Efficient TNBC immunotherapy by dual reprogramming tumor-infiltrating dendritic cells and tumor-associated macrophages with stimulus-responsive miR155 nanocomplexes.

Triple negative breast cancer (TNBC) remains to be a formidable adversary with high mortality and unfavorable prognosis. Tumor microenvironment comprises of various constituents, among them, tumor infiltrating dendritic cells (TIDCs) and tumor-associated macrophages (TAMs) which have been recognized as pivotal factors responsible for mediating immune responses. Overcoming the refractory properties of TIDCs and TAMs is critical for inducing a robust and sustained immune response against cancer cells. In this study, pH/ROS-responsive microRNA-155 (miR155) nanocomplexes (MiR@PCPmP NPs) were developed to reprogram TIDCs and TAMs for efficient TNBC immunotherapy. This nanoplatform was based on a pH/ROS cleavable copolymer of poly(ethylene glycol)-carboxydimethyl maleate-poly(ethyleneimine)-peroxalate ester-poly(ε-caprolactone) grafted with mannose moieties (PEG-CDM-PEI[Man]-ox-PCL) which self-assembled with miRNA to form nanocomplexes. In the tumor microenvironment, the nanocomplexes showed selective cellular uptake by TIDCs and TAMs through PEG detachment and mannose exposure, followed by efficient endosomal escape, cytosolic miR155 release, and the dual-reprogramming of TIDCs and TAMs. Our results showed that MiR@PCPmP NPs significantly improved antitumor immune responses with highly infiltrating CD8+ T cells while restraining immunosuppressive components in 4T1 tumor-bearing mice. Furthermore, the nanoparticles effectively suppressed both primary tumors and pulmonary metastatic nodules without obvious systemic toxicity. This research highlights the potential of dual-reprogramming of TIDCs and TAMs with the miR155 nanocomplexes as a promising strategy for TNBC immunotherapy, with potential for translation to other cancers with a similar microenvironment.

ROS-responsive Galactosylated-nanoparticles with Doxorubicin Entrapment for Triple Negative Breast Cancer Therapy.

Background: Triple negative breast cancer (TNBC) is one of the most aggressive tumors with high metastasis and mortality, which constitutes 15~20% of all breast cancers. Chemotherapy remains main therapeutic option in the treatment of patients with TNBC. Methods: We developed reactive oxygen species (ROS)-responsive galactosylated nanoparticles (DOX@NPs) as an efficiently targeted carrier for doxorubicin (DOX) delivery to inhibit the growth of TNBC in vitro and in vivo. DOX@NPs were composed of polyacrylate galactose and phenylboronic derivatives conjugation. The in vitro cytotoxicity, cellular uptake, cell apoptosis and cycle distribution of tumor cells treated with different formulations were investigated. Meanwhile in vivo biodistribution and antitumor effects were investigated in a 4T1 tumor-bearing mouse model. Results: DOX@NPs showed good ROS responsiveness and rapid DOX release in the presence of H2O2. Furthermore, our data suggested that DOX@NPs could effectively trigger tumor cells apoptosis and cycle arrest, efficiently accumulate into tumor sites, and suppress tumor growth without adverse side effects. Conclusion: Our results suggested DOX@NP with potent potential as a promising nanocarrier for TNBC therapy, which deserved further investigation for other cancer treatment.

Efficient tumor synergistic chemoimmunotherapy by self-augmented ROS-responsive immunomodulatory polymeric nanodrug.

Immunotherapy has emerged as a promising therapeutic strategy for cancer therapy. However, the therapeutic efficacy has been distracted due to poor immunogenicity and immunosuppressive tumor microenvironment. In this study, a self-augmented reactive oxygen species (ROS) responsive nanocarrier with immunogenic inducer paclitaxel (PTX) and indoleamine 2,3-dixoygenase 1 (IDO1) blocker 1-methyl-D, L-tryptophan (1-MT) co-entrapment was developed for tumor rejection. The carrier was composed of poly (ethylene glycol) (PEG) as hydrophilic segments, enzyme cleavable 1-MT ester and ROS-sensitive peroxalate conjugation as hydrophobic blocks. The copolymer could self-assemble into prodrug-based nanoparticles with PTX, realizing a positive feedback loop of ROS-accelerated PTX release and PTX induced ROS generation. Our nanoparticles presented efficient immunogenic cell death (ICD) which provoked antitumor immune responses with high effector T cells infiltration. Meanwhile immunosuppressive tumor microenvironment was simultaneously modulated with reduced regulatory T cells (Tregs) and M2-tumor associated macrophages (M2-TAMs) infiltration mediated by IDO inhibition. The combination of PTX and 1-MT achieved significant primary tumor regression and reduction of lung metastasis in 4T1 tumor bearing mice. Therefore, the above results demonstrated co-delivery of immunogenic inducer and IDO inhibitor using the ROS amplifying nanoplatform with potent potential for tumor chemoimmunotherapy.

