Targeting the transferrin receptor to develop erythropoietin for Alzheimer’s disease

Alzheimer’s disease(AD)is the sixth leading cause of death in the United States with approximately 5.8 million Americans currently living with AD.Due to the lack of a disease modifying treatment for AD and the aging baby boomer generation,this number is projected to grow to 13.8 million by 2050(Gaugler et al.,2019).Amyloid-beta(Aβ)plaque accumulation,one of the major pathological hallmarks of AD,can begin>20 years before clinical symptoms of AD.By the time AD is clinically diagnosed,neuronal loss and neuropathological lesions(Aβplaques and tau tangles)have already.

Accuracy of Ebola Information in a Knowledge Exchange Social Website (KESW)

Background: Misinformation on interactive Knowledge Exchange Social Websites (KESWs) is concerning since it can influence Internet users’ health behaviors, especially during an infectious disease outbreak. Objective: The present study seeks to examine the accuracy and characteristics of health information posted to a Knowledge Exchange Social Website (KESW). Methods: A sample of 204 answers to Ebola questions were extracted and rated for accuracy. Multiple logistic regression modeling was used to examine whether answer characteristics (best answer, professional background, statistical information, source disclosed, link, and word count) predicted accuracy. Results: Overall, only 27.0% of the posted answers were rated as “accurate”. Accuracy varied across question topics with between 11.8% - 45.5% of answers being rated as accurate. When Yahoo Answers’ “best answers” were examined, the overall accuracy was substantially higher, with 80.0% of “best answers” being rated as accurate compared to 16.0% of all other answers. Conclusion: There is need for tools to help Internet users navigate health information posted on these dynamic user-generated knowledge exchange social websites.

Online Vaccine Information in a Knowledge Exchange Social Website (KESW)

Background: The potential for misinformation on usercontrolled Knowledge Exchange Social Websites (KESWs) is concerning since it can actively influence Internet users’ knowledge, attitudes, and behaviors related to childhood vaccinations. Objective: The present study examines the accuracy and predictors of health information posted to a Knowledge Exchange Social Website (KESW). Methods: A sample of 480 answers to childhood vaccination questions were retrieved and rated for accuracy. Multiple logistic regression modeling was used to examine whether answer characteristics (best answer, professional background, statistical information, source disclosure, online link, word count, vaccine stance, and tone) predict accuracy. Results: Overall, only 56.2% of the posted answers were rated as “accurate.” Accuracy varied by topics with between 52.8% - 64.3% being rated as accurate. When Yahoo Answers’ “best answers” were examined, only 49.2% rated as accurate compared to 57.7% of all other answers, a finding attributed to widespread nominations of vaccine misinformation as “best answers” for questions addressing the side effects of vaccines. For all other types of questions, “best answers” were more likely to be accurate. Regression modeling revealed that discussions of personal choices regarding childhood vaccinations predicted the accuracy of posted answers, with those who mentioned vaccinating their own children proving more likely to communicate accurate vaccine information, and those expressing vaccine hesitancy proving more likely to share factually inaccurate statements about vaccines. Conclusion: The high prevalence of misinformation on KESWs suggests that these websites may serve as a vector for spreading vaccine misperceptions. Further research is needed to assess the impact of various KESWs and to develop effective, coordinated responses by public health agencies.

A tumor cell membrane-coated self-amplified nanosystem as a nanovaccine to boost the therapeutic effect of anti-PD-L1 antibody

To improve the response rate of immune checkpoint inhibitors such as anti-PD-L1 antibody in immunosup-pressive cancers like triple-negative breast cancer(TNBC),induction of immunogenic cell death(ICD)at tumor sites can increase the antigenicity and adjuvanticity to activate the immune microenvironment so that tumors become sensitive to the intervention of immune checkpoint inhibitors.Herein,a self-amplified biomimetic nanosystem,mEHGZ,was constructed by encapsulation of epirubicin(EPI),glucose oxidase(Gox)and hemin in ZIF-8 nanoparticles and coating of the nanoparticles with calreticulin(CRT)over-expressed tumor cell mem-brane.EPI acts as an ICD inducer,Gox and hemin medicate the cascade generation of reactive oxygen species(ROS)to strengthen the ICD effect,and CRT-rich membrane as“eat me”signal promote presentation of the released antigens by dendritic cells(DCs)to invoke the tumor-immunity cycle.The biomimetic delivery system displays an amplified ICD effect via Gox oxidation,hydroxyl radical generation and glutathione(GSH)depletion.The induced potent ICD effect promotes DCs maturation and cytotoxic T lymphocytes(CTLs)infiltration,reversing an immunosuppressive tumor microenvironment to an immunoresponsive one.Treatment with the nanosystem in combination with anti-PD-L1 antibody results in distinctive inhibition of tumor growth and lung metastasis,supporting that a potent ICD effect can significantly boost the therapeutic efficacy of the anti-PD-L1 antibody.This self-amplified biomimetic nanoplatform offers a promising means of raising the response rate of immune checkpoint inhibitors.

