Nanoparticle drug delivery systems responsive to tumor microenvironment: Promising alternatives in the treatment of triple-negative breast cancer.

The conventional therapeutic treatment of triple-negative breast cancer (TNBC) is negatively influenced by the development of tumor cell drug resistant, and systemic toxicity of therapeutic agents due to off-target activity. In accordance with research findings, nanoparticles (NPs) responsive to the tumor microenvironment (TME) have been discovered for providing opportunities to selectively target tumor cells via active targeting or Enhanced Permeability and Retention (EPR) effect. The combination of the TME control and therapeutic NPs offers promising solutions for improving the prognosis of the TNBC because the TME actively participates in tumor growth, metastasis, and drug resistance. The NP-based systems leverage stimulus-responsive mechanisms, such as low pH value, hypoxic, excessive secretion enzyme, concentration of glutathione (GSH)/reactive oxygen species (ROS), and high concentration of Adenosine triphosphate (ATP) to combat TNBC progression. Concurrently, NP-based stimulus-responsive introduces a novel approach for drug dosage design, administration, and modification of the pharmacokinetics of conventional chemotherapy and immunotherapy drugs. This review provides a comprehensive examination of the strengths, limitations, applications, perspectives, and future expectations of both novel and traditional stimulus-responsive NP-based drug delivery systems for improving outcomes in the medical practice of TNBC. This article is categorized under: Therapeutic Approaches and Drug Discovery > Emerging Technologies Nanotechnology Approaches to Biology > Nanoscale Systems in Biology Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

EGCG attenuates the neurotoxicity of methylglyoxal via regulating MAPK and the downstream signaling pathways and inhibiting advanced glycation end products formation.

Methylglyoxal (MGO), a reactive α-oxoaldehyde formed in many foods and beverages during processing and storage, has neurotoxicity. The purpose of this study was to investigate the inhibition mechanism of (-)-epigallocatechin-3-gallate (EGCG) on MGO-induced PC12 cells damage. Cell apoptosis and reactive oxygen species (ROS) level were measured with fluorescent staining methods. Western blotting was used to detect the signal transduction mechanism. The results indicated that EGCG decreased ROS level, inhibited apoptosis and increased the expression of brain-derived neurotrophic factor. Pathways analysis revealed that the neuroprotective mechanism of EGCG might rely on regulating mitogen-activated protein kinase (MAPK) and downstream pathways. Multi-spectroscopy and molecular docking indicated that EGCG inhibited MGO-derived advanced glycation end products (AGEs) formation. Moreover, the neurotoxicity of AGEs could be alleviated by EGCG. These results suggested that EGCG could attenuate MGO-induced nerve damage via regulating MAPK and downstream pathways and inhibiting AGEs formation.

Activating caspase-8/Bid/ROS signaling to promote apoptosis of breast cancer cells by folate-modified albumin baicalin-loaded nanoparticles.

Abnormal apoptosis can lead to uncontrolled cell growth, aberrant homeostasis or the accumulation of mutations. Therapeutic agents that re-establish the normal functions of apoptotic signaling pathways offer an attractive strategy for the treatment of breast cancer. Baicalin (BA) is one of the natural compounds with anti-proliferation and pro-apoptosis activities against numerous tumor cells. However, low bioavailability restricts the clinical application of BA. In order to improve its therapeutic efficacy and study the mechanism of actions, active targeting delivery systems were developed for targeting tumor environment and selective cell killing effects. It emphasized on the construction of folate-conjugated albumin nanoparticles loaded with baicalin (FA-BSANPs/BA) and mechanisms of which on the promotion of breast cancer apoptosis. The physicochemical properties and structural characteristics of FA-BSANPs/BA were investigated. Cell experiments were carried out to study the targeted anti-breast cancer effects of FA-BSANPs/BA and its mechanism. The results showed that FA-BSANPs/BA was successfully constructed with stable structural characteristics and sustained release effects. Cellular uptake and MTT showed that it increased targeted uptake efficiency and cytotoxicity. Flow cytometry and western blot confirmed that it promoted apoptosis by increasing the expression of caspase-8 and ROS, and decreasing the level of Bid. It is suggested that the pro-apoptotic mechanism of FA-BSANPs/BA is related to regulation of key proteins in extrinsic apoptotic pathway. In conclusion, FA-BSANPs/BA is a good delivery carrier and significantly inhibits the breast cancer growth compared with free BA. The mechanism of FA-BSANPs/BA promoting apoptosis of breast cancer may be due to its action on the caspase-8/Bid/ROS pathway.

