Research progress on vesicles from Chinese medicinal herbs / 浙江大学学报·医学版

Vesicles derived from Chinese medicinal herbs (VCMH) are nano-vesicular entities released by the cells of Chinese medicinal herbs. VCMHs have various biological effects and targeting characteristics, and their component chemicals and functional activities are closely related to the parent plant. VCMH differs from animal-derived vesicles in three ways: stability, specificity, and safety. There are a number of extraction and isolation techniques for VCMH, each with their own benefits and drawbacks, and there is no unified standard. When two or more approaches are used, high quantities of intact vesicles can be obtained more quickly and efficiently. The obtained VCMHs were systematically examined and evaluated. Firstly, they are generally saucer-shaped, cup-shaped or sphere, with particle size of 10-300 nm. Secondly, they contain lipids, proteins, nucleic acids and other active substances, and these components are an important part for intercellular information transfer. Finally, they mostly have good biocompatibility and low toxicity, with anti-inflammatory, antioxidant, anti-tumor and anti-fibrotic effects. As a new drug carrier, VCMHs have outstanding active targeting capabilities, and the capsule form can effectively preserve the drugs, considerably enhancing drug delivery efficiency and stability in vitro and in vivo. The modification of its vesicular structure by suitable physical or chemical means can further create more stable and precise drug carriers. This article reviews the extraction and purification techniques, activity evaluation and application of VCMH to provide information for further research and application of new active substances and targeted drug carriers.

Ginsenoside Rg_3 based liposomes target delivery of dihydroartemisinin and paclitaxel for treatment of triple-negative breast cancer / 中国中药杂志

Ginsenoside Rg_3, an active component of traditional Chinese medicine(TCM), was used as the substitute for cholesterol as the membrane material to prepare the ginsenoside Rg_3-based liposomes loaded with dihydroartemisinin and paclitaxel. The effect of the prepared drug-loading liposomes on triple-negative breast cancer in vitro was evaluated. Liposomes were prepared with the thin film hydration method, and the preparation process was optimized by single factor experiments. The physicochemical properties(e.g., particle size, Zeta potential, and stability) of the liposomes were characterized. The release behaviors of drugs in different media(pH 5.0 and pH 7.4) were evaluated. The antitumor activities of the liposomes were determined by CCK-8 on MDA-MB-231 and 4T1 cells. The cell scratch test was carried out to evaluate the effect of the liposomes on the migration of MDA-MB-231 and 4T1 cells. Further, the targeting ability of liposomes and the mechanism of lysosome escape were investigated. Finally, H9c2 cells were used to evaluate the potential cardiotoxicity of the preparation. The liposomes prepared were spheroid, with uniform particle size distribution, the ave-rage particle size of(107.81±0.01) nm, and the Zeta potential of(2.78±0.66) mV. The encapsulation efficiency of dihydroartemisinin and paclitaxel was 57.76%±1.38% and 99.66%±0.07%, respectively, and the total drug loading was 4.46%±0.71%. The accumulated release of dihydroartemisinin and paclitaxel from the liposomes at pH 5.0 was better than that at pH 7.4, and the liposomes could be stored at low temperature for seven days with good stability. Twenty-four hours after administration, the inhibition rates of the ginsenoside Rg_3-based liposomes loaded with dihydroartemisinin(70 μmol·L~(-1)) and paclitaxel on MDA-MB-231 and 4T1 cells were higher than those of the positive control(adriamycin) and free drugs(P<0.01). Compared with free drugs, liposomes inhibited the migration of MDA-MB-231 and 4T1 cells(P<0.05). Liposomes demonstrated active targeting and lysosome escape. In particular, liposomes showed lower toxicity to H9c2 cells than free drugs(P<0.05), which indicated that the preparation had the potential to reduce cardiotoxicity. The findings prove that ginsenoside Rg_3 characterized by the combination of drug and excipient is an ideal substitute for lipids in liposomes and promoted the development of innovative TCM drugs for treating cancer.

