scholarly journals Regulating the immunosuppressive tumor microenvironment to enhance breast cancer immunotherapy using pH-responsive hybrid membrane-coated nanoparticles

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Chunai Gong ◽  
Xiaoyan Yu ◽  
Wei Zhang ◽  
Lu Han ◽  
Rong Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Immunotherapy ◽  
Checkpoint Inhibitors ◽  
Adenosine Monophosphate ◽  
Great Promise ◽  
Ph Responsive ◽  
Programmed Death ◽  
Biomimetic Membrane

AbstractThe combination of an immuno-metabolic adjuvant and immune checkpoint inhibitors holds great promise for effective suppression of tumor growth and invasion. In this study, a pH-responsive co-delivery platform was developed for metformin (Met), a known immuno-metabolic modulator, and short interfering RNA (siRNA) targeting fibrinogen-like protein 1 mRNA (siFGL1), using a hybrid biomimetic membrane (from macrophages and cancer cells)-camouflaged poly (lactic-co-glycolic acid) nanoparticles. To improve the endo-lysosomal escape of siRNA for effective cytosolic siRNA delivery, a pH-triggered CO2 gas-generating nanoplatform was developed using the guanidine group of Met. It can react reversibly with CO2 to form Met-CO2 for the pH-dependent capture/release of CO2. The introduction of Met, a conventional anti-diabetic drug, promotes programmed death-ligand 1 (PD-L1) degradation by activating adenosine monophosphate-activated protein kinase, subsequently blocking the inhibitory signals of PD-L1. As a result, siFGL1 delivery by the camouflaged nanoparticles of the hybrid biomimetic membrane can effectively silence the FGL1 gene, promoting T-cell-mediated immune responses and enhancing antitumor immunity. We found that a combination of PD-L1/programmed death 1 signaling blockade and FGL1 gene silencing exhibited high synergistic therapeutic efficacy against breast cancer in vitro and in vivo. Additionally, Met alleviated tumor hypoxia by reducing oxygen consumption and inducing M1-type differentiation of tumor-related macrophages, which improved the tumor immunosuppressive microenvironment. Our results indicate the potential of hybrid biomimetic membrane-camouflaged nanoparticles and combined Met-FGL1 blockade in breast cancer immunotherapy.

scholarly journals Nanostructured Dihydroartemisinin Plus Epirubicin Liposomes Enhance Treatment Efficacy of Breast Cancer by Inducing Autophagy and Apoptosis

Nanomaterials ◽  
2018 ◽  
Vol 8 (10) ◽  
pp. 804 ◽  
Author(s):  
Ying-Jie Hu ◽  
Jing-Ying Zhang ◽  
Qian Luo ◽  
Jia-Rui Xu ◽  
Yan Yan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Therapeutic Strategy ◽  
Beclin 1 ◽  
Type I ◽  
Programmed Death ◽  
Cancer Tissues

The heterogeneity of breast cancer and the development of drug resistance are the relapse reasons of disease after chemotherapy. To address this issue, a combined therapeutic strategy was developed by building the nanostructured dihydroartemisinin plus epirubicin liposomes. Investigations were performed on human breast cancer cells in vitro and xenografts in nude mice. The results indicated that dihydroartemisinin could significantly enhance the efficacy of epirubicin in killing different breast cancer cells in vitro and in vivo. We found that the combined use of dihydroartemisinin with epirubicin could efficiently inhibit the activity of Bcl-2, facilitate release of Beclin 1, and further activate Bax. Besides, Bax activated apoptosis which led to the type I programmed death of breast cancer cells while Beclin 1 initiated the excessive autophagy that resulted in the type II programmed death of breast cancer cells. In addition, the nanostructured dihydroartemisinin plus epirubicin liposomes prolonged circulation of drugs, and were beneficial for simultaneously delivering drugs into breast cancer tissues. Hence, the nanostructured dihydroartemisinin plus epirubicin liposomes could provide a new therapeutic strategy for treatment of breast cancer.

scholarly journals Modulation of Placental Breast Cancer Resistance Protein by HDAC1 in Mice: Implications for Optimization of Pharmacotherapy During Pregnancy

2021 ◽  
Author(s):  
Chuan Wang ◽  
Dan Ma ◽  
Yimin Hua ◽  
Hongyu Duan
Keyword(s):  
Breast Cancer ◽  
Breast Cancer Resistance Protein ◽  
Negative Control ◽  
Great Promise ◽  
Cancer Resistance ◽  
Gene Expressions ◽  
Time Curve ◽  
Resistance Protein

