Hyperoside Inhibits RNF8-mediated Nuclear Translocation of ß-catenin to Repress PD-L1 Expression and Prostate Cancer.

BACKGROUND: Hyperoside is a flavonol glycoside isolated from Hypericum perforatum L. that has inhibitory effects on cancer cells; however, its effects on prostate cancer (PCa) remain unclear. Therefore, we studied the anti-PCa effects of hyperoside and its underlying mechanisms in vitro and in vivo. AIM: This study aimed to explore the mechanism of hyperoside in anti-PCa. METHODS: 3-(4,5-Dimethyl-2-Thiazolyl)-2,5-Diphenyl Tetrazolium Bromide (MTT), transwell, and flow cytometry assays were used to detect PCa cell growth, invasion, and cell apoptosis. Immunoblot analysis, immunofluorescence, immunoprecipitation, and quantitative real-time PCR (qRT-PCR) were used to analyze the antitumor mechanism of hyperoside. RESULTS: Hyperoside inhibited PCa cell growth, invasion, and cell cycle and induced cell apoptosis. Furthermore, RING finger protein 8 (RNF8), an E3 ligase that assembles K63 polyubiquitination chains, was predicted to be a direct target of hyperoside and was downregulated by hyperoside. Downregulation of RNF8 by hyperoside impeded the nuclear translocation of ß-catenin and disrupted the Wnt/ß-catenin pathway, which reduced the expression of the target genes c-myc, cyclin D1, and programmed death ligand 1 (PD-L1). Decreased PD-L1 levels contributed to induced immunity in Jurkat cells in vitro. Finally, in vivo studies demonstrated that hyperoside significantly reduced tumor size, inhibited PD-L1 and RNF8 expression, and induced apoptosis in tumor tissues of a subcutaneous mouse model. CONCLUSION: Hyperoside exerts its anti-PCa effect by reducing RNF8 protein, inhibiting nuclear translocation of ß-catenin, and disrupting the Wnt/ß-catenin pathway, in turn reducing the expression of PD-L1 and improving Jurkat cell immunity.

Breaking-Down Tumoral Physical Barrier by Remotely Unwrapping Metal-Polyphenol-Packaged Hyaluronidase for Optimizing Photothermal/Photodynamic Therapy-Induced Immune Response.

The therapy of solid tumors is often hindered by the compact and rigid tumoral extracellular matrix (TECM). Precise reduction of TECM by hyaluronidase (HAase) in combination with nanotechnology is promising for solid tumor therapeutics, yet remains an enormous challenge. Inspired by the treatment of iron poisoning, here a remotely unwrapping strategy is proposed of metal-polyphenol-packaged HAase (named PPFH) by sequentially injecting PPFH and a clinically used iron-chelator deferoxamine (DFO). The in situ dynamic disassembly of PPFH can be triggered by the intravenously injected DFO, resulting in the release, reactivation, and deep penetration of encapsulated HAase inside tumors. Such a cost-effective HAase delivery strategy memorably improves the subsequent photothermal and photodynamic therapy (PTT/PDT)-induced intratumoral infiltration of cytotoxic T lymphocyte cells and the cross-talk between tumor and tumor-draining lymph nodes (TDLN), thereby decreasing the immunosuppression and optimizing tumoricidal immune response that can efficiently protect mice from tumor growth, metastasis, and recurrence in multiple mouse cancer models. Overall, this work presents a proof-of-concept of the dynamic disassembly of metal-polyphenol nanoparticles for extracellular drug delivery as well as the modulation of TECM and immunosuppressive tumor microenvironment.

Targeting Lysosome for Enhanced Cancer Photodynamic/Photothermal Therapy in a "One Stone Two Birds" Pattern.