Protective effects of psoralen polymer lipid nanoparticles on doxorubicin - induced myocardial toxicity

Abstract Doxorubicin (DOX) induced myocardial toxicity may limit its therapeutic use in clinic. Psoralen (PSO), a major active tricyclic furocoumarin extracted from Psoralea corylifolia, is widely used as an antineoplastic agent in treatment of leukemia and other cancers. This study is aim to find the protective effect of psoralen polymer lipid nanoparticles (PSO-PLN) on doxorubicin-induced myocardial toxicity in mice. The model of myocardial toxicity induced by DOX was established. The experiment was divided into 6 groups: normal saline group, DOX + Sulfotanshinone Sodium, DOX + PSO-PLN (3 mg/kg), DOX + PSO-PLN (6 mg/kg), DOX + PSO-PLN (9 mg/ kg), DOX group. DOX alone treated mice lead to a significant decrease in the body weight, heart weight, and increase in the serum levels of lactate dehydrogenase (LDH), creatine kinase (CK) and malondialdehyde (MDA) markers of cardiotoxicity. However, DOX reduced glutathione (GSH) content and activities of antioxidant enzymes, including superoxide dismutase (SOD) and glutathione peroxidase (GPX), were recovered by PSO-PLN. And PSO-PLN also decreased markers of cardiotoxicity in the serum. Western blotting data showed that the protective effects of PSO-PLN might be mediated via regulation of protein kinase A (PKA) and p38. Our study suggest that PSO-PLN possesses antioxidant activities, inactivating PKA and p38 effect, which in turn protect the heart from the DOX-induced cardiotoxicity.

Psoralen-loaded polymeric lipid nanoparticles combined with paclitaxel for the treatment of triple-negative breast cancer.

Background: Chemotherapeutic drugs are associated with toxic effects. Metastasis is the leading cause of death in breast cancer patients. Aim: To evaluate the antitumor effect of paclitaxel (PTX) combined with psoralen-loaded polymeric lipid nanoparticles (PSO-PLNs) in triple-negative breast cancer. Methods: After treatment of samples, cell viability, apoptosis, migration, invasion, expression of proteins in the IRAK1/NF-κB/FAK signal pathway, biodistribution and pathological characteristics were detected. Results: Compared with the control group, the PTX + PSO-PLNs group showed increased apoptosis and reduced migration, invasion and expression of phosphorylated IRAK1 and NF-κB, with significant inhibition of tumor growth and lung metastases and no obvious toxicity. Conclusion: Combined administration of PTX and PSO-PLNs exerted a synergistic effect and significantly inhibited the growth and metastasis of triple-negative breast cancer.

Key Factor Regulating Inflammatory Microenvironment, Metastasis, and Resistance in Breast Cancer: Interleukin-1 Signaling.

Breast cancer is one of the top-ranked cancers for incidence and mortality worldwide. The biggest challenges in breast cancer treatment are metastasis and drug resistance, for which work on molecular evaluation, mechanism studies, and screening of therapeutic targets is ongoing. Factors that lead to inflammatory infiltration and immune system suppression in the tumor microenvironment are potential therapeutic targets. Interleukin-1 is known as a proinflammatory and immunostimulatory cytokine, which plays important roles in inflammatory diseases. Recent studies have shown that interleukin-1 cytokines drive the formation and maintenance of an inflammatory/immunosuppressive microenvironment through complex intercellular signal crosstalk and tight intracellular signal transduction, which were found to be potentially involved in the mechanism of metastasis and drug resistance of breast cancer. Some preclinical and clinical treatments or interventions to block the interleukin-1/interleukin-1 receptor system and its up- and downstream signaling cascades have also been proven effective. This study provides an overview of IL-1-mediated signal communication in breast cancer and discusses the potential of IL-1 as a therapeutic target especially for metastatic breast cancer and combination therapy and current problems, aiming at enlightening new ideas in the study of inflammatory cytokines and immune networks in the tumor microenvironment.

