Publications by authors named "Kun Shao"

66 Publications

An ultrasound-driven immune-boosting molecular machine for systemic tumor suppression.

Sci Adv 2021 Oct 20;7(43):eabj4796. Epub 2021 Oct 20.

State Key Laboratory of Fine Chemicals, Department of Pharmacy, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China.

[Figure: see text].
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http://dx.doi.org/10.1126/sciadv.abj4796DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8528430PMC
October 2021

Cancer immunogenic cell death via photo-pyroptosis with light-sensitive Indoleamine 2,3-dioxygenase inhibitor conjugate.

Biomaterials 2021 11 30;278:121167. Epub 2021 Sep 30.

State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Dalian, 116024, PR China; State Key Laboratory of Fine Chemicals, Shenzhen Research Institute, Dalian University of Technology, Nanshan District, Shenzhen, 518057, PR China. Electronic address:

Immune checkpoint blockade (ICB) therapy currently considered as to be effective way to cure cancer in clinic. However, the insufficient tumor immunogenicity and the immunosuppressive tumor microenvironment always result in diminished efficacy of immunotherapy. Herein, we report the synthesis of an organic photo-immune activator NBS-1MT, the combination of photosensitizer and Indoleamine 2,3-dioxygenase (IDO) inhibitor effectively stimulates lysosomes oxidative stress the releases inflammatory cytokines. This process triggers pyroptosis for the considerable immunogenic cell death (ICD) while reversing suppressive tumor microenvironment. The photo-immune drug shows outstanding potential to activate caspase-1and then remove gasdermin-D (GSDMD), which could stimulate pyroptosis and also inhibit the tumor growth successfully in both primary and distant tumor. Furthermore, pyroptosis activated by photodynamic therapy (PDT) promotes the immune related factors release, and enhance the intratumoral infiltration of cytotoxic T lymphocytes (CTLs) with the induction of ICD of tumor cells and the cascaded synergize with IDO inhibitor, so the general antitumor immune response could be strengthened effectively. Our research confirms that the use of NBS-1MT is a promising strategy to boost the immune response and eventually to inhibit tumor growth.
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http://dx.doi.org/10.1016/j.biomaterials.2021.121167DOI Listing
November 2021

Automatic measurement of axial vertebral rotation in 3D vertebral models.

Biomed Phys Eng Express 2021 10 20;7(6). Epub 2021 Oct 20.

Hefei University of Technology, Hefei, Anhui, People's Republic of China.

Axial Vertebral Rotation (AVR) is a significant indicator of adolescent idiopathic scoliosis (AIS). A host of methods are provided to measure AVR on coronal plane radiographs or 3D vertebral model. This paper provides a method of automatic AVR measurement in 3D vertebral model that is based on point cloud segmentation neural network and the tip of the spinous process searching algorithm. An improved PointNet using multi-input and attention mechanism named Multi-Input PointNet is proposed, which can segment the upper and lower endplates of the vertebral model accurately to determine the transverse plane of vertebral model. An algorithm is developed to search the tip of the spinous process according to the special structure of vertebrae. AVR angle is measured automatically using the midline of vertebral model and projection of-axis on the transverse plane of vertebral model based on points obtained above. We compare automatic measurement results with manual measurement results on different vertebral models. The experiment shows that automatic results can achieve accuracy of manual measurement results and the correlation coefficient of them is 0.986, proving our automatic AVR measurement method performs well.
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http://dx.doi.org/10.1088/2057-1976/ac2c55DOI Listing
October 2021

Reversing Multidrug Resistance by Inducing Mitochondrial Dysfunction for Enhanced Chemo-Photodynamic Therapy in Tumor.

ACS Appl Mater Interfaces 2021 Sep 17;13(38):45259-45268. Epub 2021 Sep 17.

State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Hi-tech Zone, Dalian 116024, P.R. China.

Efficiency of standard chemotherapy is dramatically hindered by intrinsic multidrug resistance (MDR). Recently, to amplify therapeutic efficacy, photodynamic therapy (PDT)-induced mitochondrial dysfunction by decorating targeting moieties on nanocarriers has obtained considerable attention. Nevertheless, low targeting efficiency, complex synthesis routes, and difficulty in releasing contents become the major obstacles in further clinical application. Herein, an ingenious liposomal-based nanomedicine ([email protected]) was fabricated by encapsulating a mitochondria-anchored photosensitizer (Cy-Br) and paclitaxel (PTX) for realizing enhanced cooperation therapy. At the cellular level, [email protected] could hurdle endosomal traps to localize and implement PDT in mitochondria. Intriguingly, the PDT-induced mitochondrial dysfunction led to intracellular ATP reduction, which triggered the downregulated P-glycoprotein transportation capacity and thus resulted in diminishing the efflux of chemotherapeutic agents and increasing drug uptake by drug-resistant cells. The prepared nanomedicine eminently accumulated in the tumor site and acquired enhanced therapeutic efficiency on PTX-resistant lung cancer cells, which possessed great potential in circumventing MDR tumors.
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http://dx.doi.org/10.1021/acsami.1c12725DOI Listing
September 2021

Total synthesis and biological evaluation of 7-hydroxyneolamellarin A as hypoxia-inducible factor-1α inhibitor for cancer therapy.

Bioorg Med Chem Lett 2021 10 29;50:128338. Epub 2021 Aug 29.

Laboratory for Chemistry and Life Science, Institute of Innovative Research, Tokyo Institute of Technology, Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan.

