An SS31-rapamycin conjugate via RBC hitchhiking for reversing acute kidney injury.

Mitochondrial dysfunction plays a major role in driving acute kidney injury (AKI) via alteration in energy and oxygen supply, which creates further ROS and inflammatory responses. However, mitochondrial targeting medicine in recovering AKI is challenging. Herein, we conjugated SS31, a mitochondria-targeted antioxidant tetrapeptide connecting a cleavable linker to rapamycin (Rapa), which provided specific interaction with FK506-binding protein (FKBP) in the RBCs. Once entering the bloodstream, SS31-Rapa could be directed to the intracellular space of RBCs, allowing the slow diffusion of the conjugate to tissues via the concentration gradient. The new RBC hitchhiking strategy enables the encapsulation of conjugate into RBC via a less traumatic and more natural and permissive manner, resulting in prolonging the t1/2 of SS31 by 6.9 folds. SS31-Rapa underwent the direct cellular uptake, instead of the lysosomal pathway, released SS31 in response to activated caspase-3 stimulation in apoptotic cells, favoring the mitochondrial accumulation of SS31. Combined with autophagy induction associated with Rapa, a single dose of SS31-Rapa can effectively reverse cisplatin and ischemia reperfusion-induced AKI. This work thus highlights a simple and effective RBC hitchhiking strategy and a clinically translatable platform technology to improve the outcome of other mitochondrial dysfunctional related diseases.

Mixed Ion/Electron Conductive Li3N-Mo Interphase Enabling Stable and Ultrahigh-Rate Lithium Metal Anodes.

Lithium (Li) metal is a promising anode for high-energy-density batteries; however, its practical viability is hampered by the unstable metal Li-electrolyte interface and Li dendrite growth. Herein, a mixed ion/electron conductive Li3N-Mo protective interphase with high mechanical stability is designed and demonstrated to stabilize the Li-electrolyte interface for a dendrite-free and ultrahigh-current-density metallic Li anode. The Li3N-Mo interphase is simultaneously formed and homogeneously distributed on the Li metal surface by the surface reaction between molten Li and MoN nanosheets powder. The highly ion-conductive Li3N and abundant Li3N/Mo grain boundaries facilitate fast Li-ion diffusion, while the electrochemically inert metal Mo cluster in the mosaic structure of Li3N-Mo inhibits the long-range crystallinity and regulates the Li-ion flux, further promoting the rate capability of the Li anode. The Li3N-Mo/Li electrode has a stable Li-electrolyte interface as manifested by a low Li overpotential of 12 mV and outstanding plating/stripping cyclability for over 3200 h at 1 mA cm-2. Moreover, the Li3N-Mo/Li anode inhibits Li dendrite formation and exhibits a long cycling life of 840 h even at 30 mA cm-2. The full cell assembled with LiFePO4 cathode exhibits stable cycling performance with 87.9% capacity retention for 200 cycles at 1C (1C = 170 mA g-1) as well as high rate capability of 83.7 mAh g-1 at 3C. The concept of constructing a mixed ion/electron conductive interphase to stabilize the Li-electrolyte interface for high-rate and dendrite-free Li metal anodes offers a viable strategy to develop high-performance Li-metal batteries.

Biomimetic virus-like mesoporous silica nanoparticles improved cellular internalization for co-delivery of antigen and agonist to enhance Tumor immunotherapy.

Nanocarrier antigen-drug delivery system interacts specifically with immune cells and provides intelligent delivery modes to improve antigen delivery efficiency and facilitate immune progression. However, these nanoparticles often have weak adhesion to cells, followed by insufficient cell absorption, leading to a failed immune response. Inspired by the structure and function of viruses, virus-like mesoporous silica nanoparticles (VMSNs) were prepared by simulating the surface structure, centripetal-radialized spike structure and rough surface topology of the virus and co-acted with the toll-like receptor 7/8 agonist imiquimod (IMQ) and antigens oocyte albumin (OVA). Compared to the conventional spherical mesoporous silica nanoparticles (MSNs), VMSNs which was proven to be biocompatible in both cellular and in vivo level, had higher cell invasion ability and unique endocytosis pathway that was released from lysosomes and promoted antigen cross-expression. Furthermore, VMSNs effectively inhibited B16-OVA tumor growth by activating DCs maturation and increasing the proportion of CD8+ T cells. This work demonstrated that virus-like mesoporous silica nanoparticles co-supply OVA and IMQ, could induce potent tumor immune responses and inhibit tumor growth as a consequence of the surface spike structure induces a robust cellular immune response, and undoubtedly provided a good basis for further optimizing the nanovaccine delivery system.

