A novel PDPN antagonist peptide CY12-RP2 inhibits melanoma growth via Wnt/ß-catenin and modulates the immune cells.

BACKGROUND: Podoplanin (PDPN) is a highly conserved, mucin-type protein specific to the lymphatic system. Overexpression of PDPN is associated with the progression of various solid tumors, and plays an important roles in the tumor microenvironment by regulating the immune system. However, the role of PDPN-mediated signal activation in the progression of melanoma is still unknown. METHODS: PDPN expression was first analyzed in 112 human melanoma tissue microarrays and melanoma cell lines. Functional experiments including proliferation, clone formation, migration, and metastasis were utilized to identify the suppressive effects of PDPN. The Ph.D.TM-12 Phage Display Peptide Library was used to obtain a PDPN antagonist peptide, named CY12-RP2. The immunofluorescence, SPR assay, and flow cytometry were used to identify the binding specificity of CY12-RP2 with PDPN in melanoma cells. Functional and mechanistic assays in vivo and in vitro were performed for discriminating the antitumor and immune activation effects of CY12-RP2. RESULTS: PDPN was overexpressed in melanoma tissue and cells, and inhibited melanoma cells proliferation, migration, and metastasis by blocking the EMT and Wnt/ß-catenin pathway. PDPN antagonistic peptide, CY12-RP2, could specifically bind with PDPN, suppressing melanoma various functions inducing apoptosis in both melanoma cells and 3D spheroids. CY12-RP2 also enhanced the anti-tumor capacity of PBMC, and inhibited melanoma cells growth both in xenografts and allogeneic mice model. Moreover, CY12-RP2 could inhibit melanoma lung metastasis, and abrogated the immunosuppressive effects of PDPN by increasing the proportion of CD3 + CD4 + T cells, CD3 + CD8 + T cells, CD49b + Granzyme B + NK cells, and CD11b + CD86 + M1-like macrophages and the levels of IL-1ß, TNF-α, and IFN-γ. CONCLUSIONS: This study has demonstrated the important role of PDPN in the progression of melanoma and formation of immunosuppressive environment, and provided a potential approach of treating melanoma using the novel CY12-RP2 peptide. In melanoma, PDPN is overexpressed in the cancer cells, and promotes melanoma cells growth and metastasis through activating the Wnt/ß-catenin pathway. Treatment with the PDPN antagonistic peptide CY12-RP2 could not only inhibit the melanoma growth and metastasis both in vitro and in vivo through Wnt/ß-catenin pathway blockade, but also abrogate the immunosuppressive effects of PDPN through modulating immune cells.

TCAF2 is associated with the immune microenvironment, promotes pathogenesis, and impairs prognosis in glioma.

PURPOSE: Glioma is the most common primary intracranial tumor and exhibits rapid growth and aggressiveness. TRPM8 channel-associated factor 2 (TCAF2), located in cell junctions and the plasma membrane, plays a key role in the pathogeneses of several cancers in humans. However, the role of TCAF2 in glioma has been elusive. METHODS: A combination of bioinformatic analysis using The Cancer Genome Atlas database and biological experiments, including 5-ethynyl-2'-deoxyuridine, transwell, and immunohistochemistry assays and xenotransplantation, was performed to analyze the expression level of TCAF2 and to mechanistically explore the relationship of TCAF2 with malignancy, prognosis, and the immune microenvironment in glioma. RESULTS: TCAF2 was upregulated in glioma, and its expression level correlated with tumor grade and clinical outcome. The role of TCAF2 in promoting glioma malignancy was characterized through in vitro and in vivo experiments. Additionally, we observed that TCAF2 can modulate the metabolic pathways and immune microenvironment. CONCLUSION: TCAF2 acts as an oncogene and may serve as a therapeutic target and prognostic marker in glioma.

NIR-IIb fluorescence-image guided synergistic surgery/starvation/chemodynamic therapy: an innovative treatment paradigm for malignant non-small cell lung cancers.

