Tumor-Targeted cRGD-Coated Liposomes Encapsulating Optimized Synergistic Cepharanthine and IR783 for Chemotherapy and Photothermal Therapy.

Background: Combination therapy offers superior therapeutic results compared to monotherapy. However, the outcomes of combination therapy often fall short of expectations, mainly because of increased toxicity from drug interactions and challenges in achieving the desired spatial and temporal distribution of drug delivery. Optimizing synergistic drug combination ratios to ensure uniform targeting and distribution across space and time, particularly in vivo, is a significant challenge. In this study, cRGD-coated liposomes encapsulating optimized synergistic cepharanthine (CEP; a chemotherapy drug) and IR783 (a phototherapy agent) were developed for combined chemotherapy and photothermal therapy in vitro and in vivo. Methods: An MTT assay was used to evaluate the combination index of CEP and IR783 in five cell lines. The cRGD-encapsulated liposomes were prepared via thin-film hydration, and unencapsulated liposomes served as controls for the loading of CEP and IR783. Fluorescence and photothermal imaging were used to assess the efficacy of CEP and IR783 encapsulated in liposomes at an optimal synergistic ratio, both in vitro and in vivo. Results: The combination indices of CEP and IR783 were determined in five cell lines. As a proof-of-concept, the optimal synergistic ratio (1:2) of CEP to IR783 in 4T1 cells was evaluated in vitro and in vivo. The average diameter of the liposomes was approximately 100 nm. The liposomes effectively retained the encapsulated CEP and IR783 in vitro at the optimal synergistic molar ratio for over 7 d. In vivo fluorescence imaging revealed that the fluorescence signal from cRGD-CEP-IR783-Lip was detectable at the tumor site at 4 h post-injection and peaked at 8 h. In vivo photothermal imaging of tumor-bearing mice indicated an increase in tumor temperature by 32°C within 200 s. Concurrently, cRGD-CEP-IR783-Lip demonstrated a significant therapeutic effect and robust biosafety in the in vivo antitumor experiments. Conclusion: The combination indices of CEP and IR783 were successfully determined in vitro in five cell lines. The cRGD-coated liposomes encapsulated CEP and IR783 at an optimal synergistic ratio, exhibiting enhanced antitumor effects and targeting upon application in vitro and in vivo. This study presents a novel concept and establishes a research framework for synergistic chemotherapy and phototherapy treatment.

Programmable activation of berbamine and photosensitizers for enhanced photodynamic therapy using emission-switchable upconversion nanoparticles.

Photodynamic therapy (PDT) shows great potential in precision tumor treatment. However, its efficacy is inhibited by the antioxidant defense capacities of tumor cells. To address this challenge, a near-infrared light-controlled nanosystem (UCNPs@mSiO2@Azo@ZnPc&BBM, PB@UA) was developed using emission-switchable upconversion nanoparticles (UCNPs) to independently and precisely control the release of berbamine (BBM) and activation of photosensitizer for enhanced PDT in deep tissues. Firstly, BBM release was triggered by exciting PB@UA at 980 nm. The BBM could inhibit the activities of antioxidant enzymes and disrupt calcium ion regulation, making the tumor cells more susceptible to ROS-induced cell death in the following PDT treatment. The PDT was initiated by irradiating the photosensitizers of ZnPc on PB@UA at 808 nm and achieved a tumor inhibition rate of 80.91 % in vivo, which is significantly higher than that of unique PDT (31.78 %) or BBM (11.29 %) treatment and demonstrates the potential of our strategy for improved cancer treatment.

Novel Aurora A Kinase Inhibitor Fangchinoline Enhances Cisplatin-DNA Adducts and Cisplatin Therapeutic Efficacy in OVCAR-3 Ovarian Cancer Cells-Derived Xenograft Model.