Sacubitril-valsartan cocrystal revisited: role of polymer excipients in the formulation.

Objectives: This study investigated the impact of polymer excipients on a typical cocrystal for sacubitril (SAC) and valsartan (VAL), aiming to guide optional formulation design and maximize oral bioavailability.Methods: Poly vinyl pyrrolidone (PVP) and hydroxypropyl cellulose (HPC) and hydroxypropyl methylcellulose (HPMC) were selected. The dissolution/permeation system was used to predict both the kinetics of drug supersaturation and the simple permeation. The intermolecular interaction was analyzed by 1H NMR spectroscopy and molecular dynamics simulation. Pharmacokinetic study was performed to assess the impact of polymer excipients in vivo.Results: Our study found that unappreciated excipients in the formulation, especially some polymers, might compete with the intermolecular hydrogen bonding among the cocrystals components and provide unexpected affinity, and thus leverage the therapeutic benefits. HPMC as a coating excipient used in the Entresto® tablet hampered the supersaturation of API, which led to the poor oral absorption of cocrystals. Conversely, PVP appeared to promote and maintain drug supersaturation, resulting in improved bioavailability of API.Conclusion: In conclusion, understanding the interplay between the cocrystal components and polymers is the key to optimizing the excipients to maximize the performance of cocrystal based oral drug formulation.

Combining Co-Amorphous-Based Spray Drying with Inert Carriers to Achieve Improved Bioavailability and Excellent Downstream Manufacturability.

It is crucial to improve poorly water-soluble orally administered drugs through both preclinical and therapeutic drug discovery. A co-amorphous formulation consisting of two low molecular weight (MW) molecules offers a solubility/dissolubility advantage over its crystalline form by maintaining their amorphous status. Here, we report on a co-amorphous solid dispersion (SD) system that includes inert carriers (lactose monohydrate or microcrystalline cellulose) and co-amorphous sacubitril (SAC)-valsartan (VAL) using the spray drying process. The strong molecular interactions between drugs were the driving force for forming robust co-amorphous SDs. Our system provided the highest solubility with more than ~11.5- and 3.12-times solubility increases when compared with the physical mixtures. Co-amorphous lactose monohydrate (LM) SDs showed better bioavailability of APIs (~356.27.8% and 154.01% for the relative bioavailability of LBQ 657 and valsartan, respectively). Co-amorphous inert carrier SDs possessed an excellent compressibility for the production of a direct compression pharmaceutical product. In conclusion, these brand-new co-amorphous SDs could reduce the number of unit processes to produce a final pharmaceutical product for downstream manufacturability.

Ratiometric delivery of doxorubicin and berberine by liposome enables superior therapeutic index than DoxilⓇ.

Although the appearance of Doxil alleviated the cardiotoxicity of DOX, the progression-free survival of patients was not prolonged compared with traditional medication regimens, and side effects such as hand-foot syndrome has occurred. In order to solve this dilemma, we have designed a novel co-delivery strategy to construct a co-loaded liposome of berberine (BER) and doxorubicin (DOX), which was called LipoBeDo. The optimal synergistic ratio of the two drugs was screened by cell cytotoxicity experiments in vitro, and the optimal attenuation ratio was further determined by in vivo cardiac H&E staining pathological sections. The optimal combination treatment caused a robust increase in apoptotic cells of 4T1, as compared to drug alone treatment. The prepared co-loaded liposome, LipoBeDo, had high encapsulation efficiency and good stability. The nanoliposome carrier controlled the biological fate of the drugs and maintained a pre-defined optimal ratio in vivo. The LipoBeDo significantly inhibited tumor growth in 4T1 murine mammary carcinoma model compared with Doxil (P < 0.05), and completely overcame the myocardial rupture toxicity caused by Doxil in mice. Our co-loaded liposome delivery platform technology provided a new direction for the clinical treatment of triple-negative breast cancer and the safe application of DOX.