Background: Currently, the prognosis and survival rate for patients bearing non-small cell lung cancer (NSCLC) is still quite poor, mainly due to lack of efficient theranostic paradigms to exert in time diagnostics and therapeutics. Methods: Herein, for NSCLC treatment, we offer a customized theranostic paradigm, termed NIR-IIb fluorescence diagnosis and synergistic surgery/starvation/chemodynamic therapeutics, with a newly designed theranostic nanoplatform PEG/MnCuDCNPs@GOx. The nanoplatform is composed of brightly NIR-II emissive downconversion nanoparticles (DCNPs)-core and Mn/Cu-silica shell loaded with glucose oxidase (GOx) to achieve synergistic starvation and chemodynamic therapy (CDT). Results: It is found that 10% Ce3+ doped in the core and 100% Yb3+ doped in the middle shell greatly improves the NIR-IIb emission up to even 20.3 times as compared to the core-shell DCNPs without Ce3+ doping and middle shell. The bright NIR-IIb emission of the nanoplatform contributes to sensitive margin delineation of early-stage NSCLC (diameter < 1 mm) with a signal-to-background ratio (SBR) of 2.18, and further assists in visualizing drug distribution and guiding surgery/starvation/chemodynamic therapy. Notably, the starvation therapy mediated by GOx-driven oxidation reaction efficiently depletes intratumoral glucose, and supplies H2O2 to boost the CDT mediated by the Mn2+ and Cu2+, which consequently realized a highly effective synergistic treatment for NSCLC. Conclusion: This research demonstrates an efficient treatment paradigm for NSCLC with NIR-IIb fluorescence diganosis and image-guided synergistic surgery/starvation/chemodynamic therapeutics.

Cntnap4 partial deficiency exacerbates α-synuclein pathology through astrocyte-microglia C3-C3aR pathway.

Parkinson's disease (PD) is the most common progressive neurodegenerative movement disorder, which is characterized by dopaminergic (DA) neuron death and the aggregation of neurotoxic α-synuclein. Cntnap4, a risk gene of autism, has been implicated to participate in PD pathogenesis. Here we showed Cntnap4 lacking exacerbates α-synuclein pathology, nigrostriatal DA neuron degeneration and motor impairment, induced by injection of adeno-associated viral vector (AAV)-mediated human α-synuclein overexpression (AAV-hα-Syn). This scenario was further validated in A53T α-synuclein transgenic mice injected with AAV-Cntnap4 shRNA. Mechanistically, α-synuclein derived from damaged DA neuron stimulates astrocytes to release complement C3, activating microglial C3a receptor (C3aR), which in turn triggers microglia to secrete complement C1q and pro-inflammatory cytokines. Thus, the astrocyte-microglia crosstalk further drives DA neuron death and motor dysfunction in PD. Furthermore, we showed that in vivo depletion of microglia and microglial targeted delivery of a novel C3aR antagonist (SB290157) rescue the aggravated α-synuclein pathology resulting from Cntnap4 lacking. Together, our results indicate that Cntnap4 plays a key role in α-synuclein pathogenesis by regulating glial crosstalk and may be a potential target for PD treatment.

Cleavable collagenase-assistant nanosonosensitizer for tumor penetration and sonodynamic therapy.

Sonodynamic therapy (SDT), a combination of low-intensity ultrasound with a sonosensitizer, has been explored as a promising alternative for cancer therapy. However, condensed extracellular matrix (ECM) resulting in poor perfusion and extreme hypoxia in solid tumor potentially compromises effective SDT. Herein, we develop a novel cleavable collagenase-assistant and O2-supplied nanosonosensitizer (FePO2@HC), which is embedded through fusing collagenase (CLG) and human serum albumin (HSA), followed by encapsulating Ferric protoporphyrin (FeP) and dioxygen. As a smart carrier, HSA is stimuli-responsive and collapsed by reduced glutathione (GSH) overexpressed in tumor, resulting to the release of the components in FePO2@HC. The released CLG acting as an artificial scissor, degrades the collagen fibers in tumor, thus, breaking tumor tissue and enhancing FePO2 accumulation in tumor inner with higher than that without CLG. Simultaneously, oxygen molecules are released from FePO2 in hypoxic environment and alleviate the tumor hypoxia. As a sonosensitizer, FeP is subsequently irradiated by ultrosound wave (US) and activates surrounding dioxygen to generate amount of singlet oxygen (1O2). Contributed from the ECM-degradation, such SDT-based nanosystem with increased sonosensitizer permeability and oxygen content highly improved the tumor inhibition efficacy without toxic effects. This study presents a new paradigm for ECM depletion-based strategy of deep-seated penetration, and will expand the nanomedicine application of metalloporphyrin sonosensitizers in SDT.

