Angiopep-2-modified calcium arsenite-loaded liposomes for targeted and pH-responsive delivery for anti-glioma therapy.

The blood-brain barrier (BBB) is the most critical obstacle in the treatment of central nervous system disorders, such as glioma, the most typical type of brain tumor. To overcome the BBB and enhance drug-penetration abilities, we used angiopep-2-modified liposomes to deliver arsenic trioxide (ATO) across the BBB, targeting the glioma. Angiopep-2-modified calcium arsenite-loaded liposomes (A2-PEG-LP@CaAs), with uniformly distributed hydrodynamic diameter (96.75 ± 0.57 nm), were prepared using the acetate gradient method with high drug-loading capacity (7.13 ± 0.72%) and entrapment efficiency (54.30 ± 9.81%). In the acid tumor microenvironment, arsenic was responsively released, thereby exerting an anti-glioma effect. The anti-glioma effect of A2-PEG-LP@CaAs was investigated both in vitro and in vivo. As a result, A2-PEG-LP@CaAs exhibited a potent, targeted anti-glioma effect mediated by the lipoprotein receptor-related (LRP) receptor, which is overexpressed in both the BBB and glioma. Therefore, A2-PEG-LP@CaAs could dramatically promote the anti-glioma effect of ATO, as a promising strategy for glioma therapy.

Angiopep-2 modified lipid-coated mesoporous silica nanoparticles for glioma targeting therapy overcoming BBB.

Glioma is the most typical malignant brain tumor, and the chemotherapy to glioma is limited by poor permeability for crossing blood-brain-barrier (BBB) and insufficient availability. In this study, angiopep-2 modified lipid-coated mesoporous silica nanoparticle loading paclitaxel (ANG-LP-MSN-PTX) was developed to transport paclitaxel (PTX) across BBB mediated by low-density lipoprotein receptor-related protein 1 (LRP1), which is over-expressed on both BBB and glioma cells. ANG-LP-MSN-PTX was characterized with homogeneous hydrodynamic size, high drug loading capacity (11.08%) and a sustained release. In vitro experiments demonstrated that the targeting efficiency of PTX was enhanced by ANG-LP-MSN-PTX with higher penetration ability (10.74%) and causing more C6 cell apoptosis. ANG-LP-MSN-PTX (20.6%) revealed higher targeting efficiency compared with LP-MSN-PTX (10.6%) via blood and intracerebral microdialysis method in the pharmacokinetic study. The therapy of intracranial C6 glioma bearing rats was increasingly efficient, and ANG-LP-MSN-PTX could prolong the survival time of model rats. Taken together, ANG-LP-MSN-PTX might hold great promise as a targeting delivery system for glioma treatment.

Lipid/PAA-coated mesoporous silica nanoparticles for dual-pH-responsive codelivery of arsenic trioxide/paclitaxel against breast cancer cells.

Nanomedicine has attracted increasing attention and emerged as a safer and more effective modality in cancer treatment than conventional chemotherapy. In particular, the distinction of tumor microenvironment and normal tissues is often used in stimulus-responsive drug delivery systems for controlled release of therapeutic agents at target sites. In this study, we developed mesoporous silica nanoparticles (MSNs) coated with polyacrylic acid (PAA), and pH-sensitive lipid (PSL) for synergistic delivery and dual-pH-responsive sequential release of arsenic trioxide (ATO) and paclitaxel (PTX) (PL-PMSN-PTX/ATO). Tumor-targeting peptide F56 was used to modify MSNs, which conferred a target-specific delivery to cancer and endothelial cells under neoangiogenesis. PAA- and PSL-coated nanoparticles were characterized by TGA, TEM, FT-IR, and DLS. The drug-loaded nanoparticles displayed a dual-pH-responsive (pHe = 6.5, pHendo = 5.0) and sequential drug release profile. PTX within PSL was preferentially released at pH = 6.5, whereas ATO was mainly released at pH = 5.0. Drug-free carriers showed low cytotoxicity toward MCF-7 cells, but ATO and PTX co-delivered nanoparticles displayed a significant synergistic effect against MCF-7 cells, showing greater cell-cycle arrest in treated cells and more activation of apoptosis-related proteins than free drugs. Furthermore, the extracellular release of PTX caused an expansion of the interstitial space, allowing deeper penetration of the nanoparticles into the tumor mass through a tumor priming effect. As a result, FPL-PMSN-PTX/ATO exhibited improved in vivo circulation time, tumor-targeted delivery, and overall therapeutic efficacy.

