Publications by authors named "Donglu Shi"

99 Publications

How effective is a mask in preventing COVID-19 infection?

Med Devices Sens 2021 Jan 5:e10163. Epub 2021 Jan 5.

The Materials Science and Engineering Program College of Engineering and Applied Science University of Cincinnati Cincinnati OH USA.

The main clinical characteristics of COVID-19 are respiratory symptoms that can lead to serious cardiovascular damages and severe worsening of other medical conditions. One of the major strategies in preparedness and response to COVID 19 is effective utilization of personal protective equipment (PPE) among which the masks of different kinds are on the top of the list especially for activities in the public places. However, the underlying mechanisms of masks in preventing virus transmission have not been well identified and the current experimental data still show inconsistent outcomes that may mislead the public. For instance, the early understanding of the mask functions was limited especially in the escalating phase of the COVID 19 pandemic, resulting in quite controversial remarks on masks. Although extensive studies in mask functions have been carried out ever since the COVID-19 outbreaks, most of the investigations appear to have focused on exhalation isolation of individuals who may have been infected with the disease. Less emphasis was laid on inhalation protection from virus transmission, an important aspect that undergirds the public health policies and protective strategies. This review provides the most up-to-date information on the transmission modes of COVID-19 virus in terms of droplets and aerosols. The roles of masks in disease prevention and transmission reduction are evaluated on various types, structures and functions. More important, both aspects of exhalation isolation and inhalation protection are discussed based on virus transmission modes and the effectiveness of different types of masks under varied environmental conditions.
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http://dx.doi.org/10.1002/mds3.10163DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7883189PMC
January 2021

Photosensitizer-Laden Neutrophils Are Controlled Remotely for Cancer Immunotherapy.

Cell Rep 2020 12;33(11):108499

Department of Medical Ultrasound, Shanghai Tenth People's Hospital, The Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, Shanghai 200092, P.R. China. Electronic address:

By incorporating an artificial reactive oxygen species (ROS) generation mechanism, a biotic/abiotic integration is designed to improve the anti-tumor effect of neutrophils by artificially potentiating their ROS effector mechanism in a remotely controlled route. Specifically, the photosensitizer Ce6 is nano-packaged by the albumin BSA to achieve biocompatible and efficient integration with neutrophils (NEs). Reinfusion of the engineered NEs into 4T1 tumor-bearing mice led to more Ce6 accumulation in tumors relative to Ce6 nanoformulation. At the peak of accumulation, tumor illumination activates the embedded Ce6 for ROS generation and NETosis formation. Because of the ROS-intensified cytolytic effect, the growth of 4T1 tumors is inhibited significantly. The photo-controlled process largely avoids the off-target effects observed frequently in current cell therapies. The strategy directly generates ROS effector molecules with spatiotemporal precision. This engineering approach is able to potentiate the native capacity of immune cells independent of the tumor microenvironment.
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http://dx.doi.org/10.1016/j.celrep.2020.108499DOI Listing
December 2020

Nanoparticle Delivery Systems with Cell-Specific Targeting for Pulmonary Diseases.

Am J Respir Cell Mol Biol 2021 03;64(3):292-307

Center for Lung Regenerative Medicine.

Respiratory disorders are among the most important medical problems threatening human life. The conventional therapeutics for respiratory disorders are hindered by insufficient drug concentrations at pathological lesions, lack of cell-specific targeting, and various biobarriers in the conducting airways and alveoli. To address these critical issues, various nanoparticle delivery systems have been developed to serve as carriers of specific drugs, DNA expression vectors, and RNAs. The unique properties of nanoparticles, including controlled size and distribution, surface functional groups, high payload capacity, and drug release triggering capabilities, are tailored to specific requirements in drug/gene delivery to overcome major delivery barriers in pulmonary diseases. To avoid off-target effects and improve therapeutic efficacy, nanoparticles with high cell-targeting specificity are essential for successful nanoparticle therapies. Furthermore, low toxicity and high degradability of the nanoparticles are among the most important requirements in the nanoparticle designs. In this review, we provide the most up-to-date research and clinical outcomes in nanoparticle therapies for pulmonary diseases. We also address the current critical issues in key areas of pulmonary cell targeting, biosafety and compatibility, and molecular mechanisms for selective cellular uptake.
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http://dx.doi.org/10.1165/rcmb.2020-0306TRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7909340PMC
March 2021

Bioelectricity, Its Fundamentals, Characterization Methodology, and Applications in Nano-Bioprobing and Cancer Diagnosis.

Adv Biosyst 2019 10 27;3(10):e1900101. Epub 2019 Aug 27.

Materials Science and Engineering Program, Department of Mechanical and Materials Engineering, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH, 45221, USA.

Bioelectricity is an essential characteristic of a biological system that has played an important role in medical diagnosis particularly in cancer liquid biopsy. However, its biophysical origin and measurements have presented great challenges in experimental methodologies. For instance, in dynamic cell processes, bioelectricity cannot be accurately determined as a static electrical potential via electrophoresis. Cancer cells fundamentally differ from normal cells by having a much higher rate of glycolysis resulting in net negative charges on cell surfaces. The most recent investigations on cancer cell surface charge that is the direct bio-electrical manifestation of the "Warburg Effect," which can be directly monitored by specially designed nanoprobes, has been provided. The most up-to-date research results from charge-mediated cell targeting are reviewed. Correlations between the cell surface charge and cancer cell metabolism are established based on cell/probe electrostatic interactions. Bioelectricity is utilized not only as an analyte for investigation of the metabolic state of the cancer cells, but also applied in electrostatically and magnetically capturing of the circulating tumor cells from whole blood. Also reviewed is on the isolation of Candida albicans via bioelectricity-driven nanoparticle binding on fungus with surface charges.
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http://dx.doi.org/10.1002/adbi.201900101DOI Listing
October 2019

Nanoparticle Delivery of Proangiogenic Transcription Factors into the Neonatal Circulation Inhibits Alveolar Simplification Caused by Hyperoxia.

