GSH/pH Dual Activatable Cross-linked and Fluorinated PEI for Cancer Gene Therapy Through Endogenous Iron De-Hijacking and in Situ ROS Amplification.

Ferroptosis-related cancer therapy is limited by insufficient Fe2+ /Fe3+ redox pair and hydrogen peroxide (H2 O2 ) for producing lethal hydroxyl radicals (·OH). Although exogenous iron or ROS-producing drugs can enhance ferroptosis, exploiting endogenous iron (labile iron pool, LIP) stored in ferritin and promoting ROS generation may be safer. Herein, a metal/drug-free nanomedicine is developed for responsive LIP release and H2 O2 generation on the mitochondria membranes, amplifying hydroxyl radical production to enhance ferroptosis-mediated antitumor effects. A glutathione(GSH)/pH dual activatable fluorinated and cross-linked polyethyleneimine (PEI) with dialdehyde polyethylene glycol layer nanocomplex loaded with MTS-KR-SOD (Mitochondria-targeting-sequence-KillerRed-Superoxide Dismutase) and CRISPR/Cas9-CA IX (Carbonic anhydrase IX (CA IX)) plasmids (FP@MC) are developed for enhanced ferroptosis through endogenous iron de-hijacking and in situ ROS amplification. Two plasmids are constructed to knockdown CA IX and translate KillerRed-SOD recombinant protein specifically on mitochondria membranes, respectively. The CA IX knockdown acidifies the intracellular environment, leading the release of LIP from ferritin as a "flare" to initiate endogenous chemodynamic therapy. Meanwhile, MTS-KR-SOD generates H2 O2 when irradiated by a 590 nm laser to assist chemodynamic therapy, leading to ROS amplification for mitochondria damage and lipid peroxide accumulation. The combined therapeutic effects aggravate cancer ferroptosis and suppress tumor growth, providing a new paradigm for amplifying ROS and iron ions to promote ferroptosis-related cancer therapy.

Active Ingredients from Chinese Medicine for Combination Cancer Therapy.

Combination therapy against cancer has gained increasing attention because it can help to target multiple pathways to tackle oncologic progression and improve the limited antitumor effect of single-agent therapy. Chinese medicine has been studied extensively in cancer therapy and proven to be efficacious in many cases due to its wide spectrum of anticancer activities. In this review, we aim to summarize the recent progress of active ingredients from Chinese medicine (AIFCM) in combination with various cancer therapeutic modalities, including chemotherapy, gene therapy, radiotherapy, phototherapy and immunotherapy. In addition to highlighting the potential contribution of AIFCM in combination cancer therapy, we also elucidate the underlying mechanisms behind their synergistic effect and improved anticancer efficacy, thereby encouraging the inclusion of these AIFCM as part of effective armamentarium in fighting intractable cancers. Finally, we present the challenges and future perspectives of AIFCM combination therapy as a feasible and promising strategy for the optimization of cancer treatment and better clinical outcomes.

ROS responsive polyethylenimine-based fluorinated polymers for enhanced transfection efficiency and lower cytotoxicity.

Cationic polymer polyethylenimine (PEI) plays a crucial role in gene delivery. However, high molecular weight PEI leads to higher efficient transfection efficacy and higher cytotoxicity while low molecular weight PEI exhibits lower transfection performance with lower toxicity. Therefore, effective chemical modification of PEI is required to enhance transfection activity and improve biocompatibility. Here, reactive oxygen species (ROS) responsive PEI-based fluorinated polymers (TKPF) with three degrees of fluorination (TKPF12.5%, TKPF25% and TKPF50%) were designed and synthesized by crosslinking low molecular weight PEI (PEI 1.8K) with a thioketal (TK) linker and then modifying heptafluorobutyric anhydride onto their surface. Such gene vectors exhibited the following features: (1) fluorination reduced the positive charge density and endowed hydrophobic and lipophobic characteristics to resist serum interactions; (2) The fluorophilic effect mediated efficient cellular uptake and endosomal escape; (3) ROS-responsive TK linker allowed the polyplex disassembly to decrease the cytotoxicity of the polycations and improve the release of payloads at specific sites. TKPFs attained superior transfection efficiency in multiple cell lines (293TN cells and B16F10 cells) in vitro and showed excellent biocompatibility. Notably, TKPFs also exhibited great serum resistance in gene delivery and TKPF50% transfected nearly 80% cells in the presence of 70% FBS. These results demonstrates that the fluorination and ROS responsiveness combined polycations are excellent gene-delivery vectors with serum-resistant capacity for further application.

