Publications by authors named "Weiping Gao"

44 Publications

Transport stress affects the fecal microbiota in healthy donkeys.

J Vet Intern Med 2021 Jul 31. Epub 2021 Jul 31.

National Engineering Research Center for Gelatin-based TCM, Dong-E E-Jiao Co., Ltd, Liaocheng, Shandong Province, China.

Background: With the development of large-scale donkey farming in China, long-distance transportation has become common practice, and the incidence of intestinal diseases after transportation has increased. The intestinal microbiota is important in health and disease, and whether or not transportation disturbs the intestinal microbiota in donkeys has not been investigated.

Objectives: To determine the effects of transportation on the fecal microbiota of healthy donkeys using 16S rRNA sequencing.

Animals: Fecal and blood samples were collected from 12 Dezhou donkeys before and after transportation.

Methods: Prospective controlled study. Cortisol, ACTH, and heat-shock protein 90 (HSP90) concentrations were measured. Sequencing of 16S rRNA was used to assess the microbial composition. Alpha diversity and beta diversity were assessed.

Results: Results showed significant (P < .05) increases in cortisol (58.1 ± 14.6 to 71.1 ± 9.60 ng/mL), ACTH (163.8 ± 31.9 to 315.8 ± 27.9 pg/mL), and HSP90 (10.8 ± 1.67 to 14.6 ± 1.75 ng/mL) on the day of arrival. A significantly lower (P = .04) level of bacterial richness was found in fecal samples after transportation, compared with that before transportation without distinct changes in diversity. Most notably, donkeys had significant decreases in Atopostipes, Eubacterium, Streptococcus, and Coriobacteriaceae.

Conclusions And Clinical Importance: Transportation can induce stress in healthy donkeys and have some effect on the composition of the in fecal microbiota. Additional studies are required to understand the potential effect of these microbiota changes, especially significantly decreased bacteria, on the development intestinal diseases in donkeys during recovery from transportation.
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http://dx.doi.org/10.1111/jvim.16235DOI Listing
July 2021

Puerarin protects against human retinal endothelial cells injury induced by high glucose via regulating miR-16-5p/CASP1 axis.

Gen Physiol Biophys 2021 May;40(3):235-243

Department of Ophthalmology, The Affiliated Hospital to Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China.

We aimed to investigate the effects of puerarin on high glucose (HG)-induced human retinal endothelial cells (HRECs) injury. Cells were exposed to puerarin in the presence or absence of HG challenge. Cell viability was determined using a CCK-8 assay. Then, the levels of the oxidative stress-related factors were evaluated using corresponding kits. Pyroptosis was assessed by measurement of gasdermin-N domain (GSDMD-N) and caspase-1 (CASP1) expression. Subsequently, miR-16-5p expression was detected using RT-qPCR. The levels of oxidative stress and pyroptosis were examined after miR-16-5p silencing. The Starbase database predicted that CASP1 is a potential target of miR-16-5p, which was verified through a luciferase reporter assay. Moreover, CASP1 expression was determined after miR-16-5p silencing in HG-stimulated HRECs with puerarin exposure. Results revealed that puerarin significantly enhanced cell viability and inhibited oxidative stress. Furthermore, puerarin markedly downregulated GSDMD-N and CASP1 expression, and miR-16-5p level was notably inhibited in HG-stimulated HRECs, which was reversed after puerarin intervention. Following transfection with miR-16-5p inhibitor, the effects of puerarin on cell viability, oxidative stress and pyroptosis were attenuated in HG-induced HRECs. CASP1 was confirmed as a direct target gene of miR-16-5p. Taken together, puerarin alleviates oxidative stress and pyroptosis in HG-stimulated HRECs through regulating the miR- 16-5p/CASP1 axis.
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http://dx.doi.org/10.4149/gpb_2021010DOI Listing
May 2021

Quantitative analysis and optimization design of the segmented planar integrated optical imaging system based on an inhomogeneous multistage sampling lens array.

Opt Express 2021 Apr;29(8):11869-11884

The non-uniformity of the lens array in the segmented planar integrated optical imaging system has not been studied. We design an inhomogeneous multistage sampling lens array based on a hierarchical multistage sampling lens array of the segmented planar integrated optical imaging system by changing the radius of the lenslet for frequency-selective sampling to optimize the design of the UV spatial frequency distribution. The signal transfer model of the proposed imaging system was established considering the radius of the lenslet and key waveguide parameters. Simulation results show that the proposed system produces better imaging quality owing to the selective sampling of frequency. Compared with the homogeneous multistage sampling lens array (radius of 1.8 mm), the optimal radius parameters of the inhomogeneous multistage sampling lens array are given for the same longest lens array length. Detailed calculations of the parameters of the waveguide connected to the lens array were performed. Our results provide a theoretical basis for the optimal design and process of a new segmented planar integrated optical imaging system.
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http://dx.doi.org/10.1364/OE.421298DOI Listing
April 2021

Electroacupuncture Alleviates Inflammation of Dry Eye Diseases by Regulating the 7nAChR/NF-B Signaling Pathway.

Oxid Med Cell Longev 2021 9;2021:6673610. Epub 2021 Apr 9.

Ophthalmology Department of Traditional Chinese Medicine, The First Clinical Medical College, Nanjing University of Traditional Chinese Medicine, Nanjing City, Jiangsu Province 210023, China.

Purpose: We tried to investigate whether electroacupuncture (EA) can reduce inflammation of dry eye disease (DED) by regulating 7nAChR and inhibiting the NF-B signaling pathway.

Methods: Healthy New Zealand white rabbits were treated with scopolamine hydrobromide (Scop) for 21 consecutive days to establish the DED animal model. After 21 days, EA, fluorometholone (Flu), and 7nAChR antagonist (-BGT) treatments were performed, and the Scop injection was continued until day 35. During treatment, the fluorescence staining of the corneal epithelium and the level of tear flow were observed. The influence of EA on the LG pathology and inflammatory factors ACh, 7nAChR, and NF-B was detected using the LG histopathology, transmission electron microscopy (TEM), cytokine protein chip technology, enzyme-linked immunosorbent assay (ELISA), and Western blot.