Progresses on active targeting liposome drug delivery systems for tumor therapy / 生物医学工程学杂志

Liposome is an ideal drug carrier with many advantages such as excellent biocompatibility, non-immunogenicity, and easy functionalization, and has been used for the clinical treatment of many diseases including tumors. For the treatment of tumors, liposome has some passive targeting capability, but the passive targeting effect alone is very limited in improving the drug enrichment in tumor tissues, and active targeting is an effective strategy to improve the drug enrichment. Therefore, active targeting liposome drug-carriers have been extensively studied for decades. In this paper, we review the research progresses on active targeting liposome drug-carriers based on the specific binding of the carriers to the surface of tumor cells, and summarize the opportunities, challenges and future prospects in this field.

Research progress on anti-tumor mechanisms of arsenic trioxide and its drug delivery system / 中草药

Arsenic trioxide, a mineral drug of Chinese medicine material medica with significant therapeutic effect, has been approved by USA Food and Drug Administration (FDA) for the treatment of acute promyelocytic leukemia. In recent years, it has also been found to have a great therapeutic effect on the treatment of solid tumors. The anti-tumor mechanisms mainly include promoting apoptosis, inhibiting Hedgehog signaling pathway, reversing drug resistance and inhibiting angiogenesis. However, the poor targeting ability in vivo, the rapid renal clearance rate, and the toxic and side effects of high dose on normal tissues of arsenic trioxide limit the application and clinical transformation for the treatment of solid tumor. On the basis of traditional nanoparticles, the novel drug delivery system improves the drug aggregation, controlling-release and diagnosis in tumor sites, which is of great significance in accurate treatment, improvement of bioavailability and reduction of toxic and side effects. Research progress on anti-tumor mechanisms of arsenic trioxide and its drug delivery system in recent years was summarized and analyzed in this paper, in order to provide ideas for the in-depth research and clinical application of arsenic trioxide.

Antitumor effect of umbilical cord mesenchymal stem cells:research advances / 国际药学研究杂志

Umbilical cord mesenchymal stem cells(UC-MSC)are a kind of stem cell group with high self-renewal ability and multi-directional differentiation potential. In recent years,studies have shown that UC-MSC is far more advan- tageous than the stem cells from other sources in terms of acquisition,storage and transplantation. UC-MSC also possesses the characteristics of secreting specific cytokines,playing an immunomodulatory role,or delivering”drugs”to the special tumor sites. Therefore,UC-MSC has become a promising tumor-targeting tool. This article reviews recent advances in the research on the antitumor mechanism and safety of UC-MSC.

Research progress and consideration of polymeric prodrugs / 中国药科大学学报

@#Currently the available therapies cannot satisfy all the clinical requirements, therefore advanced technologies are urgently demanded. Delivery system the polymeric prodrug based has both advantages of prodrug strategy and nanoparticle drug delivery strategy. The system can improve the drug bioavailability, enhance the drug stability, and make the drug targeting system more effective. The system can reduce the side effects and improve the therapeutic effect of drug. According to the mechanism of this drug system, passive targeting, active targeting, triggered release and co-administration were reviewed. Finally, the research prospects and issues in this field were pointed out.

Research progress on active targeting effect of chitosan nano-delivery system improving microenvironment of solid tumors / 医学研究生学报

The tumor microenvironment is closely related to the development and progression of tumors. Chitosan has become a favorable nanocarrier for its biodegradability and biocompatibility. At present，there are two kinds of targeting ways existed in the nano-delivery system，including active and passive targeting. However，the active targeting has become the mainstream of researches owing to some factors that passive targeting contributes to drug maldistribution and high therapeutic concentration. This article reviews the important components of tumor microenvironment and the active targeting of chitosan delivery systemsand summarizes the application progress on chitosan and its derivatives actively targeting multiple components in solid tumor environment as well as perspectives on some unsolved problems.