Meta-analysis of randomized controlled trials for the efficacy and safety of anti-interleukin-13 therapy with lebrikizumab in patients with uncontrolled asthma.

BACKGROUND: Several studies have evaluated the efficacy and safety of lebrikizumab treatment with uncontrolled asthma. However, most of these studies were small and conclusions were inconsistent. Furthermore, whether serum periostin can act as a good predictor of the response to lebrikizumab treatment is still not certain. METHOD: We conducted a systematic review and meta-analysis of randomized controlled trials to evaluate the efficacy and safety of lebrikizumab treatment with uncontrolled asthma. Trials were searched in PubMed, Embase, Web of Science and Cochrane. Outcome measures were the rate of asthma exacerbations, relative changes in the forced expiratory volume in the first second of expiration (FEV1) of predicted value (%) and incidence of adverse events. RESULT: Five trials were finally included. Compared with placebo lebrikizumab treatment significantly decreased the rate of exacerbations(risk ratio [RR] 0.66 [95% confidence interval {CI}, 0.54-0.80]; p < 0.0001; n = 2039) and increased FEV1% of predicted value (weighted mean difference [WMD] 5.46 [95% CI, 2.48-8.43]; p < 0.0003; n = 351). Patients with high levels of serum periostin had greater exacerbation rate reductions (RR 0.59 [95%CI, 0.50-0.70]; p < 0.00001; n = 1157) and FEV1 of predicted value improvement (WMD 7.18 [95% CI, 2.93-11.42]; p < 0.0009; n = 177) than patients with low periostin levels in exacerbation rate reductions (RR 0.73 [95% CI, 0.47-1.14]; p < 0.17; n = 882) and FEV1 of predicted value improvement (WMD3.79 [95% CI, 0.39-7.97]; p < 0.08; n = 174). There was no significant difference in the incidence of adverse events in patients with lebrikizumab compared to placebo (RR 1.03 [95% CI, 0.99-1.06]; p < 0.11; n = 2056). CONCLUSION: In patients with uncontrolled asthma, lebrikizumab treatment significantly decreased the rate of exacerbation and improved lung function, especially for patients with high periostin levels.

mPEG-b-PCL/TPGS mixed micelles for delivery of resveratrol in overcoming resistant breast cancer.

OBJECTIVE: Drug resistance remains a major challenge for effective breast cancer chemotherapy. Resveratrol (Res) is a promising candidate for overcoming cancer chemoresistance, but it has low bioavailability due to poor absorption, and ready metabolism limits its application. This study aims to develop a Res-loaded mixed micelle system to be effective on drug resistance of breast cancer cells. METHODS: A mixed micelle system made of methoxy poly (ethylene glycol)-b-polycaprolactone (mPEG-PCL) and d-α-Tocopherol polyethylene glycol succinate was prepared and Res was encapsulated to form Res-loaded mixed micelles. Furthermore, the antitumor activity against doxorubicin (Dox)-resistant breast cancer MCF-7/ADR cells was studied and the possible mechanism was elucidated. RESULTS: The mixed micellar formulation increased drug uptake efficiency of Res by Dox-resistant breast cancer MCF-7/ADR cells, and induced higher rates of apoptotic cell death, as assessed by the accumulation of Sub G1 phases of cell cycle, nucleus staining and Annexin-FITC/propidium iodide assay. Moreover, Res-loaded mixed micelles also markedly enhanced Dox-induced cytotoxicity in MCF-7/ADR cells and increased the cellular accumulation of Dox by downregulating the expression of P-glycoprotein (P-gp) and inhibiting the activity thereof. CONCLUSION: The cumulative evidence indicates that Res-loaded mixed micelles hold significant promise for the treatment of drug-resistant breast cancer.