Targeting necroptosis as an alternative strategy in tumor treatment: From drugs to nanoparticles.

Over last decades, most antitumor therapeutic strategies have focused on apoptosis, however, apoptosis resistance and immunological silence usually led to treatment failure. In this sense, triggering other programmed cell death such as necroptosis may achieve a better therapeutic efficacy and has gained widespread attentions in tumor therapy. Studies in this field have identified several types of necroptosis modulators and highlighted the therapeutic potential of necroptotic cell death in cancer. Nanoparticles further provide possibilities to improve therapeutic outcomes as an efficient drug delivery system, facilitating tumor targeting and controlled cargo release. Furthermore, some nanoparticles themselves can trigger/promote programmed necrosis through hyperthermia, ultrasound and autophagy blockage. These investigations have entered necroptosis for consideration as a promising strategy for tumor therapy, though numerous challenges remain and clinical applications are still distant. In this review, we would briefly introduce molecular mechanism and characteristics of necroptosis, and then summarize recent progress of programmed necrosis and their inducers in tumor therapy. Furthermore, the antitumor strategies that take advantages of nanoparticles to induce necroptosis are also discussed.

Polymeric indoximod based prodrug nanoparticles with doxorubicin entrapment for inducing immunogenic cell death and improving the immunotherapy of breast cancer.

Immunotherapy based on host immunity has emerged as a powerful therapeutic strategy for tumor treatment. However, utilizing the immune system against tumors often fails to result in a durable immune response due to insufficient immunogenicity and the immunosuppressive conditions in the tumor microenvironment. Herein, we developed prodrug-based nanoparticles (DOX/IND@NPs) for the codelivery of indoximod (IND), an indoleamine 2,3-dioxygenase (IDO) inhibitor that can block the IDO pathway and generate antitumor immunity, and doxorubicin, a DNA-damaging therapeutic agent that can induce tumor immunogenic cell death (ICD). The nanocarrier was designed for tumor chemoimmunotherapy, synergistically promoting immunogenicity and modulating the immunosuppressive tumor microenvironment (ITME). Our data showed that DOX induced tumor immunogenicity and increased the infiltration of CD8 + T cells into the tumor microenvironment; nevertheless, immunosuppressive immune cell components, such like regulatory T cells (Tregs), myeloid-derived suppressor cells (MDSCs), and tumor associated macrophages (TAMs), hindered the antitumor efficacy. The introduction of IND reduced the levels of these protumor immune cells within the tumor microenvironment and further enhanced CD8 + T cell infiltration and the CD8 +/Treg cell ratio. Moreover, significant reductions in vascular endothelial growth factor (VEGF), MMP9, and CD31 (a vascular marker) expression levels were observed after DOX-IND nanoparticle treatment. This resulted in obvious tumor regression in a murine breast cancer model compared to reference formulations, indicating that the codelivery of DOX and IND is a potent potential strategy for breast cancer chemoimmunotherapy.

Effect of Probiotic Supplementation on Cognitive Function and Metabolic Status in Mild Cognitive Impairment and Alzheimer's Disease: A Meta-Analysis.

Background: Alzheimer's disease (AD) is a progressive and multifactorial neurodegenerative disease accounting for 80% of dementia worldwide. Objective: To assess the influence of probiotics on cognitive function in patients with mild cognitive impairment (MCI) and AD. Methods: PubMed, Embase, and Cochrane Library databases were searched for relevant studies. Results: Six randomized controlled trials involving 462 patients with MCI and AD were included in this meta-analysis. The probiotic administration had favorable effects on homeostasis model assessment-insulin resistance [HOMA-IR; Weighted mean difference (WMD) = -0.34, 95% confidence intervals (95% CI): -0.44 to 0.24, P < 0.001, I 2 = 0%], very low-density lipoprotein levels (VLDL; WMD = -3.71, 95% CI: -6.11 to -1.32, P=0.002, I 2 = 57.7%), quantitative insulin sensitivity check index (QUICKI; WMD = 0.01, 95% CI: 0.00-0.01, P = 0.003, I 2 = 51%), and triglyceride levels (WMD = -15.65, 95% CI: -27.48 to -3.83, P = 0.009, I 2 = 63.4%) in patients with AD. However, after Hartung-Knapp adjustment, all effects were non-significant except for HOMA-IR (MD = -0.34, 95%CI = -0.58 to -0.11). The changes in the Mini-Mental State Examination, repeatable battery for the assessment of neuropsychological status, and other biomarkers of oxidative stress, inflammation, and lipid profiles (high-sensitivity C-reactive protein, malondialdehyde, and total cholesterol) were negligible. Conclusion: The findings suggested that the consumption of probiotics had favorable effects on the HOMA-IR in patients with AD. However, the probiotic treatment did not affect cognitive function, other biomarkers of oxidative stress, and other lipid profiles.

