Cancer cell membrane-coated nanoparticles: a promising anti-tumor bionic platform.

Nanoparticle (NP) drug delivery systems have shown promise in tumor therapy. However, limitations such as susceptibility to immune clearance and poor targeting in a complex intercellular environment still exist. Recently, cancer cell membrane-encapsulated nanoparticles (CCM-NPs) constructed using biomimetic nanotechnology have been developed to overcome these problems. Proteins on the membrane surface of cancer cells can provide a wide range of activities for CCM-NPs, including immune escape and homologous cell recognition properties. Meanwhile, the surface of the cancer cell membrane exhibits obvious antigen enrichment, so that CCM-NPs can transmit tumor-specific antigen, activate a downstream immune response, and produce an effective anti-tumor effect. In this review, we first provided an overview of the functions of cancer cell membranes and summarized the preparation techniques and characterization methods of CCM-NPs. Then, we focused on the application of CCM-NPs in tumor therapy. In addition, we summarized the functional modifications of cancer cell membranes and compiled the patent applications related to CCM-NPs in recent years. Finally, we proposed the future challenges and directions of this technology in order to provide guidance for researchers in this field.

Peapod-Like Structured B/N Co-Doped Carbon Nanotube Array Encapsulating MxPy (M = Fe, Co, and Ni) Nanoparticles for High-Rate Potassium Storage.

Potassium-ion batteries (PIBs) have become the desirable alternatives for lithium-ion batteries (LIBs) originating from abundant reserves and appropriate redox potential, while the considerable radius size of K+ leading to poor reaction kinetics and huge volume expansion limits the practical application of PIBs. Hybridization of transition-metal phosphides and carbon substrates can effectively optimize the obstacles of poor conductivity, sluggish kinetics, and huge volume variation. Thus, the peapod-like structural MxPy@BNCNTs (M = Fe, Co, and Ni) composites as anode materials for PIBs were synthesized through a facile strategy. Notably, the unique architecture of B/N codoped carbon nanotube array as fast ion/electron transfer pathways effectively improves the electronic conductivity of composites. The MxPy nanoparticles (NPs) are encapsulated in BNCNTs with an amorphous carbon layer (5-10 nm), which discernibly alleviate the volume changes during potassiation/depotassiation. In conclusion, the composites show a commendable cycling performance, possessing reversible capacities of 111, 152, and 122 mA h g-1 after 1000 cycles at 1.0 A g-1 with a negligible capacity loss for FeP@BNCNT, CoP/Co2P@BNCNT, and Ni2P@BNCNT electrodes, respectively. Especially, after 1000 cycles at 2.0 A g-1, the CoP/Co2P@BNCNT electrode still possesses a capacity of 87.9 mA h g-1, demonstrating excellent rate performance and long-term life. This work may offer an innovative and viable route to construct a stable architecture for solving the issue of poor stability of TMP-based anodes at a high current density.

Combination of ferroptosis and pyroptosis dual induction by triptolide nano-MOFs for immunotherapy of Melanoma.

Immunotherapy has good potential to eradicate tumors in the long term. However, due to the low immunogenicity of tumor cells, current cancer immunotherapies are not effective. To address this limitation, we constructed a BSA-FA functionalized iron-containing metal-organic framework (TPL@TFBF) that triggers a potent systemic anti-tumor immune response by inducing ferroptosis and pyroptosis in tumor cells and releasing large quantities of damage-associated molecular patterns (DAMPs) to induce immunogenicity, and showing excellent efficacy against melanoma lung metastases in vivo. This nanoplatform forms a metal-organic framework through the coordination between tannic acid (TA) and Fe3+ and is then loaded with triptolide (TPL), which is coated with FA-modified BSA. The nanoparticles target melanoma cells by FA modification, releasing TPL, Fe3+ and TA. Fe3+ is reduced to Fe2+ by TA, triggering the Fenton reaction and resulting in ROS production. Moreover, TPL increases the production of intracellular ROS by inhibiting the expression of nuclear factor erythroid-2 related factor (Nrf2). Such simultaneous amplification of intracellular ROS induces the cells to undergo ferroptosis and pyroptosis, releasing large amounts of DAMPs, which stimulate antigen presentation of dendritic cells (DCs) and the proliferation of cytotoxic T lymphocytes (CD4+/CD8 + T cells) to inhibit tumor and lung metastasis. In addition, combining nanoparticle treatment with immune checkpoint blockade (ICB) further inhibits melanoma growth. This work provides a new strategy for tumor immunotherapy based on various combinations of cell death mechanisms.