Two-Dimensional Transition Metal Chalcogenides for Alkali Metal Ions Storage.

On the heels of exacerbating environmental concerns and ever-growing global energy demand, development of high-performance renewable energy-storage and -conversion devices has aroused great interest. The electrode materials, which are the critical components in electrochemical energy storage (EES) devices, largely determine the energy-storage properties, and the development of suitable active electrode materials is crucial to achieve efficient and environmentally friendly EES technologies albeit the challenges. Two-dimensional transition-metal chalcogenides (2D TMDs) are promising electrode materials in alkali metal ion batteries and supercapacitors because of ample interlayer space, large specific surface areas, fast ion-transfer kinetics, and large theoretical capacities achieved through intercalation and conversion reactions. However, they generally suffer from low electronic conductivities as well as substantial volume change and irreversible side reactions during the charge/discharge process, which result in poor cycling stability, poor rate performance, and low round-trip efficiency. In this Review, recent advances of 2D TMDs-based electrode materials for alkali metal-ion energy-storage devices with the focus on lithium-ion batteries (LIBs), sodium-ion batteries (SIBs), potassium-ion batteries (PIBs), high-energy lithium-sulfur (Li-S), and lithium-air (Li-O2 ) batteries are described. The challenges and future directions of 2D TMDs-based electrode materials for high-performance LIBs, SIBs, PIBs, Li-S, and Li-O2 batteries as well as emerging alkali metal-ion capacitors are also discussed.

Energy-Saving Synthesis of MOF-Derived Hierarchical and Hollow Co(VO3)2-Co(OH)2 Composite Leaf Arrays for Supercapacitor Electrode Materials.

A one-step and energy-saving method was proposed to synthesize hierarchical and hollow Co(VO3)2-Co(OH)2 composite leaf arrays on carbon cloth, which expressed high capacitance (522 mF cm-2 or 803 F g-1 at the current density of 0.5 mA cm-2), good rate capability (79.5% capacitance retention after a 30-fold increase of the current density) and excellent cycling stability (90% capacitance retention after 15 000 charge-discharge cycles) when tested as a supercapacitor electrode.

Synthesis of NiMn-LDH Nanosheet@Ni3S2 Nanorod Hybrid Structures for Supercapacitor Electrode Materials with Ultrahigh Specific Capacitance.

One of the key challenges for pseudocapacitive electrode materials with highly effective capacitance output and future practical applications is how to rationally construct hierarchical and ordered hybrid nanoarchitecture through the simple process. Herein, we design and synthesize a novel NiMn-layered double hydroxide nanosheet@Ni3S2 nanorod hybrid array supported on porous nickel foam via a one-pot hydrothermal method. Benefited from the ultrathin and rough nature, the well-defined porous structure of the hybrid array, as well as the synergetic effect between NiMn-layered double hydroxide nanosheets and Ni3S2 nanorods, the as-fabricated hybrid array-based electrode exhibits an ultrahigh specific capacitance of 2703 F g-1 at 3 A g-1. Moreover, the asymmetric supercapacitor with this hybrid array as a positive electrode and wood-derived activated carbon as a negative electrode demonstrates high energy density (57 Wh Kg-1 at 738 W Kg-1) and very good electrochemical cycling stability.

Long non-coding RNA XIST promotes TGF-ß-induced epithelial-mesenchymal transition by regulating miR-367/141-ZEB2 axis in non-small-cell lung cancer.

