Nanomedicines Promote Cartilage Regeneration in Osteoarthritis by Synergistically Enhancing Chondrogenesis of Mesenchymal Stem Cells and Regulating Inflammatory Environment.

Osteoarthritis (OA) is a degenerative joint disease characterized by progressive erosion of the articular cartilage and inflammation. Mesenchymal stem cells' (MSCs) transplantation in OA treatment is emerging, but its clinical application is still limited by the low efficiency in oriented differentiation. In our study, to improve the therapeutic efficiencies of MSCs in OA treatment by carbonic anhydrase IX (CA9) siRNA (siCA9)-based inflammation regulation and Kartogenin (KGN)-based chondrogenic differentiation, the combination strategy of MSCs and the nanomedicine codelivering KGN and siCA9 (AHK-CaP/siCA9 NPs) was used. In vitro results demonstrated that these NPs could improve the inflammatory microenvironment through repolarization of M1 macrophages to the M2 phenotype by downregulating the expression levels of CA9 mRNA. Meanwhile, these NPs could also enhance the chondrogenesis of bone marrow-derived mesenchymal stem cells (BMSCs) by upregulating the pro-chondrogenic TGF-ß1, ACAN, and Col2α1 mRNA levels. Moreover, in an advanced OA mouse model, compared with BMSCs alone group, the lower synovitis score and OARSI score were found in the group of BMSCs plus AHK-CaP/siCA9 NPs, suggesting that this combination approach could effectively inhibit synovitis and promote cartilage regeneration in OA progression. Therefore, the synchronization of regulating the inflammatory microenvironment through macrophage reprogramming (CA9 gene silencing) and promoting MSCs oriented differentiation through a chondrogenic agent (KGN) may be a potential strategy to maximize the therapeutic efficiency of MSCs for OA treatment.

CAR-macrophage versus CAR-T for solid tumors: The race between a rising star and a superstar.

Adoptive cell therapy (ACT) has been demonstrated to be one of the most promising cancer immunotherapy strategies due to its active antitumor capabilities in vivo. Engineering T cells to overexpress chimeric antigen receptors (CARs), for example, has shown potent efficacy in the therapy of some hematologic malignancies. However, the efficacy of chimeric antigen receptor T cell (CAR-T) therapy against solid tumors is still limited due to the immunosuppressive tumor microenvironment (TME) of solid tumors, difficulty in infiltrating tumor sites, lack of tumor-specific antigens, antigen escape, and severe side effects. In contrast, macrophages expressing CARs (CAR-macrophages) have emerged as another promising candidate in immunotherapy, particularly for solid tumors. Now at its nascent stage (with only one clinical trial progressing), CAR-macrophage still shows inspiring potential advantages over CAR-T in treating solid tumors, including more abundant antitumor mechanisms and better infiltration into tumors. In this review, we discuss the relationships and differences between CAR-T and CAR-macrophage therapies in terms of their CAR structures, antitumor mechanisms, challenges faced in treating solid tumors, and insights gleaned from clinical trials and practice for solid tumors. We especially highlight the potential advantages of CAR-macrophage therapy over CAR-T for solid tumors. Understanding these relationships and differences provides new insight into possible optimization strategies of both these two therapies in solid tumor treatment.

Ferritin-based nanomedicine for disease treatment.

Ferritin is an endogenous protein which is self-assembled by 24 subunits into a highly uniform nanocage structure. Due to the drug-encapsulating ability in the hollow inner cavity and abundant modification sites on the outer surface, ferritin nanocage has been demonstrated great potential to become a multi-functional nanomedicine platform. Its good biocompatibility, low toxicity and immunogenicity, intrinsic tumor-targeting ability, high stability, low cost and massive production, together make ferritin nanocage stand out from other nanocarriers. In this review, we summarized ferritin-based nanomedicine in field of disease diagnosis, treatment and prevention. The different types of drugs to be loaded in ferritin, as well as drug-loading methods were classified. The strategies for site-specific and non-specific functional modification of ferritin were investigated, then the application of ferritin for disease imaging, drug delivery and vaccine development were discussed. Finally, the challenges restricting the clinical translation of ferritin-based nanomedicines were analyzed.

Anti-inflammatory therapeutic biomarkers identified of human bone marrow mesenchymal stem cell therapy on aging mice by serum proteomics and peptidomics study.