AbstractBreast cancer resistance protein (BCRP/ABCG2) is a critical drug efflux transporters by limiting drugs’ transplacental transfer rates. More investigations on the regulation of placental BCRP offer great promise for enabling pronounced progress in individualized and safe pharmacotherapy during pregnancy. Histone deacetylases (HDACs) play an important role in epigenetic regulation of placental genes. It was reported recently by us that HDAC1 was involved in placental BCRP regulation in vitro. The aim of this study was to further explore the effect of HDAC1 on placental BCRP expression and functionality in animals. Randomly assigned C57BL pregnant dams received intraperitoneal injections of a negative control siRNA or Hdac1 siRNA from embryonic day 7.5 (E7.5) to E15.5, respectively. At E16.5, glyburide (GLB), a probe for evaluating placental BCRP efflux functionality, was injected via the tail vein. Animals were sacrificed through cervical dislocation at various times (5–180 min) after drug administration. The maternal blood, placentas, and fetal-units were collected. GLB concentrations were determined by a validated high-performance liquid chromatography/mass spectrometry (HPLC-MS) assay. Real-time quantitative PCR (qRT-PCR), Western blot, and immunohistochemical (IHC) analysis were employed to identify mRNA/protein levels and localization of gene expressions, respectively. It was noted that Hdac1 inhibition significantly decreased placental Bcrp expression, with markedly increases of GLB concentrations and area under the concentration-time curve (AUC) in fetal-units. Particularly, the ratios of fetal-unit/maternal plasma GLB concentrations were also significantly elevated following Hdac1 repression. Taken together, these findings suggested that HDAC1 was involved in positive regulation of placental BCRP expression and functionality in vivo.

scholarly journals Surface-Enhanced Raman Spectroscopy for Cancer Immunotherapy Applications: Opportunities, Challenges, and Current Progress in Nanomaterial Strategies

Nanomaterials ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 1145 ◽  
Author(s):  
Shuvashis Dey ◽  
Matt Trau ◽  
Kevin M. Koo
Keyword(s):  
Raman Spectroscopy ◽  
Cancer Immunotherapy ◽  
Immune Checkpoint ◽  
Checkpoint Inhibitors ◽  
Surface Enhanced Raman Spectroscopy ◽  
Surface Enhanced ◽  
Surface Enhanced Raman ◽  
Checkpoint Receptors

Cancer immunotherapy encompasses a variety of approaches which target or use a patient’s immune system components to eliminate cancer. Notably, the current use of immune checkpoint inhibitors to target immune checkpoint receptors such as CTLA-4 or PD-1 has led to remarkable treatment responses in a variety of cancers. To predict cancer patients’ immunotherapy responses effectively and efficiently, multiplexed immunoassays have been shown to be advantageous in sensing multiple immunomarkers of the tumor microenvironment simultaneously for patient stratification. Surface-enhanced Raman spectroscopy (SERS) is well-regarded for its capabilities in multiplexed bioassays and has been increasingly demonstrated in cancer immunotherapy applications in recent years. This review focuses on SERS-active nanomaterials in the modern literature which have shown promise for enabling cancer patient-tailored immunotherapies, including multiplexed in vitro and in vivo immunomarker sensing and imaging, as well as immunotherapy drug screening and delivery.

pH-Responsive Antibacterial Resin Adhesives for Secondary Caries Inhibition

2020 ◽  
Vol 99 (12) ◽  
pp. 1368-1376
Author(s):  
J. Liang ◽  
F. Liu ◽  
J. Zou ◽  
H.H.K. Xu ◽  
Q. Han ◽  
...  
Keyword(s):  
Antibacterial Effect ◽  
Dental Restoration ◽  
Great Promise ◽  
Neutral Medium ◽  
Rrna Gene ◽  
Ph Responsive ◽  
Secondary Caries ◽  
Caries Model

Secondary caries caused by dental plaque is one of the major reasons for the high failure rate of resin composite restoration. Although antimicrobial agent–modified dental restoration systems have been researched for years, few reported intelligent anticaries materials could respond to the change of the oral environment and help keep oral eubiosis. Herein, we report tertiary amine (TA)–modified resin adhesives (TA@RAs) with pH-responsive antibacterial effect to reduce the occurrence of secondary caries. Two kinds of newly designed TA monomers were synthesized: DMAEM (dodecylmethylaminoethyl methacrylate) and HMAEM (hexadecylmethylaminoethyl methacrylate). In the minimum inhibitory concentration and minimum bactericidal concentration test against Streptococcus mutans, Streptococcus sanguinis, and Streptococcus gordonii, they exhibited antibacterial effect only in acidic medium, which preliminarily verified the acid-activated effect of TAs. Then DMAEM and HMAEM were incorporated into adhesive resin at the mass fraction of 5%, yielding TA@RAs. In vivo and in vitro tests showed that the mechanical properties and biocompatibility of the adhesive were not affected. A S. mutans biofilm model in acidic and neutral medium was used and confirmed that TA@RAs could respond to the critical pH value of de-/remineralization and acquire reversible antibiofilm effect via the protonation and deprotonation of TAs. Meanwhile, the stability of antibacterial effect was confirmed via a 5-d pH-cycling experiment and a saliva-derived biofilm aging model. Furthermore, 16S rRNA gene sequencing showed that TA@RAs could increase the diversity of the saliva-derived biofilms, which implied that the novel materials could help regulate the microbial community to a healthy one. Finally, an in vitro demineralization model and in vivo secondary caries model were applied and demonstrated that TA@RAs could prevent secondary dental caries effectively. In summary, the reversible pH-responsive and non–drug release antibacterial resin adhesives ingeniously overcome the defect of the present materials and hold great promise for clinical application.