Highly immunogenic programmed death of tumor cells, such as immunogenic cell death (ICD) and pyroptosis, strengthens antitumor responses and thus represents a promising target for cancer immunotherapy. However, the development of ICD and pyroptosis inducers remains challenging, and their efficiency is typically compromised by self-protective autophagy. Here, we report a potent ICD and pyroptosis-inducing strategy by coupling combined photodynamic/photothermal therapy (PTT/PDT) to biological processes in cancer cells. For this purpose, we rationally synthesize a lysosomal-targeting boron-dipyrromethene dimer (BDPd) with intense NIR absorption/emission, high reactive oxygen species (ROS) yield, and photothermal abilities, which can be self-assembled with Pluronic F127, producing lysosomal-acting nanomicelles (BDPd NPs) to facilitate cancer cell internalization of BDPd and generation of intracellular ROS. Owing to the favorable lysosomal-targeting ability of the morpholine group on BDPd, the intracellular BDPd NPs can accumulate in the lysosome and induce robust lysosomal damage in cancer cells upon 660 nm laser irradiation, which results in the synergetic induction of pyroptosis and ICD via activating NLRP3/GSDMD and caspase-3/GSDME pathways simultaneously. More importantly, PTT/PDT-induced self-protective autophagic degradation was blocked due to the dysfunction of lysosomes. Either intratumorally or intravenously, the injected BDPd NPs could markedly inhibit the growth of established tumor tissues upon laser activation, provoke local and systemic antitumor immune responses, and prolong the survival time in the mouse triple-negative breast cancer model. Collectively, this work represents a promising strategy to boost the therapeutic potential of PTT/PDT by coupling phototherapeutic reagents with the subcellular organelles, creating a "one stone two birds" pattern.

Anticancer Activity of Methyl Protodioscin against Prostate Cancer by Modulation of Cholesterol-Associated MAPK Signaling Pathway via FOXO1 Induction.

Methyl protodioscin (MPD), a furostanol saponin found in the rhizomes of Dioscoreaceae, has lipid-lowering and broad anticancer properties. However, the efficacy of MPD in treating prostate cancer remains unexplored. Therefore, the present study aimed to evaluate the anticancer activity and action mechanism of MPD in prostate cancer. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), wound healing, transwell, and flow cytometer assays revealed that MPD suppressed proliferation, migration, cell cycle, and invasion and induced apoptosis of DU145 cells. Mechanistically, MPD decreased cholesterol concentration in the cholesterol oxidase, peroxidase and 4-aminoantipyrine phenol (COD-PAP) assay, disrupting the lipid rafts as detected using immunofluorescence and immunoblot analyses after sucrose density gradient centrifugation. Further, it reduced the associated mitogen-activated protein kinase (MAPK) signaling pathway protein P-extracellular regulated protein kinase (ERK), detected using immunoblot analysis. Forkhead box O (FOXO)1, a tumor suppressor and critical factor controlling cholesterol metabolism, was predicted to be a direct target of MPD and induced by MPD. Notably, in vivo studies demonstrated that MPD significantly reduced tumor size, suppressed cholesterol concentration and the MAPK signaling pathway, and induced FOXO1 expression and apoptosis in tumor tissue in a subcutaneous mouse model. These results suggest that MPD displays anti-prostate cancer activity by inducing FOXO1 protein, reducing cholesterol concentration, and disrupting lipid rafts. Consequently, the reduced MAPK signaling pathway suppresses proliferation, migration, invasion, and cell cycle and induces apoptosis of prostate cancer cells.

A possible but unrecognized risk of acceptable daily intake dose triazole pesticides exposure-bile acid disturbance induced pharmacokinetic changes of oral medication.

Triazole antifungal pesticides work by inhibiting the activity of lanosterol-14-α-demethylase, a member of cytochrome P450 enzymes (CYPs), but this effect is non-specific. Bile acids (BAs) are important physical surfactants for lipids absorption in intestine, and synthesized by CYPs 7A1/27A1. Thus, we presume that triazole exposure might influence the therapeutic effect or safety of oral medication through disturbing the BAs pool, even though the exposure is under an acceptable daily intake (ADI) dose. Short- and long-term of ADI dose tebuconazole (TEB) exposure animal models were established through various routes, and statins with different hydrophilic and lipophilic properties were gavaged. It exhibited that the activity of CYP7A1/27A1 was indeed inhibited but the expression was up-regulated, the BAs pool was changed either the content and the composition, and the absorption behavior of statins with strong and medium degree of lipid-solubility were significantly changed. A series of experiments performed on models of intestinal mucus, Caco-2 cell monolayer and Caco-2/HT29 co-culture system revealed that the TEB-exposure induced BAs disturbance made impacts on drug absorption in many aspects, including drug solubility and the structure of intestinal barriers. This study suggests us to be more alert about the hazard of pesticides residues for elderly and chronically ill groups.

Unique Double Intramolecular and Intermolecular Exciton Coupling in Ethene-Bridged aza-BODIPY Dimers for High-Efficiency Near-Infrared Photothermal Conversion and Therapy.

