Explore the vast range of titles available.

Activation of scramblases is one of the mechanisms that regulates the exposure of phosphatidylserine to the cell surface, a process that plays an important role in tumour immunosuppression. Here we show that chemotherapeutic agents induce overexpression of Xkr8, a scramblase activated during apoptosis, at the transcriptional level in cancer cells, both in vitro and in vivo. Based on this finding, we developed a nanocarrier for co-delivery of Xkr8 short interfering RNA and the FuOXP prodrug to tumours. Intravenous injection of our nanocarrier led to significant inhibition of tumour growth in colon and pancreatic cancer models along with increased antitumour immune response. Targeting Xkr8 in combination with chemotherapy may represent a novel strategy for the treatment of various types of cancers. Downregulation of specific proteins named scramblases might enhance tumour immunosuppression. In this paper the authors first show that the scramblase Xrk8 is overexpressed in tumour cells upon treatment with chemotherapeutics, and then develop a nanomedicine platform for co-delivery of a cancer prodrug and an siRNA directed against the Xrk8 gene, showing therapeutic effect and enhanced immune response in animal tumour models.

The multifaceted chemo-immune resistance is the principal barrier to achieving cure in cancer patients. Identifying a target that is critically involved in chemo-immune-resistance represents an attractive strategy to improve cancer treatment. iRhom1 plays a role in cancer cell proliferation and its expression is negatively correlated with immune cell infiltration. Here we show that iRhom1 decreases chemotherapy sensitivity by regulating the MAPK14-HSP27 axis. In addition, iRhom1 inhibits the cytotoxic T-cell response by reducing the stability of ERAP1 protein and the ERAP1-mediated antigen processing and presentation. To facilitate the therapeutic translation of these findings, we develop a biodegradable nanocarrier that is effective in codelivery of iRhom pre-siRNA (pre-siiRhom) and chemotherapeutic drugs. This nanocarrier is effective in tumor targeting and penetration through both enhanced permeability and retention effect and CD44-mediated transcytosis in tumor endothelial cells as well as tumor cells. Inhibition of iRhom1 further facilitates tumor targeting and uptake through inhibition of CD44 cleavage. Co-delivery of pre-siiRhom and a chemotherapy agent leads to enhanced antitumor efficacy and activated tumor immune microenvironment in multiple cancer models in female mice. Targeting iRhom1 together with chemotherapy could represent a strategy to overcome chemo-immune resistance in cancer treatment. A pro-tumorigenic role of iRhom1 has been described in several cancer types. Here the authors show that iRhom1 regulates sensitivity to chemotherapy and immune response, as well they report that CD44 targeting nanoparticle-mediated co-delivery of iRhom1 pre-siRNA promotes anti-tumor immune responses in preclinical cancer models.

SERPINB9, an endogenous inhibitor of granzyme B (GzmB), has emerged as a critical factor in the resistance to immunotherapy by protecting cancer cells from GzmB-induced cytotoxicity. However, its role in chemosensitivity remains unknown. In this study, we show that gemcitabine (GEM) treatment upregulates SERPINB9 through transcription factor ATF-3. Interestingly, GEM also induces the expression of GzmB and knockout or knockdown of SERPINB9 results in enhanced response of tumor cells to GEM, suggesting a role of GzmB/SERPINB9 axis in regulating chemosensitivity. To facilitate the therapeutic translation of these findings, we engineer POEM nanocarrier (consisting of lipid-derivatized polylysine ( P EG- P LL- O leic acid, PPO ), and GEM-conjugated polylysine ( P EG- P LL- O A- GEM , PPOGEM ), P P O /PPOG EM ( POEM )) that is highly effective in codelivery of built-in GEM and loaded SERPINB9 short interfering RNA (siSPB9). GEM conjugation introduces an additional mechanism of carrier/siRNA interaction in addition to charge-mediated interaction and enables efficient i.v. delivery at lower N/P ratios. Here, we show that co-delivery of GEM and siSPB9 significantly improves antitumor efficacy and remodels the tumor immune microenvironment in pancreatic cancer models, supporting a promising therapeutic strategy. SERPINB9 (SPB9) has been reported as a critical factor in the resistance to immunotherapy but its role in chemosensitivity remains unknown. Here this work reports that gemcitabine (GEM) treatment leads to upregulation of SPB9 in vitro/vivo, therefore engineer a nanocarrier co-delivering GEM and siSPB9 for preclinical pancreatic cancer treatment.