7-Hydroxyneolamellarin A (7-OH-Neo A, 1), a natural marine product derived from sponge Dendrilla nigra, was first synthesized with 10% overall yield under the instruction of convergent synthetic strategy. We found that 7-OH-Neo A could attenuate the accumulation of hypoxia-inducible factor-1α (HIF-1α) protein and inhibit vascular epidermal growth factor (VEGF) transcriptional activity, showing well inhibitory effect on HIF-1 signaling pathway. Meantime, 7-OH-Neo A had the well anti-tumor activities, such as inhibiting tumor angiogenesis, proliferation, migration and invasion. More importantly, 7-OH-Neo A exhibited profound anti-tumor effect in mice breast cancer model by suppressing the accumulation of HIF-1α in tumor tissue. Mechanism study demonstrated that 7-OH-Neo A might target the protein with the ability of stabilizing HIF-1α in hypoxia. Due to the excellent water solubility, superior anti-tumor activity and good biocompatibility, 7-OH-Neo A shows the promising potential for being exploited as an anti-tumor agent in near future.
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http://dx.doi.org/10.1016/j.bmcl.2021.128338DOI Listing
October 2021

Synthesis and evaluation of 3-(phenylethynyl)-1,1'-biphenyl-2-carboxylate derivatives as new HIF-1 inhibitors.

Bioorg Chem 2021 11 21;116:105298. Epub 2021 Aug 21.

Department of Pharmaceutical Sciences, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China; State Key Laboratory of Fine Chemicals, School of Chemical Engineering, Dalian University of Technology, Dalian 116024, China. Electronic address:

Selaginellins are a type of rare natural products from the genus Selaginella with unusual alkynyl phenol skeletons and extensive biological activities. Previous structural simplification of these natural compounds afforded a series of diaryl acetylene derivatives with hypoxia-inducible factor 1 (HIF-1) inhibitory activity. In this study, we synthesized thirty compounds by stepwise optimization using methyl 3-(4-methoxylphenyl ethynyl)-[4'-methoxyl-1,1'-biphenyl]-2-carboxylate (1a) as a lead compound and evaluated their HIF-1 inhibitory activity by dual luciferase reporter assay. Among them, compound 9i displayed the most potent HIF-1 inhibitory activity (IC = 1.5 ± 0.03 μM) with relatively low cytotoxicity. Under hypoxia, compound 9i showed no effect on the accumulation of HIF-1α protein in western blot analysis, but could down-regulate the expression of VEGF mRNA, the downstream target gene of HIF-1 pathway. Cell-based activity assay demonstrated that compound 9i could inhibit the hypoxia-induced migration, invasion and proliferation of HeLa cells at the concentrations of 1 ~ 5 μM. In mouse breast cancer xenograft model, compound 9i exhibited obvious tumor growth inhibition and very low toxicity at a dose of 15 mg/kg. The results suggested that compound 9i would be a potential antitumor agent via HIF-1 pathway inhibition.
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http://dx.doi.org/10.1016/j.bioorg.2021.105298DOI Listing
November 2021

identification of circulating tumor cells in peripheral blood by fluorometric "turn on" aptamer nanoparticles.

Chem Sci 2020 Dec 22;12(9):3314-3321. Epub 2020 Dec 22.

State Key Laboratory of Fine Chemicals, Dalian University of Technology Dalian 116024 China

The detection of the circulating tumor cells (CTCs) detached from solid tumors has emerged as a burgeoning topic for cancer diagnosis and treatment. The conventional CTC enrichment and identification mainly rely on the specific binding of the antibodies on the capture interface of the magnetic nanoparticles with the corresponding biomarkers on the cell membranes. However, these methods could easily generate false-negative results due to the extremely low concentration of CTCs and the internal heterogeneity of the tumor cells. Herein, with the aim of selectively identifying CTCs and improving the detection accuracy in peripheral blood, we designed the fluorometric "turn on" Au nanoparticles (DHANs) with the modification of a tumor-targeted moiety, dehydroascorbic acid (DHA) and a fluorometric aptamer, which could be "switched-on" by an over-expressed intracellular protein, namely hypoxia-inducible factor-1α (HIF 1α). This novel nanoformulated detection platform demonstrated the great capacity for visualizing various CTCs in peripheral blood with significantly improved detection efficiency and sensitivity. As a result, the nanoplatform has a great potential to be further applied for CTC detection or , which holds promise for extensive CTC studies.
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http://dx.doi.org/10.1039/d0sc05112hDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8179407PMC
December 2020

Coinstantaneous Identification of Hepatocellular Carcinoma Circulating Tumor Cells by Dual-Targeting Magnetic-Fluorescent Nanobeads.

Nano Lett 2021 01 2;21(1):634-641. Epub 2020 Dec 2.

State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Dalian 116024, P.R. China.

Circulating tumor cells (CTCs) have been considered as a potential biomarker for evaluation of cancer metastasis and prognosis, especially in hepatocellular carcinoma (HCC). However, the isolation and detection of rare CTCs in HCC patients face enormous challenges due to omittance and nonspecific binding. We previously designed a small molecular NIR fluoresent agent, named MLP, which had high affinity with a tumor cell-overexpressed enzyme, aminopeptidase N (APN). Based on that, in this work we introduced a novel strategy via coassembling the antiepithelial cell adhesion molecule (EpCAM) antibody and MLPinto theFeO magnetic nanobeads (MB-MLP-EpCAM) to isolate and identify HCC-CTCs coinstantaneously. MB-MLP-EpCAM significantly improved the CTC-capture efficiency (>85%) without sacrificing cell viability (>90%). Most importantly, the advantages of precise dual-targetability, high resolution of fluorescence imaging, and prominent selectivity make our nanoplatform have great potential to achieve real-time identification and monitoring of CTCs clinically.
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http://dx.doi.org/10.1021/acs.nanolett.0c04180DOI Listing
January 2021

Population Pharmacokinetics and Bayesian Estimation of the Area Under the Concentration-Time Curve for Ganciclovir in Adult Chinese Renal Allograft Recipients After Valganciclovir Administration.

J Clin Pharmacol 2021 03 14;61(3):328-338. Epub 2020 Sep 14.

Center for Organ Transplantation, Ruijin Hospital, Shanghai Jiao-Tong University School of Medicine, Shanghai, P. R. China.

