[Combination of shikonin and gefitinib reverses drug resistance in human non-small cell lung cancer and its mechanism].

The occurrence and development of tumors are associated with the cell energy metabolism. Inhibiting energy metabolism of lung cancer cells is an important strategy to overcome drug resistance. Based on the cellular energy metabolism pathway, this study observed the effect of combination of shikonin(SKN) and gefitinib(GFB) on the drug resistance in non-small cell lung cancer and explored the underlying mechanism. The human non-small cell lung cancer line HCC827/GR resistant to gefitinib was used as the cell model in vitro. The CCK-8 assay and flow cytometry were employed to investigate the cell viability and apoptosis, respectively. The high performance liquid chromatography was employed to measure the intracellular accumulation of GFB. A Seahorse XFe96 Analyzer was used to detect the changes of cellular energy metabolism. Western blot was employed to determine the expression of the proteins involved in the drug resistance. The tumor-bearing nude mouse model was used to verify the efficacy of SKN+GFB in overcoming drug resistance in vivo. The results showed that SKN+GFB significantly reduced the IC_(50) of GFB on HCC827/GR cells, with the combination index of 0.628, indicating that the combination of the two drugs had a synergistic effect and promoted cell apoptosis. SKN increased the intracellular accumulation of GFB. SKN+GFB lowered the oxygen consumption rate(OCR) and glycolytic proton efflux rate(GlycoPER) in cell energy metabolism, and down-regulated the overexpression of PKM2, p-EGFR, P-gp, and HIF-1α in drug resistance. The results of reversing drug resistance test in vivo showed that GFB or SKN alone had no significant antitumor effect, while the combination at different doses induced the apoptosis of the tumor tissue and inhibited the expression of PKM2 and P-gp, demonstrating a significant antitumor effect. Moreover, the tumor inhibition rate in the high-dose combination group reached 64.01%. In summary, SKN+GFB may interfere with the energy metabolism to limit the function of HCC827/GR cells, thus reversing the GFB resistance in non-small cell lung cancer.

Microneedle-mediated nose-to-brain drug delivery for improved Alzheimer's disease treatment.

Conventional transnasal brain-targeted drug delivery strategies are limited by nasal cilia clearance and the nasal mucosal barrier. To address this challenge, we designed dissolving microneedles combined with nanocarriers for enhanced nose-to-brain drug delivery. To facilitate transnasal administration, a toothbrush-like microneedle patch was fabricated with hyaluronic acid-formed microneedles and tannic acid-crosslinked gelatin as the base, which completely dissolved in the nasal mucosa within seconds leaving only the base, thereby releasing the loaded cyclodextrin-based metal-organic frameworks (CD-MOFs) without affecting the nasal cilia and nasal microbial communities. As nanocarriers for high loading of huperzine A, these potassium-structured CD-MOFs, reinforced with stigmasterol and functionalized with lactoferrin, possessed improved physical stability and excellent biocompatibility, enabling efficient brain-targeted drug delivery. This delivery system substantially attenuated H2O2- and scopolamine-induced neurocyte damage. The efficacy of huperzine A on scopolamine- and D-galactose & AlCl3-induced memory deficits in rats was significantly improved, as evidenced by inhibiting acetylcholinesterase activity, alleviating oxidative stress damage in the brain, and improving learning function, meanwhile activating extracellular regulated protein kinases-cyclic AMP responsive element binding protein-brain derived neurotrophic factor pathway. Moreover, postsynaptic density protein PSD-95, which interacts with two important therapeutic targets Tau and ß-amyloid in Alzheimer's disease, was upregulated. This fruitful treatment was further shown to significantly ameliorate Tau hyperphosphorylation and decrease ß-amyloid by ways including modulating beta-site amyloid precursor protein cleaving enzyme 1 and a disintegrin and metalloproteinase 10. Collectively, such a newly developed strategy breaks the impasse for efficient drug delivery to the brain, and the potential therapeutic role of huperzine A for Alzheimer's disease is further illustrated.

[Effect and mechanism of Xihuang Pills on rats with precancerous lesions of breast].