Low molecular weight chitosan-based conjugates for efficient Rhein oral delivery: synthesis, characterization, and pharmacokinetics.

OBJECTIVE: This article aims to design low molecular weight chitosan (LMWC)-based conjugates of Rhein (RH) by means of an amino acid linker (Alanine) for improved solubility and enhanced bioavailability. SIGNIFICANCE: Rhein is a potential candidate for the therapy of kidney disease. However, the poor solubility, inadequate bioavailability, and lack of proper formulation restrict its clinical applicability. LMWC-drug conjugates offer the potential to improve the water-solubility of RH, increase its oral absorption, and thereby enhance its bioavailability. METHODS: The conjugates were synthesized via a carbodiimide reaction and confirmed using UV-vis, FTIR, and 1H-NMR spectroscopy. The water-solubility and in vitro release properties were evaluated. Free RH and RH-LMWC conjugates were administered at an equivalent oral gavage dose of RH at 35 mg/kg for pharmacokinetic studies in Sprague Dawley rats. RESULTS: The conjugates with RH content of 9.65% were successfully synthesized and featured a satisfactory water-solubility of 9.73 mg/mL, which exhibited a sustained release pattern over 72 h, and the enzymes present may promote the degradation of the conjugate to increase the release of Rhein. Oral administration of RH-LMWC conjugates to rats led to seven-folds and 3.1-folds increase in the T1/2 and AUC0-∞, respectively, as compared to RH suspension. CONCLUSION: The present work demonstrated that the RH-LMWC conjugates exhibited sustained release properties with outstanding oral bioavailability enhancements compared to administration of RH itself. Potentially, RH-LMWC conjugates may serve as a promising lead for developing a new platform for RH oral delivery.

[Preparation and in vitro evaluation of arsenic trioxide glioma targeting drug delivery system loaded by PAMAM dendrimers co-modified with RGDyC and PEG].

Arsenic trioxide (ATO) is an effective component of traditional Chinese medicine arsenic. The existing studies have shown its good inhibition and apoptosis ability on a variety of tumours. However, its toxicity and difficulties in the permeability into the blood brain barrier (BBB) has the limitation in the application of glioma treatment. Polyamide-amine dendrimer (PAMAM) is a synthetic polymer with many advantages, such as a good permeability, stability and biocompatibility. Additionally, the 5th generation of PAMAM is an ideal drug carrier due to its three-dimensional structure. In this study, the 5th generation of PAMAM co-modified with RGDyC and PEG, then confirmed by ¹H-NMR. The average particle size of nanoparticles was about 20 nm according to the nanoparticle size-potential analyser and transmission electron microscopy. in vitro release showed that the nanocarrier not only has the sustained release effect, but also some pH-sensitive properties. The cell results showed that PAMAM co-modified with RGDyC and PEGAM has a lower cytotoxicity than the non-modified group in vitro. Accordingly, the drug delivery system has a better anti-tumour effect across the blood brain barrier (BBB) in vitro, which further proves the tumour targeting of RGDyC.

[Optimization of Formulation of Panax notoginseng Saponins Transfersomes].