Am J Respir Crit Care Med 2020 07;202(1):100-111

Department of Pediatrics, University of Cincinnati and Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

: Advances in neonatal critical care have greatly improved the survival of preterm infants, but the long-term complications of prematurity, including bronchopulmonary dysplasia (BPD), cause mortality and morbidity later in life. Although VEGF (vascular endothelial growth factor) improves lung structure and function in rodent BPD models, severe side effects of VEGF therapy prevent its use in patients with BPD.: To test whether nanoparticle delivery of proangiogenic transcription factor FOXM1 (forkhead box M1) or FOXF1 (forkhead box F1), both downstream targets of VEGF, can improve lung structure and function after neonatal hyperoxic injury.: Newborn mice were exposed to 75% O for the first 7 days of life before being returned to a room air environment. On Postnatal Day 2, polyethylenimine-(5) myristic acid/polyethylene glycol-oleic acid/cholesterol nanoparticles containing nonintegrating expression plasmids with or cDNAs were injected intravenously. The effects of the nanoparticles on lung structure and function were evaluated using confocal microscopy, flow cytometry, and the flexiVent small-animal ventilator.: The nanoparticles efficiently targeted endothelial cells and myofibroblasts in the alveolar region. Nanoparticle delivery of either FOXM1 or FOXF1 did not protect endothelial cells from apoptosis caused by hyperoxia but increased endothelial proliferation and lung angiogenesis after the injury. FOXM1 and FOXF1 improved elastin fiber organization, decreased alveolar simplification, and preserved lung function in mice reaching adulthood.: Nanoparticle delivery of FOXM1 or FOXF1 stimulates lung angiogenesis and alveolarization during recovery from neonatal hyperoxic injury. Delivery of proangiogenic transcription factors has promise as a therapy for BPD in preterm infants.
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http://dx.doi.org/10.1164/rccm.201906-1232OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7328311PMC
July 2020

Smart Sorting of Tumor Phenotype with Versatile Fluorescent Ag Nanoclusters by Sensing Specific Reactive Oxygen Species.

Theranostics 2020 10;10(8):3430-3450. Epub 2020 Feb 10.

The Materials Science and Engineering Program, Dept. of Mechanical and Materials Engineering, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, Ohio, 45221, USA.

Reactive oxygen species (ROS) play a crucial role in cancer formation and development, especially cancer metastasis. However, lack of a precise tool, which could accurately distinguish specific types of ROS, restricts an in-depth study of ROS in cancer development and progression. Herein, we designed smart and versatile fluorescent Ag nanoclusters (AgNCs) for sensitive and selective detection of different species of ROS in cells and tissues. : Firstly, dual-emission fluorescent AgNCs was synthesized by using bovine serum albumin (BSA) to sense different types of ROS (HO, O2•-, •OH). The responsiveness of the AgNCs to different species of ROS was explored by fluorescence spectrum, hydrodynamic diameter, and so on. Furthermore, dual-emission fluorescent AgNCs was used to sense ROS in tumor with different degrees of differentiation. Finally, the relationship between specific types of ROS and tumor cell invasion was explored by cell migration ability and the expression of cell adhesion and EMT markers. : This dual-emission fluorescent AgNCs possessed an excellent ability to sensitively and selectively distinguish highly reactive oxygen species (hROS, including O•and •OH) from moderate reactive oxygen species (the form of HO), and exhibited no fluoresence and green fluorescence, respectively. The emission of AgNCs is effective in detecting cellular and tissular ROS. When cultured with AgNCs, malignant tumor cells exhibit non-fluorescence, while the benign tumor emits green and reduced red light and the normal cells appear in weak green and bright red fluorescence. We further verified that not just HO but specific species of ROS (O•and •OH) were involved in cell invasion and malignant transformation. Our study warrants further research on the role of ROS in physiological and pathophysiological processes. : Taken together, AgNCs would be a promising approach for sensing ROS, and offer an intelligent tool to detect different kinds of ROS in tumors.
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http://dx.doi.org/10.7150/thno.38422DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069096PMC
April 2021

Rapid Label-Free Isolation of Circulating Tumor Cells from Patients' Peripheral Blood Using Electrically Charged FeO Nanoparticles.

ACS Appl Mater Interfaces 2020 Jan 14;12(4):4193-4203. Epub 2020 Jan 14.

The Materials Science and Engineering Program, Dept. of Mechanical and Materials Engineering, College of Engineering and Applied Science , University of Cincinnati , Cincinnati , Ohio 45221 , United States.

Isolation of circulating tumor cells (CTCs) in peripheral blood from cancer patients bears critical importance for evaluation of therapeutic efficacy. The current CTC isolation strategies are majorly relying on either protein biomarkers or dimensional features of CTCs. In this study, we present a new methodology for CTC detection and isolation based on the surface charge of cancer cells, a bioelectrical manifestation of the "Warburg effect." Negative surface charge is a direct consequence of glycolysis of cancer cells, which can be utilized as an effective biophysical marker for CTC detection and isolation. Upon cancer cells-nanoparticle interaction via optimum incubation, serum protein-coated electrically charged nanoparticles can trap different cancer cells independent of their epithelial protein expression. In fetal bovine serum , the poly(ethyleneimine)-functionalized FeO nanoparticles, surface-decorated with protein corona, are able to efficiently capture CTCs from blood samples of colorectal cancer patients.  2-8 CTCs has been isolated from 1 mL of blood and identified by immunostaining fluorescence in situ hybridization and immunofluorescence staining in all 25 colorectal cancer patients at varied stages, while only 0-1 CTC was detected from blood samples of 10 healthy donors. Diverse CTC subpopulations of heteroploids and biomarker expression can also be detected in this strategy. The label-free, charge-based CTC method shows promise in cancer diagnosis and prognosis paving a new path for liquid biopsy.
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http://dx.doi.org/10.1021/acsami.9b16385DOI Listing
January 2020

Ca-Mediated Surface Polydopamine Engineering to Program Dendritic Cell Maturation.

ACS Appl Mater Interfaces 2020 Jan 10;12(3):4163-4173. Epub 2020 Jan 10.

Shanghai Tenth People's Hospital, The Institute for Biomedical Engineering & Nano Science , Tongji University School of Medicine , Shanghai 200092 , China.