Biomimetic Nanosonosensitizers Combined with Noninvasive Ultrasound Actuation to Reverse Drug Resistance and Sonodynamic-Enhanced Chemotherapy against Orthotopic Glioblastoma.

Glioblastoma (GBM) is the most devastating brain tumor and highly resistant to conventional chemotherapy. Herein, we introduce biomimetic nanosonosensitizer systems (MDNPs) combined with noninvasive ultrasound (US) actuation for orthotopic GBM-targeted delivery and sonodynamic-enhanced chemotherapy. MDNPs were fabricated with biodegradable and pH-sensitive polyglutamic acid (PGA) and the chemotherapeutic agent and sonosensitizer doxorubicin (DOX), camouflaged with human GBM U87 cell membranes. MDNPs presented homologous targeting accumulation and in vivo long-term circulation ability. They effectively passed through the blood-brain barrier (BBB) under US assistance and reached the orthotopic GBM site. MDNPs exhibited controllable US-elicited sonodynamic effect by generation of reactive oxygen species (ROS). ROS not only induced cancer cell apoptosis but also downregulated drug-resistance-related factors to disrupt chemoresistance and increase sensitivity to chemotherapy. The in vivo study of orthotopic GBM treatments further proved that MDNPs exhibited US-augmented synergistic antitumor efficacy and strongly prolonged the survival rate of mice. The use of low-dose DOX and the safety of US enabled repeated treatment (4 times) without obvious cardiotoxicity. This effective and safe US-enhanced chemotherapy strategy with the advantages of noninvasive brain delivery and high drug sensitivity holds great promise for deep-seated and drug-resistant tumors.

Xanthatin suppresses proliferation and tumorigenicity of glioma cells through autophagy inhibition via activation of the PI3K-Akt-mTOR pathway.

Glioma is the most common and aggressive primary brain tumor in adults with high morbidity and mortality. Rapid proliferation and diffuse migration are the main obstacles to successful glioma treatment. Xanthatin, a sesquiterpene lactone purified from Xanthium strumarium L., possesses a significant antitumor role in several malignant tumors. In this study, we report that xanthatin suppressed glioma cells proliferation and induced apoptosis in a time- and concentration-dependent manner, and was accompanied by autophagy inhibition displaying a significantly reduced LC3 punctate fluorescence and LC3II/I ratio, decreased level of Beclin 1, while increased accumulation of p62. Notably, treating glioma cells with xanthatin resulted in obvious activation of the PI3K-Akt-mTOR signaling pathway, as indicated by increased mTOR and Akt phosphorylation, decreased ULK1 phosphorylation, which is important in modulating autophagy. Furthermore, xanthatin-mediated pro-apoptosis in glioma cells was significantly reversed by autophagy inducers (rapamycin or Torin1), or PI3K-mTOR inhibitor NVP-BEZ235. Taken together, these findings indicate that anti-proliferation and pro-apoptosis effects of xanthatin in glioma are most likely by inhibiting autophagy via activation of PI3K-Akt-mTOR pathway, suggesting a potential therapeutic strategy against glioma.

Mallotucin D, a Clerodane Diterpenoid from Croton crassifolius, Suppresses HepG2 Cell Growth via Inducing Autophagic Cell Death and Pyroptosis.

