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.

Pharmacokinetics, bioavailability and metabolism of neferine in rat by LC-MS/MS and LC-HRMS.

In this study, a simple and sensitive analytical method based on liquid chromatography-tandem mass spectrometry (LC-MS/MS) was developed and validated for the determination of neferine in rat plasma. After acetonitrile-mediated protein precipitation, the samples were separated on an Acquity BEH C18 column (2.1 × 50 mm, 1.7 µm) maintained at 40°C. The mobile phase comprising 0.1% formic acid in water and acetonitrile was delivered at a flow rate of 0.4 ml/min. The mass detection was conducted using multiple reaction monitoring mode with ion transitions at 625.4 > 206.3 and m/z 622.9 > 380.9 for neferine and internal standard, respectively. The assay was demonstrated to be linear over the concentration range of 0.5-1,000 ng/ml, with correlation coefficient >0.999 (r > 0.999). The validated method was further applied to the pharmacokinetic study of neferine in rat plasma. In addition, the metabolism of neferine was investigated using high-resolution mass spectrometry. A total of six metabolites from rat liver microsomes and plasma were detected and their structures were identified according to their fragment ions. The proposed metabolic pathways of neferine were demethylation, dealkylation, dehydrogenation and glucuronidation.

Berbamine Suppresses the Progression of Bladder Cancer by Modulating the ROS/NF-κB Axis.

Berbamine (BBM), one of the bioactive ingredients extracted from Berberis plants, has attracted intensive attention because of its significant antitumor activity against various malignancies. However, the exact role and potential molecular mechanism of berbamine in bladder cancer (BCa) remain unclear. In the present study, our results showed that berbamine inhibited cell viability, colony formation, and proliferation. Additionally, berbamine induced cell cycle arrest at S phase by a synergistic mechanism involving stimulation of P21 and P27 protein expression as well as downregulation of CyclinD, CyclinA2, and CDK2 protein expression. In addition to suppressing epithelial-mesenchymal transition (EMT), berbamine rearranged the cytoskeleton to inhibit cell metastasis. Mechanistically, the expression of P65, P-P65, and P-IκBα was decreased upon berbamine treatment, yet P65 overexpression abrogated the effects of berbamine on the proliferative and metastatic potential of BCa cells, which indicated that berbamine attenuated the malignant biological activities of BCa cells by inhibiting the NF-κB pathway. More importantly, berbamine increased the intracellular reactive oxygen species (ROS) level through the downregulation of antioxidative genes such as Nrf2, HO-1, SOD2, and GPX-1. Following ROS accumulation, the intrinsic apoptotic pathway was triggered by an increase in the ratio of Bax/Bcl-2. Furthermore, berbamine-mediated ROS accumulation negatively regulated the NF-κB pathway to a certain degree. Consistent with our in vitro results, berbamine successfully inhibited tumor growth and blocked the NF-κB pathway in our xenograft model. To summarize, our data demonstrated that berbamine exerts antitumor effects via the ROS/NF-κB signaling axis in bladder cancer, which provides a basis for further comprehensive study and presents a potential candidate for clinical treatment strategies against bladder cancer.

Thirteen bisbenzylisoquinoline alkaloids in five Chinese medicinal plants: Botany, traditional uses, phytochemistry, pharmacokinetic and toxicity studies.