Growing evidence shows that lncRNA XIST functions as an oncogene accelerating tumor progression. Transforming growth factor ß (TGF-ß)-induced epithelial-mesenchymal transition (EMT) plays a key role in tumor metastasis. However, it is still unclear whether lncRNA XIST is implicated in TGF-ß-induced EMT and influences cell invasion and metastasis in non-small-cell lung cancer (NSCLC). Here, we observed increased expression of lncRNA XIST and ZEB2 mRNA in metastatic NSCLC tissues. Knockdown of lncRNA XIST inhibited ZEB2 expression, and repressed TGF-ß-induced EMT and NSCLC cell migration and invasion. Being in consistent with the in vitro findings, the in vivo experiment of metastasis showed that knockdown of lncRNA XIST inhibited pulmonary metastasis of NSCLC cells in mice. In addition, knockdown of ZEB2 expression can inhibit TGF-ß-induced EMT and NSCLC cell migration and invasion. Mechanistically, lncRNA XIST and ZEB2 were targets of miR-367 and miR-141. Furthermore, both miR-367 and miR-141 expression can be upregulated by knockdown of lncRNA XIST. Taken together, our study reveals that lncRNA XIST can promote TGF-ß-induced EMT and cell invasion and metastasis by regulating miR-367/miR-141-ZEB2 axis in NSCLC.

Lymphovascular invasion of urothelial cancer in matched transurethral bladder tumor resection and radical cystectomy specimens.

PURPOSE: Lymphovascular invasion is an independent predictor of nodal invasion and survival in patients undergoing radical cystectomy. When assessed in transurethral bladder tumor resection specimens, lymphovascular invasion could predict tumor behavior and guide treatment decisions. However, the reliability of assessing lymphovascular invasion in such specimens has not been systematically evaluated. We examined the agreement of lymphovascular invasion status in matched transurethral bladder tumor resection and cystectomy specimens. MATERIALS AND METHODS: A retrospective analysis was performed of patients undergoing transurethral bladder tumor resection within 6 weeks of cystectomy. Tumor stage and lymphovascular invasion status were assessed in transurethral bladder tumor resection specimens and compared to those in corresponding cystectomy specimens. Agreement of lymphovascular invasion status was determined using McNemar's test. RESULTS: A total of 75 patients were eligible for study. In transurethral bladder tumor resection specimens lymphovascular invasion was identified in 17 patients (23%), including 2 (8%) in the T1 and 15 (30%) in the T2 or greater groups. In matched cystectomy specimens lymphovascular invasion was identified in 30 patients (40%), including 9 (36%) in the T1 and 21 (42%) in the T2 or greater populations. A lack of lymphovascular invasion agreement was observed between transurethral bladder tumor resection and cystectomy specimens in the entire population and in patients with cT1 tumors (p = 0.009 and 0.02, respectively). However, good concordance was seen in patients with muscle invasive disease (p = 0.13). Nodal metastasis was observed in 7 of 17 patients (41%) with detectable lymphovascular invasion in the transurethral bladder tumor resection specimen. CONCLUSIONS: When lymphovascular invasion is identified in a transurethral bladder tumor resection sample, it will be present in the cystectomy sample in 65% of cases and associated with nodal metastasis in 41%. Lymphovascular invasion is a valuable histological tool in the evaluation of transurethral bladder tumor resection samples, particularly cT2 tumors, because there is significant agreement of lymphovascular invasion status at transurethral bladder tumor resection and at subsequent cystectomy.

Patterns of hematuria referral to urologists: does a gender disparity exist?

OBJECTIVES: To examine the referral patterns of hematuria within a nonprofit healthcare organization to determine the factors that influence referral. Hematuria continues to be an important sign of urologic disease, including urothelial malignancy. An increasing awareness of gender differences in tumor stage at bladder cancer presentation has led to speculation about delayed referral and diagnosis in women. However, little is known about the referral patterns of hematuria and whether gender differences exist. METHODS: The insurance records were examined from 926 consecutive adult health plan participants (559 men and 367 women) with newly diagnosed hematuria from 1998 to 2002. The patterns of urologic referral were evaluated. A Cox multivariate regression model was used to examine the relationship between urologic referral and the relevant variables. RESULTS: Overall, 263 men (47%) and 102 women (28%) were referred for urologic evaluation of hematuria, with a median follow-up of 27 and 26 months, respectively. Referral was initiated by the primary care physician in 80% of the cohort. Increased urologic referral was associated with advancing age, repeated hematuria, provider type, and male gender. The adjusted hazard ratio of male referral was 1.65 (95% confidence interval 1.31-2.08) compared with female referral. CONCLUSIONS: Primary care physicians practicing in a managed care setting are less likely to refer women for a urologic evaluation of new or first recurrent episodes of hematuria than to refer men in all patient age categories, except for 40-49 years. This apparent gender disparity could result in unequal access of specialty evaluation and could potentially delay the diagnosis of important urologic conditions.

