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.

Preparation and functional characterization of tumor-targeted folic acid-chitosan conjugated nanoparticles loaded with mitoxantrone

Folic acid conjugated chitosan was prepared by cross-linking reaction with 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride(EDC), and then used as a template to prepare folic acid-chitosan(FA-CS) conjugated nanoparticles and load mitoxantrone nanoparticles(FA-CSNP/MTX). Drug dissolution testing, CCK-8 method, and confocal microscopy were used to detect their controlled-release capability in different situations and the specific uptake by HONE1 cells. The experimental results show that the nanoparticles have uniform size distribution of 48-58 nm. The highest encapsulation rate of the particles on mitoxantrone hydrochloride(MTX) is(77.5±1.9)%, and the drug loading efficiency is(18.4±0.4)%. The sustained release effect, cell growth inhibition activity and targeting effect of the FA-CS/MTX nanoparticles are good in artificial gastric fluid and intestinal fluid. It is demonstrated that the FA-CSNP system is a potentially useful system for the targeted delivery of anticancer drug MTX.

Prognostic value and predictive threshold of tumor volume for patients with locally advanced nasopharyngeal carcinoma receiving intensity-modulated radiotherapy

Background: Gross target volume of primary tumor(GTV?P) is very important for the prognosis prediction of patients with nasopharyngeal carcinoma(NPC), but it is unknown whether the same is true for locally advanced NPC patients treated with intensity?modulated radiotherapy(IMRT). This study aimed to clarify the prognostic value of tumor volume for patient with locally advanced NPC receiving IMRT and to ind a suitable cut?of value of GTV?P for prognosis prediction.Methods: Clinical data of 358 patients with locally advanced NPC who received IMRT were reviewed. Receiver oper?ating characteristic(ROC) curves were used to identify the cut?of values of GTV?P for the prediction of diferent end?points [overall survival(OS), local relapse?free survival(LRFS), distant metastasis?free survival(DMFS), and disease?free survival(DFS)] and to test the prognostic value of GTV?P when compared with that of the American Joint Committee on Cancer T staging system.Results: The 358 patients with locally advanced NPC were divided into two groups by the cut?of value of GTV?P as determined using ROC curves: 219(61.2%) patients with GTV?P ≤46.4 mL and 139(38.8%) with GTV?P >46.4 mL. The 3?year OS, LRFS, DMFS, and DFS rates were all higher in patients with GTV?P ≤46.4 mL than in those with GTV?P > 46.4 mL(all P < 0.05). Multivariate analysis indicated that GTV?P >46.4 mL was an independent unfavorable prognostic factor for patient survival. The ROC curve veriied that the predictive ability of GTV?P was superior to that of T category(P < 0.001). The cut?of values of GTV?P for the prediction of OS, LRFS, DMFS, and DFS were 46.4, 57.9, 75.4 and 46.4 mL, respectively.Conclusion: In patients with locally advanced NPC, GTV?P >46.4 mL is an independent unfavorable prognostic indi?cator for survival after IMRT, with a prognostic value superior to that of T category.

Perspectives on bone-targeted nano-drug carriers for bone tumor treatment

Bone tumour is one of most common primary cancer which exhibits cancerous osteoblastic differentiation and malignant osteoid in patients.At present,chemotherapy(pre-and post-operative)is used as a standard treatment protocol for bone tumour.However,drugs used in the treatment of bone tumour induce high toxicity to normal tissues including anaemia,neutropenia,thrombocytopenia,and heart damage which further reduce the survival rate of patients.Therefore,there is an urgent need to develop a new therapeutic approach for the treatment such that it induce maximum cell killing effect in tumor cells while sparing the healthy bone cells.In this article,some new perspectives were provided on the development of bone-targeted nano-drug carriers for bone cancer treatment.We hope such discussions wouldencourage more detailed and careful studies to support product development of bone-targeted drug carriers for bone cancer treatment.

