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Rheumatoid arthritis (RA) is a chronic autoimmune disease that greatly affect patients' quality of life. Galangin extract is renowned for its anti-proliferative and anti-oxidative characteristics. However, galangin cytotoxicity studies are presently inadequate. We aimed to investigate the therapeutic potential of galangin on RA by investigating the PI3K/AKT signaling pathway.Fibroblast-like synovial cells (FLSs) were exposed to lipopolysaccharide (LPS) to establish an RA model

Background Combinatorial immunotherapy strategies for enhancing the responsiveness of immune system have shown great promise for cancer therapy. Engineered nanoformulation incorporated toll-like receptor (TLR) 9 agonist CpG ODN has shown more positive results in suppressing tumor growth and can significantly enhance other immunotherapy activity with combinatorial effects due to the innate and adaptive immunostimulatory effects of CpG. Results In the present work, protamine sulfate (PS) and carboxymethyl β-glucan (CMG) were used as nanomaterials to form nanoparticles through a self-assembly approach for CpG ODN encapsulation to generate CpG ODN-loaded nano-adjuvant (CNPs), which was subsequently mixed with the mixture of mouse melanoma-derived antigens of tumor cell lysates (TCL) and neoantigens to develop vaccine for anti-tumor immunotherapy. The obtained results showed that CNPs was able to effectively deliver CpG ODN into murine bone marrow-derived dendritic cells (DC) in vitro, and remarkably stimulate the maturation of DC cells with proinflammatory cytokine secretion. In addition, in vivo analysis showed that CNPs enhanced anti-tumor activity of PD1 antibody and CNPs-adjuvanted vaccine based on the mixture antigens of melanoma TCL and melanoma-specific neoantigen could not only induce anti-melanoma cellular immune responses, but also elicit melanoma specific humoral immune responses, which significantly inhibited xenograft tumor growth. Furthermore, CD16 CAR-T cells were generated by expressing CD16-CAR in CD3+CD8+ murine T cells. Conclusion Our results eventually showed that anti-melanoma antibodies induced by CNPs-adjuvanted TCL vaccines were able to collaborate with CD16-CAR-T cells to generate an enhanced targeted anti-tumor effects through ADCC (antibody dependent cell cytotoxicity) approach. CD16 CAR-T cells has thus a great potential to be an universal promising strategy targeting on solid tumor synergistic immunotherapy via co-operation with TCL-based vaccine.

Rattle-structured nanoparticles with movable cores, porous shells and hollow interiors have shown great effectiveness in drug delivery and cancer theranostics. Targeting autophagy and glucose have provided alternative strategies for cancer intervention therapy. Herein, rattle-structured polydopamine@mesoporous silica nanoparticles were prepared for in vivo photoacoustic (PA) imaging and augmented low-temperature photothermal therapy (PTT) via complementary autophagy inhibition and glucose metabolism. Methods: The multifunctional rattle-structured nanoparticles were designed with the nanocore of PDA and the nanoshell of hollow mesoporous silica (PDA@hm) via a four-step process. PDA@hm was then loaded with autophagy inhibitor chloroquine (CQ) and conjugated with glucose consumer glucose oxidase (GOx) (PDA@hm@CQ@GOx), forming a corona-like structure nanoparticle. Results: The CQ and GOx were loaded into the cavity and decorated onto the surface of PDA@hm, respectively. The GOx-mediated tumor starvation strategy would directly suppress the expression of HSP70 and HSP90, resulting in an enhanced low-temperature PTT induced by PDA nanocore. In addition, autophagy inhibition by the released CQ made up for the loss of low-temperature PTT and starvation efficiencies by PTT- and starvation-activated autophagy, realizing augmented therapy efficacy. Furthermore, the PDA nanocore in the PDA@hm@CQ@GOx could be also used for PA imaging. Conclusion: Such a "drugs" loaded rattle-structured nanoparticle could be used for augmented low-temperature PTT through complementarily regulating glucose metabolism and inhibiting autophagy and in vivo photoacoustic imaging.

BackgroundCancer synergistic therapy strategy in combination with therapeutic gene and small molecule drug offers the possibility to amplify anticancer efficiency. Colon cancer-associated transcript-1 (CCAT1) is a well identified oncogenic long noncoding RNA (lncRNA) exerting tumorigenic effects in a variety of cancers including colorectal cancer (CRC).ResultsIn the present work, curcumin (Cur) and small interfering RNA targeting lncRNA CCAT1(siCCAT1) were co-incorporated into polymeric hybrid nanoparticles (CSNP), which was constructed by self-assembling method with two amphiphilic copolymers, polyethyleneimine-poly (d,l-lactide) (PEI-PDLLA) and 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol) (DSPE-mPEG). Owing to the multicolor fluorescence characteristics of PEI-PDLLA, the constructed CSNP could be served as a theranostic nanomedicine for synchronous therapy and imaging both in vitro and in vivo. Resultantly, proliferation and migration of HT-29 cells were efficiently inhibited, and the highest apoptosis ratio was induced by CSNP with coordination patterns. Effective knockdown of lncRNA CCAT1 and concurrent regulation of relevant downstream genes could be observed. Furthermore, CSNP triggered conspicuous anti-tumor efficacy in the HT-29 subcutaneous xenografts model with good biosafety and biocompatibility during the treatment.ConclusionOn the whole, our studies demonstrated that the collaborative lncRNA CCAT1 silencing and Cur delivery based on CSNP might emerge as a preferable and promising strategy for synergetic anti-CRC therapy.Graphic abstract