Results: The EA stimulation can reduce the corneal epithelial damage and repair epithelial cell ultrastructure, promote the tear secretion, relieve the LG atrophy and decrease lipid droplet accumulation in LG acinar cell, and reduce the levels of inflammatory cytokines (i.e., IL-1, MIP-1b, TNF-, and IL-8) in the LG. The protective effect of EA on the inflammation and the ocular surface is similar to the corticosteroid Flu. EA and Flu can upregulate the expression of the 7nAChR and downregulate the expression of NF-B. The 7nAChR antagonist -BGT can reverse the protective effect of EA on the LG and the inhibitory effect on the NF-B pathway and the expression of inflammatory factors but cannot affect the expression of Flu on the NF-B pathway and inflammatory factors.

Conclusion: These results prove that EA can alleviate DEDs by stimulating the acupoints around the eyes. These beneficial effects are related to the upregulation of 7nAChR and the downregulation of NF-B in the LG. The protective effect of LG is mediated through the anti-inflammatory pathway mediated by 7nAChR. EA can reduce the NF-B P65 nuclear transcription and reduce inflammatory factors by regulating 7nAChR. This expression indicates that the 7nAChR/NF-B signaling pathway may serve as a potential therapeutic target for EA to treat DEDs.
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http://dx.doi.org/10.1155/2021/6673610DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8052151PMC
May 2021

Effects of neutron radiation on Nrf2-regulated antioxidant defense systems in rat lens.

Exp Ther Med 2021 Apr 8;21(4):334. Epub 2021 Feb 8.

Department of Ophthalmology, The Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China.

Accumulating evidence suggests that ionizing radiation (IR)-induced cataract may be associated with oxidative stress. Nuclear factor erythroid 2-related factor 2 (Nrf2) serves as a master regulator of the antioxidant defense system against oxidative stress. The present study aimed to investigate the effects of different doses of neutron radiation on the Nrf2-reegulated antioxidant defense system in rat lens and assess the status of oxidative stress. A total of 24 SD rats were randomly divided into the following four groups: i) Control group; iis) 0.4 Sv group; iii) 1.2 Sv group; and iv) 3.6 Sv group. The rats were sacrificed 7 days after radiation and lenses were dissected for histological, biochemical (malondialdehyde, glutathione and superoxide dismutase) and western blot (Nrf2, glutamate-cysteine ligase catalytic subunit and heme oxygenase 1) analyses. The morphological features of the lenses remained intact in the 0.4 Sv, 1.2 Sv and control groups, whilst the lenses in the 3.6 Sv group exhibited injuries. Results from the TUNEL assay demonstrated apparent apoptosis in lens epithelial cells following 3.6 Sv neutron radiation whereas sparse apoptosis was observed following 0.4 Sv and 1.2 Sv radiation. Malondialdehyde levels were reduced in the 0.4 Sv and 1.2 Sv groups but increased in the 3.6 Sv group, compared with those in the control group. Conversely, glutathione expression and the activity of superoxide dismutase were higher in the 0.4 Sv and 1.2 Sv groups, but lower in the 3.6 Sv group, compared with those in the control group. In addition, the total and nuclear protein levels of Nrf2 were increased following neutron radiation compared with those in the control group, though the Nrf2 protein levels decreased in the 3.6 Sv group compared with those in the 1.2 Sv group. The levels of glutamate-cysteine ligase catalytic subunit and heme oxygenase 1, downstream antioxidant enzymes of Nrf2, demonstrated the same profile as that in Nrf2. Taken together, the results of the present study suggest that neutron radiation affects Nrf2-regulated antioxidant systems in a two-stage process. Namely, the induction phase for low-dose radiation and regression phase for high-dose radiation. Therefore, it was hypothesized that activation and enhancement of the Nrf2-regulated antioxidant system may be useful in preventing or delaying IR-induced cataract, which may be extended even for other diseases associated with oxidative stress.
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http://dx.doi.org/10.3892/etm.2021.9765DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7903385PMC
April 2021

Pyridine-2,6-dicarboxaldehyde-Enabled N-Terminal In Situ Growth of Polymer-Interferon α Conjugates with Significantly Improved Pharmacokinetics and In Vivo Bioactivity.

ACS Appl Mater Interfaces 2021 Jan 31;13(1):88-96. Epub 2020 Dec 31.

Department of Geriatric Dentistry, Beijing Laboratory of Biomedical Materials, Peking University School and Hospital of Stomatology, Beijing 100081, China.

Polymer-protein conjugates are a class of biohybrids with unique properties that are highly useful in biomedicine ranging from protein therapeutics to biomedical imaging; however, it remains a considerable challenge to conjugate polymers to proteins in a site-specific, mild, and efficient way to form polymer-protein conjugates with uniform structures and properties and optimal functions. Herein we report pyridine-2,6-dicarboxaldehyde (PDA)-enabled N-terminal modification of proteins with polymerization initiators for in situ growth of poly(oligo(ethylene glycol)methyl ether methacrylate) (POEGMA) conjugates uniquely at the N-termini of a range of natural and recombinant proteins in a mild and efficient fashion. The formed POEGMA-protein conjugates showed highly retained in vitro bioactivity as compared with free proteins. Notably, the in vitro bioactivity of a POEGMA-interferon α (IFN) conjugate synthesized by this new chemistry is 8.1-fold higher than that of PEGASYS that is a commercially available and Food and Drug Administration (FDA) approved PEGylated IFN. The circulation half-life of the conjugate is similar to that of PEGASYS but is 46.2 times longer than that of free IFN. Consequently, the conjugate exhibits considerably improved antiviral bioactivity over free IFN and even PEGASYS in a mouse model. These results indicate that the PDA-enabled N-terminal grafting-from method is applicable to a number of proteins whose active sites are far away from the N-terminus for the synthesis of N-terminal polymer-protein conjugates with high yield, well-retained activity, and considerably improved pharmacology for biomedical applications.
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http://dx.doi.org/10.1021/acsami.0c15786DOI Listing
January 2021

Spatiotemporal combination of thermosensitive polypeptide fused interferon and temozolomide for post-surgical glioblastoma immunochemotherapy.