Hepatocellular carcinoma (HCC) is a major subtype of primary liver cancer with a high mortality rate. Pyroptosis and autophagy are crucial processes in the pathophysiology of HCC. Searching for efficient drugs targeting pyroptosis and autophagy with lower toxicity is useful for HCC treatment. Mallotucin D (MLD), a clerodane diterpenoid from Croton crassifolius, has not been previously reported for its anticancer effects in HCC. This study aims to evaluate the inhibitory effects of MLD in HCC and explore the underlying mechanism. We found that the cell proliferation, DNA synthesis, and colony formation of HepG2 cells and the angiogenesis of HUVECs were all greatly inhibited by MLD. MLD caused mitochondrial damage and decreased the TOM20 expression and mitochondrial membrane potential, inducing ROS overproduction. Moreover, MLD promoted the cytochrome C from mitochondria into cytoplasm, leading to cleavage of caspase-9 and caspase-3 inducing GSDMD-related pyroptosis. In addition, we revealed that MLD activated mitophagy by inhibiting the PI3K/AKT/mTOR pathway. Using the ROS-scavenging reagent NAC, the activation effects of MLD on pyroptosis- and autophagy-related pathways were all inhibited. In the HepG2 xenograft model, MLD effectively inhibited tumor growth without detectable toxicities in normal tissue. In conclusion, MLD could be developed as a candidate drug for HCC treatment by inducing mitophagy and pyroptosis via promoting mitochondrial-related ROS production.

Correction: Yu et al. Recent Advances of Mesoporous Silica as a Platform for Cancer Immunotherapy. Biosensors 2022, 12, 109.

In the published publication [...].

Recent Advances of Mesoporous Silica as a Platform for Cancer Immunotherapy.

Immunotherapy is a promising modality of treatment for cancer. Immunotherapy is comprised of systemic and local treatments that induce an immune response, allowing the body to fight back against cancer. Systemic treatments such as cancer vaccines harness antigen presenting cells (APCs) to activate T cells with tumor-associated antigens. Small molecule inhibitors can be employed to inhibit immune checkpoints, disrupting tumor immunosuppression and immune evasion. Despite the current efficacy of immunotherapy, improvements to delivery can be made. Nanomaterials such as mesoporous silica can facilitate the advancement of immunotherapy. Mesoporous silica has high porosity, decent biocompatibility, and simple surface functionalization. Mesoporous silica can be utilized as a versatile carrier of various immunotherapeutic agents. This review gives an introduction on mesoporous silica as a nanomaterial, briefly covering synthesis and biocompatibility, and then an overview of the recent progress made in the application of mesoporous silica to cancer immunotherapy.

An Urchin-Shaped Copper-Based Metalloporphyrin Nanosystem as a Sonosensitizer for Sonodynamic Therapy.

Sonodynamic therapy (SDT), as a novel cancer therapy strategy, might be a promising approach due to the depth-penetration property in tissue. Sonosensitizers are the key element for efficient SDT. However, the development of sonosensitizers with strong sonosensitization efficacy is still a significant challenge. Herein, an urchin-shaped copper-based metalloporphyrin liposome nanosystem (FA-L-CuPP) is constructed and identified as an excellent sonosensitizer. Under ultrasound (US) irradiation, FA-L-CuPP can be highly excited to generate several reactive oxygen species (ROS), such as singlet oxygen (1O2) and free radicals (⋅OH). The molecular orbital distribution calculations reveal that a strong intramolecular charge transfer might occur in the CuPP complex under US irradiation, which could afford enough energy to the surrounding O2 and H2O to concert 1O2, O2- and ⋅OH. Working as "ammunitions", the largely produced ROS can kill 4T1 tumor cells, effectively inhibiting tumor growth. This work provides an urchin-shaped nanosonosensitizer based on a copper complex, which might provide an idea to design a novel sonosensitizer for noninvasive and precise SDT antitumor applications.

Noninvasively immunogenic sonodynamic therapy with manganese protoporphyrin liposomes against triple-negative breast cancer.