Development and application of hyaluronic acid in tumor targeting drug delivery

Hyaluronic acid (HA) is a natural polysaccharide that has gained much attention due to its biocompatibility, enzyme degradation capacity and active tumor targeting capacity. Its receptor, CD44, is overexpressed in many kinds of cancers and is associated with tumor progress, infiltration and metastasis. Therefore, many researchers have developed various HA-based drug delivery systems for CD44-mediated tumor targeting. In this review, we systemically overview the basic theory of HA, its receptor and hyaluronidase, then we categorize the studies in HA-based drug delivery systems according to the functions of HA, including tumor-targeting materials, enzyme-sensitive biodegradable modality, pH-sensitive component, reduction-sensitive component, and the gel backbone. Finally, the perspective is discussed.

Transformative hyaluronic acid-based active targeting supramolecular nanoplatform improves long circulation and enhances cellular uptake in cancer therapy

Hyaluronic acid (HA) is a natural ligand of tumor-targeted drug delivery systems (DDS) due to the relevant CD44 receptor overexpressed on tumor cell membranes. However, other HA receptors (HARE and LYVE-1) are also overexpressing in the reticuloendothelial system (RES). Therefore, polyethylene glycol (PEG) modification of HA-based DDS is necessary to reduce RES capture. Unfortunately, pegylation remarkably inhibits tumor cellular uptake and endosomal escapement, significantly compromising the antitumor efficacy. Herein, we developed a Dox-loaded HA-based transformable supramolecular nanoplatform (Dox/HCVBP) to overcome this dilemma. Dox/HCVBP contains a tumor extracellular acidity-sensitive detachable PEG shell achieved by a benzoic imine linkage. The and investigations further demonstrated that Dox/HCVBP could be in a "stealth" state at blood stream for a long circulation time due to the buried HA ligands and the minimized nonspecific interaction by PEG shell. However, it could transform into a "recognition" state under the tumor acidic microenvironment for efficient tumor cellular uptake due to the direct exposure of active targeting ligand HA following PEG shell detachment. Such a transformative concept provides a promising strategy to resolve the dilemma of natural ligand-based DDS with conflicting two processes of tumor cellular uptake and nonspecific biodistribution.

Advances in designation of targeting nanocarrier-drug delivery systems for pancreatic cancer / 复旦学报（医学版）

Pancreatic ductal adenocarcinoma is a kind of neoplasms with poor neovascularization and rich matrix,which limited the delivery of cytotoxic drugs to cancer cells.Nanocarriers delivery of cytotoxic drugs to treat pancreatic cancer would overcome those biological barriers,and promote drug delivery efficiency.The designation of high targeting of pancreatic cancer cells nanoparticles and smart drug delivery system have been the key factors to improve nanocarriers' drug delivery efficiency.Here,we report the latest advanced researches in this field,including passive targeting design,active targeting design and response to the release of drug delivery design.

Analysis of problems on tumor-targeting drug delivery system / 药学实践杂志

Objective To analyze the current problems on tumor‐targeting nanoparticle drug delivery system .Methods Recent researches of tumor‐targeting nanoparticle drug delivery system were collected ,read and summarized .Results Three research fields on tumor‐targeting nanoparticle drug delivery system were reviewed in this article .Conclusion Not only a deeper understanding of the human physiology and tumor biology ,but changes in strategies and experimental methods are needed to make new achievements on nanoparticle drug delivery system .

Preparation and in vitro and in vivo evaluation of folate-BSA-coated cationic nanostructure lipid carriers / 中国药科大学学报