Aloe-emodin loaded solid lipid nanoparticles: formulation design and in vitro anti-cancer study.

Aloe-emodin (AE) is a promising anti-tumor candidate for its significant activity against various tumors such as lung cancer, hepatic cancer, breast cancer and so on. Nevertheless, AE is clinically limited due to its poor water solubility and low bioavailability. This study was designed to prepare AE-loaded solid lipid nanoparticles (AE-SLNs) in an attempt to improve the anti-cancer efficacy of AE. The AE-SLNs were prepared with optimized prescription using high pressure homogenization (HPH) technique. Ultimately, the AE-SLNs showed stable particle size at 88.9 ± 5.2 nm, ideal drug entrapment efficiency (EE) of 97.71 ± 0.5% and good stability with regard to zeta-potential as high as -42.8 mV. The in vitro release profiles revealed that AE achieved sustained release by loading into SLNs. Moreover, AE-SLNs showed significantly higher in vitro cytotoxicity against human breast cancer MCF-7 cells and human hepatoma HepG2 cells as compared to the AE solution, while they showed no significant toxicity on human mammary epithelial MCF-10A cells. Hoechst 33342 staining and Annexin V/PI double staining indicated that AE-SLNs induced higher apoptotic rates in MCF-7 cells. Further study elucidated that the improved anti-cancer efficacy may be attributed to the increased cellular uptake of AE. Based on these findings, we believe that the development of AE-SLNs is an effective way for improving the anti-cancer efficacy of AE.

Epigallocatechin-3-gallate potentiates the effect of curcumin in inducing growth inhibition and apoptosis of resistant breast cancer cells.

Drug resistance remains an on-going challenge in breast cancer chemotherapy. Combination of two or more drugs is an effective strategy to access context-specific multiple targets and overcome undesirable toxicity that is almost inevitable in single-drug chemotherapy. Many plant food-derived polyphenolic compounds have been proven to modulate many key factors responsible for cancer drug resistance, which makes them a promising group of low toxicity candidates for reversing cancer resistance. In this study, we analyzed the combination effect of two chemopreventive polyphenols, curcumin (Cur) and epigallocatechin-3-gallate (EGCG), in combating resistant breast cancer. Our present results showed that EGCG significantly enhanced the growth inhibition and apoptosis in both doxorubicin (DOX)-sensitive and resistant MCF-7 cells induced by Cur. The mechanism may be related to the further activation of caspase-dependent apoptotic signaling pathways and the enhanced cellular incorporation of Cur by inhibiting P-glycoprotein (P-gp) pump function. Moreover, Cur and EGCG in combination could enhance the toxicity of DOX and increase the intracellular level of DOX in resistant MCF-7 cells. Our findings with this practical combination of Cur and EGCG encourage us to move on to a promising strategy for successful treatment of human breast cancer resistance by combining two low-toxic chemotherapeutic agents from diet.

Potential antineoplastic effects of Aloe-emodin: a comprehensive review.