Spatial electronic communications of chromophores are both theoretically and practically fascinating. Despite intramolecular or intermolecular exciton coupling was observed in multichromophoric oligomers and J-aggregates, respectively, it is unusual that they both occur in the same molecule. Herein, ethene-bridged aza-BODIPY dimers with intramolecular exciton splitting have been developed. By encapsulating the dimer into F-127 polymer, J-type aggregated nanoparticles were produced, which showed obvious intermolecular exciton coupling and dramatically redshifted absorption and emission peaks at 936 and 1003 nm, respectively. The fabricated nanoagents have high photothermal conversion ability (η=60.3 %) and are ultra-photostable, leading to complete tumor ablation with 915 nm laser irradiation. This phototherapeutic nanoplatform through modulating both intra- and intermolecular exciton couplings is a valuable paradigm for developing photothermal agents for tumor treatment.

Engineering mitochondrial uncoupler synergistic photodynamic nanoplatform to harness immunostimulatory pro-death autophagy/mitophagy.

Generally, autophagy/mitophagy, as a highly conserved lysosomal-based catabolic pathway, compromises the photodynamic therapy (PDT) efficiency by increasing the adaptation of tumor cells toward reactive oxygen species (ROS)-triggered protein damages and mitochondrial destruction. On the other hand, excessively activated autophagy/mitophagy cascades can provoke autophagic cell death and promote the endogenous antigens release of dying cells, thus playing a vital role in initiating the antitumor immune responses. To harness the exquisite immunomodulating effect of pro-death autophagy/mitophagy, we rationally constructed a MnO2 shell-coated multifunctional porphyrinic metal-organic framework (MOF) to load carbonyl cyanide 3-chlorophenylhydrazone (CCCP). The wrapped MnO2 shell could not only prevent premature release of CCCP during blood circulation but also conquer tumor hypoxia by catalyzing the decomposition of intratumoral H2O2. After entering tumor cells, the MnO2 shell could scavenge over-expressed glutathione (GSH), resulting in burst CCCP release and GSH-depletion/O2-generation enhanced PDT. More importantly, the released CCCP acts as a mitochondrial uncoupler can elicit mitochondrial depolarization and mitophagy, which could significantly boost the autophagy/mitophagy levels generated during PDT and consequently convert the pro-survival autophagy/mitophagy to pro-death, leading tumor cells to autophagic and immunogenic cell death. In vivo results reveal that the CCCP synergistic PDT could induce excessive immunostimulatory autophagy/mitophagy associated with T-cell responses and immunological memory, leading to complete ablation of primary tumors and prevention of tumor recurrence and lung metastasis. The effectiveness of this strategy may highlight the pro-death role and immunomodulating effect of autophagy/mitophagy in cancer therapy, providing a novel yet versatile avenue to enhance the efficacy of cancer treatments.

Platycodon grandiflorus polysaccharides deeply participate in the anti-chronic bronchitis effects of platycodon grandiflorus decoction, a representative of "the lung and intestine are related".

Platycodon grandiflorus (Jacq.) A. DC. (PG) root is one of the most commonly used medicine-food materials for respiratory discomfort in Asia, usually in the form of a decoction or leaching solution. As everyone knows, both of decoction and leaching solution is a polyphase dispersion system, containing low-molecular-weight water-soluble active ingredients and hydrophilic macromolecules. This study aimed to discuss the synergistic effect of Platycodon grandiflorus polysaccharide (PGP) and platycodin D (PD) in PG decoction against chronic bronchitis (CB) and the mechanism underlying. A series of PGP, PD, and PGD + PD suspensions were administrated to CB model rats, on the levels of whole animal and in situ intestinal segment with or without mesenteric lymphatic vessels ligation. It exhibited that PGP exhibited synergistic effects with PD, on improving the histopathological abnormity, mucus secretion excess, and immunological imbalance in lung of CB model rat, closely associated with its modulations on the mucosal immunity status in small intestine. The polysaccharide macromolecules in PG decoction or leaching solution should be responsible for the modulation of pulmonary immune state, possibly through the common mucosal immune between small intestine and lung. These results might be a new perspective that illustrates the classical theory of "the lung and intestine are related" in traditional Chinese medicine.

Engineering a curcumol-loaded porphyrinic metal-organic framework for enhanced cancer photodynamic therapy.