PARP inhibitors (PARPi)‐based synthetic lethal therapy demonstrates limited efficacy for most cancer types that are homologous recombination (HR) proficient. To potentiate the PARPi application, a nanocarrier based on 5‐azacytidine (AZA)‐conjugated polymer (PAZA) for the codelivery of AZA and a PARP inhibitor, BMN673 (BMN) is developed. AZA conjugation significantly decreased the nanoparticle (NP) size and increased BMN loading. Molecular dynamics simulation and experimental validations shed mechanistic insights into the self‐assembly of effective NPs. The small PAZA NPs demonstrated higher efficiency of tumor targeting and penetration than larger NPs, which is mediated by a new mechanism of active targeting that involves the recruitment of fibronectin from serum proteins following systemic administration of PAZA NPs. Furthermore, it is found that PAZA carrier sensitize the HR‐proficient nonsmall cell lung cancer (NSCLC) to BMN, a combination therapy that is more effective at a lower AZA/BMN dosage. To investigate the underlying mechanism, the tumor immune microenvironment and various gene expressions by RNAseq are explored. Moreover, the BMN/PAZA combination increased the immunogenicity and synergized with PD‐1 antibody in improving the overall therapeutic effect in an orthotopic model of lung cancer (LLC). An ultrasmall nanocarrier for the co‐delivery of azacytidine (AZA) and BMN673 is developed. The nanocarrier is capable of recruiting fibronectin (FN) enriched protein corona, resulting in effective tumor targeting and penetration through FN/ITGA5 mediated transcytosis. Co‐delivery of AZA and BMN673 to tumors enhances the synthetic lethal therapy and elicits antitumor immune response through the epigenetic modulation of AZA. The figure is created with BioRender.com.

In the past decade, advancements in nanotechnology and our growing understanding of cancer biology and nano-bio interactions have led to the development of various nanoparticles (NPs). However, the targeting efficiency of existing NPs is still too limited to be translated into clinic. Developing new tumor targeting NPs and unveiling the targeting mechanism emerges as an ideal strategy to overcome the limitations in the current paradigm of tumor-targeted delivery and improve the therapeutic effect of anticancer agents.An ultra-small NP was first developed based on 5-azacytidine (AZA)-conjugated polymer (PAZA) for the co-delivery of AZA and BMN673. AZA conjugation significantly reduced the nanoparticle size to 12 nm, allowing efficient tumor targeting through more effective enhanced permeation and retention (EPR) effect and penetration via the in-situ formation of fibronectinenriched protein corona in the blood, which mediated transcytosis through ITGA5 receptor on tumor cells. An RNAseq-guided mechanistic study demonstrated that PAZA carrier reduced the DNA repair induced by BMN673, sensitizing HR-proficient non-small cell lung cancer (NSCLC) to BMN673. Furthermore, BMN/PAZA enhanced both innate and adaptive antitumor immune response, which was more effective at a lower dosage.Despite the improved tumor targeting with the ultra-small PAZA NPs, it is still somewhat subjected to the limitation of EPR effect. To target tumors through a mechanism independent of the EPR effect, we developed a biodegradable nanocarrier coated with chondroitin sulfate (PCLCP). PCL-CP NPs were highly effective in tumor targeting and penetration through both EPR and CD44-mediated transcytosis in tumor endothelial cells and tumor cells, resulting in superior efficiency in active tumor targeting and tumor penetration. More importantly, we discovered a novel pharmacological target, iRhom1, and elucidated its role in chemo-immuno-resistance. However, there are no small molecule drugs available for inhibiting iRhom1. Better synergy could be achieved by combining chemotherapy drugs with gene therapeutics for \"undruggable\" targets. PCL-CP was further modified to be effective in co-delivering iRhom1 pre-siRNA (pre-siiRhom) and chemotherapeutic drugs. Co-delivery of pre-siiRhom1 and a chemotherapy agent (DOX or CPT-SAHA) led to significantly enhanced antitumor efficacy and activated tumor immune microenvironment in multiple cancer models.

Activation of scramblases is one of the mechanisms that regulate the exposure of phosphatidylserine to the cell surface, a process that plays an important role in tumor immunosuppression. Here we show that chemotherapeutic agents induce overexpression of Xkr8, a scramblase activated during apoptosis, at the transcriptional level in cancer cells, both in vitro and in vivo. Given this finding, we developed a nanocarrier for co-delivery of Xkr8 siRNA and the FuOXP pro-drug to tumors. Intravenous injection of our nanocarrier led to significant inhibition of tumor growth in colon and pancreatic cancer models along with increased antitumor immune response. Targeting Xkr8 in combination with chemotherapy may represent a novel strategy for the treatment of various types of cancers. Downregulation of specific proteins named scramblases might enhance tumour immunosuppression. In this paper the authors first show that the scramblase Xrk8 is overexpressed in tumour cells upon treatment with chemotherapeutics, and then developed a nanomedicine platform for co-delivery of a cancer pro-drug and of a siRNA directed against the Xrk8 gene, showing therapeutic effect and enhanced immune response in animal tumour models.