Aging is accompanied by deterioration in physical condition, and creates high risks of diseases. Stem cell therapy exhibited promising potential in delaying aging. However, the unelucidated therapeutic mechanism limits future clinical application. Herein, to systematically understand the response to stem cell transfusion at the molecular level, we performed quantitative serum proteomic and peptidomics analyses in the 24-month-old aging mice model with or without mesenchymal stem cell (MSC) treatment. As a result, a total of 560 proteins and 2131 endogenous peptides were identified, among which, 6 proteins and 9 endogenous peptides derived from 6 precursor proteins were finally identified as therapeutic biomarkers after MSC transfusion on aging mice both by untargeted label-free quantification and targeted parallel reaction monitoring (PRM) quantification. Amazingly, the biological function of these differential proteins was mainly related to inflammation, which is not only the important hallmark of aging, but also the main cause of inducing aging. The reduction of these inflammatory protein content after MSC treatment further suggests the anti-inflammatory effect of MSC therapy reported elsewhere. Therefore, our study provides new evidence for the anti-inflammatory effect of MSC therapy for anti-aging and offers abundant data to support deeper investigations of the therapeutic mechanism of MSC in delaying aging.

Nanomedicines Reprogram Synovial Macrophages by Scavenging Nitric Oxide and Silencing CA9 in Progressive Osteoarthritis.

Osteoarthritis (OA) is a progressive joint disease characterized by inflammation and cartilage destruction, and its progression is closely related to imbalances in the M1/M2 synovial macrophages. A two-pronged strategy for the regulation of intracellular/extracellular nitric oxide (NO) and hydrogen protons for reprogramming M1/M2 synovial macrophages is proposed. The combination of carbonic anhydrase IX (CA9) siRNA and NO scavenger in "two-in-one" nanocarriers (NAHA-CaP/siRNA nanoparticles) is developed for progressive OA therapy by scavenging NO and inhibiting CA9 expression in synovial macrophages. In vitro experiments demonstrate that these NPs can significantly scavenge intracellular NO similar to the levels as those in the normal group and downregulate the expression levels of CA9 mRNA (≈90%), thereby repolarizing the M1 macrophages into the M2 phenotype and increasing the expression levels of pro-chondrogenic TGF-ß1 mRNA (≈1.3-fold), and inhibiting chondrocyte apoptosis. Furthermore, in vivo experiments show that the NPs have great anti-inflammation, cartilage protection and repair effects, thereby effectively alleviating OA progression in both monoiodoacetic acid-induced early and late OA mouse models and a surgical destabilization of medial meniscus-induced OA rat model. Therefore, the siCA9 and NO scavenger "two-in-one" delivery system is a potential and efficient strategy for progressive OA treatment.

Resveratrol improves diabetes-induced cognitive dysfunction in part through the miR-146a-5p/TXNIP axis.

Resveratrol (RSV) has been shown to have a neuroprotective effect in various central nervous system disorders, although the role of RSV in diabetes-induced cognitive dysfunction is still not fully elucidated. Here, we investigated whether RSV improved diabetes-related cognitive dysfunction in vivo and in vitro. We induced a rat diabetic model with a high-fat and high-sucrose diet followed by intraperitoneal injection of streptozotocin and a diabetic neuron cell model by stimulation with high levels of glucose. We observed that RSV improved impairment in spatial learning and memory in the Morris water maze test (MWM) and novel object recognition test (ORT) in diabetic rats. RSV reversed the reduced miR-146a-5p and upregulated thioredoxin-interacting protein (TXNIP) and inhibited the diabetes-induced increase in interleukin (IL)-1ß and tumor necrosis factor (TNF)-α levels in vivo and in vitro. RSV also inhibited diabetes-induced endoplasmic reticulum stress (ESR) by reducing ESR-related protein expression in vivo and in vitro. Moreover, inhibition of miR-146a-5p partially abolished the protective effects of RSV in HG-treated primary neurons. Additionally, we used starBase to predict that miR-146a-5p interacts with TXNIP, which we then verified using a luciferase reporter gene assay. We further observed that miR-146a-5p regulates the mRNA and protein expression of TXNIP in vitro, indicating that the miR-146a-5p/TXNIP axis is involved in the regulation of cognitive dysfunction in a rat diabetic model. Collectively, these results demonstrate that RSV plays a neuroprotective role in diabetes-associated cognitive dysfunction at least in part through regulation of the miR-146a-5p/TXNIP axis.

