Inhibitory effect of adenosine on adaptive antitumor immunity and intervention strategies / 浙江大学学报·医学版

Tumors in which the microenvironment is characterized by lack of immune cell infiltration are referred as "cold tumors" and typically exhibit low responsiveness to immune therapy. Targeting the factors contributing to "cold tumors" formation and converting them into "hot tumors" is a novel strategy for improving the efficacy of immunotherapy. Adenosine, a hydrolysis product of ATP, accumulates with a significantly higher concentration in the tumor microenvironments compared with normal tissue and exerts inhibitory effects on tumor-specific adaptive immunity. Tumor cells, dendritic cells, macrophages, and T cells express abundant adenosine receptors on their surfaces. The binding of adenosine to these receptors initiates downstream signaling pathways that suppress tumor antigen presentation and immune cell activation, consequently dampening adaptive immune responses against tumors. Adenosine down-regulates the expression of major histocompatibility complex Ⅱ and co-stimulatory factors on dendritic cells and macrophages, thereby inhibiting antigen presentation to T cells. Adenosine also inhibits ligand-receptor binding and transmembrane signaling on T cells, concomitantly suppressing the secretion of anti-tumor cytokines and impairing T cell activation. Furthermore, adenosine hinders effector T cell trafficking to tumor sites and infiltration by inhibiting chemokine secretion and KCa3.1 channels. Additionally, adenosine promotes the secretion of immunosuppressive cytokines, increases immune checkpoint protein expression, and enhances the activity of immunosuppressive cells, collectively curbing cytotoxic T cell-mediated tumor cell killing. Given the immunosuppressive role of adenosine in adaptive antitumor immunity, several inhibitors targeting adenosine generation or adenosine receptor blockade are currently in preclinical or clinical development with the aim of enhancing the effectiveness of immunotherapies. This review provides an overview of the inhibitory effects of adenosine on adaptive antitumor immunity, elucidate the molecular mechanisms involved, and summarizes the latest advances in application of adenosine inhibition strategies for antitumor immunotherapy.

Research progress of endoplasmic reticulum targeting drug delivery system for anti-tumor immunotherapy / 药学学报

Endoplasmic reticulum (ER), a multifunctional organelle in eukaryotic cells, is responsible for protein synthesis and intracellular signal transduction, which dominates cell function, survival, and apoptosis. Disequilibrium of ER homeostasis may induce ER stress, which closely intertwines with tumor occurrence and progress. A few clinical-used drugs (such as anthraquinones and oxaliplatin) can mediate the immunogenic cell death of tumor cells through excessive ER stress, and sequentially stimulate anti-tumor immune responses as well as long-term immune memory. However, these drugs often exhibit poor targeting ability and extremely low ER accumulation in tumor cells, limiting their clinical efficacy. Therefore, the researches of ER-targeted delivery of these drugs will significantly benefit the efficient and precise anti-tumor immunotherapy. In this review, we introduce the relationship between ER and tumor immunity, and summarize the ER targeting strategies for anti-tumor immunotherapy in recent years. Furthermore, we discuss the problems of existing ER targeting strategies and look into its broad prospects of application.

Mitochondria targeting drugs for neurodegenerative diseases-Design, mechanism and application

Neurodegenerative diseases (NDDs) such as Alzheimer's disease (AD) and Parkinson's disease (PD) are a heterogeneous group of disorders characterized by progressive degeneration of neurons. NDDs threaten the lives of millions of people worldwide and regretfully remain incurable. It is well accepted that dysfunction of mitochondria underlies the pathogenesis of NDDs. Dysfunction of mitochondria results in energy depletion, oxidative stress, calcium overloading, caspases activation, which dominates the neuronal death of NDDs. Therefore, mitochondria are the preferred target for intervention of NDDs. So far various mitochondria-targeting drugs have been developed and delightfully some of them demonstrate promising outcome, though there are still some obstacles such as targeting specificity, delivery capacity hindering the drugs development. In present review, we will elaborately address 1) the strategy to design mitochondria targeting drugs, 2) the rescue mechanism of respective mitochondria targeting drugs, 3) how to evaluate the therapeutic effect. Hopefully this review will provide comprehensive knowledge for understanding how to develop more effective drugs for the treatment of NDDs.