Prognostic factors of primary gastrointestinal stromal tumors： a cohort study based on high-volume centers

Objective： We aimed to evaluate the clinicopathologic characteristics, immunohistochemical expression and prognostic factors of patients with primary gastrointestinal stromal tumors（GISTs）.Methods： Data from 2,570 consecutive GIST patients from four medical centers in China（January2001–December 2015） were reviewed. Survival curves were constructed by the Kaplan-Meier method, and Cox regression models were used to identify independent prognostic factors.Results： Of the included patients, 1,375（53.5%） were male, and the patient age range was 18 to 95（median, 58）years. The tumors were mostly found in the stomach（64.5%）, small intestine（25.1%） and colorectal region（5.1%）.At the time of diagnosis, the median tumor size was 4.0（range： 0.1–55.0） cm, and the median mitotic index per 50 high power fields（HPFs） was 3（range： 0–254）. Of the 2,168 resected patients, 2,009（92.7%） received curative resection. According to the modified National Institutes of Health（NIH） classification, 21.9%, 28.9%, 14.1% and35.1% were very low-, low-, intermediate-and high-risk tumors, respectively. The rate of positivity was 96.4% for c-Kit, 87.1% for CD34, 96.9% for delay of germination 1（DOG-1）, 8.0% for S-100, 31.0% for smooth muscle actin（SMA） and 5.1% for desmin. However, the prognostic value of each was limited. Multivariate analysis showed that age, tumor size, mitotic index, tumor site, occurrence of curative resection and postoperative imatinib were independent prognostic factors. Furthermore, we found that high-risk patients benefited significantly from postoperative imatinib（P〈0.001）, whereas intermediate-risk patients did not（P=0.954）.Conclusions： Age, tumor size, mitotic index, tumor site, occurrence of curative resection and postoperative imatinib were independent prognostic factors in patients with GISTs. Moreover, determining whether intermediate-risk patients can benefit from adjuvant imatinib would be of considerable interest in future studies.

Discovering metabolic vulnerability using spatially resolved metabolomics for antitumor small molecule-drug conjugates development as a precise cancer therapy strategy

Against tumor-dependent metabolic vulnerability is an attractive strategy for tumor-targeted therapy.However,metabolic inhibitors are limited by the drug resistance of cancerous cells due to their metabolic plasticity and heterogeneity.Herein,choline metabolism was discovered by spatially resolved metabolomics analysis as metabolic vulnerability which is highly active in different cancer types,and a choline-modified strategy for small molecule-drug conjugates(SMDCs)design was developed to fool tumor cells into indiscriminately taking in choline-modified chemotherapy drugs for targeted cancer therapy,instead of directly inhibiting choline metabolism.As a proof-of-concept,choline-modified SMDCs were designed,screened,and investigated for their druggability in vitro and in vivo.This strategy improved tumor targeting,preserved tumor inhibition and reduced toxicity of paclitaxel,through targeted drug delivery to tumor by highly expressed choline transporters,and site-specific release by carboxylesterase.This study expands the strategy of targeting metabolic vulnerability and provides new ideas of developing SMDCs for precise cancer therapy.

Molecular neuro-oncology and development of targeted therapeutic strategies for brain tumors

Brain tumors are a diverse group of malignancies that remain refractory to conventional treatment approaches.Molecular neuro-oncologyhas now begun to clarify the transformed phenotype of brain tumors and identify oncogenic pathways that might be amenable to targetedtherapy.Activity of the phosphoinositide 3;kinase(PI3K)/Akt pathway is often upregulated in brain tumors due to excessive stimu-lation by growth factor receptors and Ras.Loss of function of the tumor suppressor gene PTEN also frequently contributesto

Influencing factors and solution strategies of chimeric antigen receptor T-cell therapy(CAR–T)cell immunotherapy

Chimeric antigen receptor T-cesll therapy(CAR–T)has achieved groundbreaking advancements in clinical application,ushering in a new era for innovative cancer treatment.However,the challenges associated with implementing this novel targeted cell therapy are increasingly significant.Particularly in the clinical management of solid tumors,obstacles such as the immunosuppressive effects of the tumor microenvironment,limited local tumor infiltration capability of CAR–T cells,heterogeneity of tumor targeting antigens,uncertainties surrounding CAR–T quality,control,and clinical adverse reactions have contributed to increased drug resistance and decreased compliance in tumor therapy.These factors have significantly impeded the widespread adoption and utilization of this therapeutic approach.In this paper,we comprehensively analyze recent preclinical and clinical reports on CAR–T therapy while summarizing crucial factors influencing its efficacy.Furthermore,we aim to identify existing solution strategies and explore their current research status.Through this review article,our objective is to broaden perspectives for further exploration into CAR–T therapy strategies and their clinical applications.