Biomaterials 2021 01 10;264:120447. Epub 2020 Oct 10.

Department of Geriatric Dentistry, Beijing Laboratory of Biomedical Materials, Peking University School and Hospital of Stomatology, Beijing, 100081, China; Biomedical Engineering Department, Peking University, Beijing, 100191, PR China. Electronic address:

Cancer recurrence post surgical resection is of considerable challenge especially in glioblastoma (GBM) therapy. Herein, we demonstrate that interferon-alpha (IFN) fused to a body temperature-sensitive elastin-like polypeptide (IFN-ELP(V)) formed a depot in situ when injected into GBM resection cavity in a mouse brain orthotopic model of GBM. Notably, IFN-ELP(V) in the depot showed a zero-order release kinetics, resulting in dramatically improved pharmacokinetics and biodistribution, and thus inhibited GBM recurrence by stimulating antitumor immunoresponse as compared to IFN. More importantly, when combined with subsequent intraperitoneal injection of temozolomide (TMZ), IFN-ELP(V) could much more effectively suppress post-surgical GBM recurrence than IFN, leading to a remarkably enhanced GBM-free survival rate (60%) over IFN (12.5%). Our findings implicate that the spatiotemporally-programmed combination of IFN-ELP(V) and TMZ leads to the synergy of post-surgical GBM immunochemotherapy, thereby providing a new and effective strategy for cancer therapy.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120447DOI Listing
January 2021

Effects of long-distance transportation on blood constituents and composition of the nasal microbiota in healthy donkeys.

BMC Vet Res 2020 Sep 15;16(1):338. Epub 2020 Sep 15.

College of Veterinary Medicine, Yangzhou University, 225009, Yangzhou, P.R. China.

Background: This study aims to determine the effects of transportation on the nasal microbiota of healthy donkeys using 16S rRNA sequencing.

Results: Deep nasal swabs and blood were sampled from 14 donkeys before and after 21 hours' long-distance transportation. The values of the plasma hormone (cortisol (Cor), adrenocorticotrophic hormone (ACTH)), biochemical indicators (total protein (TP), albumin (ALB), creatinine (CREA), lactic dehydrogenase (LDH), aspartate transaminase (AST), creatine kinase (CK), blood urea (UREA), plasma glucose (GLU)) and blood routine indices (white blood cell (WBC), lymphocyte (LYM), neutrophil (NEU), red blood cell (RBC), hemoglobin (HGB)) were measured. 16S rRNA sequencing was used to assess the nasal microbiota, including alpha diversity, beta diversity, and phylogenetic structures. Results showed that levels of Cor, ACTH, and heat-shock protein 90 (HSP90) were significantly increased (p < 0.05) after long-distance transportation. Several biochemical indicators (AST, CK) and blood routine indices (Neu, RBC, and HGB) increased markedly (p < 0.05), but the LYM decreased significantly (p < 0.05). Nine families and eight genera had a mean relative abundance over 1%. The predominant phyla in nasal microbiota after and before transportation were Proteobacteria, Firmicutes, Actinobacteria, and Bacteroidetes. Transportation stress induced significant changes in terms of nasal microbiota structure compared with those before transportation based on principal coordinate analysis (PCoA) coupled with analysis of similarities (ANOSIM) (p < 0.05). Among these changes, a notably gain in Proteobacteria and loss in Firmicutes at the phylum level was observed.

Conclusions: These results suggest transportation can cause stress to donkeys and change the richness and diversity of nasal microbiota. Further studies are required to understand the potential effect of these microbiota changes on the development of donkey respiratory diseases.
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http://dx.doi.org/10.1186/s12917-020-02563-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493398PMC
September 2020

Temperature-triggered micellization of interferon alpha-diblock copolypeptide conjugate with enhanced stability and pharmacology.

J Control Release 2020 12 6;328:444-453. Epub 2020 Sep 6.

Department of Geriatric Dentistry, Beijing Laboratory of Biomedical Materials, Peking University School and Hospital of Stomatology, Beijing 100081, PR China; Biomedical Engineering Department, Peking University, Beijing 100191, PR China. Electronic address:

Polypeptides are useful in designing protein-polypeptide conjugates for therapeutic applications; however, they are not satisfactory in improving the stability of therapeutic proteins and extending their in vivo half-life. Here we show that thermally-induced self-assembly (TISA) of elastin-like polypeptide diblock copolymer fused interferon alpha (IFNα-ELP) into a spherical micelle can dramatically enhance the proteolytic stability of IFNα. Notably, the circulation half-life of IFNα-ELP micelle (54.7 h) is 124.3-, 5.7-, and 1.4-time longer than those of free IFNα (0.44 h), freely soluble IFNα-ELP (9.6 h), and PEGylated IFNα (39.0 h), respectively. Importantly, in a mouse model of ovarian tumor, IFNα-ELP micelle exhibited significantly enhanced tumor retention and antitumor efficacy over free IFNα, freely soluble IFNα-ELP, and even PEGylated IFNα. These findings provide a thermoresponsive supramolecular strategy of TISA to design protein-diblock copolypeptide conjugate micelles with enhanced stability and pharmacology.
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http://dx.doi.org/10.1016/j.jconrel.2020.08.065DOI Listing
December 2020

Precision Conjugation: An Emerging Tool for Generating Protein-Polymer Conjugates.

Angew Chem Int Ed Engl 2021 05 18;60(20):11024-11035. Epub 2021 Jan 18.

Department of Geriatric Dentistry, Beijing Laboratory of Biomedical Materials, Peking University School and Hospital of Stomatology, Beijing, 100081, P. R. China.