There is an urgent and unmet need to develop effective therapies for triple negative breast cancers (TNBCs) which are much more aggressive and have poor prognosis due to lack of receptor targets for Her2-targeted and endocrine therapy. In this study we systematically evaluated the effect of Vorinostat (SAHA, a pan-HDAC inhibitor) in reactivating the expression of functional estrogen receptor α (ERα) and synergizing with tamoxifen (TAM, a selective estrogen-receptor modulator) in antitumor activity. In addition, a SAHA prodrug-based dual functional nanocarrier was developed for codelivery of SAHA and TAM for effective combination therapy. : A SAHA-containing polymeric nanocarrier, POEG- -PVDSAHA was developed via reversible addition-fragmentation transfer (RAFT) polymerization with SAHA incorporated into the polymer through a redox-responsive disulfide linkage. The effect of both free SAHA and POEG- -PVDSAHA on reactivating the expression of functional ERα was investigated in several human and murine TNBC cell lines via examining the mRNA and protein expression of ERα target genes. The cytotoxicity of free SAHA and TAM combination and TAM-loaded POEG- -PVDSAHA micelles was examined via MTT assay. The antitumor activity of TAM-loaded POEG- -PVDSAHA was investigated in a murine breast cancer model (4T1.2). : Both free SAHA and POEG- -PVDSAHA were effective in inducing the reexpression of functional estrogen receptor α (ERα), which may have helped to sensitize TNBCs to TAM. More importantly, POEG- -PVDSAHA self-assembled to form small-sized micellar carrier that is effective in formulating and codelivery of TAM. TAM-loaded POEG- -PVDSAHA micelles exhibited enhanced and synergistic cytotoxicity against TNBC cell lines compared with free SAHA, free TAM and TAM loaded into a pharmacologically inert control carrier (POEG- -PVMA). In addition, codelivery of TAM via POEG- -PVDSAHA micelles led to significantly improved antitumor efficacy in 4T1.2 tumor model compared with other groups such as combination of free SAHA and TAM and TAM-loaded POEG- -PVMA micelles. : Our prodrug-based co-delivery system may provide an effective and simple strategy to re-sensitize TNBCs to TAM-based hormone therapy.

Inhibition of Myc promotes the regression of many types of tumors, including prostate cancer. However, the success of anti-Myc therapy is hampered by the lack of a strategy to effectively deliver the inhibitors to the tumor site and by the feedback mechanisms that cancer cells use to adapt to metabolic reprogramming. The effects of Myc inhibitors (10074-G5 or 10058-F4), alone or in combination with 6-diazo-5-oxo-L-norleucine (DON), were evaluated in cultured human or murine prostate cancer cells by cell viability assay, qRT-PCR and Western blot. To facilitate the therapeutic evaluation, a prodrug conjugate of 10074-G4 and DON (10074-DON) was developed, which could be effectively loaded into a polysaccharide-based nanocarrier (PS). The treatment with Myc inhibitors led to significant induction of glutamine: fructose-6-phosphate amidotransferase-1 (GFAT1) and enhanced protein glycosylation. Mechanistically, Myc inhibition triggered GFAT1 induction through the IREα-Xbp1s pathway. The combination use of Myc inhibitors and GFAT1 inhibitor DON led to a synergistic effect in inhibiting the proliferation and migration of prostate cancer cells. Enhanced delivery of 10074-DON via the PS nanocarrier led to a significant inhibition of tumor growth along with an improvement in tumor immune microenvironment in several PCa animal models. Simultaneous targeting of Myc and GFAT-1 may represent a novel strategy for the treatment of prostate cancer.

The unique metabolic demand of cancer cells suggests a new therapeutic strategy targeting the metabolism in cancers. V9302 is a recently reported inhibitor of ASCT2 amino acid transporter which shows promising antitumor activity by blocking glutamine uptake. However, its poor solubility in aqueous solutions and tumor cells’ compensatory metabolic shift to glucose metabolism may limit the antitumor efficacy of V9302. 2-Deoxyglucose (2-DG), a derivative of glucose, has been developed as a potential antitumor agent through inhibiting glycolysis in tumor cells. In order to achieve enhanced antitumor effect by inhibiting both metabolic pathways, a 2-DG prodrug-based micellar carrier (POEG-p-2DG) was developed. POEG-p2DG well retained the pharmacological activity of 2-DG in vitro and in vivo. More importantly, POEG-p-2DG could self-assemble to form micelles that were capable of loading V9302 to achieve co-delivery of 2-DG and V9302. V9302-loaded POEG-p2DG micelles were small in sizes (~10nm), showed a slow kinetics of drug release and demonstrated targeted delivery to tumor. In addition, V9302 loaded POEG-p-2DG micelles exhibited improved anti-tumor efficacy both in vitro and in vivo with decreased toxicity compared to free drug combination. These results suggest that POEG-p2DG prodrug micelles may serve as a dual functional carrier for V9302 to achieve synergistic targeting of metabolism in cancers.