The purpose of this study was to explore the effect and mechanism of Xihuang Pills on rats with precancerous lesions of the breast. Of 48 healthy female rats, 8 were randomly selected as blank group, and the other 40 were treated with 7,12-dimethylbenzanthracene(DMBA) combined with estrogen and progestin to establish a model of precancerous lesions of the breast. The successfully modeled rats were randomly divided into a model group, a tamoxifen group(1.8 mg·kg~(-1)·d~(-1)), a Xihuang Pills low-dose group(0.3 g·kg~(-1)·d~(-1)), a medium-dose group(0.6 g·kg~(-1)·d~(-1)) and a high-dose group(1.2 g·kg~(-1)·d~(-1)). After 30 days of admi-nistration, the histopathological changes of viscera and breast were observed by haematoxylin and eosin(HE) staining, and the visceral index was calculated. Enzyme linked immunosorbent assay(ELISA) was used to detect the contents of estradiol(E_2) and progesterone(P) in serum. The protein expressions of vascular endothelial growth factor(VEGF) and fibroblast growth factor 2(FGF2) were detected by immunohistochemistry. The protein expressions of VEGF, vascular endothelial growth factor receptor 2(VEGFR2), phosphorylated-vascular endothelial growth factor receptor 2(p-VEGFR2), B-cell lymphoma-2(Bcl-2), and Bcl-2 associated X protein(Bax) were detected by Western blot and the mRNA expressions of VEGF, FGF2, CXC-chemokine receptor 4(CXCR4), cysteine aspartic acid-specific protease(caspase-3), and stromal cell-derived factor 1(SDF-1) were detected by real-time polymerase chain reaction(RT-PCR). HE staining revealed that the model group had some liver and kidney damages and severe hyperplastic mammary tissue, while the Xihuang Pills high-dose group had mild hyperplasia. Compared with the model group, the Xihuang Pills groups had lo-wer ovarian coefficient(P<0.05 or P<0.01) and Xihuang Pills high-dose group had lower uterine coefficient(P<0.01). ELISA results showed that compared with the model group, expressions of E_2 and P in Xihuang Pills high-dose group were significantly decreased(P<0.05 or P<0.01). Immunohistochemistry, Western blot and RT-PCR indicated that compared with the conditions in the model group, the protein and mRNA expressions of VEGF and FGF2 in the Xihuang Pills groups were down-regulated(P<0.05 or P<0.01), and the protein expression of Bcl-2 was lowered(P<0.01); there was a decrease in the protein expressions of VEGFR2 and p-VEGFR2(P<0.01), a down-regulation in the mRNA expressions of CXCR4 and SDF-1(P<0.01), while an increase in the mRNA expression of caspase-3(P<0.01) in both Xihuang Pills medium-dose and high-dose groups; the protein expression of Bax in Xihuang Pills high-dose group was increased(P<0.01). The above results indicated that Xihuang Pills can effectively intervene in precance-rous lesions of the breast, and the mechanism may be related to the regulation of E_2 and P secretion as well as the inhibition of angiogenesis and chemokine receptor expression, thus controlling the occurrence of precancerous lesions of the breast in rats.

[Effects of Platycodonis Radix-Curcumae Rhizoma on oral nanoparticle uptake and in vitro inhibition against breast cancer metastasis].

This study combined the herbal pair Platycodonis Radix-Curcumae Rhizoma(PR-CR) possessing an inhibitory effect on tumor cell proliferation and metastasis with the active component of traditional Chinese medicine(TCM) silibinin-loaded nanoparticles(NPs) with a regulatory effect on tumor microenvironment based on the joint effect on tumor cells and tumor microenvironment to inhi-bit cell metastasis. The effects of PR-CR on the cellular uptake of NPs and in vitro inhibition against breast cancer proliferation and metastasis were investigated to provide an experimental basis for improving nanoparticle absorption and enhancing therapeutic effects. Silibinin-loaded lipid-polymer nanoparticles(LPNs) were prepared by the nanoprecipitation method and characterized by transmission electron microscopy. The NPs were spherical or quasi-spherical in shape with obvious core-shell structure. The mean particle size was 107.4 nm, Zeta potential was-27.53 mV. The cellular uptake assay was performed by in vitro Caco-2/E12 coculture cell model and confocal laser scanning microscopy(CLSM), and the results indicated that PR-CR could promote the uptake of NPs. Further, in situ intestinal absorption assay by the CLSM vertical scanning approach showed that PR-CR could promote the absorption of NPs in the enterocytes of mice. The inhibitory effect of NPs on the proliferation and migration of 4T1 cells was analyzed using 4T1 breast cancer cells and co-cultured 4T1/WML2 cells, respectively. The results of the CCK8 assay showed that PR-CR-containing NPs could enhance the inhibition against the proliferation of 4T1 breast cancer cells. The wound healing assay indicated that PR-CR-containing NPs enhanced the inhibition against the migration of 4T1 breast cancer cells. This study enriches the research on oral absorption of TCM NPs and also provides a new idea for utilizing the advantages of TCM to inhibit breast cancer metastasis.