ITGA5 Promotes Tumor Progression through the Activation of the FAK/AKT Signaling Pathway in Human Gastric Cancer.

Background: ITGA5 is an adhesion molecule that integrates the intracellular structures with the extracellular matrix to perform biological functions. However, ITGA5 is highly expressed in a variety of tumors and is involved in tumor progression by promoting cell proliferation and metastasis. Nevertheless, little research has been performed on its function in gastric cancer. Therefore, the aim of this study was to investigate the role of ITGA5 in gastric cancer, focusing on the mechanism regulating the proliferation, invasion and migration. Methods: The expression of ITGA5 in gastric cancer tissues was assessed by the use of molecular bioinformatics databases and high-throughput sequencing of gastric cancer tissues from patients. Western blot, qPCR, and immunohistochemistry were performed to detect the expression of ITGA5 in samples from gastric cancer patients and gastric cancer cell lines. Furthermore, the ITGA5 gene was silenced and overexpressed in gastric cancer cells, and the effect on proliferation, invasion, migration, and tumorigenic ability was assessed. Results: ITGA5 mRNA and protein expression were upregulated in gastric cancer cell lines and tissues from patients, and its expression was closely associated with tumor size, lymph node metastasis, and TNM stage. In vitro and in vivo experiments showed that ITGA5 silencing resulted in the inhibition of proliferation, invasion, migration, and graft growth of gastric cancer cells; conversely, the overexpression resulted in the promotion of these cell functions. Our results finally showed that the effect of ITGA5 on proliferation, invasion, and migration of gastric cancer cells was performed through the activation of the FAK/AKT pathway. Conclusions: ITGA5 promotes proliferation, invasion, and migration of gastric cancer cells through the activation of FAK/AKT signaling pathway, suggesting that ITGA5 may be potentially considered as a new target in gastric cancer therapy.

Non-Conventional Fluorescence and Cytotoxicity of Two Aliphatic Hyperbranched Polymer Dots Having Poly(amic acid) Structures: Implications for Labeling Nanodrug Carriers.

In this study, we used one-pot A2 + B3 polymerizations to synthesize two aliphatic + alicyclic polymer dots (PDs) having non-conjugated hyperbranched structures, employing two types of dianhydrides as the A2 components, possessing bridged bicyclic alkene (PD-BT) and non-alkene (PD-ET) units, and Jeffamine T403 polyetheramine (T403) as the B3 components. We prepared PD-ET from commercially available ethylenediaminetetraacetic dianhydride (EDTAD, A2) and T403 (B3) and PD-BT from bicyclo[2.2.2]oct-7-ene-2,3,5,6-tetracarboxylic dianhydride (BCDA, A2) and T403 (B3). These two types of PDs possessed non-conjugated hyperbranched poly(amic acid) structures with terminal amino functional groups. PD-BT and PD-ET exhibited non-conventional fluorescence with emissions at 435 and 438 nm, respectively, and quantum yields of 12.8 and 14.0%, respectively. The fluorescence intensity of PD-ET was influenced by the pH, but PD-BT was less affected because of its rigid aliphatic bridged bicyclic structure. In aqueous solutions, the sizes of the PD-BT and PD-ET nanoparticles were 3-5 nm, and their net charges can be adjusted by varying the pH. These PDs were non-cytotoxic toward human MCF-7 breast cancer cells and human keratinocyte HaCaT cells at concentrations of 50 µg mL-1 for PD-BT and 500 µg mL-1 for PD-ET. Confocal microscopic bioimaging revealed that the PDs were located within the cells after treatment for 6 h. These PDs were easy to prepare, highly water-soluble, and possessed a large number of peripheral functional groups for further modification. Combined with their non-conventional fluorescence, they appear to have potential uses in bioimaging and as drug-labeling carriers.

Enhanced cancer therapeutic efficiency of NO combined with siRNA by caspase-3 responsive polymers.

