The functions of exosomes targeting astrocytes and astrocyte-derived exosomes targeting other cell types

Astrocytes are the most abundant glial cells in the central nervous system;they participate in crucial biological processes,maintain brain structure,and regulate nervous system function.Exosomes are cell-derived extracellular vesicles containing various bioactive molecules including proteins,peptides,nucleotides,and lipids secreted from their cellular sources.Increasing evidence shows that exosomes participate in a communication network in the nervous system,in which astrocyte-derived exosomes play important roles.In this review,we have summarized the effects of exosomes targeting astrocytes and the astrocyte-derived exosomes targeting other cell types in the central nervous system.We also discuss the potential research directions of the exosome-based communication network in the nervous system.The exosome-based intercellular communication focused on astrocytes is of great significance to the biological and/or pathological processes in different conditions in the brain.New strategies may be developed for the diagnosis and treatment of neurological disorders by focusing on astrocytes as the central cells and utilizing exosomes as communication mediators.

Degradation of FAK-targeting by proteolytic targeting chimera technology to inhibit the metastasis of hepatocellular carcinoma

Liver cancer is a prevalent malignant cancer,ranking third in terms of mortality rate.Metastasis and recurrence primarily contribute to the high mortality rate of liver cancer.Hepatocellular carcinoma(HCC)has low expression of focal adhesion kinase(FAK),which increases the risk of metastasis and recurrence.Nevertheless,the efficacy of FAK phosphorylation inhibitors is currently limited.Thus,investigating the mechanisms by which FAK affects HCC metastasis to develop targeted therapies for FAK may present a novel strategy to inhibit HCC metastasis.This study examined the correlation between FAK expression and the prognosis of HCC.Additionally,we explored the impact of FAK degradation on HCC metastasis through wound healing experiments,transwell invasion experiments,and a xenograft tumor model.The expression of proteins related to epithelial-mesenchymal transition(EMT)was measured to elucidate the underlying mechanisms.The results showed that FAK PROTAC can degrade FAK,inhibit the migration and invasion of HCC cells in vitro,and notably decrease the lung metastasis of HCC in vivo.Increased expression of E-cadherin and decreased expression of vimentin indicated that EMT was inhibited.Consequently,degradation of FAK through FAK PROTAC effectively suppressed liver cancer metastasis,holding significant clinical implications for treating liver cancer and developing innovative anti-neoplastic drugs.

Precision targeting in hepatocellular carcinoma:Exploring ligandreceptor mediated nanotherapy

Hepatocellular carcinoma(HCC)is the most common primary liver cancer and poses a major challenge to global health due to its high morbidity and mortality.Conventional chemotherapy is usually targeted to patients with intermediate to advanced stages,but it is often ineffective and suffers from problems such as multidrug resistance,rapid drug clearance,nonspecific targeting,high side effects,and low drug accumulation in tumor cells.In response to these limitations,recent advances in nanoparticle-mediated targeted drug delivery technologies have emerged as breakthrough approaches for the treatment of HCC.This review focuses on recent advances in nanoparticle-based targeted drug delivery systems,with special attention to various receptors overexpressed on HCC cells.These receptors are key to enhancing the specificity and efficacy of nanoparticle delivery and represent a new paradigm for actively targeting and combating HCC.We comprehensively summarize the current understanding of these receptors,their role in nanoparticle targeting,and the impact of such targeted therapies on HCC.By gaining a deeper understanding of the receptor-mediated mechanisms of these innovative therapies,more effective and precise treatment of HCC can be achieved.