Engineering of cell surfaces holds promise in manipulating cellular activities in a physicochemical route as a complement to the biological approach. Mediated by Ca, a quick and convenient yet cytocompatible method is used to achieve surface engineering, by which polydopamine nanostructures can be in situ grown onto dendritic cell (DC) surfaces within 10 min. Ca, as the physical bridge between the negative cell surface and polydopamine, avoids the direct chemical polymerization of polydopamine onto the cell surface, critically important to maintain the cell viability. As a proof of concept in potential applications, this cell surface engineering shows a good control toward DC maturation. Upon surface polydopamine engineering, bone-marrow-derived DC exhibits a unique bidirectional control of maturation. The polydopamine structure enables effective suppression of DC activation by acting as an efficient scavenger of reactive oxygen species, a key signal during maturation. Conversely, an 808 nm laser irradiation can remotely relieve the suppressed state and effectively activate DC maturation by the photoheat effect of polydopamine (39 °C). The work provides an easily implemented, straightforward approach to achieve cell surface engineering, through which the DC maturation can be controlled.
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http://dx.doi.org/10.1021/acsami.9b20997DOI Listing
January 2020

Remodeling of Cellular Surfaces via Fast Disulfide-Thiol Exchange To Regulate Cell Behaviors.

ACS Appl Mater Interfaces 2019 Dec 11;11(51):47750-47761. Epub 2019 Dec 11.

Shanghai Tenth People's Hospital, The Institute for Biomedical Engineering & Nano Science , Tongji University School of Medicine , Shanghai 200092 , China.

Remodeling of cellular surfaces is shown highly effective in the manipulation and control of cell behaviors via nonbiological means. By 5-thio-2-nitrobenzoate-mediated, fast, and reversible disulfide-thiol exchange, a sequential layer by layer assembly process was developed to grow albumin protein shells on cellular surfaces fixed by a disulfide-linked network, in a cytocompatible manner. The artificial shells, accomplished by a double-assembly process, were sustainable up to >1 day, and thereafter gradually bioabsorbed with unaffected cell viability. The surface engineering process enabled dynamic remodeling of cellular surfaces that effectively controlled cell behaviors including regulated cell proliferation, enhanced uptake efficiency of dextran-fluorescein isothiocyanate that is known for cell-impermeability, and targeted imaging. This unique approach was well-validated on tumor cells (B16), immune cells (DC2.4), and neutrophils, showing its potential universality for most of the cells that are rich in thiols. The new strategy will show promise in cell manipulation and targeted imaging.
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http://dx.doi.org/10.1021/acsami.9b17550DOI Listing
December 2019

A nano-immunotraining strategy to enhance the tumor targeting of neutrophils via in vivo pathogen-mimicking stimulation.

Biomater Sci 2019 Dec 11;7(12):5238-5246. Epub 2019 Oct 11.

Shanghai Tenth People's Hospital, The Institute for Biomedical Engineering & Nano Science (iNANO), Tongji University School of Medicine, Shanghai 200092, P.R. China.

Due to unsatisfactory tumor-targeting efficiency, hitch-hiking nanomedicines with tumor "smelling" immune cells have rapidly evolved to achieve a more precision delivery. However, the current research tends to default to the smelling capacity of neutrophils and largely overlooks the capacity of those immune cells that are heavily dependent on the pathogen exposure history of individuals. By avoiding risky strategies, such as altering the housing environment of mice for the improved activity of immune cells, we propose a new concept of nano-immunotraining strategy to quickly activate neutrophil tumor tropism and thereby give an enhanced tumor-targeting capacity. Such a strategy involves a facile construction of a vaccine-like nano-CpG adjuvant, followed by pre-immunizing on mice periodically to mimic the pathogen exposure. The results demonstrated that a significantly enhanced tumor-targeting accumulation of neutrophils harvested from nano-immunotrained mice could be achieved, either by intraperitoneal or intravenous injection. This easily accessed, reproducible, and biosafe nano-immunotraining strategy holds a great promise for more precision delivery of nanomedicines.
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http://dx.doi.org/10.1039/c9bm01278hDOI Listing
December 2019

Suppression of the innate cancer-killing activity in human granulocytes by stress reaction as a possible mechanism for affecting cancer development.

Stress 2020 01 30;23(1):87-96. Epub 2019 Jul 30.

Shanghai East Hospital, The Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, Shanghai, China.

Psychological stress may be linked to cancer incidence; however, more direct evidence is required to support this viewpoint. In this study, we investigated the effects of stress on immunosurveillance against cancer cells using a previously established examination stress model. We showed that the cancer killing activity (CKA) of granulocytes (also known as polymorphic nuclear cells, PMNs) is sharply reduced during examination stress stimulation in some donors who are psychologically sensitive to examination stress, with the concentration of plasma stress hormones (cortisone, epinephrine, and norepinephrine) increasing accordingly. The effects of stress hormones on immune cell CKA were also investigated under two co-incubation conditions, with all three hormones found to exert inhibitory effects on the CKA of PMNs and mononuclear cells. We showed that stress triggered the release of stress hormones which had profound inhibitory effects on the innate anticancer functions of PMNs. These results provide a possible explanation for the relationship between psychological stress and cancer incidence.
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http://dx.doi.org/10.1080/10253890.2019.1645112DOI Listing
January 2020

The S52F FOXF1 Mutation Inhibits STAT3 Signaling and Causes Alveolar Capillary Dysplasia.