The combination of nitric oxide (NO) and siRNA is highly desirable for cancer therapy. Here, the furoxans-grafted PEI polymer (FDP) with caspase-3 responsive cleavable DEVD linker was synthesized, and used to bind siRNAs via electrostatic interaction and self-assembled into FDP/siRNA nanoplexes by hydrophobic force. After cellular uptake and lysosomal escape, the FDP/siRNA nanoplexes could achieve GSH-triggered NO release, and then increase the activity of caspase-3. The activated caspase-3 could specifically cleave the DEVD peptide sequence and enhance cell apoptosis. With the cleavage of DEVD peptide sequence, the disassembly of FDP/siRNA nanoplexes was further promoted, thereby resulting in increased siRNAs of ~40% were released at 48 h compared with the caspase-3 non-responsive FDnP/siRNA nanoplexes. By this way, cell apoptosis promotion and cell proliferation inhibition was achieved by siRNA-based downregulation of EGFR protein and the upregulated activity of caspase-3, followed by the enhanced cascade release of NO from FDP/siRNA nanoplexes. Furthermore, in vivo results demonstrated the improved anti-cancer efficiency of FDP/siEGFR nanoplexes without any detectable side effects. Therefore, it is believed that the caspase-3 responsive cleavable furoxans-grafted PEI polymers could provide a potential and efficient enhancement for cancer therapeutic efficiency by the co-delivery of nitric oxide and siRNA.

SIMPLE Is an Endosomal Regulator That Protects Against NAFLD by Targeting the Lysosomal Degradation of EGFR.

BACKGROUND AND AIMS: NAFLD has become a tremendous burden for public health; however, there is no drug for NAFLD therapy at present. Impaired endo-lysosome-mediated protein degradation is observed in a variety of metabolic disorders, such as atherosclerosis, type 2 diabetes mellitus, and NAFLD. Small integral membrane protein of lysosome/late endosome (SIMPLE) is a regulator of endosome-to-lysosome trafficking and cell signaling, but the role that SIMPLE plays in NAFLD progression remains unknown. Here we investigated SIMPLE function in NAFLD development and sophisticated mechanism therein. APPROACH AND RESULTS: This study found that in vitro knockdown of SIMPLE significantly aggravated lipid accumulation and inflammation in hepatocytes treated with metabolic stimulation. Consistently, in vivo experiments showed that liver-specific Simple-knockout (Simple-HKO) mice exhibited more severe high-fat diet (HFD)-induced, high-fat-high-cholesterol diet (HFHC)-induced, and methionine-choline-deficient diet (MCD)-induced steatosis, glucose intolerance, inflammation, and fibrosis than those fed with normal chow (NC) diet. Meanwhile, RNA-sequencing demonstrated the up-regulated signaling pathways and signature genes involved in lipid metabolism, inflammation, and fibrosis in Simple-HKO mice compared with control mice under metabolic stress. Mechanically, we found SIMPLE directly interact with epidermal growth factor receptor (EGFR). SIMPLE deficiency results in dysregulated degradation of EGFR, subsequently hyperactivated EGFR phosphorylation, thus exaggerating NAFLD development. Moreover, we demonstrated that using EGFR inhibitor or silencing EGFR expression could ameliorate lipid accumulation induced by the knockdown of SIMPLE. CONCLUSIONS: SIMPLE ameliorated NASH by prompting EGFR degradation and can be a potential therapeutic candidate for NASH.

Retrotransverse Foramen and Retrotransverse Groove Anatomic Variations of the Atlas Vertebra in the Chinese Population.

OBJECTIVE: To analyze the prevalence of retrotransverse foramen (RTF) or retrotransverse groove (RTG) anatomic variations in Chinese atlas vertebra (C1). METHODS: Three-dimensional volume-rendered computed tomography angiography images of 427 subjects (264 males, 163 females; 17-87 years old) were reviewed and evaluated using dedicated software. The prevalence of RTF and RTG anatomic variation of C1 was analyzed. RESULTS: RTF anatomic variants were present in 50 (11.7%) atlases. Bilateral RTF, unilateral left RTF, and unilateral right RTF were present in 16 (3.8%), 20 (4.9%), and 14 (3.3%) vertebrae. Comparison between males and females revealed differences in bilateral RTF (P = 0.010) and unilateral left RTF (P = 0.008). RTG anatomic variants were present in 113 (26.5%) atlases. Bilateral RTG, unilateral left RTG, and unilateral right RTG were present in 39 (9.1%), 30 (7.0%), and 44 (10.3%) vertebrae. Comparison between males and females revealed differences in RTG (P = 0.000), bilateral RTG (P = 0.006), and unilateral left RTG (P = 0.034). RTF was detected in 36 cases on the left and 30 cases on the right. RTG was detected in 69 cases on the left and 79 cases on the right. There were no side differences in the prevalence of RTF and RTG. CONCLUSIONS: The incidence of RTG is higher than the incidence of RTF. Incidence of bilateral RTF, bilateral RTG, unilateral left RTF, unilateral left RTG, and RTG differed between males and females. Preoperative understanding of these variations using three-dimensional computed tomography angiography is helpful for safe execution of upper cervical posterior approach surgery.