OBJECTIVE: To optimize the formulation of Panax notoginseng saponins (PNS) transfersomes. METHODS: PNS transfersomes were prepared by film hydration-dispersion process. Based on the entrapment efficiency (EE) of ginsenoside Rg1 and ginsenoside Rb1, the effects of formulated quantity of sodium deoxycholate and cholesterol, the relative ion strength and pH value of hydration liquid were investigated. The formulation of PNS transfersomes were optimized by single-factor experiment and uniform design experiment. The in vitro characteristics of the optimized transfersomes were evaluated. RESULTS: The optimum formulation were as follows: egg phospholipid 0.45 g, cholesterol 0.05 g,vitamin E 0.01 g, sodium deoxycholate 0.119 g, PNS 0.1 g,10 mL of hydration liquid with pH at 4.75 (a mixture of 0.1 mol/L citric acid solution and 0.2 mol/L disodium orthophosphate solution, which corresponded to appropriate ion strength). The optimized PNS transfersomes had an average size of (121.8 ± 3.9) nm with a PDI of 0.136 ± 0.007 and a Zeta potential of (-8. 24 ± 0. 63) mV. The EE of ginsenoside Rg1 and ginsenoside Rb1 was 88.0% and 98.7% respectively. CONCLUSION: The formulation of PNS transfersomes can be optimized by uniform design experiment combined with single-factor experiment.

4-Deoxy-ε-Pyrromycinone: A Promising Drug/Lead Compound to Treat Tumors.

Background: Anthraquinone drugs are widely used in the treatment of tumors. However, multidrug resistance and severe cardiac toxicity limit its use, which have led to the discovery of new analogues. In this paper, 4-Deoxy-ε-pyrromycinone (4-Deo), belonging to anthraquinone compounds, was first been studied with the anti-tumor effects and the safety in vitro and in vivo as a new anti-tumor drug or lead compound. Methods: The quantitative analysis of 4-Deo was established by UV methodology. The anti-cancer effect of 4-Deo in vitro was evaluated by cytotoxicity experiments of H22, HepG2 and Caco2, and the anti-cancer mechanism was explored by cell apoptosis and cycle. The tumor-bearing mouse model was established by subcutaneous inoculation of H22 cells to evaluate the anti-tumor effect of 4-Deo in vivo. The safety of 4-Deo was verified by the in vitro safety experiments of healthy cells and the in vivo safety experiments of H22 tumor-bearing mice. Tumor tissue sections were labeled with CRT, HMGB1, IL-6 and CD115 to explore the preliminary anti-cancer mechanism by immunohistochemistry. Results: In vitro experiments demonstrated that 4-Deo could inhibit the growth of H22 by inducing cell necrosis and blocking cells in S phase, and 4-Deo has less damage to healthy cells. In vivo experiments showed that 4-Deo increased the positive area of CRT and HMGB1, which may inhibit tumor growth by triggering immunogenic cell death (ICD). In addition, 4-Deo reduced the positive area of CSF1R, and the anti-tumor effect may be achieved by blocking the transformation of tumor-associated macrophages (TAMs) to M2 phenotype. Conclusion: In summary, this paper demonstrated the promise of 4-Deo for cancer treatment in vitro and in vivo. This paper lays the foundation for the study of 4-Deo, which is beneficial for the further development anti-tumor drugs based on the lead compound of 4-Deo.

A self-assembly active nanomodulator based on berberine for photothermal immunotherapy of breast cancer via dual regulation of immune suppression.

Breast cancer (BC) remains a significant global health concern, especially affecting women, necessitating the development of effective treatment strategies. Photothermal immunotherapy has holds promise for addressing BC by eradicating tumors, preventing metastasis, and reducing recurrence rates. However, the dynamic amplification of indoleamine 2,3-dioxygenase 1 (IDO-1) and programmed cell death-ligand 1 (PD-L1) triggered by photothermal therapy (PTT) poses presents a significant barrier to immune cell infiltration, thus promoting immune evasion. To enhance overall efficiency, a hyaluronic acid (HA)-coated berberine (BBR)-indocyanine green self-assembly active nano modulator (HBI NDs) was successfully developed. This nano modulator aims to reverse immune resistance and further contribute to the synergistic anti-tumor effects. The prepared HBI NDs demonstrated a uniform spherical morphology, high drug loading, and favorable optical properties. The results based on in vitro cell experiments and tumor animal models confirmed that HBI NDs selectively accumulated in tumor tissues, downregulated PD-L1 and IDO-1 protein expression, and induced elevated cell apoptosis. Consequently, these effects result in efficient immune infiltration and positive anti-tumor outcomes. In conclusion, the HBI NDs nanodrug exhibits considerable potential as a novel agent for enhancing anticancer efficacy and promoting immune infiltration.