Aurora A kinase (Aurora A) is a serine/threonine kinase regulating control of multiple events during cell-cycle progression. Playing roles in promoting proliferation and inhibiting cell death in cancer cells leads Aurora A to become a target for cancer therapy. It is overexpressed and associated with a poor prognosis in ovarian cancer. Improving cisplatin therapy outcomes remains an important issue for advanced-stage ovarian cancer treatment, and Aurora A inhibitors may improve it. In the present study, we identified natural compounds with higher docking scores than the known Aurora A ligand through structure-based virtual screening, including the natural compound fangchinoline, which has been associated with anticancer activities but not yet investigated in ovarian cancer. The binding and inhibition of Aurora A by fangchinoline were verified using cellular thermal shift and enzyme activity assays. Fangchinoline reduced viability and proliferation in ovarian cancer cell lines. Combination fangchinoline and cisplatin treatment enhanced cisplatin-DNA adduct levels, and the combination index revealed synergistic effects on cell viability. An in vivo study showed that fangchinoline significantly enhanced cisplatin therapeutic effects in OVCAR-3 ovarian cancer-bearing mice. Fangchinoline may inhibit tumor growth and enhance cisplatin therapy in ovarian cancer. This study reveals a novel Aurora A inhibitor, fangchinoline, as a potentially viable adjuvant for ovarian cancer therapy.

Deciphering the molecular mechanism of tetrandrine in inhibiting hepatocellular carcinoma and increasing sorafenib sensitivity by combining network pharmacology and experimental evaluation.

CONTEXT: The mechanism of tetrandrine (TET) in hepatocellular carcinoma (HCC) progression and sorafenib (Sora) chemosensitivity deserves investigation. OBJECTIVE: Using network pharmacology approaches to elucidate the mechanisms of TET in HCC. MATERIALS AND METHODS: CCK-8, colony formation, and flow cytometry assays were used to measure cell phenotypes. BALB/c nude mice were divided into Control, Sora (10 mg/kg), TET (50 mg/kg), and TET + Sora (10 mg/kg Sora plus 50 mg/kg TET) groups to evaluate the antitumor effects of TET for 21 days. Sora and TET were given by intraperitoneal injection or oral gavage. RESULTS: For SMMC7721 (IC50 = 22.5 µM) and PLC8024 (IC50 = 18.4 µM), TET (10, 20 µM) reduced colony number (0.68 ± 0.04- and 0.50 ± 0.04-fold, 0.56 ± 0.04- and 0.42 ± 0.02-fold), induced cell cycle arrest at G0/G1 stage (1.22 ± 0.03- and 1.39 ± 0.07-fold, 1.37 ± 0.06- and 1.55 ± 0.05-fold), promoted apoptosis (2.49 ± 0.26- and 3.63 ± 0.33-fold, 2.74 ± 0.42- and 3.73 ± 0.61-fold), and inactivated PI3K/AKT/mTOR signalling. Sora (10 µM) decreased cell proliferation, enhanced apoptosis, and inhibited PI3K/AKT/mTOR signalling, and these effects were further aggravated in the combination group. Activating PI3K/AKT/mTOR reversed the effects of TET on cell proliferation and Sora sensitivity. In the combination group, tumour volumes and weights were decreased to 202.3 ± 17.4 mm3 and 151.5 ± 25.8 mg compared with Sora (510.6 ± 48.2 mm3 and 396.7 ± 33.5 mg). DISCUSSION AND CONCLUSIONS: TET enhances Sora sensitivity by inactivating PI3K/AKT/mTOR, suggesting the potential of TET as a chemosensitizer in HCC.

Cepharanthine loaded nanoparticles coated with macrophage membranes for lung inflammation therapy.