Non-cytotoxic nanoparticles re-educating macrophages achieving both innate and adaptive immune responses for tumor therapy.

Macrophages are important antigen-presenting cells to combat tumor via both innate and adaptive immunity, while they are programmed to M2 phenotype in established tumors and instead promote cancer development and metastasis. Here, we develop a nanomedicine that can re-educate M2 polarized macrophages to restore their anti-tumor activities. The nanomedicine has a core-shell structure to co-load IPI549, a PI3Kγ inhibitor, and CpG, a Toll-like receptor 9 agonist. Specifically, the hydrophobic IPI549 is self-assembled into a pure drug nano-core, while MOF shell layer is coated for CpG encapsulation, achieving extra-high total drugs loading of 44%. Such nanosystem could facilitate intracellular delivery of the payloads but without any cytotoxicity, displaying excellent biocompatibility. After entering macrophages, the released IPI549 and CpG exert a synergistic effect to switch macrophages from M2 to M1 phenotype, which enables anti-tumor activities via directly engulfing tumor cells or excreting tumor killing cytokines. Moreover, tumor antigens released from the dying tumor cells could be effectively presented by the re-educated macrophages owing to the up-regulation of various antigen presenting mediators, resulting in infiltration and activation of cytotoxic T lymphocytes. As a result, the nanosystem triggers a robust anti-tumor immune response in combination with PD-L1 antibody to inhibit tumor growth and metastasis. This work provides a non-cytotoxic nanomedicine to modulate tumor immune microenvironment by reprograming macrophages.

Balance Cell Apoptosis and Pyroptosis of Caspase-3-Activating Chemotherapy for Better Antitumor Therapy.

Chemotherapy is a standard treatment modality in clinic that exerts an antitumor effect via the activation of the caspase-3 pathway, inducing cell death. While a number of chemotherapeutic drugs have been developed to combat various types of tumors, severe side effects have been their common limitation, due to the nonspecific drug biodistribution, bringing significant pain to cancer patients. Recently, scientists found that, besides apoptosis, chemotherapy could also cause cell pyroptosis, both of which have great influence on the therapeutic index. For example, cell apoptosis is, generally, regarded as the main mechanism of killing tumor cells, while cell pyroptosis in tumors promotes treatment efficacy, but in normal tissue results in toxicity. Therefore, significant research efforts have been paid to exploring the rational modulation mode of cell death induced by chemotherapy. This critical review aims to summarize recent progress in the field, focusing on how to balance cell apoptosis and pyroptosis for better tumor chemotherapy. We first reviewed the mechanisms of chemotherapy-induced cell apoptosis and pyroptosis, in which the activated caspase-3 is the key signaling molecule for regulating both types of cell deaths. Then, we systematically discussed the rationale and methods of switching apoptosis to pyroptosis for enhanced antitumor efficacy, as well as the blockage of pyroptosis to decrease side effects. To balance cell pyroptosis in tumor and normal tissues, the level of GSDME expression and tumor-targeting drug delivery are two important factors. Finally, we proposed potential future research directions, which may provide guidance for researchers in the field.

Imatinib co-loaded targeted realgar nanocrystal for synergistic therapy of chronic myeloid leukemia.

Discovery of BCR-ABL1 tyrosine kinase inhibitors (TKIs) has revolutionized the therapy of chronic myeloid leukemia (CML), a malignant myeloproliferative disease characterized by abnormal activation of BCR-ABL fusion oncoprotein with protein tyrosine kinase (PTK) activity. However, the long-term treatment outcomes with TKIs are strongly limited by multiple drug resistances, resulting in relapse albeit with initial high response rate. Here, we reported a realgar (As4S4) nanocrystal-based delivery system to reverse drug resistance for synergistic CML therapy. While As4S4 is extremely insoluble in water, bovine serum albumin (BSA) was rationally screened to effectively stabilize As4S4 nanocrystal with uniformed size of ~40 nm. Imatinib (IMA), a representative TKIs, can be readily loaded into the hydrophobic domain of BSA to develop As4S4/IMA co-delivery system. Mechanistically, IMA inhibits PTK activity, while As4S4 degrades BCR-ABL1, which co-contribute to tumor suppression via complementary pathways for synergistic effect. Moreover, the nanosystem was modified with folic acid (FA) to enable tumor targetability, which has been demonstrated both in vitro and in vivo, resulting in robust tumor growth inhibition and significantly prolonged mice survival without any noticeable adverse effects. This work designed a synergistic nanoplatform for targeted CML therapy, provided a strategy to address the key limitation of As4S4 for biomedical applications, and highlighted the advantages of the combination between traditional Chinese and western medicine for diseases treatment.