Lyophilization enhances the stability of Panax notoginseng total saponins-loaded transfersomes without adverse effects on ex vivo/in vivo skin permeation.

Transfersomes (TFSs) have been extensively investigated to enhance transdermal drug delivery. As a colloidal dispersion system, TFSs are prone to problems such as particle aggregation and sedimentation, oxidation and decomposition of phospholipids. To enhance the stability of panax notoginseng saponins (PNS)-loaded transfersomes (PNS-TFSs) without adverse influences on their skin permeation, we prepared lyophilized PNS-loaded transfersomes (PNS-FD-TFSs), clarified their physicochemical characteristics and investigated their in vitro drug release, ex vivo skin permeation/deposition and in vivo pharmacokinetics. In this study, a simple, fast and controllable process was developed for preparing lyophilized PNS-TFSs. In the optimized PNS-FD-TFS formulation, sucrose and trehalose were added to the PNS-TFS dispersion with a mass ratio of trehalose, sucrose, and phospholipid of 3:2:1, and the mixture was frozen at -80 °C for 12 h followed by lyophilization at -45 °C and 5 Pa for 24 h. The optimized formulation of PNS-FD-TFSs was screened based on the appearance and reconstitution time of the lyophilized products, vesicle size, and PDI of the freshly reconstituted dispersions. It maintained stable physicochemical properties for at least 6 months at 4 °C. The vesicle size of PNS-FD-TFSs was below 100 nm and homogenous with a polydispersity index of 0.2 after reconstitution. The average encapsulation efficiencies of the five index saponins notoginsenoside R1 (NGR1), ginsenoside Rg1 (GRg1), ginsenoside Re (GRe), ginsenoside Rb1 (GRb1) and ginsenoside Rd (GRd) in PNS-FD-TFSs were 68.41 ± 5.77%, 68.95 ± 6.08%, 65.46 ± 10.95%, 91.50 ± 5.62% and 95.78 ± 1.70%, respectively. The reconstituted dispersions of PNS-FD-TFSs were similar to PNS-TFSs in in vitro release, ex vivo skin permeation, and deposition. The pharmacokinetic studies showed that, compared with the PNS liposomes (PNS-LPS), the PNS-FD-TFS-loaded drug could permeate through the skin and enter the blood rapidly. It can be concluded that the lyophilization process can effectively improve the stability of PNS-TFSs without compromising their transdermal absorption properties.

Strategies to Regulate the Degradation and Clearance of Mesoporous Silica Nanoparticles: A Review.

Mesoporous silica nanoparticles (MSNs) have attracted extensive attention as drug delivery systems because of their unique meso-structural features (high specific surface area, large pore volume, and tunable pore structure), easily modified surface, high drug-loading capacity, and sustained-release profiles. However, the enduring and non-specific enrichment of MSNs in healthy tissues may lead to toxicity due to their slow degradability and hinder their clinical application. The emergence of degradable MSNs provided a solution to this problem. The understanding of strategies to regulate degradation and clearance of these MSNs for promoting clinical trials and expanding their biological applications is essential. Here, a diverse variety of degradable MSNs regarding considerations of physiochemical properties and doping strategies of degradation, the biodistribution of MSNs in vivo, internal clearance mechanism, and adjusting physical parameters of clearance are highlighted. Finally, an overview of these degradable and clearable MSNs strategies for biosafety is provided along with an outlook of the encountered challenges.

Correlation between in vivo microdialysis pharmacokinetics and ex vivo permeation for sinomenine hydrochloride transfersomes with enhanced skin absorption.