Protein-polymer conjugates are increasingly being applied in biomedicine because of the unique combination of the biological activity of the proteins and the multifunctionality and flexibility of the polymers. However, traditional protein-polymer conjugation techniques suffer from some unavoidable drawbacks, including nonspecificity and low efficiency. In this Minireview, we discuss a new approach based on "precision conjugation" for the construction of the next-generation protein-polymer conjugates in a more controlled, more efficient, and tailorable fashion for a broad range of advanced applications. In illustrating the concept, we highlight two general methods: site-specific in situ growth and intrinsically disordered polypeptide fusion, with a focus on the in situ, efficient, and controllable formation of protein-polymer conjugates. At the end, the challenges associated with this emerging concept are further discussed.
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http://dx.doi.org/10.1002/anie.202003708DOI Listing
May 2021

Head-to-tail macrocyclization of albumin-binding domain fused interferon alpha improves the stability, activity, tumor penetration, and pharmacology.

Biomaterials 2020 08 23;250:120073. Epub 2020 Apr 23.

Department of Geriatric Dentistry, Beijing Laboratory of Biomedical Materials, Peking University School and Hospital of Stomatology, Beijing, 100081, China; Biomedical Engineering Department, Peking University, Beijing, 100191, China. Electronic address:

Genetic fusion of a therapeutic protein to albumin can improve its stability and pharmacokinetics, but it usually leads to considerably reduced bioactivity and poor tumor penetration due to increased steric hindrance, resulting in limited antitumor efficacy. Herein we report head-to-tail macrocyclization of albumin-binding domain fused interferon alpha (IFN-ABD) to form a cyclic fusion protein (c-IFN-ABD) with well-retained albumin-binding affinity. Notably, c-IFN-ABD showed not only greater thermal and enzymatic stability and thus antiproliferative activity than IFN-ABD and IFN due to the macrocyclization, but also exhibited considerably better pharmacokinetics than IFN and cyclic IFN owing to the albumin-binding affinity. More importantly, c-IFN-ABD showed deeper tumor penetration, greater tumor retention, and thus higher antitumor efficiency than all the controls without significant systemic side effects in mice bearing melanoma. These results implicate that head-to-tail macrocyclization of ABD fused therapeutic proteins is an enabling strategy for the design of highly potent protein therapeutics for tumor therapy.
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http://dx.doi.org/10.1016/j.biomaterials.2020.120073DOI Listing
August 2020

Polymerization-Induced Coassembly of Enzyme-Polymer Conjugates into Comicelles with Tunable and Enhanced Cascade Activity.

Nano Lett 2020 02 9;20(2):1383-1387. Epub 2020 Jan 9.

Department of Geriatric Dentistry, Beijing Laboratory of Biomedical Materials , Peking University School and Hospital of Stomatology , Beijing 100081 , China.

Living organisms utilize spatially organized enzyme complexes to carry out signal transduction and metabolic pathways in an efficient and specific way. Herein, inspired by natural enzyme complexes, we report the polymerization-induced coassembly (PICA) of enzyme-polymer conjugates into comicelles with tunable and enhanced cascade activity by using the cascade reaction implemented by glucose oxidase (GOX) and horseradish peroxidase (HRP) as a model system. Notably, the cascade activity of GOX/HRP-polymer comicelles monotonically increases with the GOX/HRP ratio. The cascade activity of GOX/HRP-polymer comicelles is up to 4.9 times higher than that of free GOX and HRP mixtures at the same GOX/HRP ratio. We further demonstrate that our system can quickly detect glucose in contrast with a commercially available glucose assay kit. These findings provide a new and general method of PICA for the controlled construction of artificial enzyme complexes with tunable and enhanced activity in enzyme cascades for advanced biomedical applications.
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http://dx.doi.org/10.1021/acs.nanolett.9b04959DOI Listing
February 2020

Introducing Temperature-Controlled Phase Transition Elastin-like Polypeptides to Transient Electronics: Realization of Proactive Biotriggered Electronics with Local Transience.

ACS Appl Mater Interfaces 2019 Dec 6;11(50):46490-46496. Epub 2019 Dec 6.

Department of Biomedical Engineering, School of Medicine , Tsinghua University , Beijing 100084 , China.

Transient electronics have dramatically changed inner-body therapy in health care. They stand out because of their harmless dissolution in the human body with no lingering electronic trash. However, high-precision biomedical implants require programmable and serial remedy operations, and controlling the whole-device destruction is not proactive and precise. Thus, a novel biotriggered and temperature-controlled transient electronics fabrication method using elastin-like polypeptides (ELPs) as triggers is proposed. Biocompatible ELPs simply mixed with trace silver nanowire (AgNW) can serve as the "switch" for the electronics to respond to local temperature changes in deionized water, exhibiting an agile response time. A ratio gradient experiment of the ELPs and AgNW shows that more programmable and precise transience properties (initial resistance, ready time, response time, and stable resistance) can be achieved by using a designated proportion. Further, we validated that the 3D-printing-based ELP-triggering transient electronics fabrication method is very simple yet effective for preparing transient wireless charging LEDs. Transient devices comprising ELPs-AgNW and PLGA-Ag respond within 160 s below 10 °C and degrade within a certain period.
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http://dx.doi.org/10.1021/acsami.9b14798DOI Listing
December 2019

Thermoresponsive and Protease-Cleavable Interferon-Polypeptide Conjugates with Spatiotemporally Programmed Two-Step Release Kinetics for Tumor Therapy.

Adv Sci (Weinh) 2019 Aug 14;6(16):1900586. Epub 2019 Jun 14.

Department of Geriatric Dentistry Beijing Laboratory of Biomedical Materials Peking University School and Hospital of Stomatology Beijing 100081 P. R. China.

Protein-polymer conjugates show improved pharmacokinetics but reduced bioactivity and tumor penetration as compared to native proteins, resulting in limited antitumor efficacy. To address this dilemma, genetic engineering of a body temperature-responsive and matrix metalloproteinase (MMP)-cleavable conjugate of interferon alpha (IFNα) and elastin-like polypeptide (ELP) is reported with spatiotemporally programmed two-step release kinetics for tumor therapy. Notably, the conjugate could phase separate to form a depot postsubcutaneous injection, leading to 1-month zero-order release kinetics. Furthermore, it could selectively be cleaved by MMPs that are overexpressed in tumors to release IFNα from ELP and thus to recover the bioactivity of IFNα. Consequently, it exhibits dramatically enhanced tumor accumulation, tumor penetration, and antitumor efficacy as compared to free IFNα in two mouse models of melanoma and ovarian tumor. These findings may provide an intelligent technology of thermoresponsive and protease-cleavable protein-polymer conjugates with spatiotemporally programmed two-step release kinetics for tumor treatment.
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http://dx.doi.org/10.1002/advs.201900586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6702759PMC
August 2019

In Situ Growth of a Cationic Polymer from the N-Terminus of Glucose Oxidase To Regulate HO Generation for Cancer Starvation and HO Therapy.