Sonodynamic therapy (SDT) is a promising approach for tumor treatment because of the noninvasion, and future would be perfect while it activates systemic immune responses through deep penetration to effectively avoid tumor recurrence. Here, a multifunctional nanosonosensitizer system (FA-MnPs) is designed by encapsulating manganese-protoporphyrin (MnP) into folate-liposomes. The nanoparticles of FA-MnPs not only exhibit excellent depth-responsive SDT but also simultaneously activate SDT-mediated immune response. Under US irradiation, FA-MnPs show the high acoustic intensity in mimic tissue up to 8 cm depth and generate amount of singlet oxygen (1O2). Density functional theory (DFT) calculations reveal that metal coordination in MnP has enhanced the US response ability. The good depth-responsed SDT of FA-MnPs efficiently suppresses the growth of not only the superficial tumors but also the deep lesion in the triple-negative breast cancer (TNBC) mice model. Importantly, FA-MnPs-induced SDT further re-polarizes immunosuppressive M2 macrophages to antitumor M1 macrophages, and elicits immunogenic cell death (ICD) to activate dendritic cells, T lymphocytes, and natural killercells (NK), which consequently trigger the antitumor immune, contributing to the tumor growth inhibition. This study put forward an idea for curing deep-seated and metastatic tumors through noninvasively depth-irradiated immunogenic SDT by reasonably designing multifunctional sonosensitizers.

In Situ Photocatalysis of TiO-Porphyrin-Encapsulated Nanosystem for Highly Efficient Oxidative Damage against Hypoxic Tumors.

Reactive oxygen species (ROS)-mediated cell apoptosis has been a significant strategy for tumor oxidative damage, while tumor hypoxia is a major bottleneck for efficiency. Here, a novel TiO-porphyrin nanosystem (FA-TiOPs) is designed by encapsulating TiO-porphyrin (TiOP) in folate-liposome. The nanosysytem can photocatalyze H2O and tumor-overexpressed H2O2, in situ generating sufficient ROS. TiOP can photosplit water to produce ·OH radical, H2O2, and O2. Generated O2 not only conquers the hypoxia of tumor environment but also can be further excited by TiOP to 1O2 for killing tumor cells. Density functional theory calculations indicate that high energy in excited state (S1) of TiOP and narrow gap energy between S1 and the triplet excited state (Tn) might contribute to the efficient photocatalytic action. Moreover, the generated and overexpressed H2O2 in tumors can also be photocatalyzed to generate 1O2 especially in acid condition, helpful to specific anticancer effect while harmless to normal tissues. This research might pave a new way to bypass the hypoxia-triggered problem for cancer therapy.

Self-Delivery Nanomedicine for O2-Economized Photodynamic Tumor Therapy.

Tumor hypoxia is the Achilles heel of oxygen-dependent photodynamic therapy (PDT), and tremendous challenges are confronted to reverse the tumor hypoxia. In this work, an oxidative phosphorylation inhibitor of atovaquone (ATO) and a photosensitizer of chlorine e6 (Ce6)-based self-delivery nanomedicine (designated as ACSN) were prepared via π-π stacking and hydrophobic interaction for O2-economized PDT against hypoxic tumors. Specifically, carrier-free ACSN exhibited an extremely high drug loading rate and avoided the excipient-induced systemic toxicity. Moreover, ACSN not only dramatically improved the solubility and stability of ATO and Ce6 but also enhanced the cellular internalization and intratumoral permeability. Abundant investigations confirmed that ACSN effectively suppressed the oxygen consumption to reverse the tumor hypoxia by inhibiting mitochondrial respiration. Benefiting from the synergistic mechanism, an enhanced PDT effect of ACSN was observed on the inhibition of tumor growth. This self-delivery system for oxygen-economized PDT might be a potential appealing clinical strategy for tumor eradication.

Metalloporphyrin Complex-Based Nanosonosensitizers for Deep-Tissue Tumor Theranostics by Noninvasive Sonodynamic Therapy.