Multi-Scale Approach for Gold Targeting in Côte d’Ivoire Paleoproterozoic Rocks

The aim of this study is to contribute to better targeting of gold prospecting areas using geospatial information. To this end, 3 mining sites were selected for the study. They are: the Sénoufo belt (Barrick Gold mine), the Yaouré complex (Perseus Mining mine) and the South Fetêkro belt (Bonikro, Hiré and Agbaou mines). For this study, a multi-scale approach was carried out at regional, mine and microscopic levels. At the regional scale, a comparative analysis of 1:200,000 scale geological maps revealed that 3 main lithologies are regularly repeated on and around the various mining sites. These are: undifferentiated volcanics, metagranodiorites and metasiltites dominated by meta-arenites. Most of these lithologies are affected by undifferentiated faults generally oriented NE-SW, N-S, ENE-WSW and WNW-ESE. In addition, gold and manganese occurrences are present on all the sites studied. At the mine scale, radarsat-1 images processing indicate that the main mining sites are generally located near or at the intersection of lineaments-oriented NE-SW or N-S on the one hand and E-W or ENE-WSW or WNW-ESE or again NW-SE on the other. These mines are also located at the interface between zones of high and low lineament density. At the microscopic scale, petrographic studies of undifferentiated volcanic samples from the various sites indicate that they consist of andesites, meta-andesites and tuffs.

Targeting therapy for hepatocellular carcinoma by delivering microRNAs as exosomal cargo

Exosomes,the smallest extracellular vesicles,have gained significant attention as key mediators in intercellular communication,influencing both physiological and pathological processes,particularly in cancer progression.A recent review article by Wang et al was published in a timely manner to stimulate future research and facilitate practical developments for targeted treatment of hepatocellular carcinoma using exosomes,with a focus on the origin from which exosomes derive.If information about the mechanisms for delivering exosomes to specific cells is incorporated,the concept of targeted therapy for hepatocellular carcinoma using exosomes could be more comprehensively understood.

Selective ischemic-hemisphere targeting Ginkgolide B liposomes with improved solubility and therapeutic efficacy for cerebral ischemia-reperfusion injury

Cerebral ischemia-reperfusion injury(CI/RI)remains the main cause of disability and death in stroke patients due to lack of effective therapeutic strategies.One of the main issues related to CI/RI treatment is the presence of the blood-brain barrier(BBB),which affects the intracerebral delivery of drugs.Ginkgolide B(GB),a major bioactive component in commercially available products of Ginkgo biloba,has been shown significance in CI/RI treatment by regulating inflammatory pathways,oxidative damage,and metabolic disturbance,and seems to be a candidate for stroke recovery.However,limited by its poor hydrophilicity and lipophilicity,the development of GB preparations with good solubility,stability,and the ability to cross the BBB remains a challenge.Herein,we propose a combinatorial strategy by conjugating GB with highly lipophilic docosahexaenoic acid(DHA)to obtain a covalent complex GB-DHA,which can not only enhance the pharmacological effect of GB,but can also be encapsulated in liposomes stably.The amount of finally constructed Lipo@GB-DHA targeting to ischemic hemisphere was validated 2.2 times that of free solution in middle cerebral artery occlusion(MCAO)rats.Compared to the marketed ginkgolide injection,Lipo@GB-DHA significantly reduced infarct volume with better neurobehavioral recovery in MCAO rats after being intravenously administered both at 2 h and 6 h post-reperfusion.Low levels of reactive oxygen species(ROS)and high neuron survival in vitro was maintained via Lipo@GB-DHA treatment,while microglia in the ischemic brain were polarized from the pro-inflammatory M1 phenotype to the tissue-repairing M2 phenotype,which modulate neuroinflammatory and angiogenesis.In addition,Lipo@GB-DHA inhibited neuronal apoptosis via regulating the apoptotic pathway and maintained homeostasis by activating the autophagy pathway.Thus,transforming GB into a lipophilic complex and loading it into liposomes provides a promising nanomedicine strategy with excellent CI/RI therapeutic efficacy and industrialization prospects.

Colon cancer and their targeting approaches through nanocarriers:A review

Colon cancer is the fifth most common type of cancer in the world.Colon cancer develops when healthy cells in the lining of the colon or rectum alter and grow uncontrollably to form a mass known as a tumor.Despite major medical improvements,colon cancer is still one of the leading causes of cancer-related mortality globally.One of the main issues of chemotherapy is toxicity related to conventional medicines.The targeted delivery systems are considered the safest and most effective by increasing the concentration of a therapeutic substance at the tumor site while decreasing it at other organs.Therefore,these delivery systems required lower doses for high therapeutic value with minimum side effects.The current review focuses on targeting therapeutic substances at the desired site using nanocarriers.Additionally,the diagnostic applications of nanocarriers in colorectal cancer are also discussed.