[Comparison of in vivo plasma pharmacokinetics and urine excretion of main components in Xihuang Formula in rats with precancerous lesions of breast cancer].

The UPLC-MS/MS was established for the determination of acetyl-11-keto-beta-boswellic acid(AKBA) and ß-boswellic acid(ß-BA), the main active components of Olibanum and Myrrha extracts in Xihuang Formula, in rat plasma and urine. The effects of compatibility on the pharmacokinetic behaviors of AKBA and ß-BA in rats were investigated, and the differences in pharmacokinetic behaviors between healthy rats and rats with precancerous lesions of breast cancer were compared. The results showed that compared with RM-NH and RM-SH groups, the AUC_(0-t) and AUC_(0-∞) of ß-BA increased(P<0.05 or P<0.01), T_(max) decreased(P<0.05 or P<0.01), and C_(max) increased(P<0.01) after compatibility. The trends of AKBA and ß-BA were the same. Compared with RM-SH group, the T_(max) decreased(P<0.05), C_(max) increased(P<0.01), and the absorption rate increased in the normal group of Xihuang Formula. The results of urinary excretion showed that there was a decreasing trend in the urinary excretion rate and total urinary excretion of ß-BA and AKBA after compatibility, but there was no statistical difference. Compared with normal group of Xihuang Formula, the AUC_(0-t) and AUC_(0-∞) of ß-BA increased(P<0.05), T_(max) increased(P<0.05), and the clearance rate decreased in the breast precancerous lesion group. AUC_(0-t) and AUC_(0-∞) of AKBA showed an increasing trend, the in vivo retention time was prolonged, and the clearance rate was reduced, but there was no significant difference compared with the normal group. The cumulative urinary excretion and urinary excretion rate of ß-BA and AKBA decreased under pathological conditions, indicating that pathological conditions could affect the in vivo process of ß-BA and AKBA, and reduce their excretion in the form of prototype drugs, showing different pharmacokine-tic characteristics from normal physiological conditions. In this study, UPLC-MS/MS analysis method was established, which was sui-table for in vivo pharmacokinetic analysis of ß-BA and AKBA. This study laid a foundation for the development of new dosage forms of Xihuang Formula.

[Effects of shell composition in shell-core structured nanoparticles on oral physiological barrier and bioavailability].

The present study prepared shell-core nanoparticles comprising poly(lactic-co-glycolic acid)(PLGA) cores encapsulated by shells composed of mixed lipids(Lipoid S100 and DSPE-PEG 2000) or polymer F127 to investigate the effects of shell composition on overcoming physiological barriers of gastrointestinal mucus and intestinal epithelial cells and improving bioavailability.The results are expected to provide references for the research on the improvement of the oral bioavailability of Chinese medicine by nanocar-riers. Silibinin(SLB) was used as a model drug to prepare PLGA nanoparticles coated with the shell of mixed lipids(SLB-LPNs) or F127(SLB-FPNs) via a modified nanoprecipitation method.Transmission electron microscopy showed that both LPNs and FPNs were spherical with a core-shell structure.The average particle sizes of SLB-LPNs and SLB-FPNs were(94.13±2.23) and(95.42±4.91) nm, respectively.The Zeta potential values were(-39.3±2.8) and(-17.0±0.2) mV, respectively.X-ray diffraction analysis revealed the presence of SLB in the two types of nanoparticles in a molecular or amorphous state.The ability of nanoparticles to cross both the mucus and epithelial barriers were evaluated using the cellular internalization kinetics assay.LPNs showed a higher rate of cell internalization than FPNs, indicating that LPNs could penetrate the mucus layer and become internalized by cells more rapidly.As revealed by the in vivo pharmacokinetic assay in rats with SLB suspension as the reference, the relative oral bioavailability of SLB-LPNs and SLB-FPNs was 400.37% and 923.31%, respectively.The effect of SLB-FPNs in improving oral bioavailability was more significant than that of SLB-LPNs.In summary, shell composition can influence the ability of nanoparticles to overcome oral physiological bar-riers, such as the mucus layer and intestinal epithelial cells, and improve oral bioavailability.Shell-core structured nanoparticles are promising nanocarriers for oral drug delivery systems.