RELEVANCE: Bisbenzylisoquinoline (BBIQ) alkaloids are generally present in plants of Berberidaceae, Monimiaceae and Ranunculaceae families in tropical and subtropical regions. Some species of these families are used in traditional Chinese medicine, with the effects of clearing away heat and detoxification, promoting dampness and defecation, and eliminating sores and swelling. This article offers essential data focusing on 13 representative BBIQ compounds, which are mainly extracted from five plants. The respective botany, traditional uses, phytochemistry, pharmacokinetics, and toxicity are summarized comprehensively. In addition, the ADME prediction of the 13 BBIQ alkaloids is compared and analyzed with the data obtained. MATERIALS AND METHODS: We have conducted a systematic review of the botanical characteristics, traditional uses, phytochemistry, pharmacokinetics and toxicity of BBIQ alkaloids based on literatures collected from PubMed, Web of Science and Elsevier during 1999-2020. ACD/Percepta software was utilized to predict the pharmacokinetic parameters of BBIQ alkaloids and their affinity with enzymes and transporters. RESULTS: Botany, traditional uses, phytochemistry, pharmacokinetic and toxicity of 13 alkaloids, namely, tetrandrine, dauricine, curine, trilobine, isotrilobine, cepharanthine, daurisoline, thalicarpine, thalidasine, isotetrandrine, liensinine, neferine and isoliensinine, have been summarized in this paper. It can't be denied that these alkaloids are important material basis of pharmacological effects of family Menispermaceae and others, and for traditional and local uses which has been basically reproduced in the current studies. The 13 BBIQ alkaloids in this paper showed strong affinity and inhibitory effect on P-glycoprotein (P-gp), with poor oral absorption and potent binding ability with plasma protein. BBIQ alkaloids represented by tetrandrine play a key role in regulating P-gp or reversing multidrug resistance (MDR) in a variety of tumors. The irrationality of their usage could pose a risk of poisoning in vivo, including renal and liver toxicity, which are related to the formation of quinone methide during metabolism. CONCLUSION: Although there is no further clinical evaluation of BBIQ alkaloids as MDR reversal agents, their effects on P-gp should not be ignored. Considering their diverse distribution, pharmacokinetic characteristics and toxicity reported during clinical therapy, the quality standards in different plant species and the drug dosage remain unresolved problems.

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.

Inhalation of Tetrandrine-hydroxypropyl-ß-cyclodextrin Inclusion Complexes for Pulmonary Fibrosis Treatment.

Pulmonary fibrosis (PF) is a kind of interstitial lung disease with the features of progressive and often fatal dyspnea. Tetrandrine (TET) is the major active constituent of Chinese herbal Stephania tetrandra S. Moore, which has already applied clinically to treat rheumatism, lung cancer, and silicosis. In this work, a tetrandrine-hydroxypropyl-ß-cyclodextrin inclusion compound (TET-HP-ß-CD) was developed for the treatment of pulmonary fibrosis via inhalation administration. TET-HP-ß-CD was prepared by the freeze-drying method and identified using the cascade impactor, differential scanning calorimetry (DSC), X-ray diffraction (XRD), and Fourier transform infrared spectrum (FT-IR). A bleomycin-induced pulmonary fibrosis rat model was used to assess the effects of inhaled TET and TET-HP-ß-CD. Animal survival, hydroxyproline content in the lungs, and lung histology were detected. The results showed that inhalation of TET-HP-ß-CD alleviated inflammation and fibrosis, limited the accumulation of hydroxyproline in the lungs, regulated protein expression in PF development, and improved postoperative survival. Moreover, nebulized delivery of TET-HP-ß-CD accumulated chiefly in the lungs and limited systemic distribution compared with intravenous administration. The present results indicated that inhalation of TET-HP-ß-CD is an attractive candidate for the treatment of pulmonary fibrosis.

A novel controlled release tetrandrine-loaded PDLLA film: evaluation of drug release and anti-adhesion effects in vitro and in vivo.