Metal complexes are widely used as anticancer drugs, while the severe side effects of traditional chemotherapy require new therapeutic modalities. Sonodynamic therapy (SDT) provides a significantly noninvasive ultrasound (US) treatment approach by activating sonosensitizers and initiating reactive oxygen species (ROS) to damage malignant tissues. In this work, three metal 4-methylphenylporphyrin (TTP) complexes (MnTTP, ZnTTP, and TiOTTP) are synthesized and encapsulated with human serum albumin (HSA) to form novel nanosonosensitizers. These nanosonosensitizers generate abundant singlet oxygen (1 O2 ) under US irradiation, and importantly show excellent US-activatable abilities with deep-tissue depths up to 11 cm. Compared to ZnTTP-HSA and TiOTTP-HSA, MnTTP-HSA exhibits the strongest ROS-activatable behavior due to the lowest highest occupied molecular orbital-lowest unoccupied molecular orbital gap energy by density functional theory. It is also effective for deep-tissue photoacoustic/magnetic resonance dual-modal imaging to trace the accumulation of nanoparticles in tumors. Moreover, MnTTP-HSA intriguingly achieves high SDT efficiency for simultaneously suppressing the growth of bilateral tumors away from ultrasound source in mice. This work develops a deep-tissue imaging-guided SDT strategy through well-defined metalloporphyrin nanocomplexes and paves a new way for highly efficient noninvasive SDT treatments of malignant tumors.

Hydrogen-Bonded Organic⁻Inorganic Hybrid Based on Hexachloroplatinate and Nitrogen Heterocyclic Cations: Their Synthesis, Characterization, Crystal Structures, and Antitumor Activities In Vitro.

Three new crystal structures containing [PtCl6]2−, pyridinium and benzimidazole groups have been prepared: [PtCl6]·(H-bzm)2·2(H2O) (1), [PtCl6]·(H-bipy)2·2(H2O) (2), [PtCl6]·(H-dimethyl-bipy)2·2(H2O) (3) [H-bzm: benzimidazole cation, H-bipy: 2,2'-bipyridine cation, H-dimethyl-bipy: 4,4'-bimethyl-2,2'-bipyridine cation]. All compounds have been fully characterized by elemental analyses, single-crystal X-ray analyses, IR spectra, TG analyses, and fluorescence studies. Single-crystal X-ray diffraction analysis suggests that the primary synthon contains ⁺N⁻H···Cl−, including ionic bonding and hydrogen bonding interactions. The dimensions are enhanced further by secondary O⁻H ∙∙Cl and N⁻H ∙∙O hydrogen bonding interactions between donor and acceptor atoms located at the periphery of these synthons. Moreover, coulombic attractions between the ions play an important role in reinforcing the structures of these complexes. In addition, antitumor activity against human lung adenocarcinoma cell line (A549) and human nasopharyngeal carcinoma cell line (CNE-2) was performed. These complexes all showed inhibition to the two cell lines, while complex 3 exhibited higher efficiency than complexes 1⁻2.

Elevation of GPRC5A expression in colorectal cancer promotes tumor progression through VNN-1 induced oxidative stress.

The clearance of oxidative stress compounds is critical for the protection of the organism from malignancy, but how this key physiological process is regulated is not fully understood. Here, we found that the expression of GPRC5A, a well-characterized tumor suppressor in lung cancer, was elevated in colorectal cancer tissues in patients. In both cancer cell lines and a colitis-associated cancer model in mice, we found that GPRC5A deficiency reduced cell proliferation and increased cell apoptosis as well as inhibited tumorigenesis in vivo. Through RNA-Seq transcriptome analysis, we identified oxidative stress associated pathways were dysregulated. Moreover, in GPRC5A deficient cells and mouse tissues, the oxidative agents were reduced partially due to increased glutathione (GSH) level. Mechanistically, GPRC5A regulates NF-κB mediated Vanin-1 expression which is the predominant enzyme for cysteamine generation. Administration of cystamine (the disulfide form of cysteamine) in GPRC5A deficient cell lines inhibited γ-GCS activity, leading to reduction of GSH level and increase of cell growth. Taken together, our studies suggest that GPRC5a is a potential biomarker for colon cancer and promotes tumorigenesis through stimulation of Vanin-1 expression and oxidative stress in colitis associated cancer. This study revealed an unexpected oncogenic role of GPRC5A in colorectal cancer suggesting there are complicated functional and molecular mechanism differences of this gene in distinct tissues.