Epidemiology and issues of NIV-treated AECOPD patients with hypercapnic respiratory failure in Shanghai: A multicentre retrospective survey.

OBJECTIVE: To investigate the epidemiology, clinical features, treatment and outcome of Noninvasive ventilation (NIV)-treated acute exacerbation of chronic obstructive pulmonary disease (AECOPD) patients in secondary hospitals of Shanghai. METHOD: Relying on Shanghai alliances for respiratory diseases, a retrospective observational study was performed in 34 secondary hospitals of Shanghai. The AECOPD patients treated with NIV and admitted to the respiratory department or respiratory intensive care unit were recruited between December 1, 2016, and November 30, 2017. RESULTS: There were 555 patients finally recruited in this study. The age was 75.8 ± 9.6 years old and 380 patients (68.5%) were male. 70.5% of all patients had respiratory acidosis (pH <7.35). 55.3% of all patients received nebulised bronchodilator and 77.7% were treated with systemic or inhaled corticosteroids during hospitalisation. 525 patients (94.6%) recovered successfully and the mortality was 3.2%. The hospitalisation was 15.3 ± 6.7 days and hospital expenses were 22 911 ± 13 595 RMB. Inadequate and nonstandard drug treatments were the most important problems during management. CONCLUSION: The NIV can be successfully used for AECOP patients in local hospitals of Shanghai, but accompanied by high costs and long hospital stays. However, the treatments for exacerbation and stable COPD patients are still insufficient.

[Analysis of Genomic Landscape in Patients with Acute Myeloid Leukemia].

OBJECTIVE: To investigate the gene mutation occurved in AML patients with 29 kinds of fusion genes and 51 kinds of tumor gene. METHODS: Next-generation sequencing (NGS) was used to detected the 49 kinds of targeted gene. FLT3 internal tandem duplication (FLT3-ITD), CALR, NPM1 and CEBPA mutation were detected by DNA-based PCR and Sanger sequencing. Twenty-nine kinds of fusion genes were dected by multiplex nested RT-PCR. RESULTS: The total gene mutation rate was 91% (109/121) in all the 121 patients. On average, 2.1 mutated genes per patient were identified, among these 121 patients, coexistence of ≥ 3 mutations was frequent (34.7%). The most commonly mutated genes were NRAS (23.96%, n=29), followed by NPM1 (14.04%, n=17), CEBPA double mutations (14.04%, n=17), KRAS (11.57%, n=14)，FLT3-ITD (10.74%, n=13), CSF3R (10.74%, n=13), TET2 (9.92%, n=12) and IDH1 (9.1%, n=11). Overall, fusion genes were detected in 47 (37.3%) patients, including AML/ETO (n=12), CBFß/MYH11 (n=11), PML/RARa (n=12), MLL rearranagement realated mutation MLL-X (n=10). TLS/ERG (n=1) and DEK/CAN (n=1) in an order of decreasing frequency. Patients with normal karyotype (NK)- AML exhibited more mutations in CEBPA, NPM1, TET2, RUNX1 and IDH1, comparing with abnormal karyotype patients. KRAS mutation in abnormal kayotype patients was significantly higher than that in normal kayotype patients (P=0.014). TP53 mutations were predominantly associated with complex cytogenetics (P=0.199). KRAS mutations were more frequent in core binding factor (CBF) acute myeloid leukemia (AML) and 11q23/MLL rearrangement leukemia, compared with NK-AML (P=0.006 and 0.003, respectively). KIT mutations predominated in CBF-AML (P=0.006). JAK2V617F mutations were detected in two patients and co-occurred with AML-ETO fusions. CONCLUSION: At least one mutation is observed in more than 90% patients. On average, more than 2 mutated genes per patient are identified. Some gene mutations are associated with gene rearrangement.