To investigate the drug release and anti-adhesion effects of a TET (tetrandrine)-loaded PDLLA (poly-DL-lactide) film. Detection of TET release in vitro was carried out by high-performance liquid chromatography (HPLC) every 2 days following immersion of the tetrandrine-loaded PDLLA film in simulated body fluid until the TET content of the eluate could not be detected. For the in vivo test, TET-loaded PDLLA films were implanted into animal laminectomy models and positive and blank control groups were also set up. Postoperative serum tests, and macroscopic and histological analyses at 1, 4, 8, and 12 weeks, were used to assess the effects of the film. Statistical analyses were performed by one-way ANOVA. The drug release of the tetrandrine-loaded PDLLA film in vitro showed two phases with a second release peak. Ultimately, the duration of continuous delivery was up to 66 days and the cumulative delivery rate was up to 93.18%. Scores for the proliferation of epidural scars or adhesion of the dura mater in the test group were much lower than those for the two control groups. Histological analysis revealed the test group had fewer inflammatory cells and fibroblasts, as well as fewer extracellular collagen fibers, and a lower histology score than those of the two control groups at all time points. Tetrandrine-loaded PDLLA film is a novel controlled drug release and anti-adhesion material in vitro and in vivo.

Pharmacokinetics of 10-hydroxycamptothecin-tetrandrine liposome complexes in rat by a simple and sensitive ultra-high performance liquid chromatography with tandem mass spectrometry.

10-Hydroxycamptothecin is a drug to cure various cancers. However, the 10-hydroxycamptothecin cannot be widely applied in clinics due to fast elimination and resistance of various cancers to the drug. Nevertheless, co-treatment with tetrandine is known to reverse the resistance of multi-drug resistant cancers, and may present an effective strategy to improve the efficacy of 10-hydroxycamptothecin. In order to improve the bioavailability and prolong the treatment time of the 10-hydroxycamptothecin in vivo, we prepared 10-hydroxycamptothecin-tetrandrine liposome complexes with 10-hydroxycamptothecin as the basic anticancer drug, tetrandrine and liposomes as carriers. In this article, an ultra-high performance liquid chromatography tandem mass spectrometry method for the analysis of 10-hydroxycamptothecin and tetrandrine in plasma has been developed, validated, and utilized to compare the pharmacokinetics of both drugs in the original dosage form and administered as liposome complexes. According to the pharmacokinetic parameters of mean residence time, half-life period and clearance rate, the 10-hydroxycamptothecin-tetrandrine liposome complexes prolongs the retention and circulation time of 10-hydroxycamptothecin in vivo, achieving a good sustained release effect. To the best of our current knowledge, the pharmacokinetic properties of 10-hydroxycamptothecin-tetrandrine liposome complexes in rats have not been reported yet. Our study can provide a helpful reference for further related study.

Interaction Effects between Doxorubicin and Hernandezine on the Pharmacokinetics by Liquid Chromatography Coupled with Mass Spectrometry.

Doxorubicin (DOX) is an effective anti-tumor drug widely used in clinics. Hernandezine (HER), isolated from a Chinese medicinal herb, has a selective inhibitory effect on DOX multidrug resistance, making DOX more effective in treating cancer. The aim of this study was to investigate the effect of the interaction of HER and DOX on pharmacokinetics. Male Sparague-Dawley rats were randomly divided into three groups: a single DOX group, a single HER group, and a combination group. Plasma concentrations of DOX and HER were determined by the LC-MS/MS method at specified time points after administration, and the main pharmacokinetic parameters were estimated. The results showed that there were significant differences in the Cmax and AUC0-∞ of DOX in the single drug group and combined drug group, indicating that HER could improve the absorption of DOX. However, DOX in combination, in turn, reduced the free drug concentration of HER, possibly because DOX enhanced the HER drug-protein binding effect. The results could be used as clinical guidance for DOX and HER to avoid adverse reactions.

Synthesis, purification, and anticancer effect of magnetic Fe3O4-loaded poly (lactic-co-glycolic) nanoparticles of the natural drug tetrandrine.