Study on the Hg0 removal characteristics and synergistic mechanism of iron-based modified biochar doped with multiple metals.

An iron-based composite adsorbent with biochar as the support was prepared by coprecipitation and the sol-gel method. Both single-iron-based modified biochar without doping with other metals and iron-based modified biochar doped with multiple metals (Ce, Cu, Co, Mn) were synthesised. The adsorption kinetics were analysed, and temperature-programmed desorption measurements were performed to reveal the inherent difference in mechanism between the oxidation and adsorption of Hg0 by the modified biochar and to elucidate the key mechanism of Hg0 removal. The results show that the removal of Hg0 by the modified biochar mainly includes adsorption and oxidation processes. The adsorption process is divided into two stages, external and internal mass transfer, both of which occur via multilayer adsorption. HgO and Hg-OM are the main forms of Hg0 present on the modified biochar surface. Doped metal oxides can play a synergistic role in enhancing the mercury removal performance of the modified biochar.

Tumor Necrosis Factor α-Induced Protein 8-Like 2 Alleviates Nonalcoholic Fatty Liver Disease Through Suppressing Transforming Growth Factor Beta-Activated Kinase 1 Activation.

BACKGROUND AND AIMS: NAFLD prevalence has increased rapidly and become a major global health problem. Tumor necrosis factor α-induced protein 8-like 2 (TIPE2) plays a protective role in a cluster of liver diseases, such as autoimmune hepatitis, hepatitis B, and hepatocellular carcinoma. However, the function of TIPE2 in NAFLD remains unknown. Here, we investigated the role of TIPE2 in the development of NAFLD. APPROACH AND RESULTS: Our study found that in vitro overexpression or knockout of TIPE2 significantly ameliorated or aggravated lipid accumulation and inflammation in hepatocytes exposed to metabolic stimulation, respectively. Consistently, in vivo hepatic steatosis, insulin resistance, inflammation, and fibrosis were alleviated in hepatic Tipe2-transgenic mice but exaggerated in hepatic Tipe2-knockout mice treated by metabolic challenges. RNA sequencing revealed that TIPE2 was significantly associated with the mitogen-activated protein kinase pathway. Mechanistic experiments demonstrated that TIPE2 bound with transforming growth factor beta-activated kinase 1 (TAK1), prevented tumor necrosis factor receptor-associated factor 6-mediated TAK1 ubiquitination and subsequently inhibited the TAK1 phosphorylation and activation of TAK1-c-Jun N-terminal kinase (JNK)/p38 signaling. Further investigation showed that blocking the activity of TAK1 reversed the worsening of hepatic metabolic disorders and inflammation in hepatic-specific Tipe2-knockout hepatocytes and mice treated with metabolic stimulation. CONCLUSIONS: TIPE2 suppresses NAFLD advancement by blocking TAK1-JNK/p38 pathway and is a promising target molecule for NAFLD therapy.

Biological activities of siRNA-loaded lanthanum phosphate nanoparticles on colorectal cancer.

Lanthanum can reduce absorption of phosphate by forming lanthanum phosphate complexes after oral administration of lanthanum carbonate tablets (FOSRENOL®) in patients. Based on the pH-responsive interaction of phosphate and lanthanum ions, the chitosan coated siRNA-loaded lanthanum phosphate nanoparticles (CS/LaP/siRNA NPs) were prepared for improving cancer treatment, in which polysaccharide chitosan was used as the outer shell to control the excessive growth of lanthanum phosphate complexes, and enable intestinal mucoadhesion. The CS/LaP/siEGFR NPs exhibited significant biological activities in human colorectal cancer HT-29 cells by the synergistic effects of siEGFRs and lanthanum ions, such as downregulation of EGFR and upregulation of miR-34a. Furthermore, significant tumor growth inhibition was observed in both transgenic C57BL/6-ApcMinC/Nju cancer mouse model and AOM/DSS chemically induced orthotopic colorectal cancer mouse model after intestinal instillation administration of CS/LaP/siEGFR NPs. Therefore, the lanthanum-based siRNA delivery system would provide a potential and efficient strategy for the treatment of colorectal cancers.