Photodynamic therapy (PDT), a non-invasive and safe treatment, is a clinical promising alternative strategy for certain cancers. Although PDT can trigger tumor specific immunity, the immunosuppressive tumor microenvironment severely limits the efficacy of photodynamic immunotherapy. Curcumol (CUR), extracted from essential oils of traditional Chinese medicine, has potential immune activation effect for cancer immunotherapy. Considering the fat solubility and volatility hinder the in vivo application of essential oils, a metal-organic framework system (Named as CuTPyP/F68) composed of porphyrin and Cu2+ was constructed for delivering CUR (Named as CUR@CuTPyP/F68). The in vitro assays proved that CUR@CuTPyP/F68 could directly kill tumor cells by the released CUR and singlet oxygen (1O2) generated under laser irradiation (marked as '+'). Moreover, CUR@CuTPyP/F68 had superior tumor targeting and retention capabilities, which effectively inhibited tumor growth in vivo with only a single dose. Finally, the mechanism of CUR-mediated enhanced PDT had been firstly proposed: (1) CUR@CuTPyP/F68(+)-treated group exhibited more CD4+ and CD8+ T cells infiltration in tumor tissue; (2) CUR@CuTPyP/F68(+)-treated group exhibited high level of IFN-γ, IL-12 and TNF-α in blood. Overall, we believe the PDT-immunotherapy strategy has great potential for the treatment of breast cancer, and this work will provide a reference for the clinical application of essential oils in cancer immunotherapy.

Protective effect of Pai-Nong-San against AOM/DSS-induced CAC in mice through inhibiting the Wnt signaling pathway.

Pai-Nong-San (PNS), a prescription of traditional Chinese medicine, has been used for years to treat abscessation-induced diseases including colitis and colorectal cancer. This study was aimed to investigate the preventive effects and possible protective mechanism of PNS on a colitis-associated colorectal cancer (CAC) mouse model induced by azoxymethane (AOM)/dextran sodium sulfate (DSS). The macroscopic and histopathologic examinations of colon injury and DAI score were observed. The inflammatory indicators of intestinal immunity were determined by immunohistochemistry and immunofluorescence. The high throughput 16S rRNA sequence of gut microbiota in the feces of mice was performed. Western blot was used to investigate the protein expression of the Wnt signaling pathway in colon tissues. PNS improved colon injury, as manifested by the alleviation of hematochezia, decreased DAI score, increased colon length, and reversal of pathological changes. PNS treatment protected against AOM/DSS-induced colon inflammation by regulating the expression of CD4+ and CD8+ T cells, inhibiting the production of HIF-α, IL-6, and TNF-α, and promoting the expression of IL-4 and IFN-γ in colon tissues. Meanwhile, PNS improved the components of gut microbiota, as measured by the adjusted levels of Firmicutes, Bacteroidetes, Proteobacteria, and Lactobacillus. PNS down-regulated the protein expression of p-GSK-3ß, ß-catenin, and c-Myc, while up-regulating the GSK-3ß and p-ß-catenin in colon tissues of CAC mice. In conclusion, our results suggested that PNS exhibits protective effect on AOM/DSS-induced colon injury and alleviates the development of CAC through suppressing inflammation, improving gut microbiota, and inhibiting the Wnt signaling pathway.

Heparin-Coated Photosensitive Metal-Organic Frameworks as Drug Delivery Nanoplatforms of Autophagy Inhibitors for Sensitized Photodynamic Therapy against Breast Cancer.

Photosensitive nanosized metal-organic frameworks (nanoMOFs) with a tunable structure and high porosity have been developed recently as nanophotosensitizers (nanoPSs) for photodynamic therapy (PDT). However, the effect of photodynamic therapy is greatly limited by the fast blood clearance and poor tumor retention of the ordinary nanoPSs. Besides, autophagy, a prosurvival self-cannibalization pathway mediated by autolysosomes, was elevated by cytotoxic reactive oxygen species (ROS) produced during PDT. Herein, a chloroquine phosphate (CQ)-loaded photosensitive nanoMOF coated by heparin was fabricated for sensitized PDT by increasing the tumor accumulation of nanoPSs and abolishing the self-protective autophagy within cancer cells. After internalization by cancer cells, the encapsulated CQ alkalizes autolysosomes and blocks the postautophagy process, which disarm the vigilant cancer cells irritated by PDT and finally enhance the therapeutic effect. Furthermore, the accompanied antiangiogenesis ability of the heparin coat also helps improve the cancer therapy outcomes. This study would open up new horizons for building heparin-coated nanoMOFs and understanding the role of autophagy in cancer therapy.