Here, we have successfully synthesised and purified multifunctional PLGA-based nanoparticles by the co-encapsulation of an anticancer drug (tetrandrine) and a magnetic material (Fe3O4). The obtained Tet-Fe3O4-PLGA NPs had a uniform spherical shape with a particle size of approximately 199 nm and a negative surface charge of -18.0 mV, displaying a high encapsulation efficiency. Furthermore, TEM studies provided representative images of the purification process of the magnetic nanoparticles with MACS® technology. The MFM and VSM results indicated that both the Fe3O4 NPs and Tet-Fe3O4-PLGA NPs were superparamagnetic. The DSC spectrum demonstrated that Tet was successfully encapsulated within the PLGA-based nanoparticles. Significantly, the release studies revealed NPs had a relatively slower release rate than free Tet after 8 h's initial burst release, which had decreased from 98% to 65% after 24 h. In vitro cellular studies revealed that NPs could effectively penetrate into A549 cells and A549 multicellular spheroids to exert cytotoxicity, displaying a significantly high anti-proliferation effect. Moreover, western blot demonstrated that the co-loaded NPs had a higher anticancer activity by injuring lysosomes to activate the mitochondria pathway and induce A549 cell apoptosis. The magnetic characteristics and high anticancer activity support the use of Tet/Fe3O4 co-loaded PLGA-based nanoparticles as a promising strategy in the treatment of lung cancer.

Neferine in the Lotus Plumule Potentiates the Antitumor Effect of Imatinib in Primary Chronic Myeloid Leukemia Cells In Vitro.

Imatinib, the prototype BCR-ABL tyrosine kinase inhibitor (TKI), is the first-line treatment for Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase. However, a subgroup of patients exhibit poor response or experience relapse. This issue may be overcome by combination therapy using natural compounds. Neferine, a major bisbenzylisoquinoline alkaloid extracted from "lotus plumule" (seed embryo of lotus) commonly used in traditional Chinese medicine and tea, was used herein in the combination treatment of CML. The MTT assay showed that neferine exerted cytotoxicity in primary CML cells in a dose-dependent manner. Moreover, low concentrations of neferine (4 and 8 µM) sensitized primary CML cells to imatinib (CI < 1), and significantly decreased its IC50 from 0.70 ± 0.10 to 0.32 ± 0.06 µM and 0.16 ± 0.02 µM, respectively. Cotreatment of neferine and imatinib significantly decreased the expression of BCR-ABL protein and its molecular chaperone heat shock protein 90 (Hsp90) mRNA and protein levels, and further decreased phospho-extracellular regulated protein kinase 1/2 (p-Erk1/2) and myeloid cell leukemia (Mcl-1) expression. These results suggest that neferine might be a potential imatinib sensitizer in CML treatment. PRACTICAL APPLICATION: In China, Lotus plumule, the green embryo of lotus, is used as a tea and as a source of herbal medicine in the treatment of anxiety, insomnia, spermatorrhea, and thirst. Additional, neferine, a bisbenzylisoquinoline alkaloid extracted from lotus plumule has been shown to have antitumor potential. Herein, the effect of neferine and imatinib cotreatment on primary CML cells obtained from CML patients was assessed, with a synergistic effect being observed between the two compounds. Therefore, neferine might be a promising natural compound to potentiate imatinib in CML patients.

Quantitative MALDI Imaging of Spatial Distributions and Dynamic Changes of Tetrandrine in Multiple Organs of Rats.