[Improvement in compatibility of hot melt pressure-sensitive adhesive with cinnamon volatile oil and in vitro transdermal property by physical blending].

Hot melt pressure-sensitive adhesive(HMPSA) has broad application potential in the field of traditional Chinese medicine(TCM) plasters due to its high drug loading, weak skin irritation, satisfactory adhesion, etc. compared with rubber plasters.However, the structure of HMPSA is prone to suffer from the damage caused by volatile oils in TCM plasters. In view of this, a kind of HMPSA with a stable structure was prepared by physical blending of DINCH, polypropylene wax and liquid rubber(LIR) in the present study, which is denoted as DPL. The dosage of cinnamon volatile oil(CVO), the model drug, was selected with viscosity, softening point and cohesion as evaluation indexes. The interaction between DPL and HMPSA was investigated by Fourier transform infrared spectroscopy(FT-IR) and differential scanning calorimetry(DSC). The compatibility of HMPSA with CVO and its transdermal ability were studied by in vitro transdermal test, adhesion, scanning electron microscopy( SEM) and rheological evaluation. The results showed that 5% CVO began to damage the structure of HMPSA. The initial adhesion and holding adhesion of DPL-modified HMPSA(DPL-HMPSA) were not significantly changed compared with those of HMPSA, whereas the 180° peel strength was decreased. FI-IR unraveled that DPL formed the n-π conjugated system with styrene-isoprene-styrene block copolymer(SIS), and there was no significant difference in the glass transition temperature according to DSC results, which indicated the good compatibility of DPL with HMPSA. With 5% CVO loaded, the drug content of DPL-HMPSA was 1. 14 times higher than that of HMPSA, and the decrease rate of drug content in DPL-HMPSA was 16% lower than that in HMPSA after 3 months. SEM demonstrated that CVO did not cause obvious structural damage to DPL-HMPSA. Rheological evaluation revealed that the storage modulus and loss factor of DPL-HMPSA were higher than those of HMPSA, and the cohesion was also stronger. The percutaneous penetration rate of cinnamaldehyde in DPL-HMPSA was 2. 25 times that of HMPSA. In conclusion, DPL-HMPSA had more stable structure, better compatibility with CVO, and higher in vitro transdermal efficiency of cinnamaldehyde than before the modification. This study can provide reference for the mitigation of the matrix structure damage caused by volatile oil components in TCM plasters and the enhancement of the content and in vitro transdermal rate of drug.

[Study on effect of SuperTab 40LL on compression characteristics of musk sustained-release mini-tablets based on mathematical models].

In this paper, co-processed lactose SuperTab 40 LL was selected as fillers to study the preparation of musk sustained-release mini-tablets in the Xihuang multiple-unit drug release system. Musk sustained-release tablets containing different proportions of SuperTab 40 LL and MCC were prepared under various pressures, and then the compressibility and compactibility of these prescriptions were evaluated by Walker, Heckel and Ryshkewitch-Duckworth equations. In addition, the fluidity of the prescriptions was evaluated by parameters of Kawakita equation. There was a comprehensive analysis of the effect of SuperTab 40 LL on musk sustained-release mini-tablets combined with the appearance of SuperTab 40 LL and their tensile strength. The results shown that SuperTab 40 LL had better compression process through the Heckel equation, and the direct compression process of drug powders with excipients can be analyzed by the Kawakita and Ryshkewitch-Duckworth equations. As a new type of co-processed lactose, SuperTab 40 LL had a good fluidity and compactibility. SuperTab 40 LL may undergo particle crushing and plastic deformation during the compression process, which increased the contact area and bonding sites between the particles, and aggregated and shaped the mixed powder easy. Moreover, MCC showed a synergistic effect, and the combined application with SuperTab 40 ll could effectively improve the fluidity and compressibility of the musk sustained-release powder. When the ratio of SuperTab 40 LL and MCC was 2∶1, musk sustained-release mini-tablets had a high drug loading capacity and good compactibility in line with the design objectives.

O/W microemulsion droplets diffuse through hydrogel network to achieve enhanced transdermal drug delivery.