Polyarginine-Mediated siRNA Delivery: A Mechanistic Study of Intracellular Trafficking of PCL-R15/siRNA Nanoplexes.

As a cell-penetrating peptide, polyarginine is widely used in drug delivery systems based on its membrane permeation ability. Previously, we developed the mPEG-PLA-b-polyarginine(R15) triblock copolymer, which exhibited a high siRNA delivery efficiency both in vitro and in vivo. As a continued effort, here the amphiphilic diblock polymer PCL-R15 was synthesized as a simplified model to further elucidate the structure-activity relationship of arginine-based amphiphilic polymers as siRNA delivery systems, and the cellular trafficking mechanisms of the PCL-R15/siRNA nanoplexes were investigated to understand the interaction patterns between the nanoplexes and cells. Compared to the R15/siRNA complexes, the introduction of PCL moiety was found to result in the stronger interactions with cells and the enhanced transfection efficiency after the formation of condensed nanoplexes. Caveolae-mediated endocytosis and clathrin-mediated endocytosis were major routes for the internalization of PCL-R15/siRNA nanoplexes. The intracellular release of siRNA from nanoplexes was confirmed by fluorescence resonance energy transfer assay. It was also noticed that the internalized PCL-R15/siRNA nanoplexes were transported through digestive routes and trapped in lysosomes, which may be the bottleneck for efficient siRNA delivery of PCL-R15/siRNA nanoplexes. This study investigated the relationship between the polymer structure of PCL-R15 and the cellular interaction patterns, which may render implications on the rational design of polyarginine-based siRNA delivery systems.

Microfluidic-Based Holonomic Constraints of siRNA in the Kernel of Lipid/Polymer Hybrid Nanoassemblies for Improving Stable and Safe In Vivo Delivery.

A safe and efficient delivery system is critical for clinical application of siRNA. However, the conventional electrostatic interaction-based siRNA nanoplexes with bulk mixing preparation were always unsatisfactory for its stability and safety. In this study, the new core-shell lipid/PCL-PEI/siRNA nanoparticles (LPS NPs) endowing holonomic constraint of siRNA in the inner core were prepared by microfluidic technology. On the microfluidic chip, siRNAs were completely compressed into the inner hydrophilic core of reverse PCL-PEI micelles at a low N/P ratio of 5, followed by coating a neutral lipid membrane to form core-shell nanoparticles, which had a uniform size (120.2 ± 1.4 nm) and a negative charge (-8.8 ± 1.6 mV). Compared to bulk mixing-based LMS NPs, the lower usage of cationic PCL-PEI materials and stronger protection of siRNA in serum were found in the microfluidic-based LPS NPs. Furthermore, it was demonstrated that the LPS NPs exhibited significant downregulation of EGFR mRNA and protein expression level both in vitro and in vivo, and showed significant inhibition of tumor growth following systemic administration along with no obvious systemic toxicity. These findings demonstrated that the microfluidic-based lipid/polymer hybrid nanoassemblies would offer a promising siRNA delivery system for clinical application.

Encapsulated microRNA by gemcitabine prodrug for cancer treatment.

Although microRNAs (miRNAs) function as the important tumor gene regulators, they still confront with many challenges in systemic delivery. Here, the amphiphilic gemcitabine-oleic acid prodrugs (GOA) binding miRNAs with hydrogen bond are assembled into nanoparticles (GOA/miR NPs) through hydrophobic interaction via denaturation-annealing processes and nano-precipitation technique. The non-cationic GOA/miR NPs with an average size of ~150 nm and a zeta potential of ~ - 15 mV exhibit a stable encapsulation of miRNAs with non-sequence selectivity. Either miR-122 or miR-34a encapsulated in the GOA/miR NPs is efficiently delivered into HepG2 cells and significantly downregulate the expression levels of target gene after lysosome escape and pH-responsive disassembly. Moreover, in vivo experiments demonstrate that the GOA/miR-122 NPs exhibit higher tumor accumulation. Compared to GOA micelles, GOA/miR-122 NPs displayed stronger tumor inhibition (73% regression) after intravenous injection in nude mice xenografted with HCC, along with rapid clearance in normal liver tissues. Furthermore, there is no significant influence on biochemical indicators and immune factors during the systematic administration of GOA/miR-122 NPs. The non-cationic GOA/miR NPs engineered by hydrogen bond interaction and hydrophobic forces show the enhanced synergistic antitumor efficacy and good biosafety, which will provide a potential nanomedcine for HCC treatment.