DNA adsorption on nanoscale zeolitic imidazolate framework-8 enabling rational design of a DNA-based nanoprobe for gene detection and regulation in living cells.

DNA functionalized nanomaterials have attracted tremendous attention for bioanalytical applications. Owing to exceptional fluorescence quenching ability, most DNA-based nanoprobes were designed with turn-on signals for target gene detection, while only a few of them could simultaneously achieve gene detection and regulation in one system. In this study, we explored the use of nanoscale zeolitic imidazolate framework-8 (ZIF-8) as a building block to construct a DNA-based nanoprobe. We found ZIF-8 could stably adsorb DNA to resist the dissociation by various biological ligands, enabling potential biological applications. However, ZIF-8 was not a nano-quencher to turn off the fluorophore labeling on the adsorbed DNA. We therefore designed a DNAzyme embedded molecular beacon (DMB) to functionalize ZIF-8. After endocytosis, ZIF-8 was disintegrated to release DMB for target mRNA detection, and the co-released Zn2+ acted as an effective cofactor to activate the embedded DNAzyme for mRNA regulation. This study provides a versatile nano-platform to realize multiple functions inside cells by using functional nucleic acids, which holds great promise for theranostic applications.

Phytantriol-based lyotropic liquid crystal as a transdermal delivery system.

The purpose of this study was examined the feasibility of using phytantriol-based cubic and hexagonal liquid crystal preparation for the percutaneous administration of trans­cinnamaldehyde (TCA). TCA-loaded lyotropic liquid crystal formulations were prepared and characterized, their skin permeability in vitro and in vivo was evaluated. Preliminary pharmacodynamics were also investigated in adjuvant arthritics (AA) rats. The formulations were identified respectively as cubic and hexagonal structure. The in vitro permeability study exhibited that both cubic and hexagonal liquid crystal improved the cumulative permeation quantity and permeation rates of TCA compared with home-made gel. The results of an in vivo transdermal permeability experiment showed that the area under the curve [AUC(0-∞)] of the hexagonal and cubic liquid crystal was 1.62 and 1.53 times higher than that of the gel group, respectively. Preliminary pharmacodynamics studies indicated that the group of high-dose TCA-loaded (200 mg·kg-1) hexagonal liquid crystal was shown to inhibit the paw swelling of AA rats, improve synovial hyperplasia and inflammatory cell infiltration, and down-regulate the levels of serum interleukin (IL)­1ß and tumor necrosis factor (TNF)­α. Furthermore, there was no significant difference in the anti-inflammatory effects of TCA-loaded hexagonal liquid crystal and the commercially available product Voltaren® emulgel®. Thus, hexagonal liquid crystal was considered as an effective delivery system for TCA.

Development and Evaluation of Minocycline Hydrochloride-Loaded In Situ Cubic Liquid Crystal for Intra-Periodontal Pocket Administration.

In the present study, an injectable in situ liquid crystal formulation was developed for local delivery of minocycline hydrochloride (MH) for chronic periodontitis treatment. The physicochemical properties, phase structures, in vitro drug release and pharmacodynamics of in situ liquid crystals were investigated. The optimal formulation (phytantriol (PT)/propylene glycol (PG)/water, 63/27/10, w/w/w) loaded with 20 mg/g MH was proved to be injectable. The precursor formulation can form a cubic phase gel in excess water in 6.97 ± 0.10 s. The results of in vitro drug release suggested the MH presented a sustained release for 4 days. Liquid crystal precursor formulation significantly reduced gingival index, probing depth and alveolar bone loss compared to the model group (p < 0.01). Besides, the pathological characteristics of model rats were improved. The results suggested that MH-loaded in situ cubic liquid crystal possessed of sustained release ability and periodontal clinical symptoms improvement. The developed in situ cubic liquid crystal may be a potentially carrier in the local delivery of MH for periodontal diseases.

High Prevalence of Erectile Dysfunction in Diabetic Men With Depressive Symptoms: A Meta-Analysis.