To overcome the poor water solubility of total flavones of Arisaematis rhizoma, microemulsions (MEs) can be used as a carrier for transdermal administration to promote their solubilization and skin permeability. Here, we investigated the physical compatibility of MEs in hydrogels and their skin permeation-enhancing effects. Transparency of microemulsion-based hydrogels (MBGs) was analyzed to evaluate ME compatibility with different hydrogel matrices. Transmission electron microscopy (TEM) and Fourier transform infrared (FTIR) spectroscopy were used to explore the microstructures of MBGs and ME-hydrogel combinations. Uniform and transparent MBG was obtained by adding 1% sodium hyaluronate (SH) to the optimized ME. MBG prepared with SH as a matrix expressed pseudoplastic-fluid and shear-thinning characteristics, making it easy to apply in clinical settings. No new FTIR peak occurred in the MBG compared with ME and hydrogel matrix, indicating a physical combination of ME and the polymer network gel. Nanoscale droplets of ME migrated in the gel network, and the migration capacity and in vitro transdermal permeation flux negatively correlated with SH concentration in the gel system. In conclusion, in MBGs, ME can keep nanoscale droplets migrating in the hydrogel network, thereby enhancing transdermal drug delivery.

TPGS assists the percutaneous administration of curcumin and glycyrrhetinic acid coloaded functionalized ethosomes for the synergistic treatment of psoriasis.

Combined therapy with anti-inflammatory drugs is preferred for the topical treatment of psoriasis, but the codelivery of drugs is restricted due to the lack of a suitable delivery system. Ethosomes with excellenttransdermal propertiesare perfect as carriers for hyperplastic skin. Therefore, glycyrrhetinic acid-D-α-tocopherol acid polyethylene glycol succinate (GA-TPGS) was synthesized, which prevented the inflammation and lipid peroxidation damage, thus effectively stabilizing the psoriasis. Then GA-TPGS was surface-modified on the curcumin (Cur) loaded ethosomes to construct curcumin-loaded GA-TPGS-modified multifunctional ethosomes (Cur@GA-TPGS-ES), exerting synergistic treatment for psoriasis. Using an interleukin-6-induced cell model, we found that Cur@GA-TPGS-ES displayed desirable suppression of inflammation response and oxidative stress damage. Compared with the ethanol solution, the percutaneous penetration rates of Cur and GA in Cur@GA-TPGS-ES were superior. In vivo microdialysis revealed similar results, suggesting an increase of transcutaneous absorption in Cur@GA-TPGS-ES. Fluorescence staining revealed that the cellular uptake and skin distribution were distinctly enhanced with the delivery by Cur@GA-TPGS-ES. After topical administration to imiquimod-induced psoriatic mice, the Cur@GA-TPGS-ES group showed powerful treatment from inflammatory infiltration inhibition of Cur, glucocorticoid-like effects of GA and anti-lipid peroxidation of TPGS. Overall, GA-TPGS mediated ethosomes possess more advantageous transdermal properties and synergistic antipsoriatic efficacy.

Tumor cell membrane-derived nano-Trojan horses encapsulating phototherapy and chemotherapy are accepted by homologous tumor cells.

Tumor cell membrane-derived nanostructures targeting homologous tumors are promising biomimetic drugs. Herein, curcumin (Cur) and chlorin e6 (Ce6) were co-loaded into PLGA nanoparticles (NPs), and then the NPs were coated with MCF-7 cell membranes (MCNPs). Cell membrane coating sharply increased the uptake of MCNPs by homologous cells, as compared to that with naked NPs. The NPs co-loaded with Cur and Ce6 (Cur/Ce6-NPs) showed a stronger proliferation-inhibitory effect on MCF-7 cells than the NP groups loaded with Cur and Ce6 alone. Cytotoxicity and apoptosis rates of MCF-7 cells in the Cur/Ce6-MCNPs group were significantly higher than those in the uncoated Cur/Ce6-NPs group. Both Cur/Ce6-NPs and Cur/Ce6-MCNPs significantly inhibited the migration of MCF-7cells, although Cur/Ce6-MCNPs showed a stronger effect. Compared to that of Cur/Ce6-NPs, the elimination of Cur/Ce6-MCNPs was both decreased and retarded, prolonging their in vivo systemic circulation and resulting in improved bioavailability. After intravenous administration for 24 h, the fluorescence intensity of drugs in the liver and spleen of the Cur/Ce6-MCNPs group was significantly weaker than that in the Cur/Ce6-NPs group, but that in tumor tissue was enhanced. Further, Cur/Ce6-MCNPs treatment achieved significantly better tumor-suppressive effects in vivo than Cur/Ce6-NPs, resulting in smaller tumor weights, increased apoptosis rates, and the down regulation of Ki67 protein in the tumor tissue. Thus, the tumor cell membrane-camouflaged nanocomposites have potential for homologous tumor-targeted therapy. Furthermore, photodynamic therapy combined with chemotherapy has promising future prospects.