Am J Respir Crit Care Med 2019 10;200(8):1045-1056

Department of Pediatrics.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal congenital disorder causing respiratory failure and pulmonary hypertension shortly after birth. There are no effective treatments for ACDMPV other than lung transplant, and new therapeutic approaches are urgently needed. Although ACDMPV is linked to mutations in the gene, molecular mechanisms through which FOXF1 mutations cause ACDMPV are unknown. To identify molecular mechanisms by which S52F FOXF1 mutations cause ACDMPV. We generated a clinically relevant mouse model of ACDMPV by introducing the S52F FOXF1 mutation into the mouse gene locus using CRISPR/Cas9 technology. Immunohistochemistry, whole-lung imaging, and biochemical methods were used to examine vasculature in lungs and identify molecular mechanisms regulated by FOXF1. FOXF1 mutations were identified in 28 subjects with ACDMPV. knock-in mice recapitulated histopathologic findings in ACDMPV infants. The S52F FOXF1 mutation disrupted STAT3-FOXF1 protein-protein interactions and inhibited transcription of , a critical transcriptional regulator of angiogenesis. STAT3 signaling and endothelial proliferation were reduced in mice and human ACDMPV lungs. S52F FOXF1 mutant protein did not bind chromatin and was transcriptionally inactive. Furthermore, we have developed a novel formulation of highly efficient nanoparticles and demonstrated that nanoparticle delivery of STAT3 cDNA into the neonatal circulation restored endothelial proliferation and stimulated lung angiogenesis in mice. FOXF1 acts through STAT3 to stimulate neonatal lung angiogenesis. Nanoparticle delivery of STAT3 is a promising strategy to treat ACDMPV associated with decreased STAT3 signaling.
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http://dx.doi.org/10.1164/rccm.201810-1897OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794119PMC
October 2019

A new DNA sensor system for specific and quantitative detection of mycobacteria.

Nanoscale 2019 Jan;11(2):587-597

Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.

In the current study, we describe a novel DNA sensor system for specific and quantitative detection of mycobacteria, which is the causative agent of tuberculosis. Detection is achieved by using the enzymatic activity of the mycobacterial encoded enzyme topoisomerase IA (TOP1A) as a biomarker. The presented work is the first to describe how the catalytic activities of a member of the type IA family of topoisomerases can be exploited for specific detection of bacteria. The principle for detection relies on a solid support anchored DNA substrate with dual functions namely: (1) the ability to isolate mycobacterial TOP1A from crude samples and (2) the ability to be converted into a closed DNA circle upon reaction with the isolated enzyme. The DNA circle can act as a template for rolling circle amplification generating a tandem repeat product that can be visualized at the single molecule level by fluorescent labelling. This reaction scheme ensures specific, sensitive, and quantitative detection of the mycobacteria TOP1A biomarker as demonstrated by the use of purified mycobacterial TOP1A and extracts from an array of non-mycobacteria and mycobacteria species. When combined with mycobacteriophage induced lysis as a novel way of effective yet gentle extraction of the cellular content from the model Mycobacterium smegmatis, the DNA sensor system allowed detection of mycobacteria in small volumes of cell suspensions. Moreover, it was possible to detect M. smegmatis added to human saliva. Depending on the composition of the sample, we were able to detect 0.6 or 0.9 million colony forming units (CFU) per mL of mycobacteria, which is within the range of clinically relevant infection numbers. We, therefore, believe that the presented assay, which relies on techniques that can be adapted to limited resource settings, may be the first step towards the development of a new point-of-care diagnostic test for tuberculosis.
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http://dx.doi.org/10.1039/c8nr07850eDOI Listing
January 2019

Electrical-Charge-Mediated Cancer Cell Targeting via Protein Corona-Decorated Superparamagnetic Nanoparticles in a Simulated Physiological Environment.

ACS Appl Mater Interfaces 2018 Dec 29;10(49):41986-41998. Epub 2018 Nov 29.

The Institute for Translational Nanomedicine, Shanghai East Hospital, the Institute for Biomedical Engineering & Nano Science , Tongji University School of Medicine , Shanghai 200092 , P. R. China.

A critical issue in nanomedicine is on the understanding of nano-bio interface behaviors, particularly when the nanoparticles are inevitably decorated by protein coronas in the physiological fluids. In this study, the effects of particle surface corona on cancer cell targeting were investigated in simulated physiological fluids. Cell targeting was achieved by two strategies: (1) using conventional epithelial cell adhesion molecule antibody-functionalized FeO nanoparticles and (2) rendering the same but naked magnetic nanoparticles electrically positively charged, enabling them to electrostatically bind onto the negatively charged cancer cells. The cell-particle electrostatic binding was found to be much stronger with faster reaction kinetics than the immunological interactions even at 4 nC. Both types of nanoparticles were decorated with various protein coronas by administration in a simulated physiological system. Well-decorated by protein coronas, the electrically charged particles retained strong electrostatic interactions with cancer cells, even upon reversal of the particle zeta potential from positive to negative. This behavior was explained by a nonuniform corona modulation of the particle surface charge distributions, exposing locally positively charged regions, capable of strong electrostatic cell binding and magnetic capturing in a physiological environment. This fundamental discovery paves new way for sensitive detection of circulating tumor cells in whole blood in clinical settings.
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http://dx.doi.org/10.1021/acsami.8b15098DOI Listing
December 2018

Highly Efficient In Vivo Targeting of the Pulmonary Endothelium Using Novel Modifications of Polyethylenimine: An Importance of Charge.

Adv Healthc Mater 2018 12 6;7(23):e1800876. Epub 2018 Nov 6.

The Materials Science and Engineering Program, Department of Mechanical and Materials Engineering, College of Engineering and Applied Sciences, University of Cincinnati, Cincinnati, OH, 45221, USA.

Pulmonary vascular disease encompasses a wide range of serious afflictions with important clinical implications. There is critical need for the development of efficient, nonviral gene therapy delivery systems. Here, a promising avenue to overcome critical issues in efficient cell targeting within the lung via a uniquely designed nanosystem is reported. Polyplexes are created by functionalizing hyperbranched polyethylenimine (PEI) with biological fatty acids and carboxylate-terminated poly(ethylene glycol) (PEG) through a one-pot 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride/N-hydroxysuccinimide reaction. Following intravenous injection, polyplexes show an exceptionally high specificity to the pulmonary microvascular endothelium, allowing for the successful delivery of stabilized enhanced green fluorescent protein (eGFP) expressing messenger ribonucleic acid (mRNA). It is further shown, quantitatively, that positive surface charge is the main mechanism behind such high targeting efficiency for these polyplexes. Live in vivo imaging, flow cytometry of single cell suspensions, and confocal microscopy are used to demonstrate that positive polyplexes are enriched in the lung tissue and disseminated in 85-90% of the alveolar capillary endothelium, whilst being sparse in large vessels. Charge modification, achieved through poly(acrylic acid) or heparin coating, drives a highly significant reduction in both targeting percentage and targeting strength, highlighting the importance of specific surface charge, derived from chemical formulation, for efficient targeting of the pulmonary microvascular endothelium.
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http://dx.doi.org/10.1002/adhm.201800876DOI Listing
December 2018

A titanium-based photo-Fenton bifunctional catalyst of mp-MXene/TiO nanodots for dramatic enhancement of catalytic efficiency in advanced oxidation processes.