Detailed spatio-temporal information on drug distribution in organs is of paramount importance to assess drug clinically-relevant properties and potential side-effects. Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI MSI) as a label-free and sensitive imaging modality provides an additional means of accurately visualizing drug and its metabolites distributions in tissue sections. However, technical limitations, complex physiochemical environment of surface and low abundance of target drugs make quantitative MALDI imaging of drug and its metabolites quite challenging. Methods: In this study, an internal standard correction strategy was applied for quantitative MALDI imaging of tetrandrine in multiple organs of rats including lung, liver, kidney, spleen, and heart. The feasibility and reliability of the developed quantitative MSI method were validated by conventional liquid chromatography-tandem MS (LC-MS/MS) analysis, and the two methods showed a significant correlation. Results: The quantitative MALDI imaging method met the requirements of specificity, sensitivity and linearity. Tissue-specific spatio-temporal distribution patterns of tetrandrine in different organs were revealed after intravenous administration in the rat. Moreover, demethylated metabolite was detected in liver tissues. Conclusions: The current work illustrates that quantitative MALDI imaging provides an alternative means of accurately addressing the problem of drug and its metabolites distribution in tissues, complementary to traditional LC-MS/MS of tissue homogenates and whole-body autoradiography (WBA). Quantitative spatio-chemical information obtained here can improve our understanding of pharmacokinetics (PK), pharmacodynamics (PD), and potential transient toxicities of tetrandrine in organs, and possibly direct further optimization of drug properties to reduce drug-induced organ toxicity.

Self-Nanoemulsifying Drug Delivery System of Tetrandrine for Improved Bioavailability: Physicochemical Characterization and Pharmacokinetic Study.

The main purpose of this study was to investigate the potential of self-nanoemulsified drug delivery system (SNEDDS) to improve the oral bioavailability of tetrandrine (Tet). SNEDDS was developed by using rational blends of excipients with good solubilizing ability for Tet which was selected based on solubility studies. Further ternary phase diagram was constructed to determine the self-emulsifying region. The optimal formulation with the best self-nanoemulsified and solubilization ability consisted of 40% (w/w) oleic acid as oil, 15% (w/w) SPC and 30% (w/w) Cremophor RH-40 as surfactant, and 15% (w/w) PEG400 as cosurfactant. The average droplet size and zeta-potential of the optimal Tet SNEDDS were 19.75±0.37 nm and 1.87±0.26 mv, respectively. The dissolute rate of Tet SNEDDS in various dissolution media was remarkably faster than Tet commercial tablet. Moreover, in vivo pharmacokinetic study results show that significant increase (p≤ 0.05) in the peak concentration (Cmax) and the area under the curve (AUC) of Tet was observed after the oral administration of Tet SNEDDS and the absorption of Tet from SNEDDS resulted in approximately 2.33-fold increase in oral bioavailability compared with the commercial tablet. Our research suggests that the prepared Tet SNEDDS could be a good candidate for improved the dissolution and oral bioavailability of Tet.

An UPLC-MS/MS method for quantifying tetrandrine and its metabolite berbamine in human blood: Application to a human pharmacokinetic study.

Tetrandrine (TET) was approved by the China Food and Drug Administration (CFDA) for the treatment of silicosis. However, patients can't use this effective drug chronically due to side effects such as hypersomnia, asthenia, etc. The purpose of this study is to develop an UPLC-MS/MS method to quantify TET and its major metabolite and apply the method in a single dose human pharmacokinetic study. A Restek UItra BiPh column (100×2.1mm, 5µm) was used with acetonitrile and 0.1% formic acid in water as the mobile phases. The mass analysis was performed in a Waters Xevo TQ mass spectrometer via multiple reaction monitoring (MRM) with positive scan mode. A one-step protein precipitation by acetonitrile was used to extract the analytes from blood sample. The method showed linearity in the concentration ranges of 2.05-1050.00ng/mL for TET and 1.27-650.00ng/mL for berbamine. The intra/inter-day precisions were less 15% for these two analytes. The extraction recoveries of these two analytes were from 75.6% to 107.8% and the matrix effects ranged from 92.4% to 110.4%. The stabilities of these compounds in plasma were evaluated by analyzing three different concentrations following storage at 25°C for 6h, and -80°C for 30days. All the samples displayed less than 15.0% variations. The validated method was applied to PK study in human and the PK parameters of TET and berbamine were determined. In conclusion, a robust and sensitive LC-MS/MS method was developed and validated. In addition, the results of human PK experiment showed that TET and berbamine could be accumulated and more study is needed to establish a reasonable dose segment.

