at all stages. The highest inhibition of fructosamine (72.27%) was achieved by chlorogenic acid (CA). Epigallocatechin gallate (EGCG) showed an 84.47% inhibition of α-dicarbonyl and 54.44% inhibition of AGEs (advanced glycation end-products). However, the inhibition of α-dicarbonyl was impacted by the presence of Cu2+. In addition, an EGCG-induced increase in the protein α-helical structure to 21.43% was observed. Overall, EGCG was the main component inhibited protein glycosylation in the simulated glycation system. Furthermore, the mechanism of inhibition was a combination of scavenging free radicals, capturing metal ions, and alleviating changes in the secondary structure of proteins.

A chlorin-lipid nanovesicle nucleus drug for amplified therapeutic effects of lung cancer by internal radiotherapy combined with the Cerenkov radiation-induced photodynamic therapy.

Traditional photodynamic therapy (PDT) requires external light excitation to produce reactive oxygen species (ROSs) for the treatment of tumors. Due to problems of light penetration, traditional PDT is limited by the location and depth of the tumor. In this study, we rationally designed and constructed a novel strategy to amplify the therapeutic effect of PDT. We prepared a chlorin-lipid nanovesicle based on the conjugates of chlorin e6 (Ce 6) and phospholipids, with the surface conjugating the aptamer for lung cancer targeting, GLT21.T. 131I-labeled bovine serum albumin (131I-BSA) was loaded into the chlorin-lipid nanovesicle cavity (131I-BSA@LCN-Apt). 131I not only plays a role in radiotherapy, but its Cerenkov radiation (CR), as an internal light source, can also stimulate Ce6 to produce ROSs without external light excitation. The in vitro and in vivo therapeutic effects in subcutaneous lung tumor models and orthotopic lung tumor models indicated that 131I-BSA@LCN-Apt produced a powerful anti-tumor effect through synergistic radiotherapy and CR-PDT, which almost caused complete tumor growth regression. After treatment, the survival time of the mice was significantly prolonged. During the treatment, no obvious side effects were found by histopathology of important organs, hematology and biochemistry analysis except the decrease of the white blood cell count (WBC). The study provides a major tool for deep-seated tumors to obtain amplified therapeutic effects by synergistic radiotherapy and CR-PDT without the use of any external light source.

An artificial metalloenzyme for catalytic cancer-specific DNA cleavage and operando imaging.

Metalloenzymes are promising anticancer candidates to overcome chemoresistance by involving unique mechanisms. To date, it is still a great challenge to obtain synthetic metalloenzymes with persistent catalytic performance for cancer-specific DNA cleavage and operando imaging. Here, an artificial metalloenzyme, copper cluster firmly anchored in bovine serum albumin conjugated with tumor-targeting peptide, is exquisitely constructed. It is capable of persistently transforming hydrogen peroxide in tumor microenvironment to hydroxyl radical and oxygen in a catalytic manner. The stable catalysis recycling stems from the electron transfer between copper cluster and substrate with well-matched energy levels. Notably, their high biocompatibility, tumor-specific recognition, and persistent catalytic performance ensure the substantial anticancer efficacy by triggering DNA damage. Meanwhile, by coupling with enzyme-like reactions, the operando therapy effect is expediently traced by chemiluminescence signal with high sensitivity and sustainability. It provides new insights into synthesizing biocompatible metalloenzymes on demand to visually monitor and efficiently combat specific cancers.

Is GSH Chelated Pt Molecule Inactive in Anti-Cancer Treatment? A Case Study of Pt6 GS4.