ACS Appl Mater Interfaces 2019 Mar 27;11(10):9756-9762. Epub 2019 Feb 27.

Department of Biomedical Engineering, School of Medicine , Tsinghua University , Beijing 100084 , China.

Hydrogen peroxide (HO)-generating enzymes (HGEs) are potentially useful for tumor therapy, but the potential is limited by the challenge in regulating HO production. Herein, we present site-specific in situ growth of a cationic polymer poly( N, N'-dimethylamino-2-ethyl methacrylate) (PDMA) from the N-terminus of glucose oxidase (GOX) to generate a site-specific and cationic GOX-PDMA conjugate with well-retained activity and enhanced stability to regulate HO generation for cancer starvation and HO therapy. Notably, the efficiency of endocytosis of the conjugate was 4-fold higher than that of free GOX. As a result, relative to free GOX, the conjugate showed 1.5-fold increased cytotoxicity, 2-fold enhanced tumor retention, and 5-fold increased tolerability after intratumoral injection. Importantly, a single intratumoral injection of the conjugate completely abolished colon tumors without detectable side effects, whereas free GOX was ineffective and systemically toxic. This chemistry may provide a new, simple, general, and efficient solution to regulate HO production and thereby to dramatically improve the antitumor efficacy of HGEs while reducing side effects.
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http://dx.doi.org/10.1021/acsami.8b20956DOI Listing
March 2019

Shape tunable gallium nanorods mediated tumor enhanced ablation through near-infrared photothermal therapy.

Nanoscale 2019 Feb;11(6):2655-2667

Technical Institute of Physics and Chemistry, Chinese Academy of Sciences, Beijing 100190, China.

To date, photothermal sensitizers include organic and inorganic nanomaterials for biomedical applications. However, the impediments of low biodegradability and potential toxicity hinder their further applications in clinics. Liquid metal nanospheres show superior photothermal effects under near-infrared laser irradiation, in addition, a transformation in shape can be triggered, which also promotes biodegradability that helps to avoid potential systemic toxicity. Here, we fabricated tunable liquid metal nanoparticles having sphere-shaped to rod-shaped characteristics, resulting in good biocompatibility, favorable photothermal conversion efficiency, and targeting capability to tumors. The synthesis strategy is easy to achieve through one-step sonication. We systematically evaluated the photothermal properties of these liquid metal nanoparticles as well as their destructive effects on tumors in a quantitative way both in vitro and in vivo under laser exposure. Results have shown for the first time in mice that gallium nanorods, regulated and controlled through the production of GaO(OH), displayed outstanding photothermal conversion efficiency and exhibited distinct temperature elevation compared to gallium nanospheres and gallium-indium alloy nanorods. These shape transformable and biocompatible gallium nanorods establish the basis for the future laser ablation of tumors to achieve enhanced therapeutic outcomes. This shape tunability of a smart nano-liquid metal directly contributes to enhanced photothermal therapy in mice and opens new opportunities for potential applications with tumor therapy and imaging.
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http://dx.doi.org/10.1039/c8nr08296kDOI Listing
February 2019

One-month zero-order sustained release and tumor eradication after a single subcutaneous injection of interferon alpha fused with a body-temperature-responsive polypeptide.

Biomater Sci 2018 Dec;7(1):104-112

Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, China.

Most therapeutic proteins except antibodies necessitate frequent dosing at high concentrations due to their short circulation half-lives, leading to limited therapeutic efficacy, serious adverse side effects and poor patient compliance. Herein we report a strategy of thermoresponsive polypeptide fusion to genetically engineer a super-long-acting interferon alpha fused with a body-temperature-responsive polypeptide. After a single subcutaneous injection in a mouse model, this interferon alpha can in situ form a depot to show a one-month zero-order sustained release, which would enable a once-trimonthly dosing in humans. As a result, it exhibits greatly enhanced tumor accumulation and tumor eradication as well as substantially improved tolerability and biosafety. This strategy provides a promising solution to dramatically enhance the pharmacological performance of therapeutic proteins with short circulation half-lives while reducing the side effects.
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http://dx.doi.org/10.1039/c8bm01096jDOI Listing
December 2018

Site-Selective in Situ Growth-Induced Self-Assembly of Protein-Polymer Conjugates into pH-Responsive Micelles for Tumor Microenvironment Triggered Fluorescence Imaging.

Biomacromolecules 2018 11 30;19(11):4472-4479. Epub 2018 Oct 30.

Department of Biomedical Engineering, School of Medicine , Tsinghua University , Beijing 100084 , China.

Self-assembly of site-selective protein-polymer conjugates into stimuli-responsive micelles is interesting owing to their potential biomedical applications, ranging from molecular imaging to drug delivery, but remains a significant challenge. Herein we report a method of site-selective in situ growth-induced self-assembly (SIGS) to synthesize site-specific human serum albumin-poly(2-(diisopropylamino)ethyl methacrylate) (HSA-PDPA) conjugates that can in situ self-assemble into pH-responsive micelles with tunable morphologies. Indocyanine green (ICG) was selectively loaded into the core of sphere-like HSA-PDPA micelles to form pH-responsive fluorescence nanoprobes. The nanoprobes rapidly dissociated into protonated individual unimers at a transition pH of around 6.5, that is the extracellular pH of tumors, which resulted in a sharp fluorescence increase and markedly enhanced cellular uptake. In a tumor-bearing mouse model, they exhibited greatly enhanced tumor fluorescence imaging as compared to ICG alone and pH-nonresponsive nanoprobes. These findings suggest that pH-responsive and site-selective protein-polymer conjugate micelles synthesized by SIGS are promising as a new class of tumor microenvironment-responsive nanocarriers for enhanced tumor imaging and therapy.
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http://dx.doi.org/10.1021/acs.biomac.8b01368DOI Listing
November 2018

Polymerization Induced Self-Assembly of a Site-Specific Interferon α-Block Copolymer Conjugate into Micelles with Remarkably Enhanced Pharmacology.