Background: The prognosis of early cardia cancer and non-cardia cancer is still controversial. It is difficult to collect a large number of cases with complete information in clinical practice. Our study was aimed to identify the differences in clinicopathological characteristics and outcomes of early cardia gastric cancer and non-cardia gastric cancer. Methods: All cases analyzed were from Surveillance, Epidemiology, and End Results database. The data of the patients with early gastric cancer from 2004 to 2010 was retrospectively analyzed. Patients were distributed to cardia cancer group and non-cardia cancer group. Univariate and multivariate analyses were performed to examine differences between groups. The competitive risk model was made to compare the association with cardia cancer and non-cardia cancer about the causes of death. Propensity score matching (PSM) was performed to reduce the bias. Results: We found that cardia cancer was more common in male patients and the White than that in non-cardia cancer at early stage, signet ring cell carcinoma was more common in non-cardia cancer, and the differentiation of non-cardia cancer was worse. Univariate analysis showed that age, marital status, race, tumor location, histology, grade, stage, and operation or not can determine the prognosis. And the prognosis of patients with cardia cancer was worse than that of non-cardia cancer, according to lymph node metastasis and the depth of tumor invasion. Multivariate analysis showed cardia cancer was an independent prognostic factor for poor prognosis. After PSM, cardia cancer still exhibited poor prognosis. Conclusions: At early stage, cardia cancer had a poor prognosis compared with non-cardia cancer. The prevention and treatment of early cardia cancer need to be seriously treated.

A major impediment in photodynamic therapy (PDT) against hypoxic tumors is that the O2-dependent PDT is seriously limited by the intrinsic hypoxic feature. Hypoxia-inducible factor-1 alpha (HIF-1α) is a key transcription factor in tumor development and especially accumulates in hypoxic tumors and has been recognized as a novel therapeutic target. Herein, we developed small molecule HIF-1α inhibitor Doxy and IR780 photosensitizer co-incorporated methoxy poly(ethylene glycol)-b-poly-(propylene sulfide) (mPEG50-b-PPS45) nanoparticles (NPs/ID) as an ROS-responsive theranostic system designed to enhance PDT efficiency by combining the benefits of anti-HIF-1α therapy and ATP depletion. NPs/ID with reinforced phototherapy response in hypoxic tumors displayed enhanced photocytotoxicity compared to NPs/I that only exhibited the PDT effect. On the other hand, NPs/ID have the capacity to reduce the supply of intracellular ATP and destabilize the intracellular redox homeostasis for enough ROS generation by suppressing the HIF-1α expression, thereby facilitating the therapeutic efficiency of PDT. Significantly, NPs/ID displayed effective tumor targeting and NIR imaging ability and an improved in vivo efficacy in a xenograft MDA-MB-231 mouse tumor model compared with bare PDT. These findings demonstrate that the ROS-responsive theranostic NPs/ID with special anti-HIF-1α and ATP depletion behavior represent an attractive approach for overcoming the problems of PDT in hypoxic tumors.

Despite advances in the development of tumor treatments, mortality from cancer continues to increase. Nanotechnology is expected to provide an innovative anti-cancer therapy, to combat challenges such as multidrug resistance and tumor recurrence. Nevertheless, tumors can greatly rely on autophagy as an alternative source for metabolites, and which desensitizes cancer cells to therapeutic stress, hindering the success of any current treatment paradigm. Autophagy is a conserved process by which cells turn over their own constituents to maintain cellular homeostasis. The multistep autophagic pathway provides potentially druggable targets to inhibit pro-survival autophagy under various therapeutic stimuli. In this review, we focus on autophagy inhibition based on functional nanoplatforms, which may be a potential strategy to increase therapeutic sensitivity in combinational cancer therapies, including chemotherapy, radiotherapy, phototherapy, sonodynamic therapy, and immunotherapy.