Platinum (Pt) drugs are widely used in anti-cancer treatment although many reports advocated that tumor cells could inactivate Pt drugs via glutathione-Pt (GSH-Pt) adducts formation. To date, GSH chelated Pt molecules have not been assessed in cancer treatment because GSH-Pt adducts are not capable of killing cancer cells, which is widely accepted and well followed. In this report, endogenous biothiol is utilized to precisely synthesize a GSH chelated Pt molecule (Pt6 GS4 ). This Pt6 GS4 molecule can be well taken up by aggressive triple negative breast cancer (TNBC) cells. Subsequently, its metabolites could enter nuclei to interact with DNA, finally the DNA-Pt complex triggers TNBC cell apoptosis via the p53 pathway. Impressively, high efficacy for anti-cancer treatment is achieved by Pt6 GS4 both in vitro and in vivo when compared with traditional first-line carboplatin in the same dosage. Compared with carboplatin, Pt6 GS4 keeps tumor bearing mice alive for a longer time and is non-toxic for the liver and kidneys. This work opens a route to explore polynuclear Pt compound with accurate architecture for enhancing therapeutic effects and reducing systemic toxicity.

Inherently PET/CT Dual Modality Imaging Lipid Nanocapsules for Early Detection of Orthotopic Lung Tumors.

Accurate diagnosis of cancer at an early stage is the key to reduce cancer mortality and improve survival. PET imaging has high sensitivity but low spatial resolution, while CT imaging has good spatial location information. Therefore, the combination of PET and CT imaging can provide complementary advantages to achieve accurate early diagnosis of tumors. However, currently developed PET or CT imaging agents have only a single function. Here, we designed and constructed a self-assembled lipid nanocapsule encapsulated with iodixanol and labeled with self-chelated 64Cu for precise PET/CT imaging of tiny lung tumor. The lipid nanocapsule self-assembled in water using LPPC-Ce6, a conjugate of chlorin e6 (Ce6) and lysophosphatidylcholine (LPPC), to form a bilayer vesicular structure. 64Cu was embedded in the center of the tetrapyrrole ring of Ce6 by natural capture ability for Cu2+ ions. GLT21.T, the aptamer targeting lung cancer, was conjugated to the surface of the lipid nanocapsules. Iodixanol was loaded into the cavity of the lipid nanocapsule (64Cu@LCI-apt). In the nanostructure, the loading of iodixanol was sufficiently high, and the specific activity could be flexibly adjusted according to imaging requirements. The prepared 64Cu@LCI-apt achieves excellent radiolabeling efficiency, stability and effective targeting of lung tumor. In an early orthotopic lung cancer model, 64Cu@LCI-apt demonstrated the capabilities of sensitive PET imaging and enhanced contrast CT imaging to enable efficient high-quality PTE/CT imaging of tiny orthotopic lung tumor with a diameter of 500 µm. 64Cu@LCI-apt has great potential for early, sensitive, and accurate diagnosis of tumors through dual-mode PET/CT imaging.

Iodine-124 Labeled Gold Nanoclusters for Positron Emission Tomography Imaging in Lung Cancer Model.

This work reports the synthesis, radiolabeling and imaging studies of iodine-124 labeled peptide modified gold nanoclusters (AuNCs) as positron emission tomography (PET) tracer for lung cancer. The novel modified Au nanoclusters were successfully synthesized by conjugation of tumortargeting peptide luteinizing hormone releasing hormone (LHRH) to human serum albumin (HAS) as a scaffold, resulting in 73% labeling yield of 124I-LHRH-HSA AuNCs. After rapid purification, the radiochemical purity was above 98%. Dynamic PET study in normal rats showed high liver accumulation and rapid lung clearance. Both the PET and fluorescence imaging in A549 xenografted tumor model demonstrated certain amount of tumor uptake. In orthotopic lung cancer model, the tumor sites could be clearly visualized between 2 to 5 hours in PET images. The higher radioactivity concentration in the left lung which inoculated orthotopic tumor than right lung also exhibited the targeting properties. The biological properties of this iodine-124 labeled nanoclusters afford potential applications for early diagnosis of lung cancer with PET.