Valganciclovir (VGCV) is the prodrug of ganciclovir (GCV). The objective of this study was to establish a population pharmacokinetic model (PPK) of GCV to investigate the PK characteristics of GCV after administration of VGCV in adult Chinese renal allograft recipients. Seventy Chinese renal allograft recipients were given 450 mg (n = 41) or 900 mg (n = 29) VGCV daily. Blood samples were drawn 0-24 hours after 5 days' therapy, and GCV plasma levels were determined. The PPK model was constructed using nonlinear mixed-effects modeling, and the Bayesian estimation of AUC was constructed for an individual patient based on limited plasma samples. The PK of GCV was best described by a 2-compartment model with a first-order absorption process. The CL/F, V /F, Q/F, V /F, K , and lag time of GCV were 15.8 ± 0.71 L/h, 10.9 ± 2.38 L, 3.98 ± 0.40 L/h, 167 ± 44.0 L, 0.23 ± 0.0078 1/h, and 0.93 ± 0.017 hours, respectively. Clearance of creatinine was found to have a significant impact on the CL/F of GCV (P < .01). Sampling strategies consisted of plasma concentrations 0 and 2 and 0, 2, and 4 hours after VGCV administration were shown to be suitable for the estimation of the GCV AUC . The PPK model was acceptable and can describe the PK of GCV in Chinese renal transplant patients administered VGCV. The AUC of GCV in Chinese renal transplant patients can be calculated by a limited sampling strategy method.
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http://dx.doi.org/10.1002/jcph.1735DOI Listing
March 2021

A tumor-to-lymph procedure navigated versatile gel system for combinatorial therapy against tumor recurrence and metastasis.

Sci Adv 2020 Sep 4;6(36). Epub 2020 Sep 4.

Department of Biomedical Engineering, The University of Texas at Austin, Austin, TX, USA.

Application of cancer vaccines is limited due to their systemic immunotoxicity and inability to satisfy all the steps, including loading of tumor antigens, draining of antigens to lymph nodes (LNs), internalization of antigens by dendritic cells (DCs), DC maturation, and cross-presentation of antigens for T cell activation. Here, we present a combinatorial therapy, based on a α-cyclodextrin (CD)-based gel system, DOX/ICG/CpG-P-ss-M/CD, fabricated by encapsulating doxorubicin (DOX) and the photothermal agent indocyanine green (ICG). Upon irradiation, the gel system exhibited heat-responsive release of DOX and vaccine-like nanoparticles, CpG-P-ss-M, along with chemotherapy- and phototherapy-generated abundant tumor-specific antigen storage in situ. The released CpG-P-ss-M acted as a carrier adsorbed and delivered antigens to LNs, promoting the uptake of antigens by DCs and DC maturation. Notably, combined with PD-L1 blocking, the therapy effectively inhibited primary tumor growth and induced tumor-specific immune response against tumor recurrence and metastasis.
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http://dx.doi.org/10.1126/sciadv.abb3116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473750PMC
September 2020

Establishment of a Liquid Chromatography-Tandem Mass Spectrometry Method for the Determination of Immunosuppressant Levels in the Peripheral Blood Mononuclear Cells of Chinese Renal Transplant Recipients.

Ther Drug Monit 2020 10;42(5):686-694

Center of Organ Transplantation, Ruijin Hospital, Jiaotong University School of Medicine, Shanghai, P.R. China.

Background: Monitoring immunosuppressant levels, such as mycophenolic acid (MPA), cyclosporin A (CsA), and tacrolimus (TAC), in peripheral blood mononuclear cells (PBMCs) could be useful in organ transplant patients administered individualized therapy. The authors developed a liquid chromatography-tandem mass spectrometry assay technique to simultaneously determine immunosuppressant levels in PBMCs and assess their pharmacokinetics in Chinese renal allograft recipients.

Methods: PBMCs were isolated from the whole blood of 27 Chinese renal transplant patients using Ficoll-Paque Plus solution, and cell number was determined; acetonitrile treatment for protein precipitation, and gradient elution was performed on an Agilent Eclipse XDB-C18 column (3.5 μm, 2.1 × 100 mm) with mobile phase: water and methanol (containing 2 mM ammonium formate); flow rate: 0.3 mL·min.

Results: The calibration curves of MPA, CsA, and TAC had a linear range (ng·mL): 0.098-39.2 (r = 0.9987), 0.255-102 (r = 0.9969), and 0.028-11.2 (r = 0.9993), respectively. The extraction effects, matrix effects, and mean relative recovery of these immunosuppressants were 70.4%-93.2%, 72.7%-96.5%, and 90.1%-112.4%, respectively. The within-day and between-day coefficients of variation were <15%. The AUC0-12 of MPA in PBMCs correlated well with those in plasma. The level of MPA, CsA, and TAC in PBMCs might be more stable during dosing interval.

Conclusions: The derived liquid chromatography-tandem mass spectrometry assay is suitable for simultaneously monitoring different immunosuppressants in PBMCs. Pharmacokinetic of MPA, CsA, and TAC displayed considerable interindividual variability. Intracellular monitoring of immunosuppressants may facilitate individualized therapy for renal allograft recipients.
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http://dx.doi.org/10.1097/FTD.0000000000000765DOI Listing
October 2020

Zinc(ii)-catalyzed intramolecular hydroarylation-redox cross-dehydrogenative coupling of N-propargylanilines with diverse carbon pronucleophiles: facile access to functionalized tetrahydroquinolines.

Chem Commun (Camb) 2020 Jul 2;56(53):7333-7336. Epub 2020 Jun 2.

Department of Pharmacy, Schoo of Chemical Engineering, Dalian University of Technology, No. 2 Linggong Road, Dalian 116024, China.

Zinc(ii)-catalyzed intramolecular hydroarylation-redox cross-dehydrogenative coupling of N-propargylanilines with two types of carbon pronucleophiles (nitromethane as a sp carbon pronucleophile and phenylacetylenes as sp carbon pronucleophiles) proceeded to give the 2-substituted tetrahydroquinolines in good yields with 100% atomic utilization without any additional external oxidants.
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http://dx.doi.org/10.1039/d0cc02921aDOI Listing
July 2020

An APN-activated NIR photosensitizer for cancer photodynamic therapy and fluorescence imaging.