Heparin modified photosensitizer-loaded liposomes for tumor treatment and alleviating metastasis in phototherapy.

Phototherapy holds promise in cancer treatment for its prominent antitumor efficacy and low systematic toxicity compared with traditional chemotherapy. However, the higher risk of tumor metastasis caused by the severe hypoxic state during phototherapy is a threat in practical use. Here, in order to tackle this challenge, we developed a delivery system via loading the photosensitizer indocyanine green (ICG) into the low molecular weight heparin (LMWH) modified liposomes (LMWH-ICG-Lip) to realize the synergistic effects between photosensitizer and drug vehicle, achieving better phototherapeutic efficacy and meanwhile alleviating the potential risk of tumor metastasis caused by phototherapy. In this system, besides elongating the photosensitizers' circulation time and enhancing their accumulating efficacy to tumor tissues, LMWH itself also exhibited anti-metastasis efficacy via inhibiting adhesion of platelets to tumor cells and decreasing migration and invasion capability of tumor cells. In vivo efficacy evaluation was conducted on orthotopic 4T1 breast cancer model, and the system of LMWH-ICG-Lip could alleviate metastasis potential of residual tumor cells after irradiation, and elicit optimistic antitumor and anti-metastasis efficacy for phototherapy.

Advances in next-generation lipid-polymer hybrid nanocarriers with emphasis on polymer-modified functional liposomes and cell-based-biomimetic nanocarriers for active ingredients and fractions from Chinese medicine delivery.

Recently, functional liposomes modified with versatile polymer and cell-based- biomimetic nanoparticles have emerged as the most advanced lipid-polymer hybrid nanocarriers (LPNs) for drug delivery. This review highlights the advances of these two LPNs in the delivery of active ingredients and fractions from Chinese medicine with promising therapeutic, chemopreventive, or chemosensitive effects. To understand their complete potency, the relationship between the nanoparticle characteristics and their in vitro and in vivo performance characteristics has been discussed. Polymer-modified liposomes and cell-based biomimetic nanoparticles are beneficial for improving absorption, modulating release, targeting and overcoming multidrug resistance, and reducing side effects. The associated challenges, current limitations, and opportunities in this field are also discussed.

Cell membrane-coated nanosized active targeted drug delivery systems homing to tumor cells: A review.

Cancer is a leading cause of mortality worldwide. Cell membrane-coated nanocarriers actively targeting tumor sites are known to circumvent the limitations of conventional treatments and nanosized drug delivery systems. Cell membrane-coated nanocarriers can evade the immune system and can target tumors, thereby exhibiting a prolonged circulation time, enhancing tumor accumulation, increasing cancer therapeutic efficacy, and facilitating tumor imaging in vivo. Numerous studies have focused on cell membrane-coated nanocarriers homing to tumors. The use of these biomimetic nanocarriers in combination with photothermal or photodynamic cancer therapy have received increasing attention. This review discusses various sources of cell membranes, which have been harnessed previously in this field and highlights the mechanism underlying the targeting action of these nanocarriers and the method of their extraction, along with the applications of biomimetic cell membrane-coated nanocarriers in cancer phototherapy and diagnosis. Finally, this review discusses prospects in methods to resist cancer metastasis.