Chem Commun (Camb) 2018 Oct;54(82):11622-11625

College of Chemistry and Materials Science, Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecule-Based Materials, Anhui Key Laboratory of Functional Molecular Solids, Anhui Normal University, 189 Jiuhua Southern Road, Wuhu, 241002, China.

mp-MXene/TiO2-x nanodots (NDs) structurally composed of microporous MXene monolayers embedded with Ti3+-doped TiO2 nanodots were developed for the first time. The drastically enhanced catalytic efficiency (as much as 13 times higher than that of P25) in degrading dye molecules over mp-MXene/TiO2-x NDs is due to a synergistic effect of the pseudo-Fenton reaction and photocatalysis.
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http://dx.doi.org/10.1039/c8cc05866kDOI Listing
October 2018

Lipid-coated superparamagnetic nanoparticles for thermoresponsive cancer treatment.

Int J Pharm 2018 Sep 5;548(1):297-304. Epub 2018 Jul 5.

James L. Winkle College of Pharmacy, University of Cincinnati, Cincinnati, OH 45267, USA. Electronic address:

Poor aqueous solubility, chemical instability, and indiscriminate cytotoxicity have limited clinical development of camptothecin (CPT) as potent anticancer therapeutic. This research aimed at fabricating thermoresponsive nanocomposites that enhance solubility and stability of CPT in aqueous milieu and enable stimulus-induced drug release using magnetic hyperthermia. 1,2-Dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) and l-α-dipalmitoylphosphatidyl glycerol (DPPG) (1:1, mol/mol) were immobilized on the surface of superparamagnetic FeO nanoparticles (SPIONs) via high affinity avidin-biotin interactions. Heating behavior was assessed using the MFG-1000 magnetic field generator. Encapsulation efficiency and drug release were quantified by fluorescence spectroscopy. Anticancer efficacy of medicated nanoparticles was measured in vitro using Jurkat cells. The results revealed that drug incorporation did not significantly alter particle size, zeta potential, magnetization, and heating properties of lipid-coated SPIONs. Drug loading efficiency was 93.2 ± 5.1%. Drug release from medicated nanoparticles was significantly faster at temperatures above the lipid transition temperature, reaching 37.8 ± 2.6% of incorporated payload after 12 min under therapeutically relevant hyperthermia (i.e., 42 °C). Medicated SPIONs induced greater cytotoxicity than CPT in solution suggesting synergistic activity of magnetically-induced hyperthermia and drug-induced apoptosis. These results underline the opportunity for thermoresponsive phospholipid-coated SPIONs to enable clinical development of highly lipophilic and chemically unstable drugs such as CPT for stimulus-induced cancer treatment.
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http://dx.doi.org/10.1016/j.ijpharm.2018.07.022DOI Listing
September 2018

Fever-Inspired Immunotherapy Based on Photothermal CpG Nanotherapeutics: The Critical Role of Mild Heat in Regulating Tumor Microenvironment.

Adv Sci (Weinh) 2018 Jun 25;5(6):1700805. Epub 2018 Mar 25.

Shanghai East Hospital The Institute for Biomedical Engineering and Nano Science Tongji University School of Medicine Shanghai 200092 P. R. China.

Although there have been more than 100 clinical trials, CpG-based immunotherapy has been seriously hindered by complications in the immunosuppressive microenvironment of established tumors. Inspired by the decisive role of fever upon systemic immunity, a photothermal CpG nanotherapeutics (PCN) method with the capability to induce an immunofavorable tumor microenvironment by casting a fever-relevant heat (43 °C) in the tumor region is developed. High-throughput gene profile analysis identifies nine differentially expressed genes that are closely immune-related upon mild heat, accompanied by IL-6 upregulation, a pyrogenic cytokine usually found during fever. When treated with intratumor PCN injection enabling mild heating in the tumor region, the 4T1 tumor-bearing mice exhibit significantly improved antitumor immune effects compared with the control group. Superb efficacy is evident from pronounced apoptotic cell death, activated innate immune cells, enhanced tumor perfusion, and intensified innate and adaptive immune responses. This work highlights the crucial role of mild heat in modulating the microenvironment in optimum for improved immunotherapy, by converting the tumor into an in situ vaccine.
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http://dx.doi.org/10.1002/advs.201700805DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6010888PMC
June 2018

"Minimalist" Nanovaccine Constituted from Near Whole Antigen for Cancer Immunotherapy.

ACS Nano 2018 07 9;12(7):6398-6409. Epub 2018 Jul 9.

Shanghai East Hospital, The Institute for Biomedical Engineering & Nano Science , Tongji University School of Medicine , Shanghai 200092 , PR China.

One of the major challenges in vaccine design has been the over dependence on incorporation of abundant adjuvants, which in fact is in violation of the "minimalist" principle. In the present study, a compact nanovaccine derived from a near whole antigen (up to 97 wt %) was developed. The nanovaccine structure was stabilized by free cysteines within each antigen (ovalbumin, OVA), which were tempospatially exposed and heat-driven to form an extensive intermolecular disulfide network. This process enables the engineering of a nanovaccine upon integration of the danger signal (CpG-SH) into the network during the synthetic process. The 50 nm-sized nanovaccine was developed comprising approximately 500 antigen molecules per nanoparticle. The nanovaccine prophylactically protected 70% of mice from tumorigenesis (0% for the control group) in murine B16-OVA melanoma. Significant tumor inhibition was achieved by strongly nanovaccine-induced cytotoxic T lymphocytes. This strategy can be adapted for the future design of vaccine for a minimalist composition in clinical settings.
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http://dx.doi.org/10.1021/acsnano.8b00558DOI Listing
July 2018

Nanomaterials for Cancer Precision Medicine.