Transdermal drug delivery systems have drawn increasing attention in recent decades. Estimation of the correlation between ex vivo permeation and in vivo absorption (EVIVC) is an indispensable issue in the research and development of transdermal pharmaceutical products. In this paper, sinomenine hydrochloride (SH) transfersomes (SHTs) were prepared with sodium deoxycholate as edge activator, while SH liposomes (SHLs) were prepared as a control preparation. The transdermal permeation characteristics differences between them were explored by an ex vivo skin permeation experiment with Franz diffusion cell and an in vivo skin/blood pharmacokinetic experiment facilitated by double-sited microdialysis sampling technique. The curves of percentage absorbed versus time (absorption curves) under the skin and in the blood were plotted according to the percentages calculated by the deconvolution approach with the application of Wagner-Nelson model, and were correlated with the ex vivo permeation curves to evaluate a level A correlation, while a level C correlation evaluation was conducted based on the in vivo steady-state blood concentration (Css) and the ex vivo steady-state transdermal permeation rate. The ex vivo permeation test indicated that the cumulative transdermal permeated amount of SH at 36 h in SHTs was about 1.7 times of that in SHLs. The skin pharmacokinetic data showed that the Css and AUC0-t of SHTs were about 8.8 and 8.0 times of those of SHLs, respectively, and the MRT0-t of SHTs was shorter. The blood pharmacokinetic data showed that the Css and AUC0-t of SHTs were about 3.7 and 2.9 times of those of SHLs, respectively. The in vivo absorption curves were correlated well with the ex vivo permeation curves. The squares of correlation coefficient (R2) for SHTs and SHLs were 0.9153 and 0.9355 respectively in the skin, were 0.8536 and 0.7747 respectively in the blood. As to level C EVIVC, there was no significant difference between the predicted Css from ex vivo and the measured Cssin vivo. The transfersomes can be employed as effective vehicles to promote the transdermal absorption of SH, and it is feasible to predict the in vivo skin/blood pharmacokinetic properties of SHLs and SHTs based on the ex vivo skin permeation characteristics.

Hierarchically structured microcapsules for oral delivery of emodin and tanshinone IIA to treat renal fibrosis.

Renal fibrosis is the expected outcome of many chronic kidney diseases, and effective treatments are needed. Emodin (EMO) and tanshinone IIA (Tan IIA) are active ingredients in traditional Chinese herbs and have been effective in treating renal fibrosis. However, their application is greatly limited by inferior oral absorption, unexpected drug-drug interactions, and their ability to influence their respective pharmacokinetic profiles when used in combination. To mitigate these limitations, a new co-delivery approach based on a nano-in-micro system was designed by embedding Tan IIA-loaded nanoparticles (Tan IIA-NPs) in EMO-containing microcapsules. Microcapsules were prepared using the sharp flow technique that resulted in uniform spherical morphology and high encapsulation efficiency and drug loading. Furthermore, the encapsulated Tan IIA-NPs within the microcapsules exhibited superior cellular internalization and transmembrane transport due to the modification with cell-penetrating peptides and polyethylene glycol that facilitated the oral absorption of Tan IIA. Additionally, this nano-in-micro system exhibited evident sequential drug release. The oral bioavailability of EMO and Tan IIA was significantly improved when they were loaded into the hierarchically structured microcapsules, ultimately contributing to superior therapeutic outcomes in rats with unilateral ureteral obstruction. Therefore, the nano-in-micro carrier designed in this study could provide an efficient strategy for the effective oral delivery of combined therapies to treat renal fibrosis.

Nanocarrier-based delivery of arsenic trioxide for hepatocellular carcinoma therapy.

Hepatocellular carcinoma (HCC) poses a severe threat to human health and economic development. Despite many attempts at HCC treatment, most are inevitably affected by the genetic instability and variability of tumor cells. Arsenic trioxide (ATO) has shown to be effective in HCC. However, time-consuming challenges, especially the optimal concentration in tumor tissue and bioavailability of ATO, remain to be overcome for its transition from the bench to the bedside. To bypass these issues, nanotechnology-based delivery systems have been developed for prevention, diagnosis, monitoring and treatment in recent years. This article is a systematic overview of the latest contributions and detailed insights into ATO-loaded nanocarriers, with particular attention paid to strategies for improving the efficacy of nanocarriers of ATO.