Acute lung injury (ALI) is a disease associated with suffering and high lethality, but to date without any effective pharmacological management in the clinic. In the pathological mechanisms of ALI, a strong inflammatory response plays an important role. Herein, based on macrophage 'homing' into inflammation sites and cell membrane coating nanotechnology, we developed a biomimetic anti-inflammation nanosystem (MM-CEP/NLCs) for the treatment of ALI. MM-CEP/NLCs were made with nanostructured lipid carriers (NLCs) coated with natural macrophage membranes (MMs) to achieve effective accumulation of cepharanthine (CEP) in lung inflammation to achieve the effect of treating ALI. With the advantage of suitable physicochemical properties of NLCs and unique biological functions of the macrophage membrane, MM-CEP/NLCs were stabilized and enabled sustained drug release, providing improved biocompatibility and long-term circulation. In vivo, the macrophage membranes enabled NLCs to be targeted and accumulated in the inflammation sites. Further, MM-CEP/NLCs significantly attenuated the severity of ALI, including lung water content, histopathology, bronchioalveolar lavage cellularity, protein concentration, and inflammation cytokines. Our results provide a bionic strategy via the biological properties of macrophages, which may have greater value and application prospects in the treatment of inflammation.

Cepharanthine inhibits hepatocellular carcinoma cell growth and proliferation by regulating amino acid metabolism and suppresses tumorigenesis in vivo.

Cepharanthine (CEP), a natural compound extracted from Stephania cepharantha Hayata, has been found to have the potential to treat a variety of tumors in recent years. This study aims to evaluate the anti-hepatocellular carcinoma (HCC) effect of CEP and determine its in-depth mechanism. In this study, Hep3B and HCCLM3 cells were selected to evaluate the antitumor effects of CEP in vitro, whereas tumor xenograft in nude mice was performed to make in vivo anti-tumor assessment. RNA-sequence (RNA-seq) was used to identify possible molecular targets and pathways. Further, gas chromatography mass spectrometry (GC-MS) was performed to assess the differential metabolites involved in mediating the effect of CEP on the HCC cell line. Our results showed that CEP treatment resulted in the dose-dependent inhibition of cell viability, migration, and proliferation and could also induce apoptosis in HCC cells. RNA-seq following CEP treatment identified 168 differentially expressed genes (DEGs), which were highly enriched in metabolism-associated pathways. In addition, CEP down-regulated many metabolites through the amino acid metabolism pathway. In vivo experiment showed that CEP significantly suppressed tumor growth. Our results indicate that CEP has significant antitumor effects and has the potential to be a candidate drug for HCC treatment.

Combination of tetrandrine and 3-n-butylphthalide protects against cerebral ischemia-reperfusion injury via ATF2/TLR4 pathway.

OBJECTIVE: Cerebral infarction (CI) is the mayor reason of death in China. Reperfusion is the only immediate treatment for acute cerebral infarction. However, blood reperfusion recovery may cause ischemia-reperfusion (I/R) injuries. The purpose of this study was to investigate the effects of Tetrandrine (TTD) and 3-n-Butylphthalide (NBP) on cerebral I/R injury. MATERIALS AND METHODS: I/R was used to establish CI model in vivo. TTD was performed to analyze cerebral infarction volume. OGD was applied to establish CI model in vitro. Flow cytometry and TUNEL assays were utilized to determine the cell death. ELISA was conducted to determine the release of cytokines. mRNA and protein expressions were detected using qRT-PCR and western blot. RESULTS: We found that NBP + TTD treatment significantly reduced cerebral infarction volume and inhibited the death of neurons in vivo. Moreover, NBP + TTD treatment suppressed the apoptosis and inflammatory response of neurons in vitro. Additionally, NBP + TTD suppressed the expression of activator transcription factor 2 (ATF2). However, overexpression of ATF2 contributed to the degeneration of neurons. Moreover, ATF2 transcriptionally activated Toll-like receptor 4 (TLR4). NBP + TTD inactivated ATF2/TLR4 signaling. CONCLUSIONS: Taken together, TTD combined with NBP protected against cerebral infarction by inhibiting the inflammatory response and neuronal cell apoptosis via inactivating ATF2/TLR4 signaling pathways. This may provide an alternative for I/R injury.

Combination Nanotherapeutics for Dry Eye Disease Treatment in a Rabbit Model.