Polymeric dual-modal imaging nanoprobe with two-photon aggregation-induced emission for fluorescence imaging and gadolinium-chelation for magnetic resonance imaging

Nanoprobes that offer both fluorescence imaging(FI)and magnetic resonance imaging(MRI)can provide supplementary information and hold synergistic advantages.However,synthesis of such dual-modality imaging probes that simultaneously exhibit tunability of functional groups,high stability,great biocompatibility and desired dual-modality imaging results remains challenging.In this study,we used an amphiphilic block polymer from(ethylene glycol)methyl ether methacrylate(OEGMA)and N-(2-hydroxypropyl)methacrylamide(HPMA)derivatives as a carrier to conjugate a MR contrast agent,Gd-DOTA,and a two-photon fluorophore with an aggregation-induced emission(AIE)effect,TPBP,to construct a MR/two-photon fluorescence dual-modality contrast agent,Gd-DOTA-TPBP.Incorporation of gadolinium in the hydrophilic chain segment of the OEGMA-based carrier resulted in a high r_(1)value for Gd-DOTA-TPBP,revealing a great MR imaging resolution.The contrast agent specifically accumulated in the tumor region,allowing a long enhancement duration for vascular and tumor contrast-enhanced MR imaging.Meanwhile,coupling TPBP with AIE properties to the hydrophobic chain segment of the carrier not only improved its water solubility and reduced its cytotoxicity,but also significantly enhanced its imaging performance in an aqueous phase.Gd-DOTA-TPBP was also demonstrated to act as an excellent fluorescence probe for two-photon-excited bioimaging with higher resolution and greater sensitivity than MRI.Since high-resolution,complementary MRI/FI dual-modal images were acquired at both cellular and tissue levels in tumor-bearing mice after application of Gd-DOTA-TPBP,it has great potential in the early phase of disease diagnosis.

Corrigendum to “A tumor cell membrane-coated self-amplified nanosystem as a nanovaccine to boost the therapeutic effect of anti-PD-L1 antibody” [Bioact. Mater. 21 299-312]

The authors regret the incorrect publication of corresponding authors for the article.The corresponding authors have been updated as Hongyan Zhu(hyzhu_hmrrc@126.com)and Kui Luo(luokui@scu.edu.cn),and the same should be updated in the supplementary file as well.

Enzyme-triggered deep tumor penetration of a dual-drug nanomedicine enables an enhanced cancer combination therapy

Cancer cells could be eradicated by promoting generation of excessive intracellular reactive oxygen species(ROS)via emerging nanomedicines.However,tumor heterogeneity and poor penetration of nanomedicines often lead to diverse levels of ROS production in the tumor site,and ROS at a low level promote tumor cell growth,thus diminishing the therapeutic effect of these nanomedicines.Herein,we construct an amphiphilic and block polymer-dendron conjugate-derived nanomedicine(Lap@pOEGMA-b-p(GFLG-Dendron-Ppa),GFLG-DP/Lap NPs)that incorporates a photosensitizer,Pyropheophorbide a(Ppa),for ROS therapy and Lapatinib(Lap)for molecular targeted therapy.Lap,an epidermal growth factor receptor(EGFR)inhibitor that plays a role in inhibiting cell growth and proliferation,is hypothesized to synergize with ROS therapy for effectively killing cancer cells.Our results suggest that the enzyme-sensitive polymeric conjugate,pOEGMA-b-p(GFLG-Dendron-Ppa)(GFLG-DP),releases in response to cathepsin B(CTSB)after entering the tumor tissue.Dendritic-Ppa has a strong adsorption capacity to tumor cell membranes,which promotes efficient penetration and long-term retention.Lap can also be efficiently delivered to internal tumor cells to play its role due to the increased vesicle activity.Laser irradiation of Ppa-containing tumor cells results in production of intracellular ROS that is sufficient for inducing cell apoptosis.Meanwhile,Lap efficiently inhibits proliferation of remaining viable cells even in deep tumor regions,thus generating a significant synergistic anti-tumor therapeutic effect.This novel strategy can be extended to the development of efficient membrane lipid-based therapies to effectively combat tumors.