LGR4 is a receptor for RANKL and negatively regulates osteoclast differentiation and bone resorption.

Tumor necrosis factor (TNF) superfamily member 11 (TNFSF11, also known as RANKL) regulates multiple physiological or pathological functions, including osteoclast differentiation and osteoporosis. TNFRSF11A (also called RANK) is considered to be the sole receptor for RANKL. Herein we report that leucine-rich repeat-containing G-protein-coupled receptor 4 (LGR4, also called GPR48) is another receptor for RANKL. LGR4 competes with RANK to bind RANKL and suppresses canonical RANK signaling during osteoclast differentiation. RANKL binding to LGR4 activates the Gαq and GSK3-ß signaling pathway, an action that suppresses the expression and activity of nuclear factor of activated T cells, cytoplasmic, calcineurin-dependent 1 (NFATC1) during osteoclastogenesis. Both whole-body (Lgr4(-/-)) and monocyte conditional knockout mice of Lgr4 (Lgr4 CKO) exhibit osteoclast hyperactivation (including elevation of osteoclast number, surface area, and size) and increased bone erosion. The soluble LGR4 extracellular domain (ECD) binds RANKL and inhibits osteoclast differentiation in vivo. Moreover, LGR4-ECD therapeutically abrogated RANKL-induced bone loss in three mouse models of osteoporosis. Therefore, LGR4 acts as a second RANKL receptor that negatively regulates osteoclast differentiation and bone resorption.

Phospholipid-stabilized mesoporous carbon nanospheres as versatile carriers for systemic delivery of amphiphobic SNX-2112 (a Hsp90 inhibitor) with enhanced antitumor effect.

Systemic delivery of amphiphobic drugs (insoluble in both water and oil) represents a formidable challenge in drug delivery. This work aimed to engineer a functional mesoporous carbon material to efficiently load SNX-2112, an amphiphobic anticancer agent, and to evaluate its performance in tumor-targeting delivery. Hydrothermal reaction combined with high-temperature activation was used to fabricate glucose-based mesoporous carbon nanospheres (MCNs). SNX-2112-loaded MCNs stabilized by phospholipid (SN-PMCNs) were prepared by the absorption/solvent diffusion/high-pressure homogenization method. The obtained SN-PMCNs were 180nm around in particle size, showing a high drug load (42.7%) and acceptable physical stability. SN-PMCNs demonstrated an enhanced in vitro antitumor effect and increased uptake into cancer cells in comparison with the formulation of SNX-2112 solution (SN-Sol). The in vivo antitumor effect and biodistribution in 4T1 xenograft tumor mice, a breast cancer model, were also significantly improved through SN-PMCNs. It was shown that specific clathrin-dependent and nonspecific caveolae-dependent endocytosis were involved in the cellular trafficking of SN-PMCNs. Glucose transporter-mediated transport, prolonged body residence time and improved biodistribution via EPR effect were the main mechanisms of enhanced antitumor effect. SN-PMCNs have presented excellent tumor targeting properties and should be a promising carrier to address the systemic delivery of SNX-2112.

PubAngioGen: a database and knowledge for angiogenesis and related diseases.

Angiogenesis is the process of generating new blood vessels based on existing ones, which is involved in many diseases including cancers, cardiovascular diseases and diabetes mellitus. Recently, great efforts have been made to explore the mechanisms of angiogenesis in various diseases and many angiogenic factors have been discovered as therapeutic targets in anti- or pro-angiogenic drug development. However, the resulted information is sparsely distributed and no systematical summarization has been made. In order to integrate these related results and facilitate the researches for the community, we conducted manual text-mining from published literature and built a database named as PubAngioGen (http://www.megabionet.org/aspd/). Our online application displays a comprehensive network for exploring the connection between angiogenesis and diseases at multilevels including protein-protein interaction, drug-target, disease-gene and signaling pathways among various cells and animal models recorded through text-mining. To enlarge the scope of the PubAngioGen application, our database also links to other common resources including STRING, DrugBank and OMIM databases, which will facilitate understanding the underlying molecular mechanisms of angiogenesis and drug development in clinical therapy.