Comparison of the Therapeutic Effects of Gold Nanoclusters and Gold Nanoparticles on Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and progressive cartilage and bone damage. In our previous studies, we found that Au clusters using glutathione as a template (GACs) produced profound anti-inflammatory effects in vitro on lipopolysaccharide (LPS)-induced inflammation in mouse macrophage RAW 264.7 cells and type II collagen-induced rat RA in vivo. In this study, we examined whether the template for Au clusters synthesis has an effect on its anti-inflammatory effect and whether Au nanoparticles with larger particle diameter produce the same anti-inflammatory effect. We synthesized Au clusters with bovine serum albumin (BSA) as a template (BACs), Au clusters with glutathione (GSH) as a template (GACs), and Au nanoparticles with glutathione as a template (GANs) and compared their anti-inflammatory effects in vitro and in vivo. These three Au nanomaterials can inhibit the production of lipopolysaccharide (LPS)-induced proinflammatory mediators and ameliorate type II collagen-induced rat RA. However, although the three Au nanomaterials produced similar anti-inflammatory effects, the GANs with larger particle sizes were less stable in vivo and accumulated in the peritoneum after intraperitoneal injection, resulting in poor absorption in vivo. The BACs showed relatively high liver accumulation due to the larger molecular weight of the outer shell. Therefore, we believe that the GACs are potential reliable nanodrugs for the treatment of RA.

Dose-Dependent Efficacy of Gold Clusters on Rheumatoid Arthritis Therapy.

Chronic inflammation and progressive bone damage in joints are two main pathological features of rheumatoid arthritis (RA). We have synthesized a gold cluster with glutathione (Au29SG27) (named GA) that can effectively suppress both inflammation and bone damage in collagen-induced arthritis (CIA) in rats. Thus, gold clusters showed great potential for the therapy of RA. However, the optimal therapeutic dose remaining has to be determined. Therapeutic effect and safety are largely relying on drug dosage. Specifying the dose-dependent effects of GA on both therapy and biosafety can facilitate its clinical transformation research. Therefore, in this study, we comprehensively evaluated the dose-dependent efficacy of GA on the 30-day toxicity and RA treatment in rats. Results showed that continuous intraperitoneal injection of GA at a dose of 15 mg/kg (Au content) for 30 days resulted in slight hematological abnormalities and increases on organ coefficients of kidney and adrenal gland, while 10 mg Au/kg did not cause any obvious toxicity and side effects. In the treatment of CIA rats, only when the dose of GA reached 5 mg Au/kg, the symptoms of RA could be significantly improved. With regard to the histopathological analysis, although a lower dose of GA can suppress inflammation and bone damage to some extent, only the 5 mg Au/kg treatment could restore them to a state close to the normal control group. Therefore, we infer that 5 mg Au/kg is the optimal dose of GA for RA therapy in rats, which provides a theoretical basis for further preclinical research.

Gold Clusters Prevent Inflammation-Induced Bone Erosion through Inhibiting the Activation of NF-κB Pathway.

Inflammation-induced bone erosion is a major pathological factor in several chronic inflammatory diseases that often cause severe outcomes, such as rheumatoid arthritis and periodontitis. Plenty of evidences indicated that the inflammatory bone destruction was attributed to an increase in the number of bone-resorbing osteoclasts. However, anti-resorptive therapy alone failed to prevent bone loss in an inflammatory condition. Conventional anti-inflammation treatments are usually intended to suppress inflammation only, but ignore debilitating the subsequent bone destruction. Therefore, inhibition of proinflammatory activation of osteoclastogenesis could be an important strategy for the development of drugs aimed at preventing inflammatory bone destruction. Methods: In this study, we synthesized a peptide coated gold cluster to evaluate its effects on inflammatory osteoclastogenesis in vitro and inflammation-induced bone destruction in vivo. The in vitro anti-inflammation and anti-osteoclastogenesis effects of the cluster were evaluated in LPS-stimulated and receptor activator of nuclear factor κB ligand (RANKL) stimulated macrophages, respectively. The LPS-induced expression of crucial pro-inflammation cytokines and RANKL-induced osteoclastogenesis as well as the activation of NF-κB pathway in both situations were detected. The inflammation-induced RANKL expression and subsequent inflammatory bone destruction in vivo were determined in collagen-immunized mice. Results: The gold cluster strongly suppresses RANKL-induced osteoclast formation via inhibiting the activation of NF-κB pathway in vitro. Moreover, treatment with the clusters at a dose of 5 mg Au/kg.bw significantly reduces the severity of inflammation-induced bone and cartilage destruction in vivo without any significant toxicity effects. Conclusion: Therefore, the gold clusters may offer a novel potent therapeutic stratagem for inhibiting chronic inflammation associated bone destruction.

