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.

The Precise Detection of HER-2 Expression in Breast Cancer Cell via Au25 Probes.

Triple-negative breast cancer (TNBC) accounts for nearly one-quarter of all breast cancer cases, but effective targeted therapies for this disease remain elusive because TNBC cells lack the expression of the most common three receptors seen in other subtypes of breast cancers. The medium-term diagnosis of breast cancers is essential for development and prognosis. According to reports, patients with TNBC may be converted to a positive epidermal growth factor receptor 2(HER-2) after chemotherapy, and trastuzumab treatment will have a better prognosis. Therefore, it is important to accurately quantify the expression of HER-2 in breast cancer cells. Herein, we design a red fluorescent Au25 probe synthesized with BSA-biotin as the ligand, which is accurately quantified by HER-2 primary antibody-biotin using the avidin system. The quantitative detection of the expression of HER-2 in breast cancers is helpful for the companion diagnostic of breast cancer treatment and provides follow-up treatment.

Dual peptide nanoparticle platform for enhanced antigen-specific immune tolerance for the treatment of experimental autoimmune encephalomyelitis.

Current therapeutic strategies for autoimmune diseases such as multiple sclerosis (MS) are directed towards nonspecific immunosuppression, which has severe side effects. The induction of antigen-specific tolerance has become an ideal therapy for autoimmune diseases. In this study, we have constructed a dual peptide nanoparticle platform, including the antigen peptide of the primary signal and inhibitory peptide of the co-stimulatory signal, for T-cell activation and to trigger antigen-specific immune tolerance to treat experimental autoimmune encephalomyelitis (EAE), a murine model for MS. The peptide LABL binding with ICAM-1 was encapsulated in PLGA nanoparticles and the antigenic peptide MOG35-55-KKK was then covalently bonded to the surface of the PLGA nanoparticles. In this way, peptide-loaded PLGA nanoparticles (NPsLABL+MOG) were developed. When the dual peptide nanoparticles were administered intravenously either prophylactically or therapeutically to MOG35-55-immunized mice, it completely prevented the occurrence of EAE in the prophylactic therapy trial and decreased inflammatory cell infiltration and the demyelination of the nerve myelin in the spinal cord in both prophylactic and therapeutic trials. In therapeutic experiments especially, the dual peptide nanoparticles a showed stronger inhibitory effect on EAE than the MOG peptide nanoparticles alone. Mechanistically, the dual peptide nanoparticles reduced MHC II and the co-stimulatory molecule CD86 expression of dendritic cells (DCs) on the surface and induced abortive T-cell activation, which eventually led to a decreased infiltration of Th1 and Th17 cells in the central nervous system and showed antigen-specific immune tolerance. The dual peptide nanoparticles have great potential for the treatment of autoimmune diseases by inducing immune tolerance.

A comparison of Remdesivir versus gold cluster in COVID-19 animal model: A better therapeutic outcome of gold cluster.

While gold compound have been approved for Rheumatoid arthritis treatment as it well suppresses inflammatory cytokines of patients, no such treatment is currently available for COVID-19 treatment in vivo . We firstly disclose gold cluster yields better therapeutic outcome than Remdesivir in COVID-19 hamster treatments as it is armed with direct inhibition viral replication and intrinsic suppression inflammatory cytokines expression. Crystal data reveals that Au (I), released from gold cluster (GA), covalently binds thiolate of Cys145 of SARS-CoV-2 Mpro. GA directly decreases SARS-CoV-2 viral replication and intrinsically down-regulates NFκB pathway therefore significantly inhibiting expression of inflammatory cytokines in cells. The inflammatory cytokines in GA-treated COVID-19 transgenic mice are found to be significantly lower than that of control mice. When COVID-19 golden hamsters are treated by GA, the lung inflammatory cytokines levels are significantly lower than that of Remdesivir. The pathological results show that GA treatment significantly reduce lung inflammatory injuries when compared to that of Remdesivir-treated COVID-19 hamsters.

Cyclic Peptide Modified Gold Clusters Induce Lung Tumor Cell Apoptosis via Generating Intracellular Oxidative Stress.

Metastatic lung cancer is the leading cause of death for cancer patients. Although many chemical drugs were developed for cancer treatment, metastatic cancer mortality did not decrease significantly. In this article, we designed an Au clusters (AuCs) modified by cyclic RGD peptides which well target the integrin of human lung carcinoma cells (A549). The RGD-AuCs could well induce A549 cells apoptosis, but have no cytotoxicity on the human bronchial epithelial cells (16HBE), which are normal cells support respiratory system. The AuCs could be internalized and localized in the lysosomes of A549 tumor cells and further release into cytoplasma. We found the ROS level was increased by AuCs, and such high ROS level finally leads to depolarization of mitochondria. Eventually, the AuCs stimulating mitochondria related apoptosis pathway to induce A549 tumor cells apoptosis. We deduce the gold clusters would be an effective therapeutic candidate to against metastatic lung tumor in the future studies.