J Am Chem Soc 2018 08 9;140(33):10435-10438. Epub 2018 Aug 9.

Department of Biomedical Engineering, School of Medicine , Tsinghua University , Beijing 100084 , China.

Conjugating a hydrophilic and protein-resistant polymer to a protein is a widely used strategy to extend the in vivo half-life of the protein; however, the benefit of the half-life extension is usually limited by the bioactivity decrease. Herein we report a supramolecular self-assembly strategy of site-specific in situ polymerization induced self-assembly (SI-PISA) to address the dilemma. An amphiphilic block copolymer (POEGMA-PHPMA) was directly grown from the C-terminus of an important therapeutic protein interferon-α (IFN) to in situ form IFN-POEGMA-PHPMA conjugate micelles. Notably, the in vitro bioactivity of the micelles was 21.5-fold higher than that of the FDA-approved PEGylated interferon-α PEGASYS. Particularly, the in vivo half-life of the micelles (83.8 h) was 1.7- and 100-fold longer than those of PEGASYS (49.5 h) and IFN (0.8 h), respectively. In a tumor-bearing mouse model, the micelles completely suppressed tumor growth with 100% animal survival, whereas at the same dose, PEGASYS and IFN were much less effective. These findings suggest that SI-PISA is promising as a next-generation technology to remarkably enhance the pharmacological performance of therapeutic proteins with short circulation half-lives.
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http://dx.doi.org/10.1021/jacs.8b06013DOI Listing
August 2018

Drug nanorods are potential new nanocarriers for intracellular protein delivery.

Theranostics 2018 21;8(14):3872-3873. Epub 2018 Jun 21.

Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, China.

Protein therapeutics are increasingly important for the treatment of many diseases; however, intracellular protein delivery remains a considerable challenge. To address this challenge, drug nanorods have emerged as new nanocarriers for enhanced intracellular protein delivery via bypassing endo-lysosomes, which was called a "drug-delivering-drug platform".
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http://dx.doi.org/10.7150/thno.27815DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6071533PMC
March 2020

Tumour-homing chimeric polypeptide-conjugated polypyrrole nanoparticles for imaging-guided synergistic photothermal and chemical therapy of cancer.

Theranostics 2018 3;8(10):2634-2645. Epub 2018 Apr 3.

Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, China.

Near-infrared (NIR)-absorbing conjugated polymer nanoparticles are interesting for imaging-guided combination therapy, especially for synergistic photothermal therapy and chemotherapy; however, most of them target tumours passively through the enhanced permeability and retention (EPR) effect, leading to low utilization efficiency. To address this problem, we report an active tumour-targeting strategy of tumour-homing chimeric polypeptide-conjugated NIR-absorbing conjugated-polymer nanoparticles as a new class of drug nanocarriers for imaging-guided combination therapy of cancer. A tumour-homing chimeric polypeptide C-ELP-F3 was genetically engineered, and chemoselectively conjugated to polypyrrole (PPy) nanoparticles via a facile thiol-maleimide coupling reaction to form ELP-F3 conjugated PPy (PPy-ELP-F3) nanoparticles. Doxorubicin (DOX) was physically adsorbed onto PPy-ELP-F3 nanoparticles to yield DOX-loaded PPy-ELP-F3 (DOX/PPy-ELP-F3) nanoparticles. The physicochemical properties of DOX/PPy-ELP-F3 were characterized. The pharmacokinetics of DOX/PPy-ELP-F3 was studied in a mouse model. The photoacoustic imaging and photothermal imaging of tumours were tested in a melanoma-bearing mouse model. The photothermal-chemical combination therapy of tumours was investigated by using melanoma cells and in a melanoma-bearing mouse model. DOX/PPy-ELP-F3 nanoparticles showed enhanced cytotoxicity to melanoma cells and improved tumour-targeting efficiency , as compared with both DOX/PPy-ELP nanoparticles without the tumour-homing function and free DOX. The photothermal effect of DOX/PPy-ELP-F3 nanoparticles could accelerate the release of DOX from PPy-ELP-F3. Under the guidance of photoacoustic and photothermal imaging, the synergy of photothermal and chemical therapy could completely abolish tumours without detectable systemic toxicity. Tumour-homing chimeric polypeptide-conjugated NIR-absorbing conjugated-polymer nanoparticles are promising as a new multifunctional drug delivery platform for highly-efficient imaging guided combination therapy.
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http://dx.doi.org/10.7150/thno.24705DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5956998PMC
May 2019

Site-selective protein modification with polymers for advanced biomedical applications.

Biomaterials 2018 09 25;178:413-434. Epub 2018 Apr 25.

Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, 100084, China. Electronic address:

Protein modification with polymers has led to intriguing and new types of bioconjugates. They combine the tunable physicochemical properties of the polymers with the specific biological activity of the proteins. These unique attributes of protein-polymer conjugates render them interesting and useful in biomedicine. However, the application potential of protein-polymer conjugates is limited by the mostly non-selective protein modification with polymers due to the lack of site-selective protein modification technology. Recent advances in site-selective protein modification and controlled polymerization have made it possible to modify proteins with polymers in a site-selective and controlled manner. In this review, recent advances in site-selective protein modification with polymers are depicted in five parts as follows: site-selective protein modification; site-selective polymer modification; site-selective in situ growth of polymers from proteins; biosafety of polymers; and biomedical applications. Site-selective protein-polymer conjugates are superior to non-selective ones in precise control of structures and functions, which makes them more interesting for advanced biomedical applications ranging from protein delivery to diagnostics. Particularly, important examples in this regard are highlighted in this review. Additionally, major challenges and future directions in this emerging research field are also discussed in the perspective section of this review.
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http://dx.doi.org/10.1016/j.biomaterials.2018.04.050DOI Listing
September 2018

Soft and Moldable Mg-Doped Liquid Metal for Conformable Skin Tumor Photothermal Therapy.