A pH-responsive natural cyclopeptide RA-V drug formulation for improved breast cancer therapy

2015 ◽  
Vol 3 (22) ◽  
pp. 4514-4523 ◽  
Author(s):  
Zeng-Ying Qiao ◽  
Di Zhang ◽  
Chun-Yuan Hou ◽  
Si-Meng Zhao ◽  
Ya Liu ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Tumor Therapy ◽  
Ph Sensitive ◽  
Drug Formulation ◽  
Ph Responsive ◽  
Breast Cancer Therapy

The co-encapsulation of RA-V cyclopeptide and SQ molecules in pH-sensitive PAE micelles for efficient tumor therapy and imaging in vitro and in vivo.

scholarly journals New emerging targets in cancer immunotherapy: the role of VISTA

ESMO Open ◽  
2020 ◽  
Vol 4 (Suppl 3) ◽  
pp. e000683 ◽  
Author(s):  
Marco Tagliamento ◽  
Paolo Bironzo ◽  
Silvia Novello
Keyword(s):  
T Cell Activation ◽  
Cell Activation ◽  
Checkpoint Inhibitors ◽  
Antitumour Activity ◽  
Therapeutic Option ◽  
Immune Surveillance ◽  
Dual Inhibitor ◽  
Programmed Death

The immune surveillance system is complex and regulated by different actors. Programmed death protein-ligand 1 (PD-L1), the only approved biomarker in clinical practice, has proven to be imperfect in selecting patients to immune checkpoint inhibitors treatment. Therefore, new biomarkers, and new therapeutic targets, are needed to maximise the efficacy of immunotherapy. V-domain Ig Suppressor of T-cell Activation (VISTA) is a programmed death protein-1 (PD-1) homolog expressed on T cells and on antigen-presenting cells, which regulates processes of activation and repression of the immune system with not yet completely clarified mechanisms. Its blockage has demonstrated in vitro and in vivo antitumour activity. The clinical research of VISTA antagonists is ongoing. Particularly, CA-170, an orally delivered dual inhibitor of VISTA and PD-L1, has shown to have clinical efficacy in phase I and II clinical trials in different advanced solid tumour types. Further data are needed to define whether this drug class can become a new therapeutic option for patients with VISTA expressing cancers.

Melatonin modifies tumor hypoxia and metabolism by inhibiting HIF-1α and energy metabolic pathway in the in vitro and in vivo models of breast cancer

2019 ◽  
Vol 2 (4) ◽  
pp. 83-98 ◽  
Author(s):  
André De Lima Mota ◽  
Bruna Vitorasso Jardim-Perassi ◽  
Tialfi Bergamin De Castro ◽  
Jucimara Colombo ◽  
Nathália Martins Sonehara ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Glucose Metabolism ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Carbonic Anhydrases ◽  
In Vivo Models ◽  
Ca Ix ◽  
Gene And Protein Expression

Breast cancer is the most common cancer among women and has a high mortality rate. Adverse conditions in the tumor microenvironment, such as hypoxia and acidosis, may exert selective pressure on the tumor, selecting subpopulations of tumor cells with advantages for survival in this environment. In this context, therapeutic agents that can modify these conditions, and consequently the intratumoral heterogeneity need to be explored. Melatonin, in addition to its physiological effects, exhibits important anti-tumor actions which may associate with modification of hypoxia and Warburg effect. In this study, we have evaluated the action of melatonin on tumor growth and tumor metabolism by different markers of hypoxia and glucose metabolism (HIF-1α, glucose transporters GLUT1 and GLUT3 and carbonic anhydrases CA-IX and CA-XII) in triple negative breast cancer model. In an in vitro study, gene and protein expressions of these markers were evaluated by quantitative real-time PCR and immunocytochemistry, respectively. The effects of melatonin were also tested in a MDA-MB-231 xenograft animal model. Results showed that melatonin treatment reduced the viability of MDA-MB-231 cells and tumor growth in Balb/c nude mice (p <0.05). The treatment significantly decreased HIF-1α gene and protein expression concomitantly with the expression of GLUT1, GLUT3, CA-IX and CA-XII (p <0.05). These results strongly suggest that melatonin down-regulates HIF-1α expression and regulates glucose metabolism in breast tumor cells, therefore, controlling hypoxia and tumor progression. 

The truncated somatostatin receptor sst5TMD4 stimulates the production of pro-angiogenic factors in in vitro and in vivo breast cancer models

2014 ◽  
Author(s):  
Raul M Luque ◽  
Mario Duran-Prado ◽  
David Rincon-Fernandez ◽  
Marta Hergueta-Redondo ◽  
Michael D Culler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Somatostatin Receptor ◽  
Angiogenic Factors ◽  
Cancer Models
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