An herbal-compound-based combination therapy that relieves cirrhotic ascites by affecting the L-arginine/nitric oxide pathway: A metabolomics-based systematic study.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional Chinese medicine boasts a 440-year-long history of treating refractory ascites via combinations of herbal medicines, called formulae. Xiaozhang Tie (XT) is a proprietary herbal-compound-based formula that has been proven to be very effective in the treatment of cirrhosis-associated ascites in clinical practice, but the mechanism of action of XT remains unknown. AIM OF THE STUDY: In this study, we used a metabolomics-based systematic method to elucidate the mechanism of XT in the treatment of cirrhotic ascites. METHODS: Decompensated liver cirrhosis was induced in rats by intraperitoneal injection of Carbon tetrachloride (CCl4). Ultra performance liquid chromatography-mass spectrometry (UPLC-MS) combined with pattern recognition approaches were used to determine differentiating metabolites relevant to XT treatment. Biomarkers were further validated by a targeted quantitative method and by the results from serum and urine analyses. Pathway analysis and correlation network construction were used to reveal the therapeutic targets associated with XT treatment, and the potential mechanisms were verified by the results from biochemical, histopathological and immunohistochemical assays. RESULTS: XT synergistically mediated the abnormalities of amino acid metabolic pathways in cirrhotic rats. XT significantly elevated the arginine levels, reduced the serum nitric oxide (NO) levels and alleviated the gastrointestinal motility disorder of cirrhotic rats. This effect of XT has been confirmed by the inhibition of the activities of inducible NO synthase and neuronal NO synthase in the small intestine. CONCLUSIONS: These results reveal that XT promotes gastrointestinal motility by acting on multiple targets in multiple pathways, of which the L-arginine/NO pathway is most affected.

Hybrid curcumin-phospholipid complex-near-infrared dye oral drug delivery system to inhibit lung metastasis of breast cancer.

Background: Oral route of administration is preferred for treating breast cancer, especially when continued disease management with good tolerability is required; however, orally administered chemotherapeutics combined with near-infrared (NIR) dyes are hindered by the low bioavailability, insufficient for the desired therapeutic efficacy. In this study, we developed a hybrid self-microemulsifying drug delivery system for co-loading curcumin-phospholipid complex and NIR dye IR780 (CUR/IR780@SMEDDS), to achieve combined phototherapeutic and chemotherapeutic effects against lung metastasis of breast cancer. Methods: CUR/IR780@SMEDDS were characterized. The efficacy against breast cancer metastasis was evaluated by photothermal and photodynamic assessment, cytotoxicity, invasion, and migration in metastatic 4T1 breast cancer cells in vitro, and in vivo oral bioavailability study in rats and pharmacodynamics studies in tumor-bearing nude mice. Results: CUR/IR780@SMEDDS improved oral bioavailability of curcumin and IR780 in rats compared with curcumin and IR780 suspensions. CUR/IR780@SMEDDS exhibited remarkable photothermal and photodynamic effects in vitro. In metastatic 4T1 breast cancer cells, CUR/IR780@SMEDDS combined with localized NIR laser irradiation induced significant cytotoxicity and inhibited invasion and migration of 4T1 cells, an outcome attributable to cumulative effects of IR780-induced hyperthermia and pharmacological effects of curcumin. In orthotopic 4T1 tumor-bearing nude mice, combination of oral administration of CUR/IR780@SMEDDS with local NIR laser irradiation inhibited tumor progression and suppressed lung metastasis.

Glutathione detonated and pH responsive nano-clusters of Au nanorods with a high dose of DOX for treatment of multidrug resistant cancer.

Effects of nanosized drug delivery systems on cancer are often compromised due to their low drug loadings, premature drug release and multi-drug resistance (MDR). Herein, we reported a glutathione detonated and pH responsive nano-cluster of Au nanorods (AuNRs) with chemotherapeutic doxorubicin (DOX) and pre-chemosensitizer polycurcumin to treat MCF-7/ADR cells. The nano-cluster was prepared by self-assembling of AuNRs conjugated with DOX and amphiphilic poly(curcumin-co-dithiodipropionic acid)-b-biotinylated poly(ethylene glycol) via an emulsion/solvent evaporation technique, termed AuNR Cluster. The AuNR Cluster had a high drug loading (31.5% DOX), presenting much better aqueous solubility and stability at physiological pH than their individual AuNRs. The AuNR Cluster could be detonated to be their individual AuNRs at an intracellular concentration level of glutathione (GSH) (5 mM) and triggered to release DOX at an acidic pH (pH 6.8 or 5.0), which effectively facilitated cellular uptake of DOX (607 vs 356 a.u. for AuNRs at 12 h) and inhibited DOX efflux (471.33 vs 39.17 a.u. for free DOX at 24 h). The IC50 value of DOX against MCF-7/ADR cells for AuNR Cluster was 4.15 µg/mL, much lower than that for free DOX (90.97 µg/mL). The AuNR Cluster took much more photothermal effects than their corresponding AuNRs and presented enhanced anti-tumor effect (IC50: 2.61 µg/mL) under 808 nm laser irradiation. STATEMENT OF SIGNIFICANCE: Nano-sized drug delivery systems for anti-MDR cancer is still a challenging task. Herein, AuNR Cluster was self-assembled by individual AuNRs via emulsion/solvent evaporation technique, having a structure consisting of hydrophobic DOX/PCDA-AuNR core and hydrophilic biotin-PEG chain shell. AuNR Cluster is detonated to disintegrate and yield its individual AuNRs at an intracellular concentration level of glutathione (5 mM) and triggered to release DOX at an acidic pH (6.8 or 5.0). In comparison with its individual AuNRs, AuNR Cluster has better water solubility and stability, greater photothermal effects under NIR irradiation, bigger cytotoxicity against MCF-7/ADR cells. AuNR Cluster is expected to be a potential nanomedicine for treatment of MDR cancer.