PURPOSE: Anti-inflammation is essential for dry eye disease. Traditional anti-inflammation agent corticosteroids applied in dry eye disease (DED) treatment could result in high intraocular pressure, especially in long-term treatment. Thus, we have prepared a liposome loading 1-bromoheptadecafluorooctane and tetrandrine (PFOB@LIP-Tet) to treat DED via anti-inflammation that hardly affects intraocular pressure in this study, which provided another therapy strategy for dry eye disease. METHODS: We firstly detected the physicochemical properties of PFOB@LIP-Tet. Next, we tested the biosafety of synthesized liposomes for corneal epithelium. Then, we explored the accumulations and distribution of PFOB@LIP-Tet both in cellular and animal models. And then, we assessed the therapeutic effects of PFOB@LIP-Tet formulations by laboratory and clinical examinations. Last, we examined the changes in eye pressure before and after treatment. RESULTS: PFOB@LIP-Tet and Tet showed a characteristic absorption peak at 282 nm while PFOB@LIP did not. Large amounts of PFOB@LIP-Tet remained on the ocular surface and accumulated in the corneal epithelial cells in DED rabbits. Corneal staining scores of DED rabbits respectively treated by ATS, PFOB@LIP-ATS, Tet-ATS and PFOB@LIP-Tet-ATS for seven days were 3.7±0.5, 3.2±0.4, 1.5±0.5 and 0.5±0.5. The expressions of related cytokines were correspondingly downregulated significantly, indicating that the inflammation of DED was successfully suppressed. The intraocular pressure changes of DED rabbits before and after treatment by PFOB@LIP-Tet showed no statistical significance. CONCLUSION: We successfully synthesized PFOB@LIP-Tet, and it could effectively treat dry eye disease via anti-inflammation but hardly affected the intraocular pressure.

Intranasal administration of dauricine loaded on graphene oxide: multi-target therapy for Alzheimer's disease.

Alzheimer's disease (AD) is a degenerative disease of the central nervous system characterized by progressive cognitive and memory-related impairment. However, current therapeutic treatments have not proved sufficiently effective, mainly due to the complicated pathogenesis of the disease. In this study, a nano-formulation of graphene oxide (GO) loaded with dauricine (Dau) was investigated in terms of the combined anti-inflammatory and anti-oxidative stress effects of Dau and the inhibition of misfolding and aggregation of the amyloid-ß (Aß) protein by GO. Both in vivo and in vitro models were induced using Aß1-42, and the formulation was administered nasally in mice. The results showed that GO loaded with Dau greatly reduced oxidative stress through increasing superoxide dismutase levels and decreasing reactive oxygen species and malondialdehyde levels in vitro; it also alleviated the cognitive memory deficits and brain glial cell activation in mice with Aß1-42-induced AD. This proved that GO loaded with Dau could protect against Aß1-42-induced oxidative damage and apoptosis in both in vitro and in vivo AD models; therefore, GO loaded with Dau has the potential to be an effective and agent for the rapid treatment of AD.

Chemomodulatory effect of neferine on DMBA-induced squamous cell carcinogenesis: Biochemical and molecular approach.