Adv Healthc Mater 2018 07 2;7(14):e1800318. Epub 2018 May 2.

Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing, 100084, China.

As a class of emerging multifunctional soft materials, gallium-based liquid metal (LM) amalgams, metal/nonmetal particles dispersed in an LM environment, suggest a combination of intriguing properties. In this article, Mg particles in gallium-indium alloy for making new conceptual biomedical materials, which can adapt to any irregular skin surface, are introduced, and superior photothermal effect with a 61.5% photothermal conversion (PTC) increase with respect to that of the LM is realized. The formation of a new intermetallic phase Mg Ga and adjustable surface roughness, which guarantees a rapid temperature increase when illuminated by laser, are found to be responsible for the photothermal effect enhancement. The obtained soft metallic mixtures also possess excellent thermal conductivity, favorable formability, together with benign biocompatibility. The potential use of the currently produced LM mixtures for conformable photothermal therapy (PTT) of skin tumors, which is hard to precisely heat otherwise via conventional ways, is explored. The soft Mg-GaIn mixtures can adapt to irregular tumor shapes to achieve conformable and minimal invasive tumor treatment. In vivo experiments on skin-tumor-bearing mice show obvious tumor growth suppression and life span extension after PTT treatment. As a novel functional PTC material, the Mg-GaIn mixtures exhibit promising potentials in the coming clinical cancer theranostics.
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http://dx.doi.org/10.1002/adhm.201800318DOI Listing
July 2018

Tumor-homing, pH- and ultrasound-responsive polypeptide-doxorubicin nanoconjugates overcome doxorubicin resistance in cancer therapy.

J Control Release 2017 Oct 31;264:66-75. Epub 2017 Aug 31.

Department of Biomedical Engineering, School of Medicine, Tsinghua University, Beijing 100084, China. Electronic address:

Nanomedicines hold promise in overcoming drug resistance in cancer therapy, but the in vivo therapeutic efficacy is limited by their inefficient tumor targeting, poor tumor penetration, low cellular uptake and insufficient drug release. Here we report tumor-homing, pH- and ultrasound-responsive polypeptide-doxorubicin nanoconjugates for overcoming doxorubicin resistance. These nanoconjugates show accelerated cellular uptake and doxorubicin release and thus enhanced cytotoxicity to doxorubicin-resistant cancer cells when exposed to ultrasound. In a doxorubicin-resistant breast cancer mouse model, they exhibited improved tumor accumulation and penetration following exposure to ultrasound. More importantly, they displayed significantly improved in vivo anticancer efficacy without appreciable side effects post ultrasound irradiation. These findings suggest that these nanoconjugates are promising as a new class of intelligent nanomedicines for overcoming drug resistance in cancer therapy.
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http://dx.doi.org/10.1016/j.jconrel.2017.08.017DOI Listing
October 2017

Anticancer activity of polysaccharide from Glehnia littoralis on human lung cancer cell line A549.

Int J Biol Macromol 2018 Jan 7;106:464-472. Epub 2017 Aug 7.

Guangzhou University of Chinese Medicine, Guangzhou, 510006, Guangdong, PR China. Electronic address:

The purpose of this study was to investigate the anticancer activity of polysaccharide (PGL) from Glehnia littoralis on human lung cancer cell line A549. Based on MTT assay, the results suggested that PGL could significantly reduce A549 cells proliferation in a time- and dose-dependent manner. In addition, PGL displayed an inhibitory activity for the A549 cells migration in Transwell migration assay. The results from both flow cytometry analysis and Hochst 3342 staining of apoptotic cells indicated that PGL could promote apoptosis, and induce cycle arrest of A549 cells. Moreover, immunofluorescence assay elucidated PGL could also down-regulate expression of proliferating cell nuclear antigen (PCNA). Overall, these results showed that PGL exerts a strong anticancer action through inhibiting the A549 cells migration, proliferation and inducing cell apoptosis. It could be a new source of natural anticancer agent against lung cancer with potential value in supplements and medicine.
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http://dx.doi.org/10.1016/j.ijbiomac.2017.08.033DOI Listing
January 2018

Glucose Oxidase-Polymer Nanogels for Synergistic Cancer-Starving and Oxidation Therapy.

ACS Appl Mater Interfaces 2017 Jul 5;9(28):23528-23535. Epub 2017 Jul 5.

Department of Biomedical Engineering, School of Medicine, Tsinghua University , Beijing 100084, China.

Glucose oxidase (GOX) can convert glucose into gluconic acid and hydrogen peroxide (HO), which is potentially useful for synergistic cancer-starving and oxidation therapy. Herein we demonstrate a glucose-responsive nanomedicine made of GOX-polymer nanogels to regulate HO production for synergistic melanoma starving and oxidation therapy. GOX-polymer nanogels showed glucose-responsive HO-generating activity in vitro, improved stability, and considerably enhanced tumor retention as compared to native GOX. More importantly, they exhibited high antimelanoma efficacy and no obvious systemic toxicity, whereas native GOX was ineffective and systemically toxic at the same dose. This work paves the way for establishing an endogenous and noninvasive cancer treatment paradigm that is based on intratumoral glucose-responsive, HO-generating chemical reactions.
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http://dx.doi.org/10.1021/acsami.7b06814DOI Listing
July 2017

The neural pathway for lacrimal gland tear secretion in New Zealand White rabbits.

Neurosci Lett 2017 05 7;649:14-19. Epub 2017 Apr 7.

Nanjing University of Traditional Chinese Medicine, Xianlin road no. 138, Qixia District, Nanjing City, Jiangsu Province 210023, China. Electronic address:

Objective: We investigated the neural pathway for tear secretion from the lacrimal gland of New Zealand White rabbits.