Hepatocellular carcinoma (HCC) is the leading cause of cancer-related death worldwide; it is highly aggressive, has a poor prognosis and is often diagnosed late in the disease course. Arsenic trioxide (ATO), an established agent for the treatment of acute promyelocytic leukemia, has shown powerful therapeutic potential in the treatment of HCC. However, its narrow therapeutic window and severe toxicity, as well as resistance to ATO, limit its application for HCC treatment. Nanocarriers have been employed to deliver ATO to achieve effective therapeutic outcomes in HCC. This review describes the application of various nanocarrier-based delivery systems for ATO to enhance the effectiveness of tumor therapy and reduce its side effects, thus making it a promising therapeutic strategy for in HCC.

Lignin-assisted construction of sub-10 nm supramolecular self-assembly for photothermal immunotherapy and potentiating anti-PD-1 therapy against primary and distant breast tumors.

Photothermal therapy (PTT) has brought hope for cancer treatments, with hyperthermia-induced immunogenic cell death (ICD), which is a critical part of therapeutically induced antitumor immune responses. Limited immune stimulation response in PTT is the primary reason for incomplete tumor ablation, therefore demonstrating urgent requirements for ICD amplifier. Herein, a sub-10 nm supramolecular nanoassembly was formed by co-assembly of clinically approved aluminum adjuvant and commonly used indocyanine green (ICG) under the assistance of lignosulfonate (LS, a green and sustainable multifunctional lignin derivative) for localized photothermal-immunotherapy of breast cancer. The overall results revealed that LS-Al-ICG is capable of inducing amplified ICD, efficiently eliciting solid immune responses through dendritic cells (DCs) activation and cytotoxic T-cell responses initiation for tumor killing. Moreover, anti-PD-1 therapy blocked the PD-1 pathway and led to remarkable anti-tumor efficacy against laser-irradiated primary tumors and distant tumors by potentiating systemic tumor specific T cell immunity. The results of this study demonstrate a handy and extensible approach for engineering green natural lignin nanoparticles for cancer immunotherapy, which shows promise for delivering other therapeutics in biomedical applications.

Cooperative coordination-mediated multi-component self-assembly of "all-in-one" nanospike theranostic nano-platform for MRI-guided synergistic therapy against breast cancer.

Carrier-free multi-component self-assembled nano-systems have attracted widespread attention owing to their easy preparation, high drug-loading efficiency, and excellent therapeutic efficacy. Herein, MnAs-ICG nanospike was generated by self-assembly of indocyanine green (ICG), manganese ions (Mn2+), and arsenate (AsO4 3-) based on electrostatic and coordination interactions, effectively integrating the bimodal imaging ability of magnetic resonance imaging (MRI) and fluorescence (FL) imaging-guided synergistic therapy of photothermal/chemo/chemodynamic therapy within an "all-in-one" theranostic nano-platform. The as-prepared MnAs-ICG nanospike had a uniform size, well-defined nanospike morphology, and impressive loading capacities. The MnAs-ICG nanospike exhibited sensitive responsiveness to the acidic tumor microenvironment with morphological transformation and dimensional variability, enabling deep penetration into tumor tissue and on-demand release of functional therapeutic components. In vitro and in vivo results revealed that MnAs-ICG nanospike showed synergistic tumor-killing effect, prolonged blood circulation and increased tumor accumulation compared to their individual components, effectively resulting in synergistic therapy of photothermal/chemo/chemodynamic therapy with excellent anti-tumor effect. Taken together, this new strategy might hold great promise for rationally engineering multifunctional theranostic nano-platforms for breast cancer treatment.

Hydroxy-safflower yellow A composites: An effective strategy to enhance anti-myocardial ischemia by improving intestinal permeability.