The C2min aptamer-modified gene delivery system for targeting ADPC/AIPC prostate cancer / 药学实践杂志

Objective To synthesize a novel prostate cancer targeting gene vector PAMAM-PEG-C2min and improve gene transfection efficiency targeting on prostate cancer. Methods The aptamer (C2min) and polyamide-amine (PAMAM) were ligated by polyethylene glycol (PEG). The structure of the synthesized PAMAM-PEG-C2min was identified by NMR. The biological characteristics of the nanoparticles were examined by the uptake experiments and gene transfection experiments (the loaded gene was siR-M) with the prostate cancer cells (PC3 and LNCaP). Besides, the in vivo targeting was investigated using in vivo image system. The in vivo targeting results indicated that PAMAM-PEG-C2min can achieve the simultaneous targeting of two prostate cancer tissues. Results The PAMAM-PEG-C2min synthesis was confirmed by NMR. Cell uptake experiments showed that the cell uptake efficiency of PAMAM-PEG-C2min was concentration dependent. In vitro experiments showed that the PC3 and LNCaP cells transfection efficiency and targeting of PAMAM-PEG modified with C2min were significantly improved compared with the PEG modified PAMAM. Conclusion PAMAM-PEG-C2min is a potential targeted drug delivery vehicle. It provides a new technology platform for comprehensive and specific targeting treatment of prostate cancer.

The progress and perspective of nanoparticle-enabled tumor metastasis treatment

As one of the most serious threats to human being, cancer is hard to be treated when metastasis happens. What's worse, there are few identified targets of metastasis for drug development. Therefore, it is important to develop strategies to prevent metastasis or treat existed metastasis. This review focuses on the procedure of metastasis, and first summarizes the targeting delivery strategies, including primary tumor targeting drug delivery, tumor metastasis targeting drug delivery and hijacking circulation cells. Then, as a promising treatment, the application of immunotherapy in tumor metastasis treatment is introduced, and strategies that stimulating immune response are reviewed, including chemotherapy, photothermal therapy, photodynamic therapy, ferroptosis, sonodynamic therapy, and nanovaccines. Finally, the challenges and perspective about nanoparticle-enabled tumor metastasis treatment are discussed.

Preparation and in vitro evaluation of arsenic trioxide-loaded glioma targeting drug delivery system iRGD/TGN-PEG-PAMAM/ATO / 中草药

Objective To construct a glioma targeting delivery system, PAMAM G5 were modified with the oligopeptide of blood brain barrier (BBB) targeting TGN and tumor targeting oligopeptide iRGD to solve the problem of non-specificity in distribution and difficulty in permeating BBB of ATO, in order to have better anti-glioma effect. Methods The physical and chemical properties of nanocarriers were investigated by 1H-NMR and transmission electron microscopy (TEM); The encapsulation efficiency and in vitro release were analyzed by inductively coupled plasma emission spectrum (ICP) and dialysis bag method; The effects of iRGD and TGN on cellular uptake of the carriers were analyzed by laser confocal and flow cytometry. The cytotoxicity of nanocarriers on brain microvascular endothelial cells (HBMEC) and glioma cells (U87), the inhibition effect on U87 cells of drug delivery systems after acrossing the BBB model in vitro were investigated by MTT method. Results The iRGD/TGN-PEG-PAMAM was synthesized successfully. The TEM results showed that iRGD/TGN-PEG-PAMAM was regular in shape and uniform in size. The particle size of iRGD/TGN-PEG-PAMAM/ATO was (24.87 ± 0.84) nm and the potential was (17.26 ± 1.64) mV. The synthesized carrier had less toxicity to HBMEC and U87 cells. The encapsulation efficiency of iRGD/TGN-PEG-PAMAM/ATO delivery system was (71.92 ± 1.17)%. The in vitro release showed that ATO had a slow release trend after entrapment, and it was more favorable for ATO release under acidic conditions. The cell uptake indicated that iRGD/TGN modification was more beneficial for U87 cell to uptake the drug delivery system. The in vitro inhibition effect on U87 cells after acrossing the BBB model showed iRGD/TGN-PEG-PAMAM/ATO had better inhibition effect on U87 cells. Conclusion The iRGD/TGN-PEG-PAMAM/ATO targeting drug delivery system has good inhibition effect on U87 cells effect after acrossing the BBB model in vitro, which provides a new strategy for the treatment of glioma.