[Plasma level of chemerin in COPD patients and the relationship between chemerin and lipid metabolism].

OBJECTIVE: To explore the change of plasma level of chemerin in chronic obstructive pulmonary disease (COPD) patients and its relationship with lipid metabolism. 
 METHODS: A total of 150 COPD patients were randomly selected and set as the COPD group and 30 healthy persons were set as the control group. The COPD group was further divided into a thin group (BMI<18.5 kg/m2, n=116) and a normal weight group (BMI≥18.5 kg/m2, n=34) according to their body mass index (BMI). Enzyme-linked immunosorbent (ELISA) was used in detection of plasma chemerin, total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), and high-density lipoprotein (HDL). The hospitalization rate in a half year and the mortality was statistically analyzed. Pearson correlation analysis was applied to analyze the relationship between plasma level of chemerin and levels of blood lipids, and Spearman rank correlation method was used to analyze the relationship between the plasma levels of chemerin or lipids and the prognosis. 
 RESULTS: Compared with the control group, plasma levels of TC, TG and HDL in the COPD group in acute exacerbation and remission stage were reduced, while plasma levels of chemerin and LDL was elevated; compared with the thin group, plasma levels of TC, TG and HDL in the normal weight group were elevated, while plasma levels of chemerin and LDL were decreased. The hospitalization rate in half year and the mortality in the thin group were higher than that in the normal weight group, and the plasma levels of TC, TG and HDL in the COPD patients with hospitalization in half year or death were lower than that in COPD patients without hospitalization, while the plasma levels of chemerin and LDL was increased (P<0.05). Pearson correlation analysis showed that plasma level of chemerin in COPD patients was negatively correlated with plasma levels of TC, TG and HDL (r=-0.695, -0.748, -0.695, P<0.05), while positively correlated with plasma levels of LDL (r=0.668, P<0.05). Spearman rank correlation analysis showed that plasma levels of TC, TG and HDL in COPD patients and hospitalization rate in half year as well as the mortality were negatively correlated (TC: r=-0.716, -0.737; TG: r=-0.748, -0.753; HDL: r=-0.736, -0.728, P<0.05), while the plasma level of chemerin or LDL and hospitalization rate in half year and the mortality were positively correlated (chemerin: r=0.753, 0.766; LDL: r=0.742, 0.755, P<0.05).
 CONCLUSION: Plasma levels of chemerin in the COPD patients are correlated with lipid metabolism. Plasma levels of chemerin and lipid are related to prognosis of COPD. The plasma levels of chemerin in patients with COPD may reflect the lipid metabolism and could be served as the index for prognostic evaluation.

[Correlations between tumor infiltrating Th17 cells and clinicopathological parameters in patients with colorectal cancer].

OBJECTIVE: To observe the correlations between the percentage of tumor infiltrating Th17 cells and clinicopathological parameters in patients with colorectal cancer (CRC). METHODS: Tumor and normal mucosal tissues were collected from 28 CRC patients. The proportions of Th17 cells in lymphocytes were detected by flow cytometry. The supernatant levels of IL-17A in cultured normal and tumor tissues were measured by ELISA. The correlations between the proportions of tumor infiltrating Th17 cells as well as the tumor supernatant levels of IL-17A and clinicopathological parameters in CRC patients were further analyzed. RESULTS: There was no significant difference in the expression of Th17 cells between normal tissues (2.24 ± 0.24)% and tumor tissues (2.47 ± 0.34)% (P>0.05). Compared with normal tissues, the supernatant levels of IL-17A in tumor tissues were significantly up-regulated [(257.74±31.36) pg/mL vs (163.53±12.62)pg/mL, P<0.05]. The proportions of tumor infiltrating Th17 cells and the tumor supernatant levels of IL-17A had no associations with age, gender, tumor location, tumor size and growth characteristics (P>0.05), but they were correlated with tumor differentiation, lymph node metastasis and TNM stage (P<0.05). No associations between the proportions of infiltrating Th17 cells as well as the supernatant levels of IL-17A in the normal tissues and all clinicopathological parameters were found (P>0.05). CONCLUSION: Th17 cells may be involved in the immunopathogenesis of the development of CRC.