Aloe-emodin (AE), a bioactive anthraquinone derived from both Aloe vera and Rheum officinale, has recently been demonstrated to have various pharmacological activities. With the widespread popularity of natural products, such as antineoplastic drugs, AE has attracted much attention due to its remarkable antineoplastic activity on multiple tumor cells involving multi-channel mechanisms, including the disruption of cell cycle, induction of apoptosis, anti-metastasis, antiangiogenic, and strengthening of immune function. Experimental data have revealed AE as a potentially potent anti-cancer candidate. Despite this, the pharmaceutical application of AE is still in a fledging period as most research has concentrated on the elucidation of the molecular mechanism of action of existing treatments, rather than the development of novel formulations. Therefore, the present review summarizes the potential toxicity, molecular mechanism, pharmacokinetic characteristics, and pharmaceutical development of AE as an antineoplastic agent. This is based on its physicochemical properties, in an attempt to encourage further research on AE as a potential anti-cancer agent.

Chinese herbal medicine-derived compounds for cancer therapy: a focus on hepatocellular carcinoma.

ETHNOPHARMACOLOGICAL RELEVANCE: Hepatocellular carcinoma (HCC) as the major histological subtype of primary liver cancer remains one of the most common malignancies worldwide. Due to the complicated molecular pathogenesis of HCC, the option for effective systemic treatment is quite limited. There exists a critical need to explore and evaluate possible alternative strategies for effective control of HCC. With a long history of clinical use, Chinese herbal medicine (CHM) is emerging as a noticeable choice for its multi-level, multi-target and coordinated intervention effects against HCC. With the aids of phytochemistry and molecular biological approaches, in the past decades many CHM-derived compounds have been carefully studied through both preclinical and clinical researches and have shown great potential in novel anti-HCC natural product development. The present review aimed at providing the most recent developments on anti-HCC compounds derived from CHM, especially their underlying pharmacological mechanisms. MATERIALS AND METHODS: A systematic search of anti-HCC compounds from CHM was carried out focusing on literatures published both in English (PubMed, Scopus, Web of Science and Medline) and in Chinese academic databases (Wanfang and CNKI database). RESULTS: In this review, we tried to give a timely and comprehensive update about the anti-HCC effects and targets of several representative CHM-derived compounds, namely curcumin, resveratrol, silibinin, berberine, quercetin, tanshinone II-A and celastrol. Their mechanisms of anti-HCC behaviors, potential side effects or toxicity and future research directions were discussed. CONCLUSION: Herbal compounds derived from CHM are of much significance in devising new drugs and providing unique ideas for the war against HCC. We propose that these breakthrough findings may have important implications for targeted-HCC therapy and modernization of CHM.

Cytokine profile of a self-healing Fonsecaea pedrosoi infection in murine model.

Chromoblastomycosis is a chronic infectious disease of the skin and subcutaneous tissue. However, the host-defence response to this fungal infection has not been investigated thoroughly. This study was carried out to analyse the sequential events and the change of local cytokine release in a murine model infected with Fonsecaea pedrosoi in footpad. The anti-inflammatory Th2 cytokine IL-10 demonstrated an upward trend up to 7 days post infection followed by a steady decline. The titers of TNF-α (a pro-inflammatory Th1 cytokine) increased up to 7 days post infection followed by a relatively steady-state until full recovery. The anti-inflammatory cytokine IL-4 showed a similar pattern as TNF-α. The pro-inflammatory cytokine IFN-γ did not increased until 7 days post infection, while demonstrated an upward trend up to 30 days when the mice reached a full recovery from infection.

Chemical components, pharmacological properties, and nanoparticulate delivery systems of Brucea javanica.

Brucea javanica has demonstrated a variety of antitumoral, antimalarial, and anti- inflammatory properties. As a Chinese herbal medicine, Brucea javanica is mainly used in the treatment of lung and gastrointestinal cancers. Pharmacological research has identified the main antitumor components are tetracyclic triterpene quassinoids. However, most of these active components have poor water solubility and low bioavailability, which greatly limit their clinical application. Nanoparticulate delivery systems are urgently needed to improve the bioavailability of Brucea javanica. This paper mainly focuses on the chemical components in Brucea javanica and its pharmacological properties and nanoparticulate formulations, in an attempt to encourage further research on its active components and nanoparticulate drug delivery systems to expand its clinical applications. It is expected to improve the level of pharmaceutical research and provide a strong scientific foundation for further study on the medicinal properties of this plant.