BACKGROUND: Neferine (NEF) is nontoxic, bisbenzylisoquinoline alkaloid is derived from the seed embryo of lotus, a familiar medicinal plant. Although several mechanisms have been planned, an evident antitumor action pathway of NEF on the oral tumor is still not known. In the current study, we aimed at investigating the protecting effect of NEF against experimental oral carcinoma and clarify its possible mechanism through the induction of apoptosis, proliferation, and inflammatory signaling pathways. METHODS: The experimental hamsters were divided into four groups (I-IV) containing six hamsters each. The group I was control group, group II and III hamsters treated with 7,12-dimethylbenz(a)anthracene (DMBA) (0.5%) alone, thrice in a week for 10 weeks, and group III and IV hamsters received oral supplementation of NEF at a concentration of 15 mg/kg bw. All the hamsters were sacrificed after 16 weeks. RESULTS: Our results revealed that DMBA treated hamsters exhibited 100% oral tumor cell formation with high-tumor incidence (TI), tumor number (TN), tumor volume (TV), decreased levels of antioxidants, increased status of lipid peroxidation (LPO), and modulated the activities of liver marker agents as well as NF-kB, cell proliferation (PCNA), and p53 proteins. NEF supplementation in DMBA treated hamsters, resulted in delayed lesion synthesis, and brought back the levels of the biochemical parameters. In addition, immunostaining of NF-kB, PCNA, and p53 showed that they were inhibited by NEF. CONCLUSION: Thus, NEF might be considered a better chemopreventive drug in an experimental model of home-based primary care (HBPC). More research is necessary to study other pathways implicated in oral carcinomas and their modulation by NEF.

Pharmacological hypothesis: TPC2 antagonist tetrandrine as a potential therapeutic agent for COVID-19.

More than ten million patients worldwide have been diagnosed with coronavirus disease 19 (COVID-19) to date (WHO situation report, 1st July 2020). There is no vaccine to prevent infection with the causative organism, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), nor a cure. In the struggle to devise potentially useful therapeutics in record time, the repurposing of existing compounds is a key route of action. In this hypothesis paper, we argue that the bisbenzylisoquinoline and calcium channel blocker tetrandrine, originally extracted from the plant Stephania tetrandra and utilized in traditional Chinese medicine, may have potential in the treatment of COVID-19 and should be further investigated. We collate and review evidence for tetrandrine's putative mechanism of action in viral infection, specifically its recently discovered antagonism of the two-pore channel 2 (TPC2). While tetrandrine's particular history of use provides a very limited pharmacological dataset, there is a suggestion from the available evidence that it could be effective at doses used in clinical practice. We suggest that further research to investigate this possibility should be conducted.

Tetrandrine enhances antitumor effects of the histone deacetylase inhibitor MS-275 in human cancer in a Bax- and p53-dependent manner.

MS-275 (Entinostat), is an oral histone deacetylase (HDAC) inhibitor with a high specificity for class 1 HDACs. As single agent, MS-275 exerts only modest antitumor activity against most solid malignancies. The use of MS-275 in combination with other anticancer agents is currently being evaluated to determine whether this approach can achieve superior therapeutic efficacy. Tetrandrine, a bisbenzylisoquinoline alkaloid isolated from the root of a Chinese medicinal herb, is safe and exhibits low toxicity, showing great potential to enhance chemotherapeutic efficacy. In the present study, we investigated the synergistic antitumor effects of MS-275 in combination with tetrandrine. Based on the results of in vitro experiments, the application of MS-275 in combination with tetrandrine induced selective apoptotic death in various cancer cells but spared normal cells. Mechanistically, the combination treatment induced a dramatic accumulation of reactive oxygen species (ROS), and a pretreatment with the ROS scavenger N-acetyl-L-cysteine (NAC) significantly prevented the cellular apoptosis induced by MS-275/tetrandrine. Moreover, molecular assays indicated that Bax and p53 were the key regulators of MS-275/tetrandrine induced apoptosis. The results of the in vivo studies were consistent with the results of the in vitro studies. Based on our findings, tetrandrine enhanced the antitumor effects of MS-275 in a Bax- and p53-dependent manner. The combination of MS-275 and tetrandrine may represent a novel and promising therapeutic strategy for cancer.

Neferine sensitized Taxol-resistant nasopharygeal carcinoma to Taxol by inhibiting EMT via downregulating miR-130b-5p.