Adv Mater 2018 Apr 5;30(17):e1705660. Epub 2018 Mar 5.

The Institute for Translational Nanomedicine, Shanghai East Hospital, the Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, Shanghai, 200092, P. R. China.

Medical science has recently advanced to the point where diagnosis and therapeutics can be carried out with high precision, even at the molecular level. A new field of "precision medicine" has consequently emerged with specific clinical implications and challenges that can be well-addressed by newly developed nanomaterials. Here, a nanoscience approach to precision medicine is provided, with a focus on cancer therapy, based on a new concept of "molecularly-defined cancers." "Next-generation sequencing" is introduced to identify the oncogene that is responsible for a class of cancers. This new approach is fundamentally different from all conventional cancer therapies that rely on diagnosis of the anatomic origins where the tumors are found. To treat cancers at molecular level, a recently developed "microRNA replacement therapy" is applied, utilizing nanocarriers, in order to regulate the driver oncogene, which is the core of cancer precision therapeutics. Furthermore, the outcome of the nanomediated oncogenic regulation has to be accurately assessed by the genetically characterized, patient-derived xenograft models. Cancer therapy in this fashion is a quintessential example of precision medicine, presenting many challenges to the materials communities with new issues in structural design, surface functionalization, gene/drug storage and delivery, cell targeting, and medical imaging.
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http://dx.doi.org/10.1002/adma.201705660DOI Listing
April 2018

Delivery of microRNA-1 inhibitor by dendrimer-based nanovector: An early targeting therapy for myocardial infarction in mice.

Nanomedicine 2018 02 18;14(2):619-631. Epub 2017 Dec 18.

Institute for Biomedical Engineering &Nano Science, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China. Electronic address:

Myocardial infarction (MI), known to be rapidly progressed and fatal, necessitates a timely and effective intervention particularly within golden 24 h. The crux is to develop a therapeutic agent that can early target the infarct site with integrated therapeutic capacity. Finding the AT receptor being most over-expressed at 24 h after MI, we developed a nanovector (AT-PEG-DGL) anchored with AT targeting peptide, and simultaneously armed it with specific microRNA-1 inhibitor (AMO-1) to attenuate cardiomyocyte apoptosis. In vivo imaging after IV administration demonstrated that AT-PEG-DGL quickly accumulated in the MI heart during the desired early period, significantly outperforming the control group without AT targeting. Most importantly, a pronounced in-vivo anti-apoptosis effect was observed upon a single IV injection. Apoptotic cell death in the infarct border zone was significantly decreased and the myocardial infarct size was reduced by 64.1% as compared with that in MI control group, promising for early MI treatment.
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http://dx.doi.org/10.1016/j.nano.2017.12.004DOI Listing
February 2018

Photo-controlled aptamers delivery by dual surface gold-magnetic nanoparticles for targeted cancer therapy.

Mater Sci Eng C Mater Biol Appl 2017 Nov 29;80:88-92. Epub 2017 Apr 29.

Shanghai East Hospital, The Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, Shanghai 200120, China; The Materials Science and Engineering Program, Dept. of Mechanical and Materials Engineering, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, OH 45221, USA.

Dual surfaced dumbbell-like gold magnetic nanoparticles (Au-FeO) were synthesized for targeted aptamers delivery. Their unique biological properties were characterized as a smart photo-controlled drug carrier. DNA aptamers targeting vascular endothelial growth factor (VEGF) were assembled onto the surface of Au-FeO by electrostatic absorption. The binding capacity of the nanoparticles with VEGF aptamers was confirmed by gel electrophoresis. The targeted recognization of ovarian cancer cells by the aptamers-functionalized Au-FeO nanoparticles (Apt-Au-FeO NPs) was observed by confocal microscopy. Apt-Au-FeO was found to bind with SKOV-3 ovarian cancer cells specifically, leading to marked intracellular release of aptamers upon plasmon-resonant light (605nm) radiation, and to enhance the in vitro inhibition against tumor cell proliferation. The results show high potential of Apt-Au-FeOas a targeted cancer hyperthermia carrier by remote control with high spatial/temporal resolution.
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http://dx.doi.org/10.1016/j.msec.2017.04.044DOI Listing
November 2017

Carbon Nanoparticle Hybrid Aerogels: 3D Double-Interconnected Network Porous Microstructure, Thermoelectric, and Solvent-Removal Functions.

ACS Appl Mater Interfaces 2017 Jul 20;9(26):21820-21828. Epub 2017 Jun 20.

The Materials Science and Engineering Program, Dept. of Mechanical and Materials Engineering, College of Engineering and Applied Science, University of Cincinnati , Cincinnati, Ohio 45221, United States.

We report reduced graphene oxide (rGO)/single-walled carbon nanotube (SWCNT) hybrid aerogels with enhanced thermoelectric (TE) performance and removal of organic solvents by designing 3D double-interconnected network porous microstructures. A convenient, cost-effective, and scalable preparation procedure is proposed compared with conventional high-temperature pyrolysis and supercritical drying techniques. The obtained hybrid aerogels are systematically characterized by apparent density, scanning electron microscopy, X-ray photoemission spectroscopy, Raman spectroscopy, and porosity. An enhanced TE performance of ZT ≈ ∼8.03 × 10 has been achieved due to the 3D double-interconnected network porous microstructure, the energy-filtering effect, and the phonon scattering at the abundant interfaces and joints. In addition, upon a large axial compression deformation, a high degree of retention of the Seebeck coefficient and a simultaneously significant enhancement of the electrical conductivity are observed. Finally, the hybrid aerogels display high capability for the removal of diverse organic solvents and good recyclability. These findings open a new avenue for exploiting aerogels with multifunctions and widening the applications of TE materials by judicious microstructure design.
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http://dx.doi.org/10.1021/acsami.7b04938DOI Listing
July 2017

Targeting and Regulating of an Oncogene via Nanovector Delivery of MicroRNA using Patient-Derived Xenografts.