Efficacy of melanoma patients treated with PD-1 inhibitors: Protocol for an overview, and a network meta-analysis of randomized controlled trials.

BACKGROUND: Melanoma is a malignant tumor of melanocytes that produces pigments and can occur in the whole body. It is characterized by strong invasiveness, high metastasis rate and poor prognosis, and brings heavy burden to patients and society. In order to find the most effective and safe treatment measures, in this study, a network meta-analysis (NMA) for randomized controlled trials (RCTs) of advanced melanoma treated with PD-1 inhibitors will be conducted based on the existing systematic reviews (SRs) of PD-1 inhibitor in the treatment of advanced melanoma. METHODS: PubMed, EMBASE, Web of Science and the Cochrane Library were searched on December 18, 2018 to obtain systematic reviews of PD-1 inhibitor in the treatment of advanced melanoma. Assessing the Methodological Quality of Systematic Reviews (AMSTAR2) will be used to assess the methodological quality of systematic reviews, Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach will be applied to evaluate the evidence quality of outcome measures, and the Cochrane's risk of bias tool will be utilized to appraise risks of bias of each embedded RCTs. And the outcomes are overall survival (OS), progression-free survival (PFS) and objective response rate (ORR). Hazard ratio (HR) or odds ratio (OR) with their 95% confidence interval (CI) were used to synthesize dichotomous outcomes, while the mean difference (MD) for the continuous variables. R3.5.1 will be used to create a network evidence map for direct and indirect comparative analysis. RESULTS: This study will provide a comprehensive summary of the current evidences related to the efficacy and safety of PD-1 inhibitor in advanced melanoma. CONCLUSION: Our findings will be useful to assist clinicians make reasonable decisions to the treatment of advanced melanoma. ETHICS AND COMMUNICATION: It is unnecessary for this NMA to acquire an ethical approval, because it is based on published researches. PROSPERO REGISTRATION NUMBER: CRD42019120017.

Regulating intracellular fate of siRNA by endoplasmic reticulum membrane-decorated hybrid nanoplexes.

Most cationic vectors are difficult to avoid the fate of small interfering RNA (siRNA) degradation following the endosome-lysosome pathway during siRNA transfection. In this study, the endoplasmic reticulum (ER) membrane isolated from cancer cells was used to fabricate an integrative hybrid nanoplexes (EhCv/siRNA NPs) for improving siRNA transfection. Compared to the undecorated Cv/siEGFR NPs, the ER membrane-decorated EhCv/siRNA NPs exhibits a significantly higher gene silencing effect of siRNA in vitro and a better antitumor activity in nude mice bearing MCF-7 human breast tumor in vivo. Further mechanistic studies demonstrate that functional proteins on the ER membrane plays important roles on improving cellular uptake and altering intracellular trafficking pathway of siRNA. It is worth to believe that the ER membrane decoration on nanoplexes can effectively transport siRNA through the endosome-Golgi-ER pathway to evade lysosomal degradation and enhance the silencing effects of siRNA.

Enhanced anti-tumor efficiency of gemcitabine prodrug by FAPα-mediated activation.

Gemcitabine (Gem) as an anti-cancer agent has been limited by its short circulation time and rapid metabolism that reflects in low tumor uptake and low therapeutic efficiency. To improve its anti-tumor activity, a novel FAPα enzyme-activated prodrug of Z-GP-Gem modified at 4-amino group of Gem was developed, which could effectively release parent Gem based on the specific cleavage via FAPα enzyme-activation in tumor microenvironment. Compared to Gem, the Z-GP-Gem prodrug exhibited significantly enhanced inhibition of both tumor growth and pulmonary metastasis in BALB/c mice bearing orthotopic breast 4T1 tumors. The Z-GP-Gem prodrug has a prolonged circulation time and a high tumor uptake based on the modification of Z-GP dipeptide at 4-amino group of Gem. These eventually caused a marked improvement in the systemic toxicity and the tumor growth inhibition in 4T1 cells. More interestingly, the unexpected depletion of tumor-associated fibroblast (TAF) was observed during the treatment of Z-GP-Gem prodrug in animal model. Therefore, these findings demonstrated that the FAPα-activated prodrug Z-GP-Gem would be a desirable approach for tumor therapy by intravenous administration.