单质粒心肌特异性缺氧调节SDF-1警戒载体在小鼠心肌梗死治疗中的应用

目的探索单质粒心肌特异性缺氧调节SDF-1警戒载体在心肌细胞中的表达及其小鼠心肌梗死治疗中的应用。方法构建单质粒SDF-1警戒载体,转染心肌细胞,观察hSDF-1表达所需氧含量和启动时间,对比单、双质粒载体hSDF-1的表达水平;构建小鼠急性心肌梗死模型,观察单质粒转染对SDF-1表达、心肌缺血区面积大小及心功能的影响;结果缺氧条件下,单质粒载体诱导SDF-1表达量为为正常氧条件下的8.6倍;在低氧后30分钟开始启动;单质粒转染效率高于双质粒转染;单质粒载体转染组心肌组织的SDF-1较非治疗组表达明显,心功明显改善(EF%:36.68±5.21VS21.1±2.12,p<0.01)。结论单质粒SDF-1警戒载体具备高效、缺氧警戒、心肌特异性的特点,是一种良好的基因工具。

Transplantation of magnetically labeled mesenchymal stem cells improves cardiac function in a swine myocardial infarction model

Background Mesenchymal stem cells （MSCs） transplantation provides a new approach for myocardial repair. However, many important fundamental questions about MSCs transplantation remain unanswered. There is an urgent need to identify MSCs from the beating heart and analyze the efficacy of this new approach. This study aimed to localize the magnetically labeled MSCs （MR-MSCs） and monitor the restorative effects of MR-MSCs with magnetic resonance （MR） imaging. Methods Acute myocardial infarction （AMI） was created in swine by a balloon occlusion of the left anterior descending coronary artery. Cells were delivered via intracoronary infusion after myocardial infarction. Infarct size change and cardiac function were assessed with 3.0T MR scanner. The results were then confirmed by histological and western blot analysis. All statistical procedures were performed with Systat （SPSS version 12.01）. Results A total of 26 swine were divided into four groups （sham-operated group, n=6; AMI group with PBS transplantation, n=6; labeled MSCs group, n=7; unlabeled MSCs group, n=7）. MSCs, MR-MSCs （10~cells） or PBS were delivered by intracoronary injection after MI and serial cardiac MR imaging studies were performed at 0, 4 and 8 weeks after transplantation. MR imaging demonstrated MI size decreased after MSCs transplantation in labeled and unlabeled groups, however, increases were seen in the AMI group at 8 weeks after MI. The left ventricular ejection fraction （LVEF） was slightly increased in the AMI group （（41.87~2.45）% vs （39.04~2.80）%, P 〉0.05）, but significantly improved in the MR-MSCs group （（56.85~1.29）% vs （40.67~2.00）%, P 〈0.05） and unlabeled group （（55.38~1.07）% vs （41.78~2.08）%, P 〈0.05） at 8 weeks after treatment. MR-MSCs were further confirmed by Prussian blue and immunofluorescent staining. Western blot analysis demonstrated that there was an increased expression of cardiomyocyte markers such as myosin heavy chain and troponin T in the MSCs treatment groups and the ratio of matrix metalloproteinase 2 to tissue inhibitor of metalloproteinase 1 decreased in the labeled group and unlabeled group compared with the AMI group and sham-operated group. Conclusion Transplanted MR-MSCs can regenerate new myocardium and prevent remolding in an MI model at 2- month follow-up and represent a preferred method to better understand the mechanisms of stem cell therapy in future clinical studies.

Cathepsin B-responsive and gadolinium-labeled branched glycopolymer-PTX conjugate-derived nanotheranostics for cancer treatment

Multi-modal therapeutics are emerging for simultaneous diagnosis and treatment of cancer.Polymeric carriers are often employed for loading multiple drugs due to their versatility and controlled release of these drugs in response to a tumor specific microenvironment.A theranostic nanomedicine was designed and prepared by complexing a small gadolinium chelate,conjugating a chemotherapeutic drug PTX through a cathepsin B-responsive linker and covalently bonding a fluorescent probe pheophorbide a(Ppa)with a branched glycopolymer.The branched prodrug-based nanosystem was degradable in the tumor microenvironment with overexpressed cathepsin B,and PTX was simultaneously released to exert its therapeutic effect.The theranostic nanomedicine,branched glycopolymer-PTX-DOTA-Gd,had an extended circulation time,enhanced accumulation in tumors,and excellent biocompatibility with significantly reduced gadolinium ion(Gd3+)retention after 96 h post-injection.Enhanced imaging contrast up to 24 h post-injection and excellent antitumor efficacy with a tumor inhibition rate more than 90%were achieved from glycopolymer-PTX-DOTA-Gd without obvious systematic toxicity.This branched polymeric prodrug-based nanomedicine is very promising for safe and effective diagnosis and treatment of cancer.