Biomaterials 2020 09 3;253:120089. Epub 2020 May 3.

State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Dalian, 116024, PR China; Shenzhen Research Institute, Dalian University of Technology, Nanshan District, Shenzhen, 518057, PR China. Electronic address:

Photodynamic therapy has been developed as a prospective cancer treatment in recent years. Nevertheless, conventional photosensitizers suffer from lacking recognition and specificity to tumors, which causing severe side effects to normal tissues, while the enzyme-activated photosensitizers are capable of solving these conundrums due to high selectivity towards tumors. APN (Aminopeptidase N, APN/CD13), a tumor marker, has become a crucial targeting substance owing to its highly expressed on the cell membrane surface in various tumors, which has become a key point in the research of anti-tumor drug and fluorescence probe. Based on it, herein an APN-activated near-infrared (NIR) photosensitizer (APN-CyI) for tumor imaging and photodynamic therapy has been firstly developed and successfully applied in vitro and in vivo. Studies showed that APN-CyI could be activated by APN in tumor cells, hydrolyzed to fluorescent CyI-OH, which specifically located in mitochondria in cancer cells and exhibited a high singlet oxygen yield under NIR irradiation, and efficiently induced cancer cell apoptosis. Dramatically, the in vivo assays on Balb/c mice showed that APN-CyI could achieve NIR fluorescence imaging (λ = 717 nm) for endogenous APN in tumors and possessed an efficient tumor suppression effect under NIR irradiation.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196320PMC
September 2020

Aminopeptidase N Activatable Fluorescent Probe for Tracking Metastatic Cancer and Image-Guided Surgery via Spraying.

J Am Chem Soc 2020 04 20;142(13):6381-6389. Epub 2020 Mar 20.

State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Hi-Tech Zone, Dalian 116024, P. R. China.

The recurrence of malignant tumors is mostly caused by incompleted surgical resection. Especially, it is difficult for surgeons to detect and accurately remove metastatic tumors by predominantly using visual examination and palpation owing to the lack of effective means to specifically distinguish the boundary range between normal and tumor tissues. Thus, the development of activated fluorescent probe with superior tumor-to-normal (T/N) tissue ratios is particularly urgent in clinics. In view of CD13/aminopeptidase N (APN) regarded as a cancer-specific biomarker, mediating with progression, invasion, and migration of malignant tumor, herein, we reported an APN-responsive fluorescent probe YH-APN and demonstrated its application to distinguish cancer cells. Through spraying manner, fluorescent superior tumor-to-normal (T/N) tissue ratios (subcutaneous transplantation tumor, 13.86; hepatic metastasis, 4.42 and 6.25; splenic metastasis, 4.99) were achieved. More importantly, we have demonstrated the ability to image metastasis tumor tissue less than 1 mm in diameter, highlighting the potential for this probe to be used as a tool in surgical resection. This research may spur the use of enzyme-activatable fluorescent probes for the progress of tumor diagnosis and image-guided surgery (IGS).
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http://dx.doi.org/10.1021/jacs.0c01365DOI Listing
April 2020

Ubiquitous antigen-specific T regulatory type 1 cells variably suppress hepatic and extrahepatic autoimmunity.

J Clin Invest 2020 04;130(4):1823-1829

Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Alberta, Canada.

Peptide MHC class II-based (pMHCII-based) nanomedicines trigger the formation of multicellular regulatory networks by reprogramming autoantigen-experienced CD4+ T cells into autoimmune disease-suppressing T regulatory type 1 (TR1) cells. We have shown that pMHCII-based nanomedicines displaying liver autoimmune disease-relevant yet ubiquitously expressed antigens can blunt various liver autoimmune disorders in a non-disease-specific manner without suppressing local or systemic immunity against infectious agents or cancer. Here, we show that such ubiquitous autoantigen-specific T cells are also awakened by extrahepatic tissue damage and that the corresponding TR1 progeny can suppress experimental autoimmune encephalomyelitis (EAE) and pancreatic β cell autoreactivity. In mice having EAE, nanomedicines displaying either ubiquitous or CNS-specific epitopes triggered the formation and expansion of cognate TR1 cells and their recruitment to the CNS-draining lymph nodes, sparing their liver-draining counterparts. Surprisingly, in mice having both liver autoimmunity and EAE, liver inflammation sequestered these ubiquitous or even CNS-specific TR1 cells away from the CNS, abrogating their antiencephalitogenic activity. In these mice, only the ubiquitous antigen-specific TR1 cells suppressed liver autoimmunity. Thus, the scope of antigen spreading in autoimmune disorders is larger than previously anticipated, involving specificities expected to be silenced by mechanisms of tolerance; the regulatory activity, but not the retention of autoreactive TR1 cells, requires local autoantigen expression.
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http://dx.doi.org/10.1172/JCI130670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7108901PMC
April 2020

Unimolecular Photodynamic O-Economizer To Overcome Hypoxia Resistance in Phototherapeutics.

J Am Chem Soc 2020 03 9;142(11):5380-5388. Epub 2020 Mar 9.

State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116024, China.