Taxol resistance led to the poor survival prognosis in advanced nasopharyngeal carcinoma (NPC). Epithelial-mesenchymal transition (EMT) plays an important role in tumor chemoresistance. Neferine (NEF) is found to sensitize the cancer cells to chemotherapeutic agents, but its effects and mechanisms on NPC Taxol resistance is unclear. In this study, we discovered that Taxol-resistant cell lines 5-8F/Taxol and CNE-1/Taxol had the greater ability to metastasis and the higher expression of EMT markers. Then we found that NEF could inhibit the viability and EMT process in the Taxol-resistant cell lines. Furthermore, we confirmed that NEF could augment therapeutic efficacy of Taxol on NPC Taxol-resistant cell lines. Further through Microarray based analysis, we found that miR-130b-5p was stably down-regulated after treating 5-8F/Taxol with NEF. Later we verified that up-regulation of miR-130b-5p could not only promote the EMT-related migration/invasion, but also impair the inhibition effects of NEF on the EMT-associated metastatic ability and the chemotherapy resistance to Taxol. In conclusion, our results firstly suggested that NEF may enhanced Taxol sensitivity in NPC Taxol-resistant cell lines through inhibition of EMT which mediated by miR-130b-5p downregulation in vitro and in vivo. NEF may be used as a Taxol sensitizer in chemotherapy of NPC.

Tetrandrine: a review of its anticancer potentials, clinical settings, pharmacokinetics and drug delivery systems.

OBJECTIVES: Tetrandrine, a natural bisbenzylisoquinoline alkaloid, possesses promising anticancer activities on diverse tumours. This review provides systematically organized information on cancers of tetrandrine in vivo and in vitro, discuss the related molecular mechanisms and put forward some new insights for the future investigations. KEY FINDINGS: Anticancer activities of tetrandrine have been reported comprehensively, including lung cancer, colon cancer, bladder cancer, prostate cancer, ovarian cancer, gastric cancer, breast cancer, pancreatic cancer, cervical cancer and liver cancer. The potential molecular mechanisms corresponding to the anticancer activities of tetrandrine might be related to induce cancer cell apoptosis, autophagy and cell cycle arrest, inhibit cell proliferation, migration and invasion, ameliorate metastasis and suppress tumour cell growth. Pharmaceutical applications of tetrandrine combined with nanoparticle delivery system including liposomes, microspheres and nanoparticles with better therapeutic efficiency have been designed and applied encapsulate tetrandrine to enhance its stability and efficacy in cancer treatment. SUMMARY: Tetrandrine was proven to have definite antitumour activities. However, the safety, bioavailability and pharmacokinetic parameter studies on tetrandrine are very limited in animal models, especially in clinical settings. Our present review on anticancer potentials of tetrandrine would be necessary and highly beneficial for providing guidelines and directions for further research of tetrandrine.

Dual variable of drug loaded micelles in both particle and electrical charge on gastric cancer treatment.

Gastric cancer is a malignant tumour characterised by the uncontrolled cell growth. The incidence and mortality of gastric cancer remain high for the invasion and metastasis. We are urgently seeking a risk-free and effective treatment strategy for gastric cancer. In this study, paclitaxel and tetrandrine were encapsulated in the inner core of micelles, and DSPE-PEG2000-CPP and HA were modified on the micellar surface. HA/CPP modified paclitaxel plus tetrandrine micelles had a suitable particle size (90 nm) for permeating tumour tissue. The zeta potential of the targeting micelles was 8.37 mV after hydrolysis by HAase solution. Results of in vitro experiments indicated that HA/CPP modified paclitaxel plus tetrandrine micelles + HAase could enhance the intracellular uptake, inhibit the formation of neovascularization, block the process of EMT and destroy the invasion and metastasis. In vivo assays indicated that HA/CPP modified paclitaxel plus tetrandrine micelles could be selectively accumulated into tumour sites and exhibited the strong antitumor activity with negligible toxicity. These results suggested that HA/CPP modified paclitaxel plus tetrandrine micelles might provide a new strategy for treating gastric cancer.

Tetrandrine Attenuated Doxorubicin-Induced Acute Cardiac Injury in Mice.