Au Clusters Treat Rheumatoid Arthritis with Uniquely Reversing Cartilage/Bone Destruction.

Super-small nanoclusters may intrinsically trigger specific molecular pathway for disease treatment in vitro/vivo. To prove the hypothesis the super-small nanoclusters, e.g., Au clusters, are directly used to treat rheumatoid arthritis (RA) in vitro/vivo. RA is a chronic autoimmune disease that is characterized by the inflammation of joints and the unreversible destruction of the cartilage/bone. Au clusters significantly suppress lipopolysaccharide (LPS)-induced proinflammatory mediator production in the murine macrophage cell line by inhibiting the signaling pathways that regulate the major proinflammatory mediator genes. In preclinical rat RA studies, Au clusters strongly prevent type II collagen-induced rat RA without systemic side effects. Compared with the clinical first-line anchored anti-RA drug, methotrexate, Au clusters equally inhibit inflammation in vivo. Type II collagen-induced rat RA is characterized with the destruction of cartilage/bone; treatment with Au clusters reverses the destruction of cartilage/bone to its normal state. This is because Au clusters directly inhibit receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclast differentiation and function through the downregulation of osteoclast-specific genetic marker expression. However the methotrexate almost has no positive effect for this key issue in rat RA therapy. These data prove that the super-small nanoclusters, e.g., Au clusters, could be a novel candidate nanodrug for RA treatment.

Surface-Functionalized Modified Copper Sulfide Nanoparticles Enhance Checkpoint Blockade Tumor Immunotherapy by Photothermal Therapy and Antigen Capturing.

Nanomaterial-based tumor photothermal therapy (PTT) has attracted increasing attention and been a promising method for cancer treatment because of its low level of adverse effects and noninvasiveness. However, thermotherapy alone still cannot control tumor metastasis and recurrence. Here, we developed surface-functionalized modified copper sulfide nanoparticles (CuS NPs). CuS NPs can not only be used as photothermal mediators for tumor hyperthermia but can adsorb tumor antigens released during hyperthermia as an antigen-capturing agent to induce antitumor immune response. We selected maleimide polyethylene glycol-modified CuS NPs (CuS NPs-PEG-Mal) with stronger antigen adsorption capacity, in combination with an immune checkpoint blocker (anti-PD-L1) to evaluate the effect of hyperthermia, improving immunotherapy in a 4T1 breast cancer tumor model. The results showed that hyperthermia based on CuS NPs-PEG-Mal distinctly increased the levels of inflammatory cytokines in the serum, leading to a tumor immunogenic microenvironment. In cooperation with anti-PD-L1, PTT mediated by CuS NPs-PEG-Mal enhanced the number of tumor-infiltrating CD8+ T cells and inhibited the growth in primary and distant tumor sites of the 4T1 tumor model. The therapeutic strategies provide a simple and effective treatment option for metastatic and recurrent tumors.

Peptide-Templated Gold Clusters as Enzyme-Like Catalyst Boost Intracellular Oxidative Pressure and Induce Tumor-Specific Cell Apoptosis.

