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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.

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.

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.

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 le...

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.

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&rsquo, 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 &alpha, &nu, &beta, 3 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.

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 (Pt(6)GS(4)). This Pt(6)GS(4) 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 Pt(6)GS(4) both in vitro and in vivo when compared with traditional first-line carboplatin in the same dosage. Compared with carboplatin, Pt(6)GS(4) 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.

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.

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.