GSH-sensitive polymeric prodrug: Synthesis and loading with photosensitizers as nanoscale chemo-photodynamic anti-cancer nanomedicine

Precisely delivering combinational therapeutic agents has become a crucial challenge for anti-tumor treatment. In this study, a novel redox-responsive polymeric prodrug(molecular weight,MW: 93.5 k Da) was produced by reversible addition-fragmentation chain transfer(RAFT) polymerization. The amphiphilic block polymer-doxorubicin(DOX) prodrug was employed to deliver a hydrophobic photosensitizer(PS), chlorin e6(Ce6), and the as-prepared nanoscale system [NPs(Ce6)] was investigated as a chemo-photodynamic anti-cancer agent. The glutathione(GSH)-cleavable disulfide bond was inserted into the backbone of the polymer for biodegradation inside tumor cells, and DOX conjugated onto the polymer with a disulfide bond was successfully released intracellularly. NPs(Ce6) released DOX and Ce6 with their original molecular structures and degraded into segments with low MWs of 41.2 k Da in the presence of GSH. NPs(Ce6) showed a chemo-photodynamic therapeutic effect to kill 4 T1 murine breast cancer cells, which was confirmed from a collapsed cell morphology, a lifted level in the intracellular reactive oxygen species, a reduced viability and induced apoptosis. Moreover, ex vivo fluorescence images indicated that NPs(Ce6) retained in the tumor, and exhibited a remarkable in vivo anticancer efficacy. The combinational therapy showed a significantly increased tumor growth inhibition(TGI,58.53%). Therefore, the redox-responsive, amphiphilic block polymeric prodrug could have a great potential as a chemo-photodynamic anti-cancer agent.

Efficiently tracking of stem cells in vivo using different kinds of superparamagnetic iron oxide in swine with myocardial infarction

Background Superparamagnetic iron oxide （SPIO） particles have shown much promise as a means to visualize labeled cells using molecular magnetic resonance imaging （MRI）. Micrometer-sized superparamagnetic iron oxide （MPIO）particles and nanometer-sized ultrasmall superparamagnetic iron oxide （USPIO） are two kinds of SPIO widely used for monitoring stem cells migration. Here we compare the efficiency of two kinds of SPIO during the use of stem cells to treat acute myocardial infarction （AMI）.Methods An AMI model in swine was created by 60 minutes of balloon occlusion of the left anterior descending coronary artery. Two kinds of SPIO particles were used to track after intracoronary delivered 107 magnetically labeled mesenchymal stem cells （MR-MSCs）. The distribution and migration of the MR-MSCs were assessed with the use of 3.0T MR scanner and then the results were confirmed by histological examination.Results MR-MSCs appeared as a local hypointense signal on T2 -weighted MRI and there was a gradual loss of the signal intensity after intracoronary transplantation. All of the hypointense signals in the USPIO-labeled group were found on T2 -weighted MRI, contrast to noise ratio （CNR） decreased in the MPIO-labeled group （16.07±5.85 vs. 10.96±1.34）and USPIO-labeled group （11.72±1.27 vs. 10.03±0.96） from 4 to 8 weeks after transplantation. However, the hypointense signals were not detected in MPIO-labeled group in two animals. MRI and the results were verified by histological examination.Conclusions We demonstrated that two kinds of SPIO particles in vitro have similar labeling efficiency and viability.USPIO is more suitable for labeling stem cells when they are transplanted via a coronary route.

Dendron-polymer hybrid mediated anticancer drug delivery for suppression of mammary cancer

Dendron-polymer-based nanoscale and stimuli-responsive drug delivery systems have shown great promise in tumor-targeting accumulation without significant toxicity.Here we report a dendronized polymer-doxorubicin(DOX)hybrid(DPDH)with an improved in vivo drug delivery efficiency for cancer therapy compared with a linear polymer-DOX conjugate(LPDC).The in vitro drug release profile of DOX indicates that DPDH displays pH-responsive drug release due to cleavage of hydrazone bonds since a greater amount of DOX is released at pH 5.2 at a faster rate than at pH 7.4.DPDH efficiently enters 4 T1 cells and releases DOX to induce cytotoxicity and apoptosis.Owing to the dendronzied structure,DPDH has a significantly longer blood circulation time than LPDC.DPDH substantially enhances the therapeutic efficacy to suppress tumor growth in a 4 T1 mammary cancer model than LPDC as well as free drug,evidenced from tumor growth inhibition,TUNEL assessment and histological analysis.Biosafety of DPDH is also confirmed from hemolysis,body weight shifts during treatment and pathological analysis.This study demonstrates the use of dendronized polymer-DOX hybrids for specific drug molecules is a promising approach for drug delivery.