A pilot clinical study of developing an External Assist Targeting Device for rapid and precise renal calyx access during percutaneous nephrolithotomy

Objective:To design a device to increase the accuracy of the targeting process and reduce the radiation exposure to both the patients and the medical staff.Methods:We analyzed the inherent problem and designed the External Assist Targeting Device(EATD)to assist in the alignment of needle targeting on the desired renal calyx under fluoroscopic guidance.The EATD was designed to allow rapid and precise access to calyces at all angles,with a simple two-step puncture protocol developed for puncturing a target renal calyx.We then tested the device in a pilot human trial with four patients.Results:In experiments with phantom models,the time for successful targeting was reduced by 31%using the device.The mean fluoroscopic time was reduced by 40%.In initial human trial,the puncture time was shortened by 66%and the radiation dose was decreased by 65%compared to free-hand technique.No complication was observed during the trial.Conclusion:The EATD was found to be cost effective,portable,simple to set up,and safe to operate for assisting in the percutaneous nephrolithotomy procedures.Our preliminary tests showed high degree of accuracy in gaining precise access to a targeted renal calyx with much shorter time and lesser radiation dose.The EATD also has the potential to be used to access other organs with precision under fluoroscopic guidance.

Molecular mechanisms targeting drug-resistance and metastasis in colorectal cancer:Updates and beyond

Colorectal cancer(CRC)is the third most diagnosed malignancy and a major leading cause of cancer-related deaths worldwide.Despite advances in therapeutic regimens,the number of patients presenting with metastatic CRC(mCRC)is increasing due to resistance to therapy,conferred by a small population of cancer cells,known as cancer stem cells.Targeted therapies have been highly successful in prolonging the overall survival of patients with mCRC.Agents are being developed to target key molecules involved in drug-resistance and metastasis of CRC,and these include vascular endothelial growth factor,epidermal growth factor receptor,human epidermal growth factor receptor-2,mitogen-activated extracellular signal-regulated kinase,in addition to immune checkpoints.Currently,there are several ongoing clinical trials of newly developed targeted agents,which have shown considerable clinical efficacy and have improved the prognosis of patients who do not benefit from conventional chemotherapy.In this review,we highlight recent developments in the use of existing and novel targeted agents against drug-resistant CRC and mCRC.Furthermore,we discuss limitations and challenges associated with targeted therapy and strategies to combat intrinsic and acquired resistance to these therapies,in addition to the importance of implementing better preclinical models and the application of personalized therapy based on predictive biomarkers for treatment selection.

Targeting endoplasmic reticulum stress signaling in ovarian cancer therapy

The endoplasmic reticulum(ER),an organelle present in various eukaryotic cells,is responsible for intracellular protein synthesis,post-translational modification,and folding and transport,as well as the regulation of lipid and steroid metabolism and Ca2+homeostasis.Hypoxia,nutrient deficiency,and a low pH tumor microenvironment lead to the accumulation of misfolded or unfolded proteins in the ER,thus activating ER stress(ERS)and the unfolded protein response,and resulting in either restoration of cellular homeostasis or cell death.ERS plays a crucial role in cancer oncogenesis,progression,and response to therapies.This article reviews current studies relating ERS to ovarian cancer,the most lethal gynecologic malignancy among women globally,and discusses pharmacological agents and possible targets for therapeutic intervention.