Screening of metabolites in the treatment of liver cancer xenografts HepG2/ADR by psoralen-loaded lipid nanoparticles.

OBJECTIVE: Our study aimed to find potential biomarkers for drug resistance in liver cancer cells using metabolomics and further to evaluate the potential of psoralen-loaded polymer lipid nanoparticles (PSO-PLNs) to reverse the resistance of cells to doxorubicin. METHODS: We used LC-MS-based non-targeted metabolomics, also known as global metabolite profiling, to screen in serum and urine of mice engrafted with a liver cancer cell line sensitive (HepG2/S) or resistant to doxorubicin (HepG2/ADR) for differentially regulated metabolites. We subsequently quantified the abundance of these metabolites in serum and the urine of mice. The mice were engrafted with HepG2 cells resistant against doxorubicin and were treated with I) doxorubicin, II) a combination of doxorubicin and psoralen and III) a combination of doxorubicin and psoralen packed in polymer lipid nanoparticles. RESULTS: Metabolites found to be differentially present in urine of mice engrafted with resistant HepG2 cells were: hippuric acid, hyaluronic acid, pantothenic acid, and betaine; retinoic acid and α-linolenic acid were found to be reduced in serum samples of mice with HepG2 cells resistant to doxorubicin. The targeted analysis showed that the degree of regression of metabolic markers in groups differed: treatment group 2 had stronger degree of regression than treatment group 1 and the negative control group had the smallest, which indicates that the PSO-PLNs have superior properties compared with other treatments. CONCLUSION: Psoralen reverses drug resistance of liver cancer cells and its efficacy can be increased by encapsulation in polymer lipid nanoparticles.

A review of nanoparticle drug delivery systems responsive to endogenous breast cancer microenvironment.

Breast cancer, as a malignant disease that seriously threatens women's health, urgently needs to be researched to develop effective and safe therapeutic drugs. Nanoparticle drug delivery systems (NDDS), provide a powerful means for drug targeting to the breast cancer, enhancing the bioavailability and reducing the adverse effects of anticancer drug. However, the breast cancer microenvironment together with heterogeneity of cancer, impedes the tumor targeting effect of NDDS. Breast cancer microenvironment, exerts endogenous stimuli, such as hypoxia, acidosis, and aberrant protease expression, shape a natural shelter for tumor growth, invasion and migration. On the basis of the ubiquitous of endogenous stimuli in the breast cancer microenvironment, researchers exploited them to design the stimuli-responsive NDDS, which response to endogenous stimulus, targeted release drug in breast cancer microenvironment. In this review, we highlighted the effect of the breast cancer microenvironment, summarized innovative NDDS responsive to the internal stimuli in the tumor microenvironment, including the material, the targeting groups, the loading drugs, targeting position and the function of stimuli-responsive nanoparticle drug delivery system. The limitations and potential applications of the stimuli-responsive nanoparticle drug delivery systems for breast cancer treatment were discussed to further the application.

Polymeric Lipid Hybrid Nanoparticles as a Delivery System Enhance the Antitumor Effect of Emodin in Vitro and in Vivo.