Aberrant regulation of angiogenesis supply sufficient oxygen and nutrients to exacerbate tumor progression and metastasis. Taking this hallmark of cancer into account, reported here is a self-monitoring and triple-collaborative therapy system by auto-fluorescent polymer nanotheranostics which could be concurrently against angiogenesis and tumor cell growth by combining the benefits of anti-angiogenesis, RNA interfere and photothermal therapy (PTT). Auto-fluorescent amphiphilic polymer polyethyleneimine-polylactide (PEI-PLA) with positive charge can simultaneously load hydrophobic antiangiogenesis agent combretastatin A4 (CA4), NIR dye IR825 and absorb negatively charged heat shock protein 70 (HSP70) inhibitor (siRNA against HSP70) to construct self-monitoring nanotheranostics (NPICS). NPICS can effectively restrain the expression of HSP70 to reduce their endurance to the IR825-mediated PTT, leading to an enhanced photocytotoxicity. In a xenograft mouse tumor model, NPICS show an effect of inhibition of tumor angiogenesis and also display a highly synergistic anticancer efficacy with NIR laser irradiation. Significantly, based on its inherent auto-fluorescence, PEI-PLA not only serves as the drug carrier, but also as the self-monitor to real-time track NPICS biodistribution and tumor accumulation via fluorescence imaging. Moreover, IR825 endows NPICS could also be used as photoacoustic (PA) agents for in vivo PA imaging. This nanoplatform shows enormous potentials in cancer theranostics.

Triple-negative breast cancer (TNBC) is the most lethal subtype of breast cancer and significantly associated with poor prognosis and high risk of recurrence. miR-34a has been identified as a potent tumor suppressor whose expression is dramatically downregulated in TNBC. Currently, rectification of miRNA abnormality serves as a novel tumor therapeutic strategy. miR-34a is thus used as powerful antitumor agent for miRNA-based therapy against TNBC. However, miRNA-based antitumor therapy is challenged by effective targeted delivery of miRNA. In the present study, nanodiamond (ND), protamine (PS) and folic acid (FA) were used to construct ND-based layer-by-layer nanohybrids through a self-assembly approach for targeted miR-34a delivery in TNBC cells and xenograft TNBC tumors. We found that the targeted delivery of miR-34a remarkably suppressed cell proliferation, migration and induced the apoptosis of TNBC cells in vitro and inhibited tumor growth in vivo via down-regulating Fra-1 expression. The data suggest a great potential of ND-based nanohybrids for targeted intratumoral delivery of miR-34a for TNBC therapy.

Replacement of downregulated tumor‐suppressive microRNA (Ts‐miRNA) is recognized as an alternative approach for tumor gene therapy. However, in situ monitoring of miRNA replacement efficacy in a real‐time manner via noninvasive imaging is continually challenging. Here, glutathione (GSH)‐activated light‐up peptide‐polysaccharide‐inter‐polyelectrolyte nanocomplexes are established through self‐assembly of carboxymethyl dextran with disulfide‐bridged (“S—S”) oligoarginine peptide (S‐Arg4), in which microRNA‐34a (miR‐34a) and indocyanine green (ICG) are simultaneously embedded and the nanocomplexes are subsequently stabilized by intermolecular cross‐linking. Upon confinement within the robust nanocomplexes, the near‐infrared fluorescence (NIRF) of ICG is considerably quenched (“off”) due to the aggregation‐caused quenching effect. However, after intracellular delivery, the disulfide bond in S‐Arg4 can be cleaved by intracellular GSH, which leads to the dissociation of nanocomplexes and triggers the simultaneous release of miR‐34a and ICG. The NIRF of ICG is concomitantly activated through dequenching of the aggregated ICG. Very interestingly, a good correlation between time‐dependent increase in NIRF intensity and miR‐34a replacement efficacy is found in nanocomplexes‐treated tumor cells and tumor tissues through either intratumoral or intravenous injections. Systemic nanocomplexes‐mediated miR‐34a replacement significantly suppresses the growth of HepG‐2‐ and MDA‐MB‐231‐derived tumor xenografts, and provides a pronounced survival benefit in these animal models.

Metastatic relapse, development of drug resistance in cancer cells and adverse side effects of chemotherapeutic agents are the major obstacles for effective chemotherapy against triple-negative breast cancer. To address these problems, miR-34a, a potent endogenous tumor suppressive molecule in breast cancer, was co-encapsulated with doxorubicin (DOX) into hyaluronic acid (HA)-chitosan (CS) nanoparticles (NPs) and simultaneously delivered into breast cancer cells for improved therapeutic effects of drug. DOX-miR-34a co-loaded HA-CS NPs were successfully prepared through ionotropic gelation method in water. In vitro and in vivo experiments showed that miR-34a and DOX can be efficiently encapsulated into HA-CS NPs and delivered into tumor cells or tumor tissues and enhance anti-tumor effects of DOX by suppressing the expression of non-pump resistance and anti-apoptosis proto-oncogene Bcl-2. In addition, intracellular restoration of miR-34a inhibited breast cancer cell migration via targeting Notch-1 signaling. The obtained data suggest that co-delivery of DOX and miR-34a could achieve synergistic effects on tumor suppression and nanosystem-based co-delivery of tumor suppressive miRNAs and chemotherapeutic agents may be a promising combined therapeutic strategy for enhanced anti-tumor therapy.