Tumor hypoxia has proven to be the major bottleneck of photodynamic therapy (PDT) to clinical transformation. Different from traditional O delivery approaches, here we describe an innovative binary photodynamic O-economizer (PDOE) tactic to reverse hypoxia-driven resistance by designing a superoxide radical (O) generator targeting mitochondria respiration, termed SORgenTAM. This PDOE system is able to block intracellular O consumption and down-regulate HIF-1α expression, which successfully rescues cancer cells from becoming hypoxic and relieves the intrinsic hypoxia burden of tumors in vivo, thereby sparing sufficient endogenous O for the PDT process. Photosensitization mechanism studies demonstrate that SORgenTAM has an ideal intersystem crossing rate and triplet excited state lifetime for generating O through type-I photochemistry, and the generated O can further trigger a biocascade to reduce the PDT's demand for O in an O-recycble manner. Furthermore, SORgenTAM also serves to activate the AMPK metabolism signaling pathway to inhibit cell repair and promote cell death. Consequently, using this two-step O-economical strategy, under relatively low light dose irradiation, excellent therapeutic responses toward hypoxic tumors are achieved. This study offers a conceptual while practical paradigm for overcoming the pitfalls of phototherapeutics.
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http://dx.doi.org/10.1021/jacs.0c00734DOI Listing
March 2020

NIR Light-Driving Barrier-Free Group Rotation in Nanoparticles with an 88.3% Photothermal Conversion Efficiency for Photothermal Therapy.

Adv Mater 2020 Mar 5;32(11):e1907855. Epub 2020 Feb 5.

State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Hi-Tech Zone, Dalian, 116024, China.

Traditional photothermal therapy requires high-intensity laser excitation for cancer treatments due to the low photothermal conversion efficiency (PCE) of photothermal agents (PTAs). PTAs with ultra-high PCEs can decrease the required excited light intensity, which allows safe and efficient therapy in deep tissues. In this work, a PTA is synthesized with high PCE of 88.3% based on a BODIPY scaffold, by introducing a CF "barrier-free" rotor on the meso-position (tfm-BDP). In both the ground and excited state, the CF moiety in tfm-BDP has no energy barrier to rotation, allowing it to efficiently dissipate absorbed (NIR) photons as heat. Importantly, the barrier-free rotation of CF can be maintained after encapsulating tfm-BDP into polymeric nanoparticles (NPs). Thus, laser irradiation with safe intensity (0.3 W cm , 808 nm) can lead to complete tumor ablation in tumor-bearing mice after intravenous injection of tfm-BDP NPs. This strategy of "barrier-free rotation" provides a new platform for future design of PTT agents for clinical cancer treatment.
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http://dx.doi.org/10.1002/adma.201907855DOI Listing
March 2020

Catalase-based liposomal for reversing immunosuppressive tumor microenvironment and enhanced cancer chemo-photodynamic therapy.

Biomaterials 2020 03 2;233:119755. Epub 2020 Jan 2.

State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Dalian, 116024, PR China; Shenzhen Research Institute, Dalian University of Technology, Nanshan District, Shenzhen, 518057, PR China. Electronic address:

Photodynamic therapy (PDT) and chemotherapy has been applied as a prospective approach in tumor therapeutics. However, suffering from the inherent hypoxia status in tumor microenvironment (TME), the anticancer efficiency is enormously restricted, especially PDT. Herein, we develop a unique liposomal encapsulated catalase (CAT), lyso-targeted NIR photosensitizer (MBDP) and doxorubicin (Dox), forming [email protected]@CAT, to increase tumor oxygenation by catalyzing intratumoral high-expressed HO for enhancing the combination of chemo-PDT. Moreover, the enhanced tumoral oxygenation not only facilitates singlet oxygen (O) production but also reverses immunosuppressive TME by modulating immune cytokines to favor antitumor immunities, which significantly induce tumor death. Notably, this system also realizes specific tumor recognition to folate receptor upregulated tumors and improves intratumoral accumulation. This work provides an effective strategy to promote tumor therapeutic index, which may possess a promising future in clinical application.
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http://dx.doi.org/10.1016/j.biomaterials.2020.119755DOI Listing
March 2020

Automatic generation of pedicle contours in 3D vertebral models.

Comput Biol Med 2020 01 26;116:103565. Epub 2019 Nov 26.

The Second Hospital of Anhui Medical University, Hefei, Anhui, PR China. Electronic address:

Objectives: Pedicle location and recognition play important roles in spinal morphology analysis and orthodontic screw implantation, which can help doctors avoid injuring the pedicle during screw implantation. However, because of the complex spatial structures of vertebrae and the close connection between the pedicle and other parts of the vertebrae, it is challenging to locate and recognize the pedicle of the vertebral arch in 2D or 3D vertebral images.

Methods: In this paper, based on deep learning technology, we propose a method for automatically recognizing the vertebral pedicle in individual vertebral models and drawing pedicle contours. The goal is to provide references so doctors can simulate the pedicle screw implantation operation to prevent screw deviation and further enhance the automation of our team's scoliosis-correction assistive system. First, we preprocess the individual vertebral models to obtain their point clouds. Then, we use a modified PointNet model to segment the pedicle areas from the individual vertebral point clouds. We use the segmentation results to automatically fit the cross-sections of pedicles and finally generate the pedicle contours as surgical references.

Results: The experiments show that the method can generate contours quickly and accurately with a small amount of manual adjustment and can provide good references for simulating screw placement.

Conclusions: The efficiency of generating pedicle contours during the process of simulated screw placement is greatly improved, and the difficulty of using our simulation system has also been greatly reduced, both of which play essential roles in pedicle screw implantation and the formulation of surgical plans.
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http://dx.doi.org/10.1016/j.compbiomed.2019.103565DOI Listing
January 2020

MicroRNA Detection with Turnover Amplification via Hybridization-Mediated Staudinger Reduction for Pancreatic Cancer Diagnosis.

J Am Chem Soc 2019 12 12;141(51):20490-20497. Epub 2019 Dec 12.

State Key Laboratory of Fine Chemicals , Dalian University of Technology , 2 Linggong Road , High-tech District, Dalian 116024 , PR China.