This study aimed to evaluate the therapeutic efficacy of Emodin-loaded polymer lipid hybrid nanoparticles (E-PLNs) for breast cancer. The size, Zeta potential, surface morphology, encapsulation efficiency, stability, in vitro drug release of E-PLNs prepared by the nanoprecipitation method were characterized. The uptake, in-vitro cytotoxicities and apoptosis of free drug, E-PLNs were investigated against MCF-7 cells. The efficacy of E-PLNs in tumor bearing nude mice has also been studied.The average particle size of the experimentally prepared E-PLNs was (122.7±1.79) nm, and the encapsulation rate was 72.8%. Compared with free Emodin (EMO), E-PLNs showed greater toxicity to MCF-7 cells by promoting the uptake of EMO, and can promote the early apoptosis of MCF-7 cells. In addition to the morphological changes of apoptotic cells, the ratio of Bax/Bcl-2 was significantly increased, which indicated that E-PLNs can induce apoptosis in MCF-7 cells to achieve anticancer effect. Finally, E-PLNs significantly inhibited tumor growth by more than 60%, which may be related to its passive targeting effect on tumor site. Our results suggest that E-PLNs have shown good anti-breast cancer effect than free EMO. Moreover, the effect of E-PLNs on MCF-7 cells is mainly related to the induction of apoptosis.

Role of inflammatory microenvironment: potential implications for improved breast cancer nano-targeted therapy.

Tumor cells, inflammatory cells and chemical factors work together to mediate complex signaling networks, which forms inflammatory tumor microenvironment (TME). The development of breast cancer is closely related to the functional activities of TME. This review introduces the origins of cancer-related chronic inflammation and the main constituents of inflammatory microenvironment. Inflammatory microenvironment plays an important role in breast cancer growth, metastasis, drug resistance and angiogenesis through multifactorial mechanisms. It is suggested that inflammatory microenvironment contributes to providing possible mechanisms of drug action and modes of drug transport for anti-cancer treatment. Nano-drug delivery system (NDDS) becomes a popular topic for optimizing the design of tumor targeting drugs. It is seen that with the development of therapeutic approaches, NDDS can be used to achieve drug-targeted delivery well across the biological barriers and into cells, resulting in superior bioavailability, drug dose reduction as well as off-target side effect elimination. This paper focuses on the review of modulation mechanisms of inflammatory microenvironment and combination with nano-targeted therapeutic strategies, providing a comprehensive basis for further research on breast cancer prevention and control.

Strategies for Preparing Different Types of Lipid Polymer Hybrid Nanoparticles in Targeted Tumor Therapy.

At present, cancer is one of the most common diseases in the world, causing a large number of deaths and seriously affecting people's health. The traditional treatment of cancer is mainly surgery, radiotherapy or chemotherapy. Conventional chemotherapy is still an important treatment, but it has some shortcomings, such as poor cell selectivity, serious side effects, drug resistance and so on. Nanoparticle administration can improve drug stability, reduce toxicity, prolong drug release time, prolong system half-life, and bring broad prospects for tumor therapy. Lipid polymer hybrid nanoparticles (LPNs), which combine the advantages of polymer core and phospholipid shell to form a single platform, have become multi-functional drug delivery platforms. This review introduces the basic characteristics, structure and preparation methods of LPNs, and discusses targeting strategies of LPNs in tumor therapy in order to overcome the defects of traditional drug therapy.

Effects of immune cells and cytokines on inflammation and immunosuppression in the tumor microenvironment.

Chronic inflammation and immune responses are two core element that characterize the tumor microenvironment. A large number of immune/inflammatory cells (including tumor associated macrophages, neutrophils and myeloid derived suppressor cells) as well as cytokines (such as IL-6, IL-10, TGF-ß) are present in the tumor microenvironment, which results in both a chronic inflammatory state and immunosuppression. As a consequence tumor cell migration, invasion, metastasis and anticancer drug sensitivity are modulated. On the one hand, secreted cytokines change the function of cytotoxic T lymphocytes and antigen presenting cells, thereby inhibiting tumor specific immune responses and consequently inducing a special immunosuppressive microenvironment for tumor cells. On the other hand, tumor cells change the differentiation and function of immune/inflammatory cells in the tumor microenvironment especially via the NF-κB and STAT3 signaling pathways. This may promote proliferation of tumor cells. Here we review these double edged effects of immune/inflammatory cells and cytokines on tumor cells, and explored their interactions with inflammation, hypoxia, and immune responses in the tumor microenvironment. The tumor inflammatory or immunosuppressive reactions mediated by the high activity of NF-κB or STAT3 can occur alone or simultaneously, and there is a certain connection between them. Inhibiting the NF-κB or STAT3 signaling pathway is likely to curb the growth of tumor cells, reduce the secretion of pro-inflammatory factors, and enhance the anti-tumor immune response.