Hydroxy-safflower yellow A (HSYA) is the chief component of safflower against myocardial ischemia (MI), and belongs to biopharmaceutics classification system (BCS) III drugs. Its structure contains multiple hydroxyl groups, contributing to its high polarity and poor oral bioavailability. The main objective of this study was to probe the potential of oral penetration enhancer n-[8-(2-hydroxybenzoyl) amino] sodium octanoate (SNAC) and cationic copolymer Eudragit®EPO (EPO) to promote absorption of HSYA. HSYA composites (SNAC-HSYA-EPO) were formed by hydrogen bonding and van der Waals force. SNAC-HSYA-EPO has biocompatibility, and can improve the membrane fluidity, uptake, transport, and penetration of Caco-2 cells. The mechanism of promoting of SNAC-HSYA-EPO may be related to energy and P-glycoprotein (P-gp) when compared with the inhibitor NaN3 and verapamil group. In the pharmacokinetic (PK) results, SNAC-HSYA-EPO significantly improved oral bioavailability. Pharmacodynamics (PD) results determined that SNAC-HSYA-EPO could improve the symptoms of MI. The mechanism of the SNAC-HSYA-EPO anti-MI is related to alleviating inflammation and anti-apoptosis to protect the heart. In summary, SNAC-HSYA-EPO prepared in this study possessed a complete appearance, high recombination rate and excellent oral permeability promoting ability. SNAC-HSYA-EPO has the potential to improve oral bioavailability and further enhance the anti-MI effect of HSYA.

Baicalin Magnesium Salt Attenuates Lipopolysaccharide-Induced Acute Lung Injury via Inhibiting of TLR4/NF-κB Signaling Pathway.

Baicalin (BA) magnesium salt (BA-Mg) is a good water-soluble ingredient extracted from Scutellaria baicalensis Georgi, a commonly used traditional Chinese medicine. This study is aimed at investigating whether BA-Mg could exert a better protective effect on lipopolysaccharide- (LPS-) induced acute lung injury (ALI) in mice and illuminate the underlying mechanisms in vivo and in vitro. Mice were intraperitoneally administrated with equimolar BA-Mg, BA, and MgSO4 before LPS inducing ALI. Lung tissues and bronchoalveolar lavage fluid were collected for lung wet/dry ratio, histological examinations, cell counts, and biochemical analyses at 48 h post-LPS exposure. Meanwhile, the protein expressions of TLR4/NF-κB signaling pathway and proinflammatory cytokines in lung tissues and lung bronchial epithelial cells (BEAS-2B) were detected. The results showed BA-Mg pronouncedly ameliorated LPS-induced inflammatory response and histopathological damages, elevated antioxidant enzyme activity (SOD), and downregulated myeloperoxidase (MPO) and malonaldehyde (MDA) levels through the inhibition of TLR4/NF-κB signaling pathway activation. Moreover, the effect of BA-Mg was significantly better than that of BA and MgSO4 in ameliorating symptoms. Overall, BA-Mg can effectively relieve inflammatory response and oxidative stress triggered by LPS, indicating it may be a potential therapeutic candidate for treating ALI.

MMP2-responsive dual-targeting drug delivery system for valence-controlled arsenic trioxide prodrug delivery against hepatic carcinoma.

Arsenic trioxide (ATO) is the active ingredient in traditional Chinese medicine, i.e., Arsenic, which has shown excellent therapeutic effects on hepatocellular carcinoma. However, due to its poor tumor distribution and high toxicity, the mass adoption of ATO in clinical applications has been severely impeded. In this study, matrix metalloproteinase 2 (MMP2)-responsive cleaved cell-penetrating peptide (PF) and folate (FA) co-modified liposome coated calcium arsenate nanoparticles (FA/PF-LP-CaAs) were fabricated based on these two considerations: (1) The tumor microenvironment characterized by overexpressed MMP2 in extracellular matrix and folate receptor on the cell membrane can enhance drug accumulation and accelerate endocytosis; (2) leveraging different toxicity of arsenic in different valence states, i.e., AsV can be reduced to more toxic AsIII by glutathione in tumor cells. Furthermore, FA/PF-LP-CaAs could be responsively degraded by the mild acidic tumor environment, and the degraded product could escape from lysosomes after endocytosis. More importantly, in light of the in vivo biodistribution and pharmacodynamic studies, the vehicle was able to accumulate in the tumor efficiently. Also, it was able to exhibit excellent anti-tumor efficacy with minimized side effects when compared to single-modified counterparts. Thus, the novel strategy based on the tumor microenvironment proposed in this work can enhance the tumor-targeting efficiency and intratumor toxicity.