Theranostics 2017 15;7(3):677-693. Epub 2017 Jan 15.

Department of Oral and Maxillofacial-Head Neck Oncology, Ninth People's Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai 200011, P. R. China;; Shanghai Key Laboratory of Stomatology, Shanghai 200011, P. R. China.

In precision cancer nanomedicine, the key is to identify the oncogenes that are responsible for tumorigenesis, based on which these genetic drivers can be each specifically regulated by a nanovector-directed, oncogene-targeted microRNA (miRNA) for tumor suppression. Fibroblast Growth Factor Receptor 3 (FGFR3) is such an oncogene. The molecular tumor-subtype harboring FGFR3 genomic alteration has been identified via genomic sequencing and referred to as the FGFR3-driven tumors. This genomics-based tumor classification provides further rationale for the development of the FGFR3-targeted miRNA replacement therapy in treating patients with FGFR3 gene abnormity. However, successful miRNA therapy has been hampered by lacking of an efficient delivery vehicle. In this study, a nanovector is developed for microRNA-100 (miR-100) -mediated FGFR3 regulation. The nanovector is composed of the mesoporous magnetic clusters that are conjugated with ternary polymers for efficient miRNA delivery. The miRNA-loading capacity of the nanovector is found to be high due to the polycation polymer functionalized mesoporous structure, showing excellent tumor cell transfection and pH-sensitive miRNA release. Delivery of miR-100 to cancer cells effectively down-regulates the expression of FGFR3, inhibits cell proliferation, and induces cell apoptosis . Patient-derived xenografts (PDXs) are used to evaluate the efficacy of miRNA delivery in the FGFR3-driven tumors. Notably, sharp contrasts are observed between the FGFR3-driven tumors and those without FGFR3 genomic alteration. Only the FGFR3-driven PDXs are significantly inhibited via miR-100 delivery while the non-FGFR3-driven PDXs are not affected, showing promise of precision cancer nanomedicine.
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http://dx.doi.org/10.7150/thno.16357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5327642PMC
October 2017

Site-Specific Biomimetic Precision Chemistry of Bimodal Contrast Agent with Modular Peptides for Tumor-Targeted Imaging.

Bioconjug Chem 2017 02 20;28(2):330-335. Epub 2017 Jan 20.

The Institute for Translational Nanomedicine, Shanghai East Hospital; The Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine , Shanghai 200092, P. R. China.

Various biomimetic nanoparticles have been fabricated for cancer nanotheranostics with a diverse range of proteins. However, the operating mechanisms of these reactions are still unclear, especially on the interaction between metal ions and protein, the precise binding sites, and the existence format of nanoparticles. Assuming the shortening of the amino acids sequence into several, namely short peptides, it would be much easier to investigate the biomimetic reaction mechanism. In this study, a modular peptide, possessing Au ion coordination motifs and a Gd ion chelation sequence, is designed and synthesized. This peptide is experimentally found effective in site-specific biomimetic synthesis of paramagnetic fluorescent gold nanoclusters (pAuNCs) with a quantum yield of 6.8%, deep red emission at 676 nm, and potent relaxivity. The gel electrophoresis result declares that the two imaging motifs in pAuNCs are quite stable. In vivo fluorescence-magnetic resonance bimodal imaging show significant tumor enhancement by pAuNCs in tumor-bearing mice. In vivo biodistribution and toxicity studies reveal that pAuNCs can be gradually cleared from the body without damage. This study presents a modular peptide that can incubate multifunctional nanoparticles in a biomimetic fashion and hopefully provides a strategy for the investigation of the mechanism of protein-mediated biomimetic synthesis.
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http://dx.doi.org/10.1021/acs.bioconjchem.6b00712DOI Listing
February 2017

Preparation, characterization, biotoxicity, and biodistribution of thermo-responsive magnetic complex micelles formed by MnZnFeO and a PCL/PEG analogue copolymer for controlled drug delivery.

J Mater Chem B 2017 Jan 8;5(2):296-306. Epub 2016 Dec 8.

Key Laboratory of Advanced Civil Engineering Materials (Tongji University), Ministry of Education, Shanghai 201804, China.

A thermo-responsive PCL/PEG analogue copolymer (PCL-[b-P(MEOMA-co-OEGMA)]) with a lower critical solution temperature (LCST) of 40.4 °C at an MEOMA/OEGMA molar ratio of 87 : 13 was designed and synthesized. The copolymer was subsequently labeled by coupling with fluorescein isothiocyanate (FITC). Thermo-responsive magnetic PCL-[b-P(MEOMA-co-OEGMA)]/MnZnFeO (MZF) complex micelles were prepared by a self-assembly method. Doxorubicin (DOX) was loaded into the magnetic complex micelles as a model drug, and the DOX-MZF-micelles showed well-controlled thermo-responsive release both at externally fixed temperatures and in the presence of an alternating magnetic field (AMF). Both the blank polymer micelles and the magnetic complex micelles exhibited excellent stability in normal saline and serum. Based on the detection of the FITC fluorescence signal, the micelles were found to be effectively labeled by FITC. Furthermore, the biological toxicity of micelles was studied in vitro and in vivo. In vitro toxicity studies to evaluate cell viability and cell toxicity were performed by employing WST-1 and LDH release assays using HL7702 cells, respectively. In vivo biotoxicity studies were conducted in ICR mice through a series of tests: general conditions, body weight shifts, serum biochemistry profiles, and organ coefficient tests. All the biological toxicity results obtained from the blank polymer micelles and the magnetic complex micelles indicated their good biocompatibility and nontoxicity. The in vivo biodistribution studies of the FITC-labeled magnetic complex micelles were performed in the ICR mice. The copolymer was cleared by the kidney and spleen, while the MZF nanoparticles were cleared by the liver in time, causing no adverse effects on organisms. The thermo-responsive magnetic complex micelles were shown to be an ideal nanocarrier for anticancer drug delivery in terms of controlled release, stability, biocompatibility and safety.
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http://dx.doi.org/10.1039/c6tb02788aDOI Listing
January 2017

Correction: Reversible PEGylation and Schiff-base linked imidazole modification of polylysine for high-performance gene delivery.