The progress of novel drug delivery systems / 药学学报

The development of pharmaceuticals has been providing many kinds of novel drug delivery systems, which are important for improving therapeutic effect and one of the most important fields in pharmaceutics. According to their application, we can generally divide the novel drug delivery systems into three categories:quickly performed drug delivery system, long-term drug delivery system and high effective drug delivery system. Some diseases, such as asthma, angina pectoris and migraine, require therapeutics urgently, and the drugs have to be absorbed in several minutes. Therefore, quickly performed drug delivery systems are developed, such as oral disintegrating tablets and nasal spray. For normal tablets and capsules, especially the drugs with short blood half life, the drug concentration in blood shows obvious peak-valley phenomenon, which reduces the therapeutic effect and requires multiple administration. To solve this problem, sustained drug release system was developed, which could release the drugs slowly and sustainably even in zero-order kinetics. The pulse drug delivery system was developed that can delayed and pulsed release drug for one or several times. This system is especially useful in the management of asthma and heart disease, which are often found in midnight or early morning when patients are in bed. Transdermal drug delivery system could release drugs sustainably and deliver the drugs through skin to blood circulation, providing long term activity. The water-insoluble drugs are difficult for pharmaceutical development, thus many methods were developed to improve the solubility and bioavailability of drugs. Although biopharmaceuticals are important for disease treatment, the application shadows by the poor stability and low bioavailability. Thus the biopharmaceutical delivery system was developed, which mainly focused on structure modification and encapsulation by carriers. Considering therapeutic effect requires interaction between drugs and their targets, it is important to deliver drugs to their targets. Therefore, targeting delivery systems were developed, which mainly based on the nanoparticles. Furthermore, on-demand release drug delivery systems are also developed with the property of environment-triggered drug release. In conclusion, the novel drug delivery systems were reviewed in this study.

Research progress of static magnetic field targeting drug delivery system in tumor diagnosis and therapy / 国际生物医学工程杂志

Chemotherapy is one of the traditional tumors treatment solutions.Chemotherapy has the feature of tissue non-specificity,which can cause side effects on normal cells while inhibiting tumor cell growth.Magnetic targeting drug delivery system (MTDDS) employs biocompatible and stable magnetic nanoparticles (MNP) as drug carries to transport and accumulate anticancer drugs to the specific tumor tissues under the guidance of external magnetic field.This technology not only improves the efficiency of drug delivery and antitumor activity,but also reduces the drug dosage and side effects.The properties of drug-loaded MNPs and the applied external magnetic field are the main factors that affecting the MNPs targeting to the tumor tissues.The effectiveness of the targeted delivery of the drug-loaded magnetic nanoparticles mainly depends on the form and strength of the magnetic field at the target site.That is,whether there is sufficient strength to attract and retain NMPs,and to promote antitumor drug release at the tumor region.In this paper,the research progress of static magnetic field targeting drug delivery system in tumor diagnosis and therapy was summarized,which can provide some basic information for the relative scientific researches.

Novel liposomal drug delivery system actively targeting Cryptococcus neoformans and elimination of infection / 药学学报

The purpose of this study is to develop a liposomal drug delivery system actively targeting Cryptococcus neoformans and explore its feasibility in therapy of cryptococcal infection. The specific fungibinding peptide was screened from 12-mer random phage display library, and linked to PEG-DSPE as the functional material of liposomes. The targeting capability of peptide-modified liposomes were investigated by fungi binding assay in vitro and fluorescence imaging in vivo. Itraconazole as a model drug were then encapsulated in the liposomes and were evaluated in pharmacodynamic test in vitro and for therapeutic effects against cryptococcal meningitis complicated with pulmonary cryptococcosis in vivo. The results showed that the peptide (sequence:NNHREPPDHRTS) could selectively recognize Cryptococcus and effectively mediate the corresponding liposomal formulation to accumulate in the infection site in vivo. This peptide-modified liposome has a small particle size (mean diameter of 88.25±2.43 nm) with a homogeneous distribution and high encapsulation efficiency (88.05±0.25%) of itraconazole. After intravenous administration, the pathogens were obviously eliminated in lung and brain, and the life-span of model mice were significantly prolonged, suggesting a promising potential of this cryptococcosis targeting strategy.