Enhancing the Antitumor Effect of Doxorubicin with Photosensitive Metal-Organic Framework Nanoparticles against Breast Cancer.

Breast cancer is one of the most common malignant tumors in women. The existence of multiple breast cancer subtypes often leads to chemotherapy failure or the development of drug resistance. In recent years, photodynamic therapy has been proven to enhance the sensitivity of tumors to chemotherapeutic drugs. Porphyrin-based metal-organic framework (MOF) materials could simultaneously be used as carriers for chemotherapy and photosensitizers in photodynamic therapy. In this paper, doxorubicin hydrochloride (DOX) was loaded in porphyrin MOFs, and the mechanism of the synergistic effect of the DOX carriers and photodynamic therapy on breast cancer was investigated. In vitro and in vivo experiments have shown that MOFs could prolong the residence time of DOX in tumor tissues and promote the endocytosis of DOX by tumor cells. In addition, adjuvant treatment with photodynamic therapy can promote breast cancer tumors to resensitize to DOX and synergistically enhance the chemotherapy effect of DOX. Therefore, this study can provide effective development ideas for reversing drug resistance during breast cancer chemotherapy and improving the therapeutic effect of chemotherapy on breast cancer.

Lactonic sophorolipid-induced apoptosis in human HepG2 cells through the Caspase-3 pathway.

Liver cancer, one of the most common types of cancer in the world, is the second leading cause of death for cancer patients. For liver cancer, there is an urgent need for an effective treatment with no or less toxic side effects. Lactonic sophorolipids (LSL), as a potential anticancer drug, has attracted wide attention of pharmaceutical researchers with its good biological activities. The effects of LSL and cell death inhibitors were measured by MTT test on HepG2 cells. Meanwhile, the morphology of the cells was observed under a microscope. The apoptosis rate was detected by flow cytometry, and the expression levels of enzyme activity of Caspase-3 and Caspase-9 were measured by detection kits. Meanwhile, mRNA levels of Apaf-1, Caspase-3, Bax, and Bcl-2 were measured by quantitative real-time RT-PCR; protein levels of Caspase-3, Cleaved Caspase-3, Bax, and Bcl-2 were measured by western blot. LSL can inhibit the proliferation of cells, and it is possible to induce apoptosis in cells. The HepG2 cells with LSL co-culture exhibited typical apoptotic morphology, and the expression levels of enzyme activity of Caspase-3 and Caspase-9 increased (P< 0.05). We also found that LSL increases cell apoptosis rate and regulates the expression of genes and proteins associated with apoptosis through the Caspase-3 pathway. These results indicate that LSL may be one of the potential drug candidates to inhibit the proliferation and induce apoptosis in HepG2 cells.Key points• LSL, which is of good biological activities such as anti-bacterium, virus elimination, and inflammatory response elimination, has been firstly used to intervene in vitro to investigate its effect on HepG2 cell proliferation.• LSL can inhibit the proliferation of cells, and it is possible to induce apoptosis in HepG2 cells through the Caspase-3 pathway.• The mechanism of LSL action on HepG2 cell proliferation was firstly also discussed, which provides a certain experimental reference for the clinical treatment of liver cancer.

Antifungal evaluation of traditional herbal monomers and their potential for inducing cell wall remodeling in Candida albicans and Candida auris.

Traditional herbal monomers (THMs) are widely distributed in many traditional Chinese formulas (TCFs) and decoctions (TCDs) and are frequently used for the prevention and treatment of fungal infections. The antifungal activities of five common THMs, including sodium houttuyfonate (SH), berberine (BER), palmatine (PAL), jatrorrhizine (JAT) and cinnamaldehyde (CIN), and their potential for inducing cell wall remodeling (CWR), were evaluated against Candida albicans SC5314 and Candida auris 12372. SH/CIN plus BER/PAL/JAT showed synergistic antifungal activity against both Candida isolates. Furthermore, SH-associated combinations (SH plus BER/PAL/JAT) induced stronger exposure of ß-glucan and chitin than their counterparts, while CIN triggered more marked exposure compared with CIN-associated combinations (CIN plus BER/PAL/JAT). Collectively, this study demonstrated the anti-Candida effect and the CWR induction potential of the five THMs and their associated combinations, providing a possibility of their in vivo application against fungal-associated infections.