Compatibility art of traditional Chinese medicine: from the perspective of herb pairs.

ETHNOPHARMACOLOGICAL RELEVANCE: Over the past decades, research of traditional Chinese medicine (TCM) mainly focused on developing potential candidates from Chinese medicinal herbs, while the wisdom of applying these traditional herbs has not been paid as much attention as it deserves. As is well-known, multi-herb therapy is one of the most important characteristics of TCM, but the modernization drive of this conventional wisdom has faced many obstacles due to its unimaginable complexity. Herb pairs, the most fundamental and the simplest form of multi-herb formulae, are a centralized representative of Chinese herbal compatibility. In light of their simplicity and the basic characteristics of complex formulae, herb pairs are of great importance in the studies of herb compatibility. MATERIALS AND METHODS: A systematic search of herb pair related research was carried out using multiple online literature databases, books and monographs published in the past 20 years. RESULTS: A comprehensive introduction to the compatibility of TCM, the position of herb pairs in TCM and the progresses of several famous herb pairs were provided in this review. Furthermore, the clinical study and the future research trends of herb pairs were also discussed. CONCLUSIONS: Herb pairs have played, and may continue to play a key role in full investigation of general herb compatibility for their indispensable position in TCM. Much more research is needed for the standardization, safety evaluation, and mechanism exploration of herb pairs.

[Application research of hot-melt extrusion in preparation of solid dispersion].

Hot-melt extrusion (HME) is mainly used to enhance the dissolution rate and bioavailability of poorly water soluble drugs. It has many advantages, such as simple process, continuous operation, high efficiency, on-line monitoring and so on. HME provides an innovative approach, which has been concerned by pharmaceutical workers, for preparation of solid dispersion abroad. This article reviews recent advances on preparation of solid dispersion by HME in preparation processing, carrier materials and quality evaluation in order to further promote and apply HME in preparation of solid dispersion.

Emodin loaded solid lipid nanoparticles: preparation, characterization and antitumor activity studies.

The objective of the present study was to prepare and characterize emodin (EMO)-loaded solid lipid nanoparticles (E-SLNs) and evaluate their antitumor activity in vitro. EMO and pharmaceutical lipid material were used to prepare E-SLNs by high pressure homogenization (HPH). Poloxamer 188 and Tween 80 were used as surfactants. The physicochemical properties of the E-SLNs were investigated by particle size analysis, zeta potential measurement, drug entrapment efficiency (EE), stability and in vitro drug release behavior. The E-SLNs showed stable particle size at 28.6 ± 3.1 nm, ideal drug EE and relative long-term physical stability after being stored for 4 months. The drug release of E-SLNs could last 72 h and exhibited a sustained profile, which made it a promising vehicle for oral drug delivery. MTT assay showed that E-SLNs could significantly enhance the in vitro cytotoxicity against human breast cancer cell line MCF-7 and MDA-MB-231 cells compared to the EMO solution, while free EMO, blank SLNs (B-SLNs) and E-SLNs all showed no significant toxicity to human mammary epithelial line MCF-10A cells. Flow cytometric analysis demonstrated that E-SLNs also showed more significant cell cycle arrest effect in MCF-7 cells compared to bulk EMO solution. Hoechst 33342 staining and Annexin V-FITC/PI double staining further confirmed that E-SLNs induced higher apoptotic rates in MCF-7 cells, indicating that cell cycle arrest and apoptosis maybe the underlying mechanism of the enhanced cytotoxicity. Taken together, it seems that HPH was a simple, available and effective method for preparing high quality E-SLNs to enhance its aqueous solubility. Moreover, these results suggest that the delivery of EMO as lipid nanoparticles maybe a promising approach for cancer therapy.