@#Folic acid(FA)was conjugated with bovine serum albumin(BSA)to form targeting material. BSA-coated cationic nanostructure lipid carriers(BSA-cNLCs)and folate-BSA-coated cationic nanostructure lipid carriers(FA-BSA-cNLCs)were prepared by film dispersion. The particle sizes of BSA-cNLCs and FA-BSA-cNLCs were 81. 4 nm and 79. 8 nm, while their Zeta potentials were +5. 12 mV and +3. 74 mV. Both nanostructure lipid carriers showed spherical shape. Paclitaxel encapsulation efficiency of them were more than 97%, with drug loading efficiency of about 3. 7%. In vitro experiments confirmed that the uptake of FA-BSA-cNLCs by overexpressed folate receptor SKOV3 cells was significantly higher than that of BSA-cNLCs, demonstrating that FA-BSA-cNLCs were obviously targeted to SKOV3. Blood and tumor pharmacokinetics showed that there was no significant differences between BSA-cNLCs and FA-BSA-cNLCs. This suggested that modified FA on the surface of the preparation had no effect on its in vivo behavior. Tumor inhibition of BSA-cNLCs and FA-BSA-cNLCs were 72. 08% and 80. 75%, repectively, which indicateds that FA-BSA-cNLCs improve anticancer efficacy in vitro and in vivo, and that it could be a potential preparation for the treatment of cancer.

Research advances in drug delivery system targeting immune system / 中国药科大学学报

Drug delivery system targeting immune system plays an important role in the treatment of inflammatory diseases.Drug delivery system targeting immune system could target immune cells or immune organs.It could be divided into active targeting mediated by the interaction of ligand-receptor or antigen-antibody and passive targe-ting mediated by pH;particles and so on.This review summarizes new progress for drug delivery system targeting immune system;which provides a theoretical reference for designing the safe and effective drug delivery system and providing efficient and safe treatment for inflammatory diseases.

Research Progress on Novel Carrier-modified Methods and Evaluation of Active Targeting Antitumor Preparation / 中草药·英文版

This article mainly introduced novel carrier-modified methods for active targeting antitumor preparation as well as their evaluation methodology in recent years. By reviewing related domestic and overseas literatures, the up-to-date scientific researches concerning active targeting antitumor preparation were elaborated and the problems existing in present studies were discussed. Numerous valid vector-embellished methods had been discovered with excellent targeting effects, and the significant progress was acquired for the evaluation tools in vitro and in vivo. The active targeting agent would be a major direction in prospective tumor or cancer therapeutic regimen. © 2014 Tianjin Press of Chinese Herbal Medicines.

Preparation of brain active-targeting endomorphin loaded nanoparticles and study on its effects of passing across blood brain barrier / 国际生物医学工程杂志

Objective To prepare a novel brain active-targeting endomorphin (EM) loaded hyperbranched polyglycerols-poly (lactic-co-glycolic acid) (HBPG-PLGA) nanoparticles (NPs) and study its mechanism of passing across blood brain barrier (BBB) in brain microvascular endothelial cells (BMEC).Methods The OX26 (transferring receptor monoclonal antibody) conjugated EM loaded HBPG-PLGA NPs was constructed according to water-in-oil-in-water emulation solvent evaporation technique as a novel biodegradable brain active-targeting drug delivery system.The properties of the NPs were evaluated by transmission electron microscope (TEM) in vitro.Through flow cytometry and laser scanning confocal microscope,the mechanism of passing across BBB was evaluated.Results The preparation methodology of NPs was optimized and established.The mean diameter was (170±20) nm and Zeta potential was about-27 mV.Core-shell construction was showed on TEM.Cellular uptake study showed that the uptake of NPs was via a caveolae-mediated endocytic pathway,then endomorphin and carrier were divided into two parts in BMEC.Conclusions The OX26 conjugated EM loaded NPs were stable,and demonstrate remarkable effects on crossing BBB.Cellular uptake by BMEC is a very important mechanism of the NPs' brain activating-targeting effect.