The occurrence of and development in the early pathological stage of pancreatic cancer has proved to be associated with microRNAs. However, it remains a great challenge to directly monitor low-expression, and downregulation of, microRNA among living cells, tissues, and serum samples. In this work, Staudinger reduction is first applied in intracellular microRNA detection, establishing a set of smart hybridization-mediated Staudinger reduction probes () which contain designed oligonucleotide sequences. Meanwhile, 40 serum samples (healthy people (6), patients with pancreatitis (22), and pancreatic cancer patients (12)) are tested for exploring the potential clinical application. Of note, the molecules bound to nucleic acid confine the reactive site to close proximity in a compact space, and nonconnected product from Staudinger reaction facilitates turnover amplification to an ameliorative detection limit (1.3 × 10 M). Moreover, compared with qRT-PCR, a low false positive signal and an excellent specificity makes the probe more suitable and convenient for pancreatic cancer diagnosis in blood samples. For practical applications, enable accurate differentiation in cell and tissue samples under both 488 and 785 nm and have good coherence to known research. As a proof of concept, the reliable results in distinguishing pancreatic cancer patients from different morbid stages might supply a feasible method for endogenous microRNA detection in fundamental research and clinical diagnostics.
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http://dx.doi.org/10.1021/jacs.9b11272DOI Listing
December 2019

Intracellular MicroRNA imaging using telomerase-catalyzed FRET ratioflares with signal amplification.

Chem Sci 2019 Aug 7;10(29):7111-7118. Epub 2019 Jun 7.

State Key Laboratory of Fine Chemicals , Dalian University of Technology , High-tech District , Dalian 116024 , P. R. China . Email:

Intracellular microRNA (miRNA) detection has attracted increasing attention, resulting in significant achievements. However, the development of an available tool that possesses a satisfactory signal-to-background ratio and high sensitivity for miRNA detection remains challenging. Herein, a class of telomerase-catalyzed FRET (fluorescence resonance energy transfer) ratioflares has been developed for the accurate sensing of low-abundance cancer-related miRNA both in a fluorescence assay and living cell imaging with signal amplification capacity. In this work, endogenous telomerase is led in a miRNA test system with signal amplification for the first time, wherein telomerase extends hexamer telomeric repeats (TTAGGG) using the 3' end of the capture probe as the primer. The synergetic work of telomerase and the catalyst strand () makes the target miRNA circulate in the system, resulting in high sensitivity and an enhanced FRET signal an improved detection limit of 2.27 × 10 M. Meanwhile, telomerase-catalyzed FRET ratioflares allow the difference between cancer cells and normal cells to be increased reliably. Furthermore, low false positive signals resulting from chemical interference and minimized system fluctuations are achieved through ratiometric measurements.
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http://dx.doi.org/10.1039/c9sc02301aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6677110PMC
August 2019

High prevalence of non-O157 Shiga toxin-producing Escherichia coli in beef cattle detected by combining four selective agars.

BMC Microbiol 2019 09 5;19(1):213. Epub 2019 Sep 5.

State Key Laboratory of Infectious Disease Prevention and Control, National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Changping, Beijing, China.

Background: Shiga toxin-producing Escherichia coli (STEC) are emerging foodborne pathogens that are public health concern. Cattle have been identified as the major STEC reservoir. In the present study, we investigated the prevalence and characteristics of STEC strains in beef cattle from a commercial farm in Sichuan province, China.

Results: Among 120 beef cattle fecal samples, stx genes were positive in 90% of samples, as assessed using TaqMan real-time PCR, and 87 (72.5%) samples were confirmed to yield at least one STEC isolate by culture using four selective agars, MacConkey, CHROMagar™ ECC, modified Rainbow® Agar O157, and CHROMagar™ STEC, from which 31, 32, 91, and 73 STEC strains were recovered, respectively. A total of 126 STEC isolates were selected and further characterized. Seventeen different O:H serotypes were identified, all of which belonged to the non-O157 serotypes. One stx subtype (stx) and three stx subtypes (stx, stx, and stx) were present among these isolates. The intimin encoding gene eae, and other adherence-associated genes (iha, saa, and paa) were present in 37, 125, 74, and 30 STEC isolates, respectively. Twenty-three isolates carried the virulence gene subA, and only one harbored both cnf1 and cnf2 genes. Three plasmid-origin virulence genes (ehxA, espP, and katP) were present in 111, 111, and 7 isolates, respectively. The 126 STEC isolates were divided into 49 pulsed-field gel electrophoresis (PFGE) patterns.

Conclusions: Our study showed that the joint use of the selective MacConkey and modified Rainbow® Agar O157 agars increased the recovery frequency of non-O157 STEC strains in animal feces, which could be applied to other samples and in regular STEC surveillance. Moreover, the results revealed high genetic diversity of non-O157 STEC strains in beef cattle, some of which might have the potential to cause human diseases.
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http://dx.doi.org/10.1186/s12866-019-1582-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728992PMC
September 2019

Structure-activity relationships study of neolamellarin A and its analogues as hypoxia inducible factor-1 (HIF-1) inhibitors.

Bioorg Med Chem Lett 2019 08 15;29(16):2327-2331. Epub 2019 Jun 15.

Department of Pharmacy, School of Chemical Engineering, Dalian University of Technology, Dalian 116023, China; State Key Laboratory of Fine Chemicals, Dalian University of Technology, Dalian 116023, China.

The novel marine pyrrole alkaloid neolamellarin A derived from sponge has been shown to inhibit hypoxia-induced HIF-1 activity. In this work, we designed and synthesized neolamellarin A and its series of derivatives by a convergent synthetic strategy. The HIF-1 inhibitory activity and cytotoxicity of these compounds were evaluated in Hela cells by dual-luciferase reporter gene assay and MTT assay, respectively. The results showed that neolamellarin A 1 (IC = 10.8 ± 1.0 μM) and derivative 2b (IC = 11.9 ± 3.6 μM) had the best HIF-1 inhibitory activity and low cytotoxicity. Our SAR research focused on the effects of key regions aliphatic carbon chain length, aromatic ring substituents and C-7 substituent on biological activity, providing a basis for the subsequent research on the development of novel pyrrole alkaloids as HIF-1 inhibitors and design of small molecule probes for target protein identification.
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http://dx.doi.org/10.1016/j.bmcl.2019.06.017DOI Listing
August 2019

A nitroxyl-responsive near-infrared fluorescent chemosensor for visualizing HS/NO crosstalk in biological systems.