Targeting triple-negative breast cancer:A clinical perspective

Triple-negative breast cancer(TNBC)is a disease with often an aggressive course and a poor prognosis compared to other subtypes of breast cancer.TNBC accounts for approximately 10%–15%of all diagnosed breast cancer cases and represents a high unmet need in the field.Up to just a few years ago,chemotherapy was the only systemic treatment option for this subtype(1).To date,TNBC is considered a heterogeneous disease.One of the existing classifications is based on the analysis of mRNA expression in 587 TNBC cases,in which Lehman et al.proposed six subtypes of TNBC as follows:two basal-like(BL1 and BL2)subtypes,a mesenchymal(M)subtype,a mesenchymal stem-like(MSL)subtype,an immunomodulatory(IM)subtype,and a luminal androgen receptor(LAR)subtype(2).Later studies have demonstrated that the IM and MSL subtypes do not correlate with independent subtypes but reflect background expression by dense infiltration of tumor-infiltrating lymphocytes(TILs)or stromal cells.According to this finding,the classification of TNBC has been revised into the following four subtypes:basal 1,basal 2,LAR,and mesenchymal subtypes(3).Over the last years,several new strategies have been investigated for the treatment of patients with TNBC.Among them,immunotherapy,antibody drug conjugates,new chemotherapy agents,and targeted therapy have been and are currently being developed.The present article aims to provide an updated overview on the different treatment options that are now available or are still under investigation for patients with TNBC.

Therapeutic challenge for immunotherapy targeting cold colorectal cancer: A narrative review

Cold colorectal tumors are not likely to trigger a robust immune response and tend to suppress the immune response.There may be three reasons.First,the complex tumor microenvironment of cold colorectal cancer(CRC)leads to tolerance and clearance of immunotherapy.Second,the modification and concealment of tumor-specific targets in cold CRC cause immune escape and immune response interruption.Finally,the difference in number and function of immune cell subsets in patients with cold CRC makes them respond poorly to immunotherapy.Therefore,we can only overcome the challenges in immunotherapy of cold CRC through in-depth research and understanding the changes and mechanisms in the above three aspects of cold CRC.

Targeting KRAS in pancreatic adenocarcinoma:Progress in demystifying the holy grail

Pancreatic cancer(PC)remains one of the most challenging diseases,with a very poor 5-year overall survival of around 11.5%.Kirsten rat sarcoma virus(KRAS)mutation is seen in 90%-95%of PC patients and plays an important role in cancer cell proliferation,differentiation,metabolism,and survival,making it an essential mutation for targeted therapy.Despite extensive efforts in studying this oncogene,there has been little success in finding a drug to target this pathway,labelling it for decades as“undruggable”.In this article we summarize some of the efforts made to target the KRAS pathway in PC,discuss the challenges,and shed light on promising clinical trials.

pH-sensitive polymeric micelles triggered drug release for extracellular and intracellular drug targeting delivery

Most of the conventional chemotherapeutic agents used for cancer chemotherapy suffer from multidrug resistance of tumor cells and poor antitumor efficacy.Based on physiological differences between the normal tissue and the tumor tissue,one effective approach to improve the efficacy of cancer chemotherapy is to develop pH-sensitive polymeric micellar delivery systems.The copolymers with reversible protonationedeprotonation core units or acid-liable bonds between the therapeutic agents and the micelle-forming copolymers can be used to form pH-sensitive polymeric micelles for extracellular and intracellular drug smart release.These systems can be triggered to release drug in response to the slightly acidic extracellular fluids of tumor tissue after accumulation in tumor tissues via the enhanced permeability and retention effect,or they can be triggered to release drug in endosomes or lysosomes by pH-controlled micelle hydrolysis or dissociation after uptake by cells via the endocytic pathway.The pH-sensitive micelles have been proved the specific tumor cell targeting,enhanced cellular internalization,rapid drug release,and multidrug resistance reversal.The multifunctional polymeric micelles combining extracellular pH-sensitivity with receptor-mediated active targeting strategies are of great interest for enhanced tumor targeting.The micelles with receptor-mediated and intracellular pH targeting functions are internalized via receptor-mediated endocytosis followed by endosomal-pH triggered drug release inside the cells,which reverses multidrug resistance.The pH sensitivity strategy of the polymeric micelles facilitates the specific drug delivery with reduced systemic side effects and improved chemotherapeutical efficacy,and is a novel promising platform for tumor-targeting drug delivery.