CSTM-g-PEG-FA nanoparticles for gene delivery / 中国药学杂志

OBJECTIVE: To synthesize a water-soluble cationic polymer of quatemized chitosan modified by folic-acid for active targeting and to study its role as a gene vector. METHODS: Folic-acid was connected to quatemized chitosan by bi-functional PEG, CSTM-g-PEG-FA/pDNA nanoparticles were prepared by self-assembly, and the gene transfection efficiency mediated by the nanoparticles into 293T cells in vitro was observed. RESULTS: When weight ratio of CSTM-g-PEG-FA/pDNA was 5 or greater than 5, pDNA was completely wrapped. And the transfection efficiency of CSTM-g-PEG-FA/pDNA nanoparticles was significantly higher than CSTM/pDNA nanoparticles. CONCLUSION: Cationic polymer CSTM-g-PEG-FA can electrostatically bind and condense anionic DNA into nanometersized particles and has the function of active targeting.

Preparation and anti-tumor effect in vitro of doxorubicin-loaded targeting micelles modified by folic acid / 中国药学杂志

OBJECTIVE: To prepare doxorubicin (DOX)-loaded micelles based on folic acid-modified cholesterol-glycol chitosan (FCHGC), and study its physicochemical properties and cytotoxicity in vitro. METHODS: FCHGC copolymer was synthesized by conjugating carboxyl groups of folic acid with the primary amino groups of cholesterol-modified glycol chitosan (CHGC) in the presence of coupling agent. FCHGC conjugate was characterized by 1H-NMR and fluorescence measurement using pyrene as a probe. The DOX-loaded micelles were prepared by an emulsion/solvent evaporation method. The size and shape of the micelles were analyzed by dynamic light scattering (DLS) and transmission electron microscopy (TEM). DOX release behavior was studied in vitro by a dialysis method in phosphate buffer saline (PBS, pH 7.4). The cytotoxicity and celluar uptake of drug-loaded micelles in vitro were investigated by 3-(4, 5-dimethyl thiazol-2-yl)-2, 5-diphenyl tetrazolium bromide (MTT) assay and flow cytometry. RESULTS: The critical aggregation concentration (CAC) of the FCHGC micelles in aqueous solution was 0.0163 mg·mL-1. Its particle size was 227 nm. The drug loading and encapsulation efficiency of DOX-loaded FCHGC (DFCHGC) micelles were 10.5% and 78.5%, respectively. The shape of DFCHGC micelles was almost spherical. DOX was released from DOX-loaded micelles in a biphasic manner, which displayed an initial rapid release phase and a later sustained release phase. The 50% inhibitory concentrations (IC50) of DOX, DOX-loaded CHGC (DCHGC) and DFCHGC micelles, incubated with folate receptor (FR)-negative A549 cells for 48 h, were 1.493, 0.620 and 0.974 μg·mL-1, respectively. Therefore, DCHGC micelles exhibited much more potent cytotoxicity against A549 cells than DFCHGC micelles. In FR-positive HeLa cells, the IC50 values of DOX, DCHGC and DFCHGC micelles were 1.398, 0.662 and 0.259 μg·mL-1, respectively. The DFCHGC micelles showed the greatest cytotoxicity among three DOX formulations for HeLa cells. And DFCHGC micelles exhibited greater cellular uptake than free DOX and DCHGC micelles in HeLa cells. CONCLUSION: The FCHGC micelles as a drug carrier for DOX delivery show selectively targeting to FR-positive cells, and improve the anti-tumor activity of DOX. These results suggested that FCHGC micelles could be a potential carrier for active targeting drug delivery.

Active tumor targeting drug delivery system: The current status / 第二军医大学学报

Active tumor targeting drug delivery system( ATTDDS) can selectively combine with and react to the target tissue at the cellular or sub-cellular level, making it possible for drugs to be distributed in a controlled manner and released in a slow and continuous manner, subsequently resulting in enhanced anti-cancer drugs effects and reduced adverse effects on normal tissues. Although there are many problems need to be solved in research on ATTDDS, and there is still a long way to go before it can be used clinically, its roles in overcoming adverse effects of cancer treatment and improving the therapeutic effect are valuable. Generally, ATTDDS is an ideal anti-tumor drug dosage and has a promising prospect. This paper introduces the effects and characteristics of various types of ATTDDS as well as their problems and countermeasures, hoping to provide research ideas and methods for the anti-tumor targeted drug delivery.