Chem Commun (Camb) 2019 Jul;55(59):8583-8586

State Key Laboratory of Fine Chemicals, Dalian University of Technology, 2 Linggong Road, Dalian, 116024, P. R. China and Shenzhen Research Institute, Dalian University of Technology, Gaoxin South fourth Road, Nanshan District, Shenzhen 518057, P. R. China.

We present a near-infrared (NIR) fluorescent probe, NR-HNO, which was successfully applied to visualizing H2S/NO "crosstalk" by the fluorescence detection of nitroxyl with a fast response time (5 min) and a large Stokes shift (131 nm) in living cells and tissue; it was also used to image nitroxyl in live mice.
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http://dx.doi.org/10.1039/c9cc04060aDOI Listing
July 2019

Suppression of a broad spectrum of liver autoimmune pathologies by single peptide-MHC-based nanomedicines.

Nat Commun 2019 05 14;10(1):2150. Epub 2019 May 14.

Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, T2N 4N1, Canada.

Peptide-major histocompatibility complex class II (pMHCII)-based nanomedicines displaying tissue-specific autoantigenic epitopes can blunt specific autoimmune conditions by re-programming cognate antigen-experienced CD4+ T-cells into disease-suppressing T-regulatory type 1 (TR1) cells. Here, we show that single pMHCII-based nanomedicines displaying epitopes from mitochondrial, endoplasmic reticulum or cytoplasmic antigens associated with primary biliary cholangitis (PBC) or autoimmune hepatitis (AIH) can broadly blunt PBC, AIH and Primary Sclerosing Cholangitis in various murine models in an organ- rather than disease-specific manner, without suppressing general or local immunity against infection or metastatic tumors. Therapeutic activity is associated with cognate TR1 cell formation and expansion, TR1 cell recruitment to the liver and draining lymph nodes, local B-regulatory cell formation and profound suppression of the pro-inflammatory capacity of liver and liver-proximal myeloid dendritic cells and Kupffer cells. Thus, autoreactivity against liver-enriched autoantigens in liver autoimmunity is not disease-specific and can be harnessed to treat various liver autoimmune diseases broadly.
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http://dx.doi.org/10.1038/s41467-019-09893-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6517389PMC
May 2019

imaging of aminopeptidase N activity in hepatocellular carcinoma: a migration model for tumour using an activatable two-photon NIR fluorescent probe.

Chem Sci 2019 Feb 27;10(6):1619-1625. Epub 2018 Nov 27.

State Key Laboratory of Fine Chemicals , Dalian University of Technology , 2 Linggong Road , Dalian 116024 , P. R. China . Email:

CD13/aminopeptidase N (APN), which is a zinc-dependent metalloproteinase, plays a vital role in the growth, migration, angiogenesis, and metastasis of tumours. Thus, molecular imaging of endogenous APN levels is considerably significant for investigating APN and its different functions. In this study, a novel two-photon near-infrared (NIR) fluorescence probe was prepared to perform and tracking of APN. The -terminal alanyl site of probe was accurately hydrolysed to the amino group, thereby liberating strong fluorescence owing to the recovery of the Intramolecular Charge Transfer (ICT) effect. By considering its outstanding selectivity, ultra-sensitivity (DL 0.25 ng mL) and favourable biocompatibility, the probe was used to distinguish between normal cells (LO2 cells) and cancer cells (HepG-2 and B16/BL6 cells). Furthermore, migration of hepatocellular carcinoma cells was apparently inhibited by ensuring that the APN catalytic cavity was occupied by bestatin. The identification of three-dimensional (3D) fluorescence in cancer tissues was completed under two-photon excitation coupled with lighting up hepatocellular carcinoma tumours ; this revealed that probe is an effective tool for detecting APN, thereby assisting in the early diagnosis of tumour in clinical medicine.
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http://dx.doi.org/10.1039/c8sc04685aDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6368242PMC
February 2019

Superoxide Radical Photogenerator with Amplification Effect: Surmounting the Achilles' Heels of Photodynamic Oncotherapy.

J Am Chem Soc 2019 02 30;141(6):2695-2702. Epub 2019 Jan 30.

State Key Laboratory of Fine Chemicals , Dalian University of Technology , Dalian 116024 , China.

Strong oxygen dependence, poor tumor targeting, and limited treatment depth have been considered as the "Achilles' heels" facing the clinical usage of photodynamic therapy (PDT). Different from common approaches, here, we propose an innovative tactic by using photon-initiated dyad cationic superoxide radical (O) generator (ENBOS) featuring "0 + 1 > 1" amplification effect to simultaneously overcome these drawbacks. In particular, by taking advantage of the Förster resonance energy transfer theory, the energy donor successfully endows ENBOS with significantly enhanced NIR absorbance and photon utility, which in turn lead to ENBOS more easily activated and generating more O in deep tissues, that thus dramatically intensifies the type I PDT against hypoxic deep tumors. Moreover, benefiting from the dyad cationic feature, ENBOS achieves superior "structure-inherent targeting" abilities with the signal-to-background ratio as high as 25.2 at 48 h post intravenous injection, offering opportunities for accurate imaging-guided tumor treatment. Meanwhile, the intratumoral accumulation and retention performance are also markedly improved (>120 h). On the basis of these unique merits, ENBOS selectively inhibits the deep-seated hypoxic tumor proliferation at a low light-dose irradiation. Therefore, this delicate design may open new horizons and cause a paradigm change for PDT in future cancer therapy.
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http://dx.doi.org/10.1021/jacs.8b13141DOI Listing
February 2019

Limited sampling strategy for the estimation of the area under the concentration-time curve for ganciclovir in Chinese adult renal allograft recipients.

Eur J Clin Pharmacol 2019 May 14;75(5):677-686. Epub 2019 Jan 14.

