Publications by authors named "Yanxin Qi"

28 Publications

  • Page 1 of 1

Comparison of Autogenous Tooth Materials and Other Bone Grafts.

Tissue Eng Regen Med 2021 Jun 30;18(3):327-341. Epub 2021 Apr 30.

Department of Oral and Maxillofacial Surgery, Graduate School of Clinical Dentistry, Korea University, Seoul, 02841, Republic of Korea.

Autogenous odontogenic materials are a new, highly biocompatible option for jaw restoration. The inorganic component of autogenous teeth acts as a scaffold to maintain the volume and enable donor cell attachment and proliferation; the organic component contains various growth factors that promote bone reconstruction and repair. The composition of dentin is similar to that of bone, which can be a rationale for promoting bone reconstruction. Recent advances have been made in the field of autogenous odontogenic materials, and studies have confirmed their safety and feasibility after successful clinical application. Autogenous odontogenic materials have unique characteristics compared with other bone-repair materials, such as the conventional autogenous, allogeneic, xenogeneic, and alloplastic bone substitutes. To encourage further research into odontogenic bone grafts, we compared the composition, osteogenesis, and development of autogenous odontogenic materials with those of other bone grafts. In conclusion, odontogenic bone grafts should be classified as a novel bone substitute.
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http://dx.doi.org/10.1007/s13770-021-00333-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8169722PMC
June 2021

Effects of Physical Stimulation in the Field of Oral Health.

Scanning 2021 7;2021:5517567. Epub 2021 Apr 7.

Stomatological Materials Laboratory, School of Stomatology, Shandong First Medical University & Shandong Academy of Medical Sciences, Tai'an, Shandong 271016, China.

Physical stimulation has been widely used in clinical medicine and healthcare due to its noninvasiveness. The main applications of physical stimulation in the oral cavity include laser, ultrasound, magnetic field, and vibration, which have photothermal, cavitation, magnetocaloric, and mechanical effects, respectively. In addition, the above four stimulations with their unique biological effects, which can play a role at the gene, protein, and cell levels, can provide new methods for the treatment and prevention of common oral diseases. These four physical stimulations have been used as important auxiliary treatment methods in the field of orthodontics, implants, periodontal, dental pulp, maxillofacial surgery, and oral mucosa. This paper systematically describes the application of physical stimulation as a therapeutic method in the field of stomatology to provide guidance for clinicians. In addition, some applications of physical stimulation in specific directions are still at the research stage, and the specific mechanism has not been fully elucidated. To encourage further research on the oral applications of physical stimulation, we elaborate the research results and development history of various physical stimuli in the field of oral health.
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http://dx.doi.org/10.1155/2021/5517567DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8049832PMC
April 2021

Dual Cross-linked HHA Hydrogel Supplies and Regulates MΦ2 for Synergistic Improvement of Immunocompromise and Impaired Angiogenesis to Enhance Diabetic Chronic Wound Healing.

Biomacromolecules 2020 09 21;21(9):3795-3806. Epub 2020 Aug 21.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China.

Immunocompromise and impaired angiogenesis of diabetes lead to chronic inflammation when wounds occur, which is the primary reason for the long-term incurable nature of diabetic chronic wounds. Herein, a high-molecular-weight hyaluronic acid (HHA) hydrogel is developed to supply and regulate M2 phenotype macrophages (MΦ2) for synergistic improvement of immunocompromise and impaired angiogenesis. MΦ2 are seeded on the Cu-HHA/PVA hydrogels prepared by Cu cross-linking of low degree and physical cross-linking (one freeze-thaw cycle and unique lyophilization) to form Cu-HHA/[email protected]Φ2 hydrogels. The Cu-HHA/[email protected]Φ2 hydrogel can directly supply the MΦ2 in the wound site, maintain the consistent phenotype of loaded MΦ2, and transform the M1 phenotype macrophages (MΦ1) in the wound bed to MΦ2 by HHA. Furthermore, Cu could be released from the hydrogels to further stimulate angiogenesis, thus accelerating the wound-healing phase transition from inflammation to proliferation and remodeling. The average wound area after the 0.5Cu-HHA/[email protected]Φ2 (ionic cross-linking degree 0.5%) treatment was much smaller than that of other diabetic groups at day 12 and close to that of the wild nondiabetic control group. Therefore, this facile hydrogel strategy with multiple modulation mechanisms of immunocompromise and angiogenesis may act as a safe and effective treatment strategy for a diabetic chronic wound.
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http://dx.doi.org/10.1021/acs.biomac.0c00891DOI Listing
September 2020

Photoactivated polyprodrug nanoparticles for effective light-controlled Pt(iv) and siRNA codelivery to achieve synergistic cancer therapy.

J Mater Chem B 2020 07;8(27):5903-5911

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China.