Measuring the Targeting Accuracy of China’s Urban Dibao System

After China eradicated absolute poverty in 2020,the problems of relative poverty and urban poverty will draw more attention.Social protection system in urban areas lays the groundwork for economic transition and social stability.The targeting accuracy of urban minimum livelihood guarantee(Dibao)system is the key to the success of the system.After analyzing urban Dibao’s targeting practice and performance with household survey data,this study found that the issuance of Dibao payments took account of household income,assets and demographic characteristics to ensure minimum livelihood guarantee and meet recipients’urgent needs.This practice is of great importance during China’s economic transition.Under the multidimensional review mechanism,the exclusion error of urban Dibao is in the range of 38.45% and 66.28%,and the inclusion error is between 54.59% and 69.17%.By 2013,Dibao’s targeting efficiency improved significantly over 2007.In evaluating Dibao’s targeting efficiency,it is more appropriate to adopt multidimensional criteria instead of income alone.Multidimensional evaluation is also of great importance for evaluating Dibao’s targeting policy.

Molecular targeting agents associated with transarterial chemoembolization or radiofrequency ablation in hepatocarcinoma treatment

Hepatocellular carcinoma(HCC)is the fifth most common cause of cancer in the world.According to Barcelona Clinic Liver Cancer modified criteria,patients with early stage disease are candidate to radiofrequency ablation(RFA),while patients with intermediate stage HCC are usually treated by transarterial chemoembolization(TACE).TACE and RFA induce a transient devascularisation effect followed by strong neoangiogenic stimulus.In fact,after these procedures,it has been demonstrated an up-regulation of pro-angiogenic and growth factors such as vascular endothelial growth factor-A,which might contribute to accelerated progression in patients with incomplete response.Several studies have demonstrated that MAP-kinase and AKT pathways,in addition to neo-angiogenesis,have an important role in the development of HCC.In advanced HCC,anti-angiogenic therapy and tyrosine kinases inhibitors showed potential clinical benefit.Actually,a number of clinical studies are ongoing testing these agents in combination with TACE or RFA.In this paper,we have reviewed the most recent preclinical and clinical results of such trials.

Chemotherapy and molecular targeting therapy for recurrent cervical cancer

For patients with primary stage IVB, persistent, or recurrent cervical cancer, chemotherapy remains the standard treatment, although it is neither curative nor associated with long-term disease control. In this review, we summarized the history of treatment of recurrent cervical cancer, and the current recommendation for chemotherapy and molecular targeted therapy. Eligible articles were identified by a search of the MEDLINE bibliographical database for the period up to November 30, 2014. The search strategy included the following any or all of the keywords： ＂uterine cervical cancer＂, ＂chemotherapy＂, and ＂targeted therapies＂. Since cisplatin every 21 days was considered as the historical standard treatment for recurrent cervical cancer, subsequent trials have evaluated and demonstrated activity for other agents including paclitaxel, gemcitabine, topotecan and vinorelbine among others. Accordingly, promising agents were incorporated into phase III trials. To examine the best agent to combine with cisplatin, several landmark phase III clinical trials were conducted by Gynecologic Oncology Group （GOG） and Japan Clinical Oncology Group （JCOG）. Through, GOG204 and JCOG0505, paclitaxel/cisplatin （TP） and paclitaxel/carboplatin （TC） are now considered to be the recommended therapies for recurrent cervical cancer patients. However, the prognosis of patients who are already resistant to chemotherapy, are very poor. Therefore new therapeutic strategies are urgently required. Molecular targeted therapy will be the most hopeful candidate of these strategies. From the results of GOG240, bevacizumab combined with TP reached its primary endpoint of improving overall survival （OS）. Although, the prognosis for recurrent cervical cancer patients is still poor, the results of GOG240 shed light on the usefulness of molecular target agents to chemotherapy in cancer patients. Recurrent cervical cancer is generally considered incurable and current chemotherapy regiments offer only modest gains in OS, particularly for patients with multiple poor prognostic factors. Therefore, it is crucial to consider not only the survival benefit, but also the minimization of treatment toxicity, and maximization of quality of life （QOL）.