J Mater Chem B 2017 Jan 8;5(1):181. Epub 2016 Dec 8.

National Engineering Research Center for Biomaterials, Sichuan University, Chengdu 610064, China.

Correction for 'Reversible PEGylation and Schiff-base linked imidazole modification of polylysine for high-performance gene delivery' by Xiaojun Cai et al., J. Mater. Chem. B, 2015, 3, 1507-1517.
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http://dx.doi.org/10.1039/c6tb90173eDOI Listing
January 2017

Redox-mediated dissociation of PEG-polypeptide-based micelles for on-demand release of anticancer drugs.

J Mater Chem B 2016 Dec 21;4(48):7859-7869. Epub 2016 Nov 21.

School of Chemical Engineering, Northwest University, Xi'an, P. R. China.

Intelligent nanoparticles are capable of prolonged blood circulation without leakage of the payload and fast drug release upon exposure to environmental stimuli, such as redox stimuli, and therefore are highly desirable for cancer therapy. In this study, polymeric micelles were designed and developed with a hydrophilic poly(ethylene glycol) (PEG) shell and a hydrophobic poly-l-phenylalanine (PPhe) core, linked by a redox cleavable bond, i.e. mPEG-SS-PPhe. The mPEG-SS-PPhe micelles were loaded with the anticancer drug doxorubicin (DOX) and shown an on-demand release profile in the presence of redox agents such as glutathione (GSH). Remarkably, the GSH-triggered micellar dissociation accelerated in vitro release of DOX 4.87 fold faster at 10 mM GSH than that without GSH at 12 h. An enhanced inhibitory effect of DOX-loaded mPEG-SS-PPhe micelles was achieved by improving the intracellular GSH levels. Confocal laser scanning microscopy and flow cytometric analyses of HeLa cells further confirmed that DOX accumulation was accelerated by elevating the extracellular GSH concentrations. In addition, mPEG-SS-PPhe micelles showed excellent biocompatibility on L929 and HeLa cell lines. These redox-sensitive polymeric micelles may provide more possibilities as promising carriers for on-demand drug release in a controlled manner.
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http://dx.doi.org/10.1039/c6tb02364aDOI Listing
December 2016

Green Synthesis of Sub-10 nm Gadolinium-Based Nanoparticles for Sparkling Kidneys, Tumor, and Angiogenesis of Tumor-Bearing Mice in Magnetic Resonance Imaging.

Adv Healthc Mater 2017 Feb 22;6(4). Epub 2016 Dec 22.

The Institute for Translational Nanomedicine, Shanghai East Hospital, The Institute for Biomedical Engineering and Nano Science, Tongji University School of Medicine, Shanghai, 200092, P. R. China.

Gadolinium (Gd)-based nanoparticles are known for their high potential in magnetic resonance imaging (MRI). However, further MRI applications of these nanoparticles are hampered by their relatively large sizes resulting in poor organ/tumor targeting. In this study, ultrafine sub-10 nm and biocompatible Gd-based nanoparticles are synthesized in a bioinspired, environmentally benign, and straightforward fashion. This novel green synthetic strategy is developed for growing dextran-coated Gd-based nanoparticles ([email protected]). The as-prepared [email protected] is not only biocompatible but also stable with a sub-10 nm size. It exhibits higher longitudinal and transverse relaxivities in water (r and r values of 5.43 and 7.502 s × 10 m of Gd , respectively) than those measured for Gd-DTPA solution (r and r values of 3.42 and 3.86 s × 10 m of Gd , respectively). In vivo dynamic T -weighted MRI in tumor-bearing mice shows [email protected] can selectively target kidneys and tumor, in addition to liver and spleen. [email protected] is found particularly capable for determining the tumor boundary with clearly enhanced tumor angiogenesis. [email protected] is also found cleared from body gradually mainly via hepatobiliary and renal processing with no obvious systemic toxicity. With this green synthesis strategy, the sub-10 nm [email protected] presents promising potentials for translational biomedical imaging applications.
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http://dx.doi.org/10.1002/adhm.201600865DOI Listing
February 2017

Biomarkerless targeting and photothermal cancer cell killing by surface-electrically-charged superparamagnetic FeO composite nanoparticles.

Nanoscale 2017 Jan;9(4):1457-1465

The Institute for Translational Nanomedicine, Shanghai East Hospital, the Institute for Biomedical Engineering & Nano Science, Tongji University School of Medicine, Shanghai 200092, PR China. and The Materials Science and Engineering Program, Dept. of Mechanical and Materials Engineering, College of Engineering and Applied Science, University of Cincinnati, Cincinnati, Ohio 45221, USA.

A major challenge in cancer therapy is localized targeting of cancer cells for maximum therapeutic effectiveness. However, due to cancer heterogeneities, the biomarkers are either not readily available or specific for effective targeting of cancer cells. The key, therefore, is to develop a new targeting strategy that does not rely on biomarkers. A general hallmark of cancer cells is the much increased level of glycolysis. The loss of highly mobile lactate from the cytoplasm inevitably removes labile inorganic cations to form lactate salts and acids as part of the lactate cycle, creating a net of negative surface charges. This net of negative charges on cancer cell surfaces biophysically distinguishes themselves from normal cells. In this study, cancer cells are targeted by using positively-charged, fluorescent, superparamagnetic FeO-composite nanoparticles. The positively-charged FeO composite nanoparticles bind predominantly to cancer cells due to their negatively-charged surfaces. Upon electrical-charge-mediated FeO nanoparticle binding onto cancer cells, irradiation by using an 808 nm laser is subsequently applied to induce photothermal hyperthermia that kills the cancer cells directly. The negatively-charged composite nanoparticles are found, however, not to target and bind the cancer cells due to the electrostatic repulsive force between them. This unique strategy paves a new path for effective targeting and direct cancer cell killing without relying on any biomarkers and anticancer drugs.
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http://dx.doi.org/10.1039/c6nr07161aDOI Listing
January 2017
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