Methods: Nine healthy adult New Zealand White rabbits were randomly divided into three experimental groups, namely, an irritant-stimulated group, a non-stimulated group, and a saline-stimulated group. Sanitized dry cotton swabs with menthol were used to wipe both of the rabbits' eyelids in the irritant-stimulated group, and the non-stimulated group and saline- stimulated group were compared as controls. The animals in the three groups were killed 2h later and the expressions of c-Fos in the frontal cortex, hippocampus, hypothalamus, pons, and medulla oblongata of the rabbits were detected using immunofluorescence labeling. According to the distribution of c-Fos protein expression, 12 healthy adult New Zealand rabbits were similarly divided into three groups for retrograde tract tracing via pseudorabies virus (PRV) injection into the lacrimal gland. Immunofluorescence labeling was used to analyze PRV-infected neurons in the brains of rabbits after survival for 30h, 38h, and 46h.

Results: The most c-Fos-positive immunolabeled cells were observed in the menthol-stimulated group, whereas fewer c-Fos-positive immunolabeled cells were observed in the saline-stimulated group.The non-treated group showed the least c-Fos-positive immunolabeled cells. At 30h after PRV injection, PRV-positive neurons were found only in the superior salivary nucleus of the pons (SSN). At 38h, PRV-infected neurons were observed in the lateral nucleus of the superior olive (LSO) and the medial nucleus of the superior olive (MSO). At 46h, PRV-infected neurons were found in the nucleus of the trapezoid body (Tz) and the hypothalamic paraventricular nucleus (PVN), and their distributions were dense in the LSO and MSO.

Conclusions: Menthol-induced c-Fos protein expression and PRV-mediated tract tracing suggest that in New Zealand White rabbits, the neural pathway that regulates tear secretion from the lacrimal gland proceeds from the PVN to the superior olivary complex of the pons to the SSN and finally to the lacrimal gland.
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http://dx.doi.org/10.1016/j.neulet.2017.04.012DOI Listing
May 2017

Thermally Triggered in Situ Assembly of Gold Nanoparticles for Cancer Multimodal Imaging and Photothermal Therapy.

ACS Appl Mater Interfaces 2017 Mar 17;9(12):10453-10460. Epub 2017 Mar 17.

Department of Biomedical Engineering, School of Medicine, Tsinghua University , Beijing 100084, China.

The assembly of gold nanoparticles (AuNPs) to AuNP assemblies is of interest for cancer therapy and imaging. Herein we introduce a new and general paradigm, thermally triggered AuNP assembly, for the development of novel intelligent platforms for cancer photothermal therapy (PTT) and multimodal imaging. Site-specific conjugation of a thermally sensitive elastin-like polypeptide (ELP) to AuNPs yields thermally sensitive ELP-AuNPs. Interestingly, ELP-AuNPs can in situ form AuNP assemblies composed of short necklace-like gold nanostructures at elevated temperatures and thus show strong near-infrared light absorption and high photothermal effect. These thermally responsive properties of ELP-AuNPs enable simultaneous photothermal/photoacoustic/X-ray computed tomographic imaging and PTT of melanoma after single intratumoral injection of ELP-AuNPs. The thermally triggered assembly of a variety of nanoparticles with optical, electronic, and magnetic properties into nanoparticle assemblies may open new ways for the establishment of intelligent platforms for various applications in biomedicine.
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http://dx.doi.org/10.1021/acsami.6b16408DOI Listing
March 2017

A Fast and Efficient Replacement of CTAB with MUA on the Surface of Gold Nanorods Assisted by a Water-Immiscible Ionic Liquid.

Small 2017 03 9;13(11). Epub 2017 Jan 9.

Beijing National Laboratory for Molecular Science, CAS Key Laboratory of Colloid, Interface, Chemical Thermodynamics, Institute of Chemistry, Chinese Academy of Sciences, Beijing, 100190, P. R. China.

The synthesis and surface modification of gold nanorods (GNRs) is one of the most important and basic issues in nanoscience. Most of the widely investigated GNRs are coated with a cetyltrimethylammonium bromide(CTAB) bilayer. Here, a highly efficient method is proposed to replace CTAB from the surface of GNRs with a bifunctional 11-mercaptoundecanoic acid in order to decrease the possible toxicity caused by CTAB. This ligand exchange is achieved in a biphasic mixture of an aqueous solution and a water-immiscible ionic liquid (IL), [BMIM][Tf N]. That is, by mixing IL, mercaptoundecanoic acid (MUA)/IL (200 × 10 m) and a concentrated aqueous solution of GNRs together, followed by vortex stirring for 90 s, CTAB-capped GNRs with varying aspect ratios can be turned into corresponding MUA-capped GNRs with the same aspect ratio. Furthermore, the formed MUA-capped GNRs can be obtained in a large quantity and stored as powders for easy use. The MUA-capped GNRs with improved biocompatibility and colloidal stability are well suited for further biological functionalization and potential applications. This IL-assisted ligand exchange can reverse the surface charge, enhance the stability of GNRs, and suppress its cytotoxicity.
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http://dx.doi.org/10.1002/smll.201602809DOI Listing
March 2017

In Situ Growth of Self-Assembled Protein-Polymer Nanovesicles for Enhanced Intracellular Protein Delivery.

ACS Appl Mater Interfaces 2017 Jan 9;9(3):2023-2028. Epub 2017 Jan 9.

Department of Biomedical Engineering, School of Medicine, Tsinghua University , Beijing 100084, P. R. China.

We report a new and general method, in situ growth, for designing self-assembled protein-polymer nanovesicles for intracellular protein delivery.In situ polymerization of a water-soluble monomer from a protein attached with a polymerization initiator yields amphiphilic protein conjugates of a water-insoluble polymer. These conjugates can in situ self-assemble into nanostructures with tunable morphologies from spheres to vesicles. Interestingly, an exogenous protein can be in situ encapsulated inside protein-polymer nanovesicles for enhanced intracellular protein delivery. The in situ growth method may open up new opportunities for designing a variety of self-assembled protein-polymer nanostructures tailored to specific applications.
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http://dx.doi.org/10.1021/acsami.6b14132DOI Listing
January 2017
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