One Stone Four Birds:A Novel Liposomal Delivery System Multi-functionalized with Ginsenoside Rh2 for Tumor Targeting Therapy

Liposomes hold great potential in anti-cancer drug delivery and the targeting treatment of tumors.However,the clinical therapeutic efficacy of liposomes is still limited by the complexity of tumor microenvironment(TME)and the insufficient accumulation in tumor sites.Meanwhile,the application of cholesterol and polyethylene glycol(PEG),which are usually used to prolong the blood circulation and stabilize the structure of liposomes respectively,has been questioned due to various disadvantages.Herein,we developed a ginsenoside Rh2-based multifunctional liposome system(Rh2-lipo)to effectively address these challenges once for all.Different with the conventional’wooden’liposomes,Rh2-lipo is a much more brilliant carrier with multiple functions.In Rh2-lipo,both cholesterol and PEG were substituted by Rh2,which works as membrane stabilizer,long-circulating stealther,active targeting ligand,and chemotherapy adjuvant at the same time.Firstly,Rh2 could keep the stability of liposomes and avoid the shortcomings caused by cholesterol.Secondly,Rh2-lipo showed a specifically prolonged circulation behavior in the blood.Thirdly,the accumulation of the liposomes in the tumor was significantly enhanced by the interaction of glucose transporter of tumor cells with Rh2.Fourth,Rh2-lipo could remodel the structure and reverse the immunosuppressive environment in TME.When tested in a 4T1 breast carcinoma xenograft model,the paclitaxel-loaded Rh2-lipo realized high efficient tumor growth suppression.Therefore,Rh2-lipo not only innovatively challenges the position of cholesterol as a liposome component,but also provides another innovative potential system with multiple functions for anti-cancer drug delivery.

Effects of targeting magnetic drug nanoparticles on human cholangiocarcinoma xenografts in nude mice

BACKGROUND: Targeting is a new therapeutic tool for malignant tumor as a result of combining nanotechnology with chemotherapeutics. The aim of our study was to investigate the effects of magnetic nanoparticles enveloping a chemotherapeutic drug on human cholangiocarcinoma xenografts in nude mice. METHODS: The human cholangiocarcinoma xenograft model was established in nude mice with the QBC939 cell line. The nude mice were randomly assigned to 7 groups. 0.9% saline or magnetic nanoparticles, including high (group 2), medium (group 4) and low (group 5) dosages, were given to nude mice through the tail vein 20 days after the QBC939 cell line was implanted. Calculations were made 35 days after treatment in order to compare the volumes, inhibition ratios and growth curves of the tumors in each group. Mice in each group were sacrificed randomly to collect tumor tissues and other organs for electron microscopy and pathological examination. RESULTS: The high and medium dosage groups were significantly different from the control group (P<0.05). The tumor inhibition ratios for the high, medium and low dosage groups were 39.6%, 14.6% and 7.9%, respectively. The tumor growth curve of groups 5, 4, and 2 changed slowly in turn. The high and medium groups showed cell apoptosis under an electron microscope. CONCLUSION: Magnetic nanoparticles can inhibit the growth of human cholangiocarcinoma xenografts in nude mice.

Molecular targeting to treat gastric cancer

Trastuzumab that targets human epidermal growth factor receptor 2(HER2) protein is the only approved molecular targeting agent for treating gastric cancer in Japan and the outcomes have been favorable. However,trastuzumab is effective for only 10% to 20% of the population with gastric cancer that expresses HER2 protein. Molecular targeting therapy with bevacizumab against vascular endothelial growth factors(VEGF) and with cetuximab and panitumumab against the epidermal growth factors pathway that have been approved for treating colorectal cancer are not considered effective for treating gastric cancer according to several clinical trials. However,ramucirumab that targets VEGF receptor-2 prolonged overall survival in a large phase Ⅲ clinical trial and it might be an effective molecular targeting therapy for gastric cancer. The significance of molecular targeting therapy for gastric cancer remains controversial. A large-scale randomized clinical trial of novel molecular targeting agents with which to treat gastric cancer is needed.