Anticancer metallodrugs that aim to physiological characters unique to tumor microenvironment are expected to combat drug tolerance and side-effects. Recently, owing to the fact that reactive oxygen species' is closely related to the development of tumors, people are committed to developing metallodrugs with the capacity of improving the level of reactive oxygen species level toinduce oxidative stress in cancer cells. Herein, we demonstrated that peptide templated gold clusters with atomic precision preferably catalyze the transformation of hydrogen peroxide into superoxide anion in oxidative pressure-type tumor cells. Firstly, we successfully constructed gold clusters by rationally designing peptide sequences which targets integrin ανß3 overexpressed on glioblastoma cells. The superoxide anion, radical derived from hydrogen peroxide and catalyzed by gold clusters, was confirmed in vitro under pseudo-physiological conditions. Then, kinetic parameters were evaluated to verify the catalytic properties of gold clusters. Furthermore, these peptide decorated clusters can serve as special enzyme-like catalyst to convert endogenous hydrogen peroxide into superoxide anion, elevated intracellular reactive oxygen species levels, lower mitochondrial membrane potential, damage biomacromolecules, and trigger tumor cell apoptosis consequently.

Turning On/Off the Anti-Tumor Effect of the Au Cluster via Atomically Controlling Its Molecular Size.

We reported two Au clusters with precisely controlled molecular size (Au5Peptide3 and Au22Peptide10) showing different antitumor effects. In vitro, both Au5Peptide3 and Au22Peptide10 were well taken up by human nasopharyngeal cancer cells (CNE1 cells). However, only Au5Peptide3 significantly induced CNE1 cell apoptosis. Further studies showed that CNE1 cells took up Au5Peptide3 (1.98 × 10-15 mol/cell), and 9% of them entered mitochondria (0.186 × 10-15 mol/cell). As a comparison, the uptake of Au22Peptide10 was only half the amount of Au5Peptide3 (1.11 × 10-15 mol/cell), and only 1% of them entered mitochondria (0.016 × 10-15 mol/cell). That gave 11.6-fold more Au5Peptide3 in mitochondria of CNE1 cells than Au22Peptide10. Further cell studies revealed that the antitumor effect may be due to the enrichment of Au5Peptide3 in mitochondria. Au5Peptide3 slightly decreased the Mcl-1 (antiapoptotic protein of mitochondria) and significantly increased the Puma (pro-apoptotic protein of mitochondria) expression level in CNE1 cells, which resulted in mitochondrial transmembrane potential change and triggered the caspase 9-caspase 3-PARP pathway to induce CNE1 cell apoptosis. In vivo, CNE1 tumor growth was significantly suppressed by Au5Peptide3 in the xenograft model after 3 weeks of intraperitoneal injection. The TUNEL and immuno-histochemical studies of tumor tissue verified that CNE1 cell apoptosis was mainly via the Puma and Mcl-1 apoptosis pathway in the xenograft model, which matched the aforementioned CNE1 cell studies in vitro. The discovery of Au5 but not Au22 suppressing tumor growth via the mitochondria target was a breakthrough in the nanomedical field, as this provided a robust approach to turn on/off the nanoparticles' medical properties via atomically controlling their sizes.

Au Nanoclusters and Photosensitizer Dual Loaded Spatiotemporal Controllable Liposomal Nanocomposites Enhance Tumor Photodynamic Therapy Effect by Inhibiting Thioredoxin Reductase.