Application of nanomaterials in the treatment of rheumatoid arthritis.

Rheumatoid Arthritis (RA) is a chronic autoimmune disease, which mainly causes inflammation of the synovial joints and destruction of cartilage and bone tissue. At present, a variety of clinical drugs have been applied in the treatment of rheumatoid arthritis. With the development of nanotechnology, more and more nano-drugs have been applied in the treatment of rheumatoid arthritis due to the unique physical and chemical properties of nanomaterials. Treatment of RA with nanomaterials can improve bioavailability and selectively target damaged joint tissue. In this review, we summarized the progress of the application of nanomaterials in the treatment of rheumatoid arthritis and also proposed challenges faced by nanomaterials in the treatment of rheumatoid arthritis.

Trp2 Peptide-Assembled Nanoparticles with Intrinsically Self-Chelating 64Cu Properties for PET Imaging Tracking and Dendritic Cell-Based Immunotherapy against Melanoma.

Dendritic cell-based immunotherapy, in which the antigen is effectively delivered to dendritic cells and then the dendritic cells stimulated by the antigen migrate to draining lymph nodes (DLNs) to induce the CD8+ T-cell immune response, shows great promise for tumor immunotherapy. In this study, we used coassembled nanoparticles formed by Trp2 antigen and the conjugates of short-chain poly(ethylene glycol) (PEG) and pyropheophorbide-A (PPa) (Trp2/PPa-PEGm) to deliver Trp2 to DCs. Intrinsically self-chelating 64Cu of coassemblies could be used to sensitively image the migration of DCs in vivo by positron emission tomography (PET) imaging. The coassemblies of the Trp2 antigen were efficiently engulfed by DCs without causing DC cytotoxicity in vitro and induced DC maturation. After injection of DCs labeled by coassemblies of the Trp2 antigen, the homing of DCs to DLNs in vivo could be sensitively observed by PET imaging. The C57BL/6 mice injected with DCs containing the Trp2/PPa-PEGm NP showed antigen-specific immune responses including enhanced interferon-γ (IFN-γ) production, splenocyte proliferation, and percentage of IFN-γ-secreting CD8+ T cells. In addition, C57BL/6 mice inoculated with B16-F10 tumor cells showed delayed tumor growth after immunization with the Trp2/PPa-PEGm NP-labeled DC vaccine and enhanced infiltration of CD8+ T cells in tumors.

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.

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.

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.

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.

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.

Vibrio cholerae O139 multiple-drug resistance mediated by Yersinia pestis pIP1202-like conjugative plasmids.

A conjugative plasmid, pMRV150, which mediated multiple-drug resistance (MDR) to at least six antibiotics, including ampicillin, streptomycin, gentamicin, tetracycline, chloramphenicol, and trimethoprim-sulfamethoxazole, was identified in a Vibrio cholerae O139 isolate from Hangzhou, eastern China, in 2004. According to partial pMRV150 DNA sequences covering 15 backbone regions, the plasmid is most similar to pIP1202, an IncA/C plasmid in an MDR Yersinia pestis isolate from a Madagascar bubonic plague patient, at an identity of 99.99% (22,180/22,183 nucleotides). pMRV150-like plasmids were found in only 7.69% (1/13) of the O139 isolates tested during the early period of the O139 epidemic in Hangzhou (1994, 1996, and 1997); then the frequency increased gradually from 60.00% (3/5) during 1998 and 1999 to 92.16% (47/51) during 2000 to 2006. Most (42/51) of the O139 isolates bearing pMRV150-like plasmids were resistant to five to six antibiotics, whereas the plasmid-negative isolates were resistant only to one to three antibiotics. In 12 plasmid-bearing O139 isolates tested, the pMRV150-like plasmids ranged from approximately 140 kb to 170 kb and remained at approximately 1 or 2 copies per cell. High (4.50 x 10(-2) and 3.08 x 10(-2)) and low (0.88 x 10(-8) to 3.29 x 10(-5)) plasmid transfer frequencies, as well as no plasmid transfer (under the detection limit), from these O139 isolates to the Escherichia coli recipient were observed. The emergence of pMRV150-like or pIP1202-like plasmids in many bacterial pathogens and nonpathogens occupying diverse niches with global geographical distribution indicates an increasing risk to public health worldwide. Careful tracking of these plasmids in the microbial ecosystem is warranted.

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.