BACKGROUND: Erectile dysfunction (ED) may be common among diabetic men with depressive symptoms (DS), but its prevalence is still debated. AIM: To conduct a meta-analysis of the prevalence of ED in diabetic men with DS compared to those without DS, calculating the relative odds ratios (ORs) and 95% CIs. METHODS: PubMed, MEDLINE, Embase, and Web of Science were searched up to January 2018. All the studies assessing the risk of ED among diabetic men having DS were reviewed. 2 Authors independently assessed literature and extracted information eligibility. Any disagreement was resolved by a third reviewer. Newcastle-Ottawa quality assessment scale was used to evaluate study quality in meta-analyses. We calculated the ORs with 95% CIs using software Stata, Version 12.0; StataCorp, College Station, TX). Data were pooled using a fixed or random effects model according to heterogeneity. Sensitivity analyses were conducted to assess potential bias. This study was conducted according to the guidelines for Meta-Analyses and Systematic Reviews of Observational Studies. OUTCOMES: The strength of the association between DS and the prevalence of ED was evaluated using ORs and 95% CIs. RESULTS: 5 Studies were eligible for the present analysis, reporting on a total of 2525 diabetic men. Mean age of patients ranged from 42.37-61.65 years in the included studies. The overall prevalence of ED in diabetic men with DS was 74.2% (95% CI 59.0-89.4). The overall prevalence of ED in diabetic men without DS was 37.4% (95% CI 16.2-58.6). The pooled crude OR for these 5 studies was 6.40 (95% CI 2.11-19.38, P < .05, I2 = 94.6%). The pooled OR of 4 multi-variate analyses was 3.08 (95% CI 1.32-4.85, P < .001, I2 = 83.5%). CLINICAL IMPLICATIONS: Diabetic men with DS had a significantly increased prevalence of ED, suggesting that ED should be of concern to clinicians when managing diabetic men with DS. STRENGTHS & LIMITATIONS: A strength of this study is that it is the first meta-analysis to assess the prevalence of ED in diabetic men with DS and quantitatively analyze the association between DS and ED risk among diabetic men. A limitation is that all included studies were cross-sectional studies, which may generate bias. CONCLUSION: The present meta-analysis of 5 cross-sectional studies suggests that diabetic men showing DS, compared to the diabetic men without DS, have more risk of ED. Further larger prospective cohorts with more power or meta-analysis based on individual patient data need to be conducted to confirm this association. Wang X, Yang X, Cai Y, et al. High Prevalence of Erectile Dysfunction in Diabetic Men With Depressive Symptoms: A Meta-Analysis. J Sex Med 2018;15:935-941.

Targeted blockade of TGF-ß and IL-6/JAK2/STAT3 pathways inhibits lung cancer growth promoted by bone marrow-derived myofibroblasts.

To investigate the role of TGF-ß and IL-6 in myofibroblasts (MFs) - lung cancer cell interactions, lung cancer cells (Lewis and CTM-167 cell lines) were stimulated by IL-6, MF-conditioned medium (MF-CM) or MFs, with or without TGF-ß signaling inhibitor - SB431542 and/or JAK2/STAT3 inhibitor - JSI-124. MFs were stimulated by TGF-ß, cancer cell-CM or cancer cells, with or without SB431542 and JSI-124. Cell proliferation, the levels of cytokines, expression of mRNA and protein were determined. Mice bearing xenograft tumors were intraperitoneally treated with SB431542 or JSI-124 and monitored for up to 45 days. In co-culture systems, MFs secreted high levels of IL-6, while cancer cells produced high levels of TGF-ß. Recombinant IL-6 and MF-CM activated STAT3 and upregulated TGF-ß in cancer cells. In contrast, cancer cell-CM or TGF-ß stimulated MFs to produce IL-6. Blockade of JAK2/STAT3 and TGF-ß signaling by specific inhibitors significantly inhibited cell proliferation in vitro and tumor growth in vivo of lung cancer cells. Our study demontrated that the TGF-ß and IL-6/JAK2/STAT3 signaling pathways form a positive feedback signaling loop that mediated the interactions between MFs and lung cancer cells. Targeted inhibiton of this signaling loop could be a new approach for lung cancer prevention and therapy.

HII mesophase as a drug delivery system for topical application of methyl salicylate.