Oxidative damage is closely involved in the development of doxorubicin- (DOX-) induced cardiotoxicity. It has been reported that tetrandrine can prevent the development of cardiac hypertrophy by suppressing reactive oxygen species- (ROS-) dependent signaling pathways in mice. However, whether tetrandrine could attenuate DOX-related cardiotoxicity remains unclear. To explore the protective effect of tetrandrine, mice were orally given a dose of tetrandrine (50 mg/kg) for 4 days beginning one day before DOX injection. To induce acute cardiac injury, the mice were exposed to a single intraperitoneal injection of DOX (15 mg/kg). The data in our study showed that tetrandrine prevented DOX-related whole-body wasting and heart atrophy, decreased markers of cardiac injury, and improved cardiac function in mice. Moreover, tetrandrine supplementation protected the mice against oxidative damage and myocardial apoptotic death. Tetrandrine supplementation also reduced ROS production and improved cell viability after DOX exposure in vitro. We also found that tetrandrine supplementation increased nuclear factor (erythroid-derived 2)-like 2 (Nrf2) expression and activity in vivo and in vitro. The protection of tetrandrine supplementation was blocked by Nrf2 deficiency in mice. In conclusion, our study found that tetrandrine could improve cardiac function and prevent the development of DOX-related cardiac injury through activation of Nrf2.

Speed of action and stage specificity of Bencha-loga-wichian, a Thai traditional antipyretic formulation, against Plasmodium falciparum and the chloroquine-potentiating activity of its active compounds, tiliacorinine and yanangcorinine.

ETHNOPHARMACOLOGICAL RELEVANCE: Bencha-loga-wichian (BLW), a Thai traditional antipyretic formulation, has been reported to have promising antiplasmodial activity, and it was previously revealed that tiliacorinine and yanangcorinine, isolated from Tiliacora triandra, were the active compounds. However, the mechanisms of action of BLW have not been investigated. In addition, these active compounds are bisbenzylisoquinoline alkaloids, many compounds of which have been reported to potentiate the efficacy of chloroquine. AIMS OF THE STUDY: To investigate the antiplasmodial mechanisms of action of BLW and evaluate the effects of chloroquine combined with tiliacorinine or yanangcorinine. MATERIALS AND METHODS: Chloroquine-resistant Plasmodium falciparum (PfW2) strains at the ring, trophozoite, and schizont stages were exposed to the extracts or compounds for 2, 4, 6, 8, 10, 12, 24 or 48 h. The percentages of parasitemia were determined by flow cytometry, and their morphologies were examined by Giemsa-stained smear to evaluate the speed of action and stage specificity. For the drug combination assay, a modified fixed-ratio isobologram method was used. RESULTS: The antiplasmodial activity of BLW possessed a slow onset of action and was the most effective against ring-stage parasites. After 48 h of extracts or compounds exposure, most of the treated parasites, at all stages, turned to the pyknotic form and could not recover even after extracts or compounds removal. The results suggested that these extracts and compounds could kill the parasites or possess parasiticidal effects. In addition, the combination of chloroquine with tiliacorinine or yanangcorinine demonstrated a synergistic effect, indicating that these compounds could potentiate chloroquine efficacy against chloroquine-resistant parasites. CONCLUSION: The antiplasmodial mechanisms of action of BLW appeared to differ from that of chloroquine and other current antimalarial drugs. In addition, tiliacorinine and yanangcorinine, the active compounds of BLW, could potentiate the efficacy of chloroquine. Accordingly, BLW was shown to be a good candidate for development as a new antimalarial and useful for drug combination therapy.

Intranasal tetrandrine temperature-sensitive in situ hydrogels for the treatment of microwave-induced brain injury.