Polymeric-based microneedle arrays as potential platforms in the development of drugs delivery systems.

BACKGROUND: Microscopic patches as quite promising platforms in transdermal drug delivery suffer from conventional injections. In other hand, a wide range of pharmacokinetics, ranging from fast oral administration to sustained drug delivery, can be implemented with the help of microneedle arrays (MNAs). AIM OF REVIEW: Hence, in this paper, we overviewed different kinds of MNAs such as solid/coated, hollow, porous, hydrogel/swellable, and merged-tip geometry followed by introducing different types of material (silicon, glass, ceramics, dissolving and biodegradable polymers, and hydrogel) used for fabrication of MNAs. Afterwards, some conventional and brand-new simple and customizable MN mold fabrication techniques were surveyed. Polymeric MNAs have received a great deal of attention due to their potential biocompatibility and biodegradability in comparison to other materials. Therefore, we also covered different kinds of polymers such as hydrogel/swellable, dissolving and biodegradable analogues used for the development of MNAs as potential candidates in drug delivery systems (DDSs). Finally, we discussed different challenges and future perspectives in the aspect of MNAs-based drug delivery platforms. KEY SCIENTIFIC CONCEPTS OF REVIEW: This review may provide guidelines for the rational design of polymeric MNAs-based DDSs for promising programmable drug release and enhanced therapeutic effect.

Design and development of spirulina polysaccharide-loaded nanoemulsions with improved the antitumor effects of paclitaxel.

Aims: In this study, we prepared spirulina polysaccharides into spirulina polysaccharide-loaded nanoemulsions (SPS-NEs), and determined the antitumor effect of SPS-NEs, when combined with paclitaxel (PTX).Methods: SPS-NEs were prepared by a phase transformation method. The Characterisation and stability of SPS-NEs was measured. The antitumor effect of SPS-NEs combined with PTX was determined by S180 cells or RAW 264.7 macrophages and S180 tumour-bearing mice.Results: SPS-NEs were spherical and stable, the particle size of SPS-NEs was 84.6 ± 3.31 nm, PDI = 0.235 ± 0.02. PTX + SPS-NEs exhibited a much greater toxicity against RAW 264.7 cells than PTX. PTX + SPS-NEs increased the release of NO, IL-6 and TNF-α, and the expression of p-p65 NF-κB, p-I-κB, TLR4. In addition, PTX + SPS-NEs significantly inhibited tumour growth by 72.82% and increased the secretion of serum IL-2, TNF-α and IFN-γ.Conclusions: SPS-NEs can regulate immunity through TLR4/NF-κB signalling pathways, which enhances the anti-tumour effect of PTX.

Chemokines and chemokine receptors: A new strategy for breast cancer therapy.

Chemokines and chemokine receptors not only participate in the development of tissue differentiation, hematopoiesis, inflammation, and immune regulation but also play an important role in the process of tumor development. The role of chemokines and chemokine receptors in tumors has been emphasized in recent years. More and more studies have shown that chemokines and chemokine receptors are closely related to the occurrence, angiogenesis, metastasis, drug resistance, and immunity of breast cancer. Here, we review recent progression on the roles of chemokines and chemokine receptors in breast cancer, and discuss the possible mechanism in breast cancer that might facilitate the development of new therapies by targeting chemokines as well as chemokine receptors. Chemokines and chemokine receptors play an important role in the occurrence and development of breast cancer. In-depth study of chemokines and chemokine receptors can provide intervention targets for breast cancer biotherapy. The regulation of chemokines and chemokine receptors may become a new strategy for breast cancer therapy.

Vitamin K1 Inhibition of Renal Crystal Formation through Matrix Gla Protein in the Kidney.