Urothelial carcinoma with divergent histologic differentiation (mixed histologic features) predicts the presence of locally advanced bladder cancer when detected at transurethral resection.

OBJECTIVES: The histologic classification of bladder tumors remains an important predictor of treatment response and patient outcome, with pure nonurothelial tumors associated with poorer outcome compared with pure urothelial carcinoma (UC). Little, however, is known about the significance of UC with divergent (mixed) histologic features at transurethral resection of bladder tumor (TURBT). This study examined the incidence, pathologic spectrum, and clinical significance of this phenomenon. METHODS: The histologic patterns of 448 consecutive TURBT and 295 subsequent cystectomy specimens from this subgroup were analyzed. The type of divergent tumor differentiation observed in the mixed histologic type cases was categorized and quantified. Pure non-UC cases were excluded. Various clinicopathologic parameters were compared between the mixed histologic type and pure UC cohorts. RESULTS: UC with mixed histologic features was identified in 25% of all TURBT specimens and was uniformly (100%) high grade and invasive (99%). The most common mixed histologic components were squamous (40%) and glandular (18%). Eleven percent of cases had multiple mixed histologic types. Compared with the pure high-grade UC, UCs with mixed histologic features were associated with muscle invasion at TURBT (chi-square test, P <0.001) and with extravesical disease at cystectomy (chi-square test, P = 0.0001). The presence of mixed histologic features at TURBT was an independent predictor of extravesical disease in a multivariate logistic model (P = 0.007). However, it was not significant for disease-specific survival in the univariate (P = 0.17) or multivariate (P = 0.68) models. CONCLUSIONS: The results of our study have shown that the presence of mixed histologic features at TURBT indicates locally aggressive disease. Patients with mixed histologic features might benefit from an aggressive multimodality treatment strategy.

Cystectomy delay more than 3 months from initial bladder cancer diagnosis results in decreased disease specific and overall survival.

PURPOSE: Some groups hypothesize that a delay in cystectomy may result in higher pathological stage and possibly alter survival in patients with bladder cancer. The timing of this delay has been somewhat arbitrary. We evaluated the timing from T2 bladder cancer diagnosis to cystectomy, its impact on survival and potential causes of delay. MATERIALS AND METHODS: A contemporary cohort of 214 consecutive patients presented with clinical T2 bladder cancer and underwent radical cystectomy as primary therapy. Clinicopathological parameters were maintained in an institutional database. A review of time to cystectomy, pathological stage, disease specific survival and OS was performed. Variables were tested in univariate and multivariate analyses. The log rank test was used for exploratory analyses to determine meaningful delay cutoff points. RESULTS: Mean followup and time to cystectomy in the entire cohort was 40 months and 60 days, respectively. A significant disease specific survival and OS advantage was observed in patients undergoing cystectomy by 93 days or less (3.1 months) compared to greater than 93 days (p = 0.05 and 0.02, respectively). Pathological staging was similar between the groups (p = 0.15). A multivariate benefit in OS was observed in patients treated with timely cystectomy. The most common factor contributing to cystectomy delay was scheduling delay, as seen in 46% of cases. CONCLUSIONS: A cystectomy delay of 3.1 months undermines patient survival, likely through the development of micrometastases, since local stage progression is not apparent at this point. Most delays are avoidable and should be minimized. Despite the need for second opinions and the impact of busy surgical schedules clinicians must strive to schedule patients efficiently and complete surgical treatment within this time frame.