The brain is the most sensitive organ to microwave radiation. However, few effective drugs are available for the treatment of microwave-induced brain injury due to the poor drug permeation into the brain. Here, intranasal tetrandrine (TET) temperature-sensitive in situ hydrogels (ISGs) were prepared with poloxamers 407 and 188. Its characteristics were evaluated, including rheological properties, drug release in vitro, and mucosal irritation. The pharmacodynamics and brain-targeting effects were also studied. The highly viscous ISGs remained in the nasal cavity for a long time with the sustained release of TET and no obvious ciliary toxicity. Intranasal temperature-sensitive TET ISGs markedly improved the spatial memory and spontaneous exploratory behavior induced by microwave with the Morris water maze (MWM) and the open field test (OFT) compared to the model. The ISGs alleviated the microwave-induced brain damage and inhibited the certain mRNA expressions of calcium channels in the brain. Intranasal temperature-sensitive TET ISGs was rapidly absorbed with a shorter Tmax (4.8 h) compared to that of oral TET (8.4 h). The brain targeting index of intranasal temperature-sensitive TET ISGs was as 2.26 times as that of the oral TET. Intranasal temperature-sensitive TET ISGs are a promising brain-targeted medication for the treatment of microwave-induced brain injury.

Preparation and characterisation of tetrandrine nanosuspensions and in vitro estimate antitumour activity on A549 lung cancer cell line.

Aim: The aim of this study was to improve solubility and antitumour ability in vitro of tetrandrine (Tet) via preparing nanosuspensions (NSs).Methods: The Tet-NSs were prepared by wet media milling. The Tet-CCS-NS was prepared with croscarmellose sodium (CCS) as single stabiliser. The Tet-HACC-TPGS-NS was manufactured with D-α-tocopheryl polyethylene glycol 1,000 succinate (TPGS) and hydroponically trimethyl ammonium chloride chitosan (HACC) as combined stabilisers. Physicochemical properties of the NSs such as particle size, surface morphologies, crystallinity and molecular interactions were investigated. In addition, the in vitro dissolution and antitumour activities using A549 human lung cancer cells were evaluated.Results: The mean particle sizes and Zeta potential of freshly prepared Tet-CCS-NS, Tet-HACC-TPGS-NS were 469.1 ± 14nm and 157.3 ± 5nm, -29.4 ± 0.26 mV and 23.3 ± 0.36 mV, respectively. In comparison to pure Tet, the cumulative dissolution of Tet-NSs were increased by 4 ∼ 5 times in 2 h. In vitro antitumour studies on Tet- NSs in A549 cells, the cell survival rate of the Tet-NSs at high concentration (30-50µg/ml) were less than 10% within 48 h. Meanwhile, Tet-NSs were revealed to induce A549 cells apoptosis and promote cell uptake.Conclusion: The present study has proved that the Tet-NSs can increase Tet solubility as well as improve Tet antitumour activity in vitro.

Metal ion-responsive nanocarrier derived from phosphonated calix[4]arenes for delivering dauricine specifically to sites of brain injury in a mouse model of intracerebral hemorrhage.

Primary intracerebral hemorrhage (ICH) is a leading cause of long-term disability and death worldwide. Drug delivery vehicles to treat ICH are less than satisfactory because of their short circulation lives, lack of specific targeting to the hemorrhagic site, and poor control of drug release. To exploit the fact that metal ions such as Fe2+ are more abundant in peri-hematomal tissue than in healthy tissue because of red blood cell lysis, we developed a metal ion-responsive nanocarrier based on a phosphonated calix[4]arene derivative in order to deliver the neuroprotective agent dauricine (DRC) specifically to sites of primary and secondary brain injury. The potential of the dauricine-loaded nanocarriers for ICH therapy was systematically evaluated in vitro and in mouse models of autologous whole blood double infusion. The nanocarriers significantly reduced brain water content, restored blood-brain barrier integrity and attenuated neurological deficits by inhibiting the activation of glial cells, infiltration by neutrophils as well as production of pro-inflammatory factors (IL-1ß, IL-6, TNF-α) and matrix-metalloprotease-9. These results suggest that our dauricine-loaded nanocarriers can improve neurological outcomes in an animal model of ICH by reducing inflammatory injury and inhibiting apoptosis and ferroptosis.