The main objective of this study was to develop reversed hexagonal (HII) mesophase for transdermal delivery of methyl salicylate. The formulation was prepared, characterized and evaluated for its skin penetration in vitro and skin retention in vivo. Preliminary pharmacodynamics and skin irritation were also investigated. The formulation was identified as hexagonal structure. In vitro study exhibited that HII mesophase enhanced the skin permeation by delivering 2.61 times more methyl salicylate than the commercially available cream. Meanwhile, HII mesophase presented higher bioavailability as AUC(0-24) and AUC(0-∞) were 32.894µg·mL-1 and 32.935µg·mL-1 respectively, while the cream were 12.791µg·mL-1 and 12.970µg·mL-1. Preliminary pharmacodynamics studies demonstrated that HII mesophase possessed anti-inflammatory and analgesic effects for inhibiting paw edema, granuloma and pain. MeSa HII mesophase showed no skin irritation on the normal rat skin. Thus, HII mesophase was considered as an effective delivery system for MeSa.

An injectable in situ hexagonal mesophase system for local delivery of minocycline hydrochloride: Preparation and pharmacodynamics in rats.

In this study, an optimized in situ reversed hexagonal mesophase loaded with minocycline hydrochloride (MH) was developed for the chronic periodontitis treatment. The in situ hexagonal liquid crystals (ISH2) comprised phytantriol (PT), propylene glycol (PG), water and vitamin E acetate (VitEA). The physicochemical properties, in vitro drug release and the therapeutic effects on chronic periodontitis of the formed samples were tested. The injectable liquid crystal-forming systems were characterized by crossed-polarized light microscopy, small angle X-ray scattering, and rheological measurements. The optimal ISH2 (PT/PG/water/VitEA, 56:27:10:7, w/w/w/w) loaded with 20 mg·g-1 MH was proved to be injectable with suitable pH, and was able to sustain the drug release for 10 days. The pharmacodynamic studies of the optimal formula were performed on male SPF rats, the Periocline® ointment was used as a control. The investigated ISH2 loaded with MH was demonstrated to be effective for periodontal treatment with significantly improved gingival index, pocket depth and alveolar bone loss. The developed ISH2 may be a promising application for local delivery system of MH in treating periodontal diseases.

[Preparation and evaluation of intra-articular injectable sinomenine hydrochloride-loaded in situ liquid crystals].

Phytantriol (PT), ethanol (ET) and water were used to prepare in situ cubic liquid crystal (ISV2). The pseudo-ternary phase diagram of PT-ET-water was constructed and isotropic solution formulations were chosen for further optimization. The physicochemical properties of isotropic solution formulations were evaluated to optimize the composition of ISV2. In situ hexagonal liquid crystals (ISH2) were prepared based on the composition of ISV2 with the addition of vitamin E acetate (VitEA) and the amount of VitEA was optimized by in vitro release behavior. The phase structures of liquid crystalline gels formed by ISV2 and ISH2 in excess water were confirmed by crossed polarized light microscopy and small angle X-ray scattering, respectively. Rheological properties of ISV2 and ISH2 were studied by a DHR-2 rheometer. In vitro drug release studies were conducted by using a dialysis membrane diffusion method. Pharmacokinetics was investigated by determination of sinomenine hydrochloride (SMH) concentration in synovial membrane after intra-articular injection of SMH-loaded ISH2 in adjuvant-induced arthritis rats. The optimal ISV2 (PT/ET/water, 64 : 16 : 20, w/w/w) loaded with 6 mg x g(-1) of SMH showed a suitable pH, injectable and formed a cubic liquid crystalline gel in situ with minimum water absorption in the shortest time. The optimal ISV2 was able to sustain the drug release for 144 h. The optimal ISH2 system was prepared by addition of 5% VitEA into PT in the optimal ISV2 system. This ISH2 (PT/VitEA/ET/water, 60.8 : 3.2 : 16 : 20, w/w/w/w) was an injectable isotropic solution with suitable pH. The new ISH2 was able to sustain the drug release for more than 240 h. Local pharmacokinetics study indicated that the retention time and AUC(0-∞) of ISH2 group were increased significantly compared with that of SMH solution group and the AUC(0-∞) of ISH2 group was 6.01 times higher than that of SMH solution group. The developed ISH2 was suitable for intra-articular injection that may apply to patients in the treatment of rheumatoid arthritis.