BACKGROUND AND OBJECTIVES: Vitamin K (VK) plays a major role in modifying the binding of calcium in bones and blood vessels. Understanding the effect of VK on crystal formation in the kidney would contribute to advancing the treatment and prevention of kidney stones. METHODS: Rats were treated with vitamin K1 (VK1) for 8 weeks. VK1 levels were detected and crystal formation were observed. HK2 cells were exposed to calcium oxalate monohydrate crystals. Apoptosis and cell viability were detected. Crystal deposition was analyzed using atomic absorption assay. The adenovirus vectors expressing matrix Gla protein (MGP) and siMGP were constructed to elucidate the effect and mechanism of VK1 on crystal formation. MGP expression in vivo and in vitro was analyzed by Western blot. The mRNA levels of monocyte chemoattractant protein-1 (MCP-1) and collagen I was measured by semiquantitative RT-PCR. RESULTS: The concentrations of VK1 in whole blood and kidney tissues rose under treatment with VK1. Crystal formation was inhibited from the second to the 6th week, the frequency and quality of crystal formation decreased significantly, and the location of crystal formation was limited to a greater extent in the rats treated by VK1 compared to the control group. Warfarin treatment in the crystals-exposed HK2 cells significantly increased the number of crystals adhering to cells and the number of apoptotic cells and reduced cell viability. VK1 treatment reversed warfarin's above influence. VK1 inhibited the upregulations of MCP-1 and collagen I in kidney tissues under crystal load. VK1 treatment increased MGP expression in vivo and in vitro, and MGP is necessary for VK1 to play a role in crystal deposition in cells. CONCLUSIONS: VK1 treatment can inhibit the formation of renal crystals in vivo. VK1 increases MGP expression and functions through MGP to reduce crystal deposition in cells and provide cell protection. Our findings suggest that VK1 treatment could be a potential strategy for the treatment and prevention of nephrolithiasis.

Nanotargeted agents: an emerging therapeutic strategy for breast cancer.

Breast cancer is the most common female cancer worldwide and represents 12% of all cancer cases. Improvements in survival rates are largely attributed to improved screening and diagnosis. Conventional chemotherapy remains an important treatment option but it is beset with poor cell selectivity, serious side effects and resistance. Nanoparticle drug delivery systems bring promising opportunities to breast cancer treatment. They may improve chemotherapy by targeting drugs to tumors, generating high drug concentrations at tumors providing slow release of the drug, increased drug stability and concomitant reductions in side effects. The nanotechnology-based drug delivery approaches and the current research and application status of nano-targeted agents for breast cancer are discussed in this review to provide a basis for further study on targeted drug delivery systems.

A review of pharmacological and clinical studies on the application of Shenling Baizhu San in treatment of Ulcerative colitis.

ETHNOPHARMACOLOGICAL RELEVANCE: The prescription of Shenling Baizhu San (SLBZS) was derived from the Song Dynasty "Taiping Huimin Heji Ju Fang", which was a representative prescription for treating spleen asthenic diarrhea. The prescription comprised of 10 herbs for treating weak spleen and stomach. It describes symptoms like eating less, loose stools, cough, shortness of breath and tired limbs. SLBZS has been reported to be capable of eliminating discomfort when it is administered for treating irritable bowel syndrome and diarrhea. This traditional Chinese medicine (TCM) formula has been widely used for improving gastrointestinal dysfunction and modifying the immune response to inflammation. AIM OF THE STUDY: This review is aimed to provide the up-to-date information on the pharmacology and clinical research of SLBZS in the treatment of ulcerative colitis (UC), and to discuss the research findings and possible deficiencies, hoping to better guide the clinical application and scientific research of SLBZS in the treatment of UC. MATERIALS AND METHODS: Relevant studies from 2004 to 2018 on SLBZS in the treatment of UC mechanism and curative effect were collected from ancient books, pharmacopoeia, reports, thesis via library and Digital databases (PubMed, CNKI, Google Scholar, Web of Science, SciFinder, Springer, Elsevier, etc). RESULTS: SLBZS could regulate inflammatory factors and intestinal flora, and ERK/p38 MAPK signaling pathway may be one of its targets. In addition, clinical research results show that SLBZS has a good therapeutic effect on UC, and the adverse reactions are small. CONCLUSION: Although SLBZS has achieved some success in the treatment of UC, there are still some scientific gaps. There is a lack of uniform standards for constructing UC animal models, and some methods of modeling through environmental and dietary interventions are not reproducible, and there is a lack of uniform dosing regimen standards. SLBZS doses follow the tradition and lack toxicological validation. Therefore, more specific toxicological research models are essential. The clinical application of SLBZS requires reassessment and standardization. Although all clinical research reports randomly assigned patients to different groups, most did not describe a detailed method of randomization and no description of the analysis data. In addition, extensive in vitro studies and further in-depth molecular studies are essential for the determination of mechanisms that have been performed in all in vivo experiments on animal models and patients.