Engineered mesenchymal stem cells as targeting therapeutic carriers in cancer therapy / 中国药科大学学报

@#Mesenchymal stem cells(MSCs)were derived from the early development stage of mesoderm and ectoderm and considered as one of the important members of stem cells family. Besides that, MSCs can be isolated easily and don′t have a limitation of moral and ethical problems. Moreover, MSCs can be expanded in vitro which make it possible to use in industrial preparation. Moreover, MSCs possess low immunogenicity and has the ability to home to damaged tissues, tumors, and metastases. Therefore, MSCs possess a set of fairly unique properties which make them ideally suited for clinical applications. This review summarizes the main properties of MSCs and its new progress in drug delivery system in the field of cancer therapy as a basis of further utility of engineered MSCs in the design of targeting drug delivery system.

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.

Advances in the treatment of Eisenmenger syndrome / 临床儿科杂志

Eisenmenger syndrome (ES) was considered as a surgical contraindication in the past time. Only a few patients got lung transplantations or heart-lung transplantations due to lack of donors. Most of the patients had to choose conservative treatment to prolong their survival time. Recently, some clinical trials indicated targeted therapies in pulmonary arterial hypertension (PAH) were effective for the treatment of ES. This article reviewed the recent advances in this area.

Advances in anti-VEGF/VEGFR targeting drugs for corneal neovascularization / 中华实验眼科杂志

Cornea is an important part of the refractive media.Healthy cornea is clear and avascular.Corneal avascularity is necessary for the preservation of optimal vision and is maintained by a balance between angiogenic and antiangiogenic factors.In a variety of pathologic conditions,the balance between angiogenic and antiangiogenic factors may be tipped towards angiogenic molecules,leading to corneal neovascularization (CNV).Recent research showed that vascular endothelial growth factor (VEGF) is an important factor responsible for CNV.Over the past several years,the safety and efficacy of several new agents targeting VEGF or VEGF receptor (VEGFR) have been verifies in many ocular neovascularization diseases such as age-related macular degeneration, diabetic retinopathy, neovascular glaucoma,retinopathy of prematurity and CNV.These agents not only have revolutionized the therapy of ocular neovascularized disease but also have great potential for other blinding conditions such as CNV.These agents have great potential for the treatment of CNV.This article reviewed the most promising anti-VEGF/VEGFR therapies.

Design,synthesis and anti-tumor activities in vitro of novel 3-substituted indolin-2-one compounds / 药学实践杂志

Objective To compose and evaluate anti‐tumor activities of 3‐substituted indole‐2‐one compounds which may have dual inhibitory activities against both tubulin protein and VEGFR‐2 tyrosine kinase .Methods Target compounds were prepared starting from substituted aniline viacondensation ,cyclization and reduction .Results 11 target compounds were syn‐thesized and all the compounds displayed moderate anti‐proliferative activities against three tumor cell lines .Compound j9 showed a certain inhibitory activity against both VEGFR‐2 kinase and tubulin protein in vitro .Conclusion This series of indo‐lin‐2‐one derivatives were found to be a novel kind of multi‐target inhibitor .