Recent progress on nanoparticle-based drug delivery systems for cancer therapy

The development of cancer nanotherapeutics has attracted great interest in the recent decade. Cancer nanotherapeutics have overcome several limitations of conventional therapies, such as nonspecific biodistribution, poor water solubility, and limited bioavailability. Nanoparticles with tuned size and surface characteristics are the key components of nanotherapeutics, and are designed to passively or actively deliver anti-cancer drugs to tumor cells. We provide an overview of nanoparticle-based drug delivery methods and cancer therapies based on tumor-targeting delivery strategies that have been developed in recent years.

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.

Effect of the structure of ginsenosides on the in vivo fate of their liposomes

To utilize themultiple functions and give full play of ginsenosides,a variety of ginsenosides with different structures were prepared into liposomes and evaluated for their effect on the stability,pharmacokinetics and tumor targeting capability of liposomes.The results showed that the position and number of glycosyl groups of ginsenosides have significant effect on the in vitro and in vivo properties of their liposomes.The pharmacokinetics of ginsenosides liposomes indicated that the C-3 sugar group of ginsenosides is beneficial to their liposomes for longer circulation in vivo.The C-3 and C-6 glycosyls can enhance the uptake of their liposomes by 4T1 cells,and the glycosyls at C-3 position can enhance the tumor active targeting ability significantly,based on the specific binding capacity to Glut 1 expressed on the surface of 4T1 cells.According to the results in the study,ginsenoside Rg3 and ginsenoside Rh2 are potential for exploiting novel liposomes because of their cholesterol substitution,long blood circulation and tumor targeting capabilities.The results provide a theoretical basis for further development of ginsenoside based liposome delivery systems.

Selection of DNA aptamer that specific binding human carcinoembryonic antigen in vitro

Objective：To select the specific aptamer of carcinoembryonic antigen （CEA）, one of the most attractive molecule for cancer target therapy and imaging. Methods： Seven rounds in vitro selection were performed against the purified CEA protein. Ligand-mediated target purification and Co-immunoprecipitation were adopted to verify the specific binding of the aptamer to the purified and native protein separately. Results：The CEA-specific aptamer which can bind both the purified and native protein with the high specificity was obtained. Conclusion：This is the first time the CEA specific apatmer was produced. The results in this study provides the preliminary evidence for further investigation and application of CEA-aptamer in the future.

Enhanced lysosome escape mediated by 1,2-dicarboxylic-cyclohexene anhydride-modified poly-L-lysine dendrimer as a gene delivery system

Antisense oligodeoxynucleotide(ASODN)can directly interfere a series of biological events of the target RNA derived from tumor cells through Watson-Crick base pairing,in turn,plays antitumor therapeutic roles.In the study,a novel HIF-1αASODN-loaded nanocomposite was formulated to efficiently deliver gene to the target RNA.The physicochemical properties of nanocomposite were characterized using TEM,FTIR,DLS and zeta potentials.The mean diameter of resulting GEL-DGL-FA-ASODN-DCA nanocomposite was about 170–192 nm,and according to the agarose gel retardation assay,the loading amount of ASODN accounted for 166.7 mg/g.The results of cellular uptake showed that the nanocomposite could specifically target to HepG2 and Hela cells.The cytotoxicity assay demonstrated that the toxicity of vectors was greatly reduced by using DCA to reversibly block the cationic DGL.The subcellular distribution images clearly displayed the lysosomal escape ability of the DCA-modified nanocomposite.In vitro exploration of molecular mechanism indicated that the nanocomposite could inhibit m RNA expression and HIF-1αprotein translation at different levels.In vivo optical images and quantitative assay testified that the formulation accumulated preferentially in the tumor tissue.In vivo antitumor efficacy research confirmed that this nanocomposite had significant antitumor activity and the tumor inhibitory rate was 77.99%.These results manifested that the GEL-DGL-FA-ASODNDCA nanocomposite was promising in gene therapeutics for antitumor by interacting directly with target RNA.