A novel polysaccharide from Lentinus edodes mycelia protects MIN6 cells against high glucose-induced damage via the MAPKs and Nrf2 pathways.

BACKGROUND: Diabetes mellitus is one of the most widespread diseases in the world, high glucose can damage islet cells, it is important to discover new natural products to inhibit high glucose damage. The protective effects and mechanisms of a novel Lentinus edodes mycelia polysaccharide (LMP) against damage induced by high glucose in MIN6 cells were explored. METHODS: Cell viability, malondialdehyde (MDA) inhibition, lactate dehydrogenase (LDH) release and the activity of superoxide dismutase (SOD) were evaluated under 40 mM glucose with or without LMP for 48 h. Cell signaling pathway analysis was performed to investigate the possible mechanisms of the protective effects of LMP in MIN6 cells. RESULTS: The results showed that LMP could increase cell viability and the activity of SOD, decrease the reactive oxygen species ( ROS) production, and reduce the MDA content and LDH release in high glucose-induced MIN6 cells. Moreover, LMP prevented high glucose-induced apoptosis by decreasing the expression of Bax and the activation of caspase-1 and caspase-3. Cell signaling pathway analysis showed that p38 mitogen-activated protein kinase (MAPK) and JNK pathways were inhibited and the Nrf2 pathway was activated after treated with LMP. CONCLUSION: The protective effects of LMP against MIN6 cells damage induced by high glucose might rely on the regulation of the MAPK and Nrf2 pathways. These results indicated that LMP had great potential as a therapeutic agent for the treatment of diabetes mellitus.

Psoralen-loaded lipid-polymer hybrid nanoparticles enhance doxorubicin efficacy in multidrug-resistant HepG2 cells.

BACKGROUND: Psoralen (PSO), a major active component of Psoralea corylifolia, has been shown to overcome multidrug resistance in cancer. A drug carrier comprising a lipid-monolayer shell and a biodegradable polymer core for sustained delivery and improved efficacy of drug have exhibited great potential in efficient treatment of cancers. METHODS: The PSO-loaded lipid polymer hybrid nanoparticles were prepared and characterized. In vitro cytotoxicity assay, cellular uptake, cell cycle analysis, detection of ROS level and mitochondrial membrane potential (ΔΨm) and western blot were performed. RESULTS: The P-LPNs enhanced the cytotoxicity of doxorubicin (DOX) 17-fold compared to free DOX in multidrug resistant HepG2/ADR cells. Moreover, P-LPNs displayed pro-apoptotic activity, increased levels of ROS and depolarization of ΔΨm. In addition, there were no signifi-cant effects on cellular uptake of DOX, cell cycle arrest, or the expression of P-glycoprotein. Mechanistic studies suggested that P-LPNs enhanced DOX cytotoxicity by increased release of cytochrome c and enhanced caspase3 cleavage, causing apoptosis in HepG2/ADR cells. CONCLUSION: The lipid-polymer hybrid nanoparticles can be considered a powerful and promising drug delivery system for effective cancer chemotherapy.