Monoterpenes-containing PEGylated transfersomes for enhancing joint cavity drug delivery evidenced by CLSM and double-sited microdialysis.

The synovial tissues are natural sites of drug delivery for the treatment of rheumatoid arthritis. Our previous study showed that mixed monoterpenes edge-activated PEGylated transfersomes (MMPTs) could significantly enhance the percutaneous absorption of sinomenine (SIN), an anti-inflammation drug. The aim of this study was to investigate the potential of MMPTs for delivery of SIN to the synovial tissues in joint cavities. To this end, conventional liposomes (LPSs) were used as a reference. Transmission electron microscope, constant pressure extrusion method, and differential scanning calorimetry (DSC) were used for physicochemical characterization of the formulations. Confocal laser scanning microscopy (CLSM) and double-sited microdialysis coupled with LC-MS/MS were exploited to study the distribution of MMPTs in different skin layers and pharmacokinetics of SIN in the blood and the joint cavities. The results showed that mixed monoterpenes could significantly enhance the elasticity of MMPTs, evidenced by a decrease in the main transition temperature (Tm) and transition enthalpy (△H). CLSM analyses demonstrated that MMPTs were distributed in deep layers of the skin, indicating that MMPTs might transport SIN through the skin. In contrast, LPSs were confined in the stratum corneum, which deterred SIN from penetrating through the skin. The results from double-sited microdialysis pharmacokinetics showed that in the joint cavities the steady state concentration (Css) and AUC0→t of SIN from MMPTs were 2.1-fold and 2.5-fold of those from LPSs, respectively. In contrast, in the blood the Css and AUC0→t of SIN from MMPTs were about 1/3 of those from LPSs. This study suggested that MMPTs could enhance the delivery of SIN to the joint cavities. A combination of CLSM and double-sited microdialysis could give an insight into the mechanism of transdermal and local drug delivery.

[Determination of vitexin-rhamnoside in Beagle dog plasma and preliminary pharmacokinetics of Yixintong sustained release tablets].

OBJECTIVE: To develop an HPLC method to determine vitexin-rhamnoside in plasma of Beagle dogs and study the pharmacokinetics and bioavailability of Yixintong sustained release tablets in Beagle dogs. METHOD: A newly-developed HPLC method using C18 column and methanol-acetonitrile-tetrahydrogenfuran-0.5% acetic acid (1:1:19.4:78.6) as mobile phase was validated, and then was employed to determine vitexin-rhamnoside in plasma of Beagle dogs after oral administration of Yixintong sustained release tablets and general tablets. The main pharmacokinetic parameters were estimated by pharmacokinetic program 3p87. The non-compartmental pharmacokinetic parameters were also calculated on basis of the statistic moment theory. RESULT: The pharmacokinetic profiles of Yixintong sustained release tablets and the general tablets were fitted to a one-and two-compartment open model, respectively. The T1/2, Tmax, AUC0-infinity and MRT for Yixintong sustained release tablets were 5.22 h, 4.0 h, 6,792.75 ng x h x mL(-1) and 8.4 h, respectively, compared with 8.94 h, 1.0 h, 5,880.4 ng x h x mL(-1) and 6.1 h for the general tablets. The relative bioavailability of the Yixintong sustained release tablets was 115.5% in Beagle dogs. CONCLUSION: The sustained-release characteristic of Yixintong sustained release tablets were confirmed by pharmacokinetic study.