Interleukin-6: a villain in the drama of pancreatic cancer development and progression

BACKGROUND： Pancreatic ductal adenocarcinoma（PDAC）is a devastating malignancy with a poor prognosis and little treatment options. The development and progression of the disease is fostered by inflammatory cells and cytokines. One of these cytokines is interleukin-6（IL-6）, which plays an important role in a wide range of biologic activities.DATA SOURCES： A systematic search of PubMed was performed to identify relevant studies using key words such as interleukin-6,inflammatory cytokines, inflammation and pancreatic cancer or PDAC. Articles related to IL-6 and pancreatic cancer were systematically reviewed.RESULTS： IL-6 is elevated in the serum of pancreatic cancer patients and correlates with cachexia, advanced tumor stage and poor survival. Its expression is enhanced by hypoxia and proteins involved in pancreatic cancer development like Kras,mesothelin or ZIP4. IL-6 in turn contributes to the generation of a pro-tumorigenic microenvironment and is probably involved in angiogenesis and metastasis. In experimental mouse models of PDAC, IL-6 was important for the development and progression of precursor lesions.CONCLUSION： IL-6 emerges as a key player in pancreatic cancer development and progression, and hence should be considered as a new therapeutic target.

Enhanced permeability and retention effect based nanomedicine, a solution for cancer

Tumor-targeting is becoming more and more important for cancer chemotherapy. Though many molecular-target drugs have been developed in the past two decades which shed some light on targeted tumor therapy,clinical results of those molecular-target drugs are not so encouraging especially for solid tumors, problems mostly relating to the heterogeneity and mutations of target molecules in human solid tumors. More general tumor-targeting strategy is thus anticipated. In this regard, the enhanced permeability and retention(EPR) effect which is a unique phenomenon of solid tumors based on the anatomical and pathophysiological nature of tumor blood vessels, is receiving more and more attentions. This EPR effect now served as a standard for tumor-targeted macromolecular anticancer therapy, namely nanomedicine. Many nanoplatforms have been developed as targeted drug delivery systems, including liposome, polymeric micelles, polymer conjugate, nanoparticles. Ample macromolecular drugs are now approved for clinical use or in clinical stage development, all of which by taking advantage of EPR effect, show superior in vivo pharmacokinetics and remarkable tumor selectivity, resulting in improved antitumor effects with less adverse effects. We thus believe EPR-based nanomedicine will be a solution for cancer in the future, whereas further consideration of factors involved in EPR effect and strategies to augment/improve EPR effect are warranted.

Harnessing bacteria for tumor therapy:Current advances and challenges

After a century of standstill,bacteria-based tumor therapy has resurged recently benefiting from the revolution of tumor immunotherapy,which provides unique solutions to tackle the obstacles of traditional tumor treatments.Obligate and facultative anaerobes with active tropism can selectively colonize at tumor sites and suppress tumor growth via different mechanisms,serving as attractive tools for tumor treatment either as a monotherapy or combining with other therapies for synergistic anti-tumor effects.In this critical review,we introduce the recent advances of bacteria-based tumor therapy from the following aspects.First,the general properties of bacteria are reviewed emphasizing on their structural components related to tumor immunotherapy,and the main bacteria that have been used in tumor therapy are listed.Then,the benefits of bacteria for tumor therapy are illustrated,such as tumor targetability,deep penetration,and facile genetic engineering for attenuation,enhanced efficacy,as well as bioimaging.Next,anti-tumor mechanisms of bacteria are summarized,which refer to intrinsic tumoricidal activities,immune activation,bacteria metabolism,and their capability to regulate gut microbiota homeostasis.Moreover,bacteria could act as carriers to deliver various types of therapeutics to achieve combination therapy with improved efficacy.In addition,several challenges for anti-tumor applications of bacteria are discussed regarding the delivery,efficacy and safety issues,and potential solutions are also provided.Finally,the possible improvements and perspectives are discussed in the end,which provide a guideline for the design of advanced bacteria-based tumor therapeutics in the future.