Determination of cepharanthine in rat plasma by LC-MS/MS and its application to a pharmacokinetic study.

CONTEXT: Cepharanthine (CPA) has been reported to possess a wide range of pharmacological activities. OBJECTIVE: This study investigates the pharmacokinetic characteristics after oral or intravenous administration of CPA by using a sensitive and rapid LC-MS/MS method. MATERIALS AND METHODS: A sensitive and rapid LC-MS/MS method was developed for the determination of CPA in Sprague-Dawley rat plasma. Twelve rats were equally randomized into two groups, including the intravenous group (1 mg/kg) and the oral group (10 mg/kg). Blood samples (250 µL) were collected at designated time points and determined using this method. The pharmacokinetic parameters were calculated. RESULTS: The calibration curve was linear within the range of 0.1-200 ng/mL (r = 0.999) with the lower limit of quantification at 0.1 ng/mL. After 1 mg/kg intravenous injection, the concentration of CPA reached a maximum of 153.17 ± 16.18 ng/mL and the t1/2 was 6.76 ± 1.21 h. After oral administration of 10 mg/kg of CPA, CPA was not readily absorbed and reached Cmax 46.89 ± 5.25 ng/mL at approximately 2.67 h. The t1/2 was 11.02 ± 1.32 h. The absolute bioavailability of CPA by oral route was 5.65 ± 0.35%, and the bioavailability was poor. DISCUSSION AND CONCLUSIONS: The results indicate that the bioavailability of CPA was poor in rats, and further research should be conducted to investigate the reason for its poor bioavailability and address this problem.

Cepharanthine Induces Autophagy, Apoptosis and Cell Cycle Arrest in Breast Cancer Cells.

BACKGROUND: Cepharanthine (CEP) is a biscoclaurine alkaloid extracted from Stephania cepharantha and has been shown to have an anti-tumour effect on different types of cancers. However, the anti-cancer effect of CEP on human breast cancer cells is still unclear. METHODS: We used MTT, clone formation, in vitro scratch, invasion and migration assays to confirm the inhibitory role of CEP on the proliferation of breast cancer cells. Flow cytometry, plasmid construction and western blot analysis were used to study the detailed mechanisms. RESULTS: Our study showed that CEP could inhibit cell proliferation by inducing autophagy, apoptosis, and G0/G1 cell cycle arrest of breast cancer cells. Furthermore, we found that CEP induced autophagy and apoptosis by inhibiting the AKT/mTOR signalling pathway. CONCLUSION: We found that CEP could inhibit growth and motility of MCF-7 and MDA-MB-231 breast cancer cell. Our study revealed an anti-tumour effect of CEP on breast cancer cells and suggests that CEP could be a potential new clinical therapy for breast cancer.

Targeting vincristine plus tetrandrine liposomes modified with DSPE-PEG2000-transferrin in treatment of brain glioma.

Glioma is the most frequent primary tumor, and the treatment efficiency is unsatisfactory for the obstacle of the blood brain barrier (BBB), the multidrug resistance (MDR) and the properties of cancer cell invasion and vasculogenic mimicry (VM) formation. In this study, a kind of TF modified vincristine plus tetrandrine liposomes was developed to overcome those limitations. In vitro results showed that TF modified vincristine plus tetrandrine liposomes with suitable physicochemical property could enhance the transport across the BBB, increase the cellular uptake, inhibit the MDR, and block the cancer cell invasion and VM channels. In vivo results demonstrated that TF modified vincristine plus tetrandrine liposomes could significantly prolong the circulation time, obviously accumulate in brain tumor location, thus leading to a robust anticancer efficacy in glioma-bearing mice. These data suggest that TF modified vincristine plus tetrandrine liposomes offer a promising strategy for treating brain glioma.

A novel tetrandrine-loaded chitosan microsphere: characterization and in vivo evaluation.