Curcumin-loaded redox-responsive mesoporous silica nanoparticles for targeted breast cancer therapy.

HYPOTHESIS: The antitumor applications of curcumin (CUR) are limited because of its low water solubility, poor stability, and low bioavailability. We developed novel nanocarrier systems for tumour targeting and controlled CUR release and evaluated their therapeutic efficacy. EXPERIMENTS: The surface of mesoporous silica nanoparticles (MSN) was modified with hyaluronan (HA) or polyethyleneimine-folic acid (PEI-FA) via disulfide bonds. The capacity of the resultant nanocarriers (MSN-HA and MSN-PEI-FA, respectively) for CUR delivery was evaluated in a breast cancer cell line and a mouse xenograft model. FINDINGS: MSN/CUR-PEI-FA and MSN/CUR-HA were cytotoxic to MDA-MB-231 breast cancer cells. Both formulations showed an enhanced cellular uptake compared with that of a non-targeted nanocarrier, with a greater cellular uptake of FA-modified nanoparticles than that of HA-modified nanoparticles. Accordingly, MSN-PEI-FA showed more precise targeting and higher accumulation in tumours than did MSN-HA, as visualized by live imaging. Both types of nanoparticles had good biocompatibility and low toxicity, and MSN/CUR-PEI-FA inhibited the tumour growth to a greater degree than did free CUR. Thus, MSN/CUR-PEI-FA are a promising drug delivery system for the treatment of breast cancer.

[Research progress on Chinese medicines with topical administration in umbilical region].

Based on the Chinese medicines with topical administration in umbilical region approved by China Food and Drug Administration (CFDA), this paper would comb and analyze their dosage forms, varieties and clinical applications. On the other hand, through consulting literature materials, the research progress was reviewed and the main challenges faced by the medicines were discussed in detail as well. This paper elaborates that the preparations with topical administration in umbilical region, as an important branch in Chinese medicine external therapy, have unique advantages. However, there are still some problems such as rough workmanship, lacking internationally accepted quality control standards, scarcity of pharmacological and clinical evidences and biopharmaceutical researches. Meanwhile, proper measures and suggestions are put forward.

A Novel Solubility-Enhanced Rubusoside-Based Micelles for Increased Cancer Therapy.

Many anti-cancer drugs have a common problem of poor solubility. Increasing the solubility of the drugs is very important for its clinical applications. In the present study, we revealed that the solubility of insoluble drugs was significantly enhanced by adding rubusoside (RUB). Further, it was demonstrated that RUB could form micelles, which was well characterized by Langmuir monolayer investigation, transmission electron microscopy, atomic-force microscopy, and cryogenic transmission electron microscopy. The RUB micelles were ellipsoid with the horizontal distance of ~25 nm and vertical distance of ~1.2 nm. Insoluble synergistic anti-cancer drugs including curcumin and resveratrol were loaded in RUB to form anti-cancer micelles RUB/CUR + RES. MTT assay showed that RUB/CUR + RES micelles had more significant toxicity on MCF-7 cells compared to RUB/CUR micelles + RUB/RES micelles. More importantly, it was confirmed that RUB could load other two insoluble drugs together for remarkably enhanced anti-cancer effect compared to that of RUB/one drug + RUB/another drug. Overall, we concluded that RUB-based micelles could efficiently load insoluble drugs for enhanced anti-cancer effect.