Preparation and functional study of pH-sensitive amorphous calcium phosphate nanocarriers

Recently,multifunctional nanoparticles have shown great prospects in cancer treatment,which have the ability to simultaneously deliver the drug,image and target tumor cells.In this paper,we designed a luminescent nanoparticles platform based on hydrothermal hyaluronic acid/amorphous calcium phosphate(HA-FCNs/ACP)with multifunctional properties for drug delivery,bio-imaging,and targeting treatment.HA-FCNs/ACP shows an ability to load curcumin(Cur)with pH-sensitive responsive drug release behavior and excellent biocompatibility.HA-FCNs/ACP dispersed in the cytoplasm through the overexpressed CD44 receptor that is actively targeted into human lung cancer cells(A549 cells).Meanwhile,the viability of A549 cells was significantly inhibited in vitro.The prepared HA-FCNs and HA-FCNs/ACP both exhibit excellent targeted bioimaging performance on cancer cells.Hence,the as-prepared nanoparticles have promising applications in treating tumor disease.

Towards automated organs at risk and target volumes contouring: Defining precision radiation therapy in the modern era

Precision radiotherapy is a critical and indispensable cancer treatment means in the modern clinical workflow with the goal of achieving“quality-up and cost-down”in patient care.The challenge of this therapy lies in developing computerized clinical-assistant solutions with precision,automation,and reproducibility built-in to deliver it at scale.In this work,we provide a comprehensive yet ongoing,incomplete survey of and discussions on the recent progress of utilizing advanced deep learning,semantic organ parsing,multimodal imaging fusion,neural architecture search and medical image analytical techniques to address four corner-stone problems or sub-problems required by all precision radiotherapy workflows,namely,organs at risk(OARs)segmentation,gross tumor volume(GTV)segmentation,metastasized lymph node(LN)detection,and clinical tumor volume(CTV)segmentation.Without loss of generality,we mainly focus on using esophageal and head-and-neck cancers as examples,but the methods can be extrapolated to other types of cancers.High-precision,automated and highly reproducible OAR/GTV/LN/CTV auto-delineation techniques have demonstrated their effectiveness in reducing the inter-practitioner variabilities and the time cost to permit rapid treatment planning and adaptive replanning for the benefit of patients.Through the presentation of the achievements and limitations of these techniques in this review,we hope to encourage more collective multidisciplinary precision radiotherapy workflows to transpire.

The next generation of cancer management

As readers of Cancer Biology and Medicine well know,there has been a seismic shift in human molecular biology over the past few years,as momentous in its own way as the discovery of the double-helical structure of DNA by Watson and Crick 60 years ago,the elucidation of the genetic code shortly thereafter,the advent of recombinant DNA and gene cloningin the 1970s, and the introduction of the polymerase chain reaction in the mid-1980s.

Exosomes derived from tumor adjacent fibroblasts efficiently target pancreatic tumors

The application of extracellular vesicles,particularly exosomes(EXs),is rapidly expanding in the field of medicine,owing to their remarkable properties as natural carriers of biological cargo.This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues(NAF-EXs)for personalized medicine,which can be derived at the time of diagnosis by endoscopic ultrasound.Herein,we show that exosomes(EXs)derived from NAFs demonstrate differential bio-physical characteristics,efficient cellular internalization,drug loading efficiency,pancreatic tumor targeting and delivery of payloads.NAF-derived EXs(NAF-EXs)were used for loading ormeloxifene(ORM),a potent anti-cancer and desmoplasia inhibitor as a model drug.We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype,which may be due to regulation of Ca^(2+) influx in fibroblast cells.NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition(EMT)and repressed tumor growth in xenograft mouse model.In conclusion,our data suggests preferential tropism of NAF-EXs for PDAC tumors,thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs.Additionally,it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.