In this study, novel tetrandrine-loaded chitosan microspheres were prepared by the emulsion cross-linking method. The systems were then characterized for physicochemical properties and in vitro drug release. In addition, the pharmacokinetics and tissue distribution of microspheres were further verified in animal models. Particle-size distribution indicated that the size of microspheres was within the range of 7-15 µm, with a median diameter of 12.4 µm. The drug loading and entrapment efficiency of the formulation were 34.6%±12.5% and 87.3%±9.7% (mean ± SD), respectively. In vitro release showed a typical sustained and long-term drug release behavior. The Higuchi equation was the model that fit best with release data. Maintaining a relatively constant plasma concentration in the long-term drug treatment is an outstanding pharmacokinetic advantage of tetrandrine microspheres in vivo. Moreover, compared with tetrandrine solution, tetrandrine microspheres produced a lower drug concentration in the heart, liver, and kidneys. This indicated that the microspheres used in this study were preferable for targeting lung tissue versus other tissues. No damage to the tissues of the lung was found in histopathological examination.

Multifunctional targeting vinorelbine plus tetrandrine liposomes for treating brain glioma along with eliminating glioma stem cells.

Malignant brain glioma is the most lethal and aggressive type of cancer. Surgery and radiotherapy cannot eliminate all glioma stem cells (GSCs) and blood-brain barrier (BBB) restricts the movement of antitumor drugs from blood to brain, thus leading to the poor prognosis with high recurrence rate. In the present study, the targeting conjugates of cholesterol polyethylene glycol polyethylenimine (CHOL-PEG2000-PEI) and D-a-tocopheryl polyethylene glycol 1000 succinate vapreotide (TPGS1000-VAP) were newly synthesized for transporting drugs across the BBB and targeting glioma cells and GSCs. The multifunctional targeting vinorelbine plus tetrandrine liposomes were constructed by modifying the targeting conjugates. The studies were undertaken on BBB model, glioma cells, GSCs, and glioma-bearing mice. In vitro results showed that multifunctional targeting drugs-loaded liposomes with suitable physicochemical property could enhance the transport drugs across the BBB, increase the intracellular uptake, inhibit glioma cells and GSCs, penetrate and destruct the GSCs spheroids, and induce apoptosis via activating related apoptotic proteins. In vivo results demonstrated that multifunctional targeting drugs-loaded liposomes could significantly accumulate into brain tumor location, show the specificity to tumor sites, and result in a robust overall antitumor efficacy in glioma-bearing mice. These data suggested that the multifunctional targeting vinorelbine plus tetrandrine liposomes could offer a promising strategy for treating brain glioma.

A novel injectable phospholipid gel co-loaded with doxorubicin and bromotetrandrine for resistant breast cancer treatment by intratumoral injection.

Systemically administered anticancer treatments were greatly limited by extensive side effects mainly due to nonspecific distributions in vivo, and multidrug resistance in various tumors. A phospholipids-based in situ-forming gel platform has been developed for the concurrent delivery of doxorubicin (DOX) and bromotetrandrin (W198). Phospholipid gel containing DOX and W198 remained in a solution (sol) state before injection and underwent rapid gelation after injection in vivo. The release of DOX and W198 from phospholipid gel (PG) was sustained in vitro for over 20 days (d). DOX and W198 from PG achieved prolonged release for over two weeks in rats via subcutaneous injection. Compared with repeated injections of free drug, eliminated cardiac toxicity and less bone marrow inhibition were observed for DOX and W198-loaded PG (DOX/W198-PG) in normal rats via subcutaneous injection. Also, a single intratumoral injection of DOX/W198-PG in the resistant MCF-7/Adr xenograft-bearing mice showed much better antitumor efficacy compared to other treatment groups. In sum, DOX/W198-PG was well demonstrated to achieve sustained drug release both in vitro and in vivo with eliminated toxicity and improved antitumor efficacy by reversing the multidrug resistance in breast cancers.