Rosmarinic acid, the active component of Salvia miltiorrhizae, improves gliquidone transport by regulating the expression and function of P-gp and BCRP in Caco-2 cells.

Salvia miltiorrhiza (Danshen) is typically used in the treatment of diabetic complications and is often co-prescribed with gliquidone in China. However, whether danshen affects the absorption of gliquidone has not been elucidated. In this study, the effects of an aqueous extract of danshen (danshen injection, DSI) and its primary compounds (danshensu, protocatechuic aldehyde, rosmarinic acid and salvianolic acid B) on gliquidone transport across Caco-2 monolayer cells was investigated. DSI enhanced the transport of gliquidone in Caco-2 cell monolayers from the apical (AP) to basolateral (BL) sides and from the BL to AP sides. Rosmarinic acid (RA) also significantly increased the Papp (AP-BL) value for gliquidone transport. Verapamil (a P-gp inhibitor) and Ko143 (a BCRP inhibitor) inhibited the BL-AP transport of gliquidone and promoted the AP-BL transport of gliquidone, whereas MK571 (an MRP1 inhibitor), probenecid (an MRP2 inhibitor), and benzbromarone (an MRP3 inhibitor) had no effect on gliquidone transport. RA also enhanced the intracellular accumulation of Rho123 and Hoechst 33342. The expression of P-gp and BCRP was significantly downregulated, and P-gp ATPase activity was promoted by RA in a dose-dependent manner. These results indicate that an aqueous extract of danshen can increase the transport of gliquidone in Caco-2 cell monolayers and that RA may be the primary compound associated with this activity, which is in agreement with RA simultaneously suppressing the function and expression of P-gp and BCRP.

Multi-path tumor inhibition via the interactive effects between tumor microenvironment and an oxygen self-supplying delivery system for a photosensitizer.

The tumor microenvironment (TME) affects not only tumor growth and metastasis, but also therapy efficacy. In the present study, an oxygen self-supplying delivery system for a photosensitizer (O2-PDS), with an oxygen source of calcium peroxide (CPO), has been designed to induce multi-path tumor apoptosis through interactive effects with the TME. In anti-tumor experiments, the CPO decomposition and O2 released from the O2-PDS are site-activated and accelerated by high interstitial pressure and low pH level of the TME. The CPO decomposition products of O2 and Ca2+ lead to direct tumor apoptosis by irradiation generated singlet oxygen and mitochondrial calcium overload. The decomposition products of OH- and O2 relieves the acid and hypoxic state of TME, inducing a decrease in tumor proliferation and metastasis. This multi-path tumor apoptosis leads to a positive therapeutic effect on an animal tumor model and nontoxicity in normal tissue.

Targeting Forward and Reverse EphB4/EFNB2 Signaling by a Peptide with Dual Functions.

The tyrosine kinase receptor EphB4 is frequently overexpressed in ovarian and other solid tumors and is involved in interactions between tumor cells and the tumor microenvironment, contributing to metastasis. Trans-interaction between EphB4 and its membrane-bound ligand ephrin B2 (EFNB2) mediates bi-directional signaling: forward EFNB2-to-EphB4 signaling suppresses tumor cell proliferation, while reverse EphB4-to-EFNB2 signaling stimulates the invasive and angiogenic properties of endothelial cells. Currently, no small molecule-based, dual-function, EphB4-binding peptides are available. Here, we report our discovery of a bi-directional ephrin agonist peptide, BIDEN-AP which, when selectively internalized via receptor-mediated endocytosis, suppressed invasion and epithelial-mesenchymal transition of ovarian cancer cells. BIDEN-AP also inhibited endothelial migration and tube formation. In vivo, BIDEN-AP and its nanoconjugate CCPM-BIDEN-AP significantly reduced growth of orthotopic ovarian tumors, with CCPM-BIDEN-AP displaying greater antitumor potency than BIDEN-AP. Both BIDEN-AP and CCPM-BIDEN-AP compromised angiogenesis by downregulating epithelial-mesenchymal transition and angiogenic pathways. Thus, we report a novel EphB4-based therapeutic approach against ovarian cancer.

Multiboosting of Cancer Immunotherapy by a Core-Shell Delivery System.