Center for Organ Transplantation, Rui-Jin Hospital, Shanghai Jiao-Tong University School of Medicine, 197 Ruijin Er Road, Shanghai, 200025, People's Republic of China.

Objectives: Valganciclovir (VGCV) treatment is recommended for the prevention of cytomegalovirus (CMV) infection in renal allograft recipients. The aim of the present study is to investigate the pharmacokinetic characteristics of ganciclovir (GCV) after administration of VGCV in Chinese adult renal allograft recipients and estimate the exposure to GCV using limited sampling strategy (LSS).

Methods: Forty Chinese renal allograft recipients were given 450 mg or 900 mg VGCV daily. Blood samples were drawn before treatment and 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 h after 5 days of VGCV therapy, and the plasma concentrations of VGCV and GCV were determined using a liquid chromatography-mass spectrometry assay. The major pharmacokinetic parameters for GCV and VGCV were determined using a noncompartmental assay. Multiple stepwise linear regression analysis was conducted to establish a model equation for the estimation of the GCV AUC in Chinese patients using LSS.

Results: In the 450 and 900 mg groups, the C for VGCV was 0.2 ± 0.10 and 0.4 ± 0.16 mg/L, respectively; the C for GCV was 4.2 ± 1.1 and 8.6 ± 1.6 mg/L, respectively; and the AUC for GCV was 28.4 ± 8.4 and 60.7 ± 17.5 mg·h/L, respectively. For the establishment of LSS models, 40 patients were divided into the training group (n = 24) and validation group (n = 16). The model equations used for the calculation of AUC for GCV were established in the training group by using multiple linear regression assay. Equations including AUC = 8.1 + 29.7 × C + 5.7 × C (r = 0.91) and AUC = - 0.4 + 11.0 × C + 2.1 × C + 13.7 × C (r = 0.98) were acceptable. The %MPE and %MAPE values obtained from the validation group for the two model equations were 5.89 ± 14.5% and 12.1 ± 9.53%, and - 1.30 ± 4.40% and 3.28 ± 3.11%, respectively.

Conclusions: The LSS models that included C and C or C, C, and C in the estimation of AUC for GCV had favorable performance and can be used for therapeutic drug monitoring in the prevention of CMV infection using VGCV in Chinese renal allograft recipients.
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http://dx.doi.org/10.1007/s00228-018-02613-wDOI Listing
May 2019

Population Pharmacokinetics and Bayesian Estimation of Mycophenolic Acid Exposure in Chinese Renal Allograft Recipients After Administration of EC-MPS.

J Clin Pharmacol 2019 04 10;59(4):578-589. Epub 2018 Dec 10.

Organ Transplantation Center, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

The aim of the present study is to establish a population pharmacokinetic (PPK) model of mycophenolic acid (MPA) and limited sampling strategy models for the estimation of MPA exposure in Chinese adult renal allograft recipients following oral administration of enteric coated mycophenolate sodium (EC-MPS). A total of 74 sets of full pharmacokinetic profiles and 47 sets of MPA-sparing samples were collected from 102 renal transplant recipients who received oral EC-MPS. The MPA concentration was determined by an enzyme-multiplied immunoassay technique, and the pathophysiologic data were recorded. The PPK model was constructed using nonlinear mixed-effects modeling, and the limited sampling strategy models for MPA were established by using multiple regression analysis and the maximum a posteriori Bayesian assay based on 2 to 4 sampling time points following EC-MPS administration. The pharmacokinetics of MPA were best described by a 2-compartment model with a first-order absorption process and a lag time of absorption. The clearance of MPA was 12.3 ± 1.14 L/h. Comedicating with cyclosporine A was found to have a significant impact on the clearance/bioavailability of MPA (P < .01). Sampling strategies consisted of plasma concentration at 1.5, 2, 4 (C1.5-C2-C4) hours and 1.5, 2, 4, 6 (C1.5-C2-C4-C6) hours after EC-MPS administration were shown to be suitable for the estimation of the MPA area under the concentration-time curve in these patients. The PPK model was acceptable and can describe the pharmacokinetics of MPA in Chinese renal transplant recipients administered EC-MPS. The area under the concentration-time curve of MPA in Chinese renal transplant recipients could be estimated through a limited sampling strategy method, based on which individualized immunosuppressive regimens could be designed.
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http://dx.doi.org/10.1002/jcph.1352DOI Listing
April 2019

Nanoparticles for Immune Stimulation Against Infection, Cancer, and Autoimmunity.

ACS Nano 2018 11 15;12(11):10621-10635. Epub 2018 Oct 15.

Julia McFarlane Diabetes Research Centre (JMDRC) and Department of Microbiology, Immunology and Infectious Diseases, Snyder Institute for Chronic Diseases and Hotchkiss Brain Institute, Cumming School of Medicine , University of Calgary , Calgary , Alberta T2N 4N1 , Canada.

Vaccination using nanocarrier-based delivery systems has recently emerged as a promising approach for meeting the continued challenge posed by infectious diseases and cancer. A diverse portfolio of nanocarriers of various sizes, compositions, and physical parameters have now been developed, and this diversity provides an opportunity for the rational design of vaccines that can mediate targeted delivery of various antigens and adjuvants or immune regulatory agents in ways unachievable with classical vaccination approaches. This flexibility allows control over the characteristics of vaccine-elicited immune responses such that they can be tailored to be effective in circumstances where classical vaccines have failed. Furthermore, the utility of nanocarrier-based immune modulation extends to the treatment of autoimmune disease where precisely targeted inhibition of immune responses is desirable. Clearly, the selection of appropriate nanocarriers, antigens, adjuvants, and other components underpins the efficacy of these nanoimmune interventions. Herein, we provide an overview of currently available nanocarriers of various types and their physical and pharmacological properties with the goal of providing a resource for researchers exploring nanomaterial-based approaches for immune modulation and identify some information gaps and unexplored questions to help guide future investigation.
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http://dx.doi.org/10.1021/acsnano.8b05950DOI Listing
November 2018
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