Antitumor drug carriers based on folate-conjugated polymers: Investigation and application / 国际药学研究杂志

Targeted therapies for cancer have many advantages, such as strong harmful effects on tumor cell and low adverse effect. Due to the fact that the folate receptor is a highly selective tumor marker overexpressed on the surface of many cancer cells, antitumor agents are taigetedly delivered to tumor tissues or cells via endocytosis mediated by folate receptor to improve the therapeutic efficiency. At present, the technology of folate receptor targeting drug delivery attracts extensive attention. Folate-targeted polymer-anti-tumor drug conjugates, which use polymer as the carrier coupling the targeting ligand folic acid and anticancer drugs, can significantly extend the drug half-life, increase drug stability and solubility, and reduce the side effects of drugs remarkably. All these characteristics indicate that folic acid polymer-drug conjugates have a good application prospect. This review covers the various types of folate receptor-mediated polymeric antitumer drugs conjugates, with special emphasis on the more recent ones and their mechanism aspects. © 2006 Editorial office of Foreign Medical Sciences.

Development of PEG-PLGA nanoparticles as drug carrier with tumor-targeted therapy / 国际外科学杂志

In recent years, tumor is a refractory disease occurring frequently which is the main cause of death. Surgery, radiotherapy and chemotherapy are the usual therapeutic tools. However,radiotherapy and chemotherapy have serious side-effects and surgery can not be used effectively when metastasis happened. Therefore, tumor-targeted therapy has developed as a better way to cure tumor. Development of research on the use of PEG-PLGA nanoparticles as drug carriers are reviewed in this article, furthermore, problems about that are analysed.

Preliminary Comparison between rRTA : DS27 and ricin: DS27 as Immunotoxins / 中国肿瘤生物治疗杂志

Objective: Immunotoxin rRTA:DS27, which was prepared by conjugating DS27 with recombinanl ricin a chain, was compared with ricin:DS27 as immunotoxins. Methods: System analysis were performed regard to their cell-specific cytotoxicity, inhibition on the proliferation of hemoapeutic potential cells, immunogold-labelled intracellular routing and effect of NH_(4)Cl on the cytotoxicity. Results: Results showed that rRTA: DS27 got a more specific cytotoxicity and a weaker inhibition on the proliferation of hemoapeutic potential cells than ricin:DS27, NH_(4)Cl could obsolutelyy enhence the cytotoxicity of rRTA:DS27. Conclusion: rRTA:DS27 had more advantages than ricin: DS27 as immunotoxins.

Advances in research on target-oriented drug delivery system of Chinese materia medica / 中草药

Target-oriented drug delivery systems(TODDS) of Chinese materia medicia(CMM) is ascribed as preparations in which active fractions or single ingredient extracted from CMM or natural medicines are directly delivered with the help of different carriers to target organs,target tissues,and target cells or intracellula.Recent advances of research on TODDSs of CMM classified according to carriers,such as liposomes,microspheres,nanocapsules,and emulsions are reviewed.In addition,due to the specific actions of CMM on intestinal diseases,oral colon targeting drug delivery system is considered substantials for TODDSs of CMM.Domestic researches on TODDS of CMM in its initial stage are limited to formulations using single natural active ingredient as raw material.While the fewer TODDSs using CMM active fractions or formula recipes are underway,which relates to the tremendous difficulties in both establishment of quality standard for CMM active fractions and technology for preparation of CMM.Nevertheless one of the important goals for the development on preparation of CMM is TODDS.

A comparative study of targeting drug magnetic nanoparticles and other chemotherapy drugs on human cholangiocarcinoma xenografts / 中国普通外科杂志

Objective To study the effect of magnetic nanoparticles on human cholangiocarcinoma xenograft in nude mice, and compared with otherchemotherapy drugs Methods We established human cholangiocarcinoma xenograft in nude mice with QBC939 cell line.The nude mice were devided into 4 groups randomly.Saline,5-FU, Gemcitabine and magnetic nanoparticles were given to nude mice through tail vein on 20d after implanting QBC939 cell line. Calculations were done at different time after treatment in order to compare tumor volume,inhibition ratio of tumor and tumor growth curve of each group. The nude mice were killed on 35d after treatment to harvest tissue for electron microscopic examination to observe ultra-structural changes. Results The tumor volume of control, 5-FU, magnetic nanoparticles and Gemcitabine groups was (2256.1?267.1) mm3, (2096.5?237.9)mm3,(1392.2?189)mm3, and (1534.9?115 )mm3 respectively.The last two groups have significant difference compared to the first two groups(P