The synergy of chemotherapy and antiangiogenesis therapy is a new strategy for cancer treatment. In this paper, a well-developed core-shell nanoparticle loaded with gambogic acid (GA), heparin (HP), and the immunoadjuvant cytosine-phosphate-guanine oligonucleotide (CpG ODN), called GHC NP, was constructed to treat hepatocellular carcinoma. GHC NPs with liver targeting activity can effectively inhibit tumor cell proliferation and angiogenesis. With the delivery of nanocarriers and the assistance of GA and HP, the GHC NPs can more effectively upregulate cytotoxic T cell (CTL) levels, promote helper T cell (Th cell) differentiation, and induce Th1 immune responses in long-term treatment compared with single CpG ODN. This synergistically enhanced immunotherapy might have universal application in cancer treatments.

Metformin Reduces Renal Uptake of Radiotracers and Protects Kidneys from Radiation-Induced Damage.

Metformin is the most widely prescribed drug for type 2 diabetes. Chemically, metformin is a hydrophilic base that functions as an organic cation, suggesting that it may have the capacity to inhibit the tubular reabsorption of peptide radiotracers. The purpose of this study was to investigate whether metformin could reduce renal uptake of peptidyl radiotracers and serve as a radioprotective agent for peptide receptor radionuclide therapy (PRRT). METHODS: We used two radiolabeled peptides: a 68Ga-labeled cyclic (TNYL-RAW) peptide (68Ga-NOTA-c(TNYL-RAW) (NOTA: 1,4,7 triazacyclononane-1,4,7-trisacetic acid) targeting EphB4 receptors and an 111In- or 64Cu-labeled octreotide (111In/64Cu-DOTA-octreotide) (DOTA: 1,4,7,10 triazacyclododecane-1,4,7,10-tetraacetic acid) targeting somatostatin receptors. Each radiotracer was injected intravenously into normal Swiss mice or tumor-bearing nude mice in the presence or absence of metformin administered intravenously or orally. Micropositron emission tomography or microsingle-photon emission computed tomography images were acquired at different times after radiotracer injection, and biodistribution studies were performed at the end of the imaging session. To assess the radioprotective effect of metformin on the kidneys, normal Swiss mice received two doses of 111In-DOTA-octreotidein the presence or absence of metformin, and renal function was analyzed via blood chemistry and histology. RESULTS: Intravenous injection of metformin with 68Ga-NOTA-c(TNYL-RAW) or 111In-DOTA-octreotide reduced the renal uptake of the radiotracer by 60% and 35%, respectively, compared to uptake without metformin. These reductions were accompanied by greater uptake in the tumors for both radiolabeled peptides. Moreover, the renal uptake of 111In-DOTA-octreotide was significantly reduced when metformin was administered via oral gavage. Significantly more radioactivity was recovered in the urine collected over a period of 24 h after intravenous injection of 64Cu-DOTA-octreotide in mice that received oral metformin than in mice that received vehicle. Finally, coadministration of 111In-DOTA-octreotide with metformin mitigated radio-nephrotoxicity. CONCLUSION: Metformin inhibits kidney uptake of peptidyl radiotracers, protecting the kidney from nephrotoxicity. Further studies are needed to elucidate the mechanisms of these finding and to optimize mitigation of radiation-induced damage to kidney in PRRT.

Efficient Targeting Drug Delivery System for Lewis Lung Carcinoma, Leading to Histomorphological Abnormalities Restoration, Physiological and Psychological Statuses Improvement, and Metastasis Inhibition.

Lung cancer is a kind of malignant tumor with high morbidity and metastasis tendency. Gambogic acid (GA) has demonstrated significant antitumor activity in vitro, but its poor water-solubility and adverse effects restrict its application in vivo and in clinic. In this study, a passive-targeting GA delivery system was prepared for orthotopic Lewis lung carcinoma model mice. Besides the ∼7 µm size distribution, slow and steady in vitro drug release in a week, high targeting effect to lung, effective restoration of histomorphological abnormalities in lung, maintaining on bodyweight, and prolongation on survival time, excellent improvements of the GA-loaded particles on physiological and psychological statuses and obvious inhibition on tumor metastasis to liver have also been observed, through the measurements of Porsolt forced swim, hypoxic tolerance time, ultrastructure of pulmonary capillary, pulmonary vascular permeability, and hepatic histological change. These results suggest that this GA-loaded particle may be an ideal approach to achieve satisfactory therapeutic function on lung cancer.