Photodynamic therapy (PDT) is a minimally invasive therapeutic procedure of tumors with high selectivity and low side effect. However, it is usually not efficient in long-lasting tumor control. One of the main reasons is tumor cells develop some protective mechanisms that help them to deal with oxidative stress in the environment. The thioredoxin system in cancer is an important antioxidant defense system. Au nanoclusters could effectively inhibit thioredoxin reductase (TrxR) in tumor cell cytoplasm. Herein, Au nanoclusters and photosensitizer Chlorine 6 (Ce6) are co-loaded in spatiotemporal controllable liposomal nanocomposites. pH responsive molecule inserted in lipid bilayer greatly contributes to the instability of the lipid membrane in lysosomal at low pH environment. Then the payloads can rapidly release into cytoplasm. Au nanoclusters effectively inhibit TrxR in cytoplasm and enhance the photodynamic-induced intracellular reactive oxygen-free radical concentration, improving the effect of PDT. Breast cancer is chosen as a tumor model and the Au nanoclusters and photosensitizer co-loaded liposomal nanocomposites are studied to improve the effect of PDT both in vitro and in vivo, and its corresponding mechanism is investigated. This study develops a new application of gold nanoclusters and provides a new train of thoughts for enhancing the effect of PDT.

Ultrasmall [(64)Cu]Cu nanoclusters for targeting orthotopic lung tumors using accurate positron emission tomography imaging.

Positron emission tomography (PET) imaging has received special attention owing to its higher sensitivity, temporal resolution, and unlimited tissue penetration. The development of tracers that target specific molecules is therefore essential for the development and utility of clinically relevant PET procedures. However, (64)Cu as a PET imaging agent generally has been introduced into biomaterials through macrocyclic chelators, which may lead to the misinterpretation of PET imaging results due to the detachment and transchelation of (64)Cu. In this study, we have developed ultrasmall chelator-free radioactive [(64)Cu]Cu nanoclusters using bovine serum albumin (BSA) as a scaffold for PET imaging in an orthotopic lung cancer model. We preconjugated the tumor target peptide luteinizing hormone releasing hormone (LHRH) to BSA molecules to prepare [(64)Cu]CuNC@BSA-LHRH. The prepared [(64)Cu]Cu nanoclusters showed high radiolabeling stability, ultrasmall size, and rapid deposition and diffusion into tumor, as well as predominantly renal clearance. [(64)Cu]CuNC@BSA-LHRH showed 4 times higher tumor uptake compared with that of [(64)Cu]CuNC@BSA by analyzing the (64)Cu radioactivity of tissues via gamma counting. The PET imaging using [(64)Cu]Cu nanoclusters as tracers showed more sensitive, accurate, and deep penetration imaging of orthotopic lung cancer in vivo compared with near-infrared fluorescence imaging. The nanoclusters provide biomedical research tools for PET molecular imaging.

Cytotoxicity and therapeutic effect of irinotecan combined with selenium nanoparticles.

Although chemotherapeutic drugs are widely applied for clinic tumor treatment, severe toxicity restricts their therapeutic efficacy. In this study, we reported a new form of selenium, selenium nanoparticles (Nano Se) which have significant lower toxicity and acceptable bioavailability. We investigated Nano Se as chemotherapy preventive agent to protect against toxicities of anticancer drug irinotecan and synergistically enhance the anti-tumor treatment effect in vitro and in vivo. The underlying mechanisms were also investigated. The combination of Nano Se and irinotecan showed increased cytotoxic effect with HCT-8 tumor cells likely by p53 mediated apoptosis. Nano Se inhibited growth of HCT-8 tumor cells partially through caspases mediated apoptosis. In vivo experiment showed Nano Se at a dose of 4 mg/kg/day significantly alleviated adverse effects induced by irinotecan (60 mg/kg) treatment. Nano Se alone treatment did not induce any toxic manifestations. The combination of Nano Se and irinotecan dramatically inhibited tumor growth and significantly induced apoptosis of tumor cells in HCT-8 cells xenografted tumor. Tumor inhibition rate was about 17.2%, 48.6% and 62.1% for Nano Se, irinotecan and the combination of Nano Se and irinotecan, respectively. The beneficial effects of Nano Se for tumor therapy were mainly ascribed to selectively regulating Nrf2-ARE (antioxidant responsive elements) pathway in tumor tissues and normal tissues. Our results suggest Nano Se is a promising selenium species with potential application in cancer treatment.