Endo/lysosomal escape and the subsequent controllable/precise release of drugs and genes are key challenges for efficient synergistic cancer therapy. Herein, we report a photoactivated polyprodrug nanoparticle system (PPNPsiRNA) centered on effective light-controlled codelivery of Pt(iv) prodrug and siRNA for synergistic cancer therapy. Under green-light irradiation, PPNPsiRNA can sustainedly generate oxygen-independent azidyl radicals to facilitate endo/lysosomal escape through the photochemical internalization (PCI) mechanism. Besides, concurrent Pt(ii) release and siRNA unpacking could occur in a controllable manner after the decomposition of Pt(iv), main chain shattering of photoactivated polyprodrug and the PPNPsiRNA disassociation. Based on these innovative features, excellent synergistic therapeutic efficacy of chemo- and RNAi therapies of PPNPsiBcl-2 could be achieved on ovarian cancer cells under light irradiation. The facile synthesized and prepared photoactivatable polyprodrug nanoparticle system provides a new strategy for effective gene/drug codelivery, where controllable endo/lysosomal escape and the subsequent drug/gene release/unpacking play vital roles, which could be adopted as a versatile codelivery nanoplatform for the treatment of various cancers.
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http://dx.doi.org/10.1039/d0tb01103gDOI Listing
July 2020

A portable fast neutron irradiation system for tumor therapy.

Appl Radiat Isot 2020 Jun 21;160:109138. Epub 2020 Mar 21.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, PR China.

A portable neutron tube was introduced as a small-sized (weight≤14.4 kg, power consumption ≤50W and cost≤ $100,000) neutron accelerator and applied for irradiation therapy on cancer. The effect of growth-inhibiting in vitro by neutrons irradiation on HeLa cells (human cervical cancer cells) was evaluated by colony formation assays, and cell apoptosis was evaluated by Flow Cytometry. A polyethylene protection device as the neutron moderator was designed and connected to the neutron tube to shield normal tissue and organs of the test animals from scatter radiation. Hematology and blood biochemistry were investigated to evaluate the protective effect of polyethylene. U14 (mice cervical cancer cell) tumor-bearing mice were further investigated to determine the tumor suppression effect of neutron irradiation. We found that cells showed a dose-dependent relationship after fast neutrons irradiation at different dose (1.11 Gy, 2.23 Gy, 3.34 Gy and 4.45Gy). Furthermore, in vivo experiments showed that the anti-tumor effect on U14 tumor-bearing mice greatly depended on the neutron irradiation dose. A high dose of fast neutron irradiation (26.73 Gy) could have tumor growth rate only 12.31% compared to 56.07% with control group. All the blood cell counts and blood biochemistry parameters were in the standard value ranges. Immunohistochemistry examinations clearly indicated the apoptosis cells in tumor tissues by the TUNEL assay. This work provides useful evidences on cancer irradiation therapy using fast neutron in pre-clinical study. And the neutron therapy system device has great potential to be a more convenient tool in clinical application with significantly lower power consumption, irradiation toxicity and cost.
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http://dx.doi.org/10.1016/j.apradiso.2020.109138DOI Listing
June 2020

mRNA Vaccines Encoding the HA Protein of Influenza A H1N1 Virus Delivered by Cationic Lipid Nanoparticles Induce Protective Immune Responses in Mice.

Vaccines (Basel) 2020 Mar 10;8(1). Epub 2020 Mar 10.

Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Institute of Military Veterinary Medicine, Academy of Military Medical Sciences, Academy of Military Sciences, Changchun 130000, Jilin, China.

The design of the mRNA vaccine involves the selection of in vitro transcription (IVT) systems and nonviral delivery vectors. This study aimed to verify the effect of 5' and 3' untranslated region (UTR) sequences on the translation efficiency of mRNA. Three modes of IVT-mRNA systems (IVT-mRNA-n1/n2/n3) with diverse UTRs were constructed, and EGFP (enhanced green fluorescent protein) and HA (hemagglutinin) gene of H3N2 influenza virus were introduced into each of them. The results showed that the mode of 5' and 3' UTRs originating from human β-globulin was better than the mode of UTRs from human α-globulin, and the n3 mode was the best. mEGFP-n3, mH3HA-n3, and mLuciferease-n3 were prepared to compare the effect of cationic lipid nanoparticle (LNP) with that of mannose-conjugated LNP (LNP-Man) on the efficiency of gene delivery. The results showed that the effect of LNP-Man was better than that of LNP both in vitro and in vivo. Choosing appropriate ligands might help in vaccine design. After selecting the IVT-mRNA-n3 system and delivery vectors, mRNA vaccines were constructed against the H1N1 influenza virus, and C57BL/6 mice were immunized through intranasal administration. The results showed that mRNA vaccines could elicit both humoral and cellular immune responses and completely protect mice from the tenfold LD H1N1 influenza virus challenge.
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http://dx.doi.org/10.3390/vaccines8010123DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7157730PMC
March 2020

Antigen-enabled facile preparation of MOF nanovaccine to activate the complement system for enhanced antigen-mediated immune response.

Biomater Sci 2019 Oct 11;7(10):4022-4026. Epub 2019 Sep 11.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun, Jilin 130022, P. R. China.

Since current subunit vaccines are limited by a short half-life in vivo and weak immune responses when used alone without adjuvants, there is an unmet need for combing carriers with complement activation signals to interrupt outbreaks in real-time. Amino-functionalized zirconium-based MOFs (UiO-AM) could activate the complement system, which plays an important role in innate and adaptive immunity. Our data provide design principles for studies on complement activation as a safe vaccine carrier that can effectively enhance immune responses against antigens in vivo.
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http://dx.doi.org/10.1039/c9bm01145eDOI Listing
October 2019

Amino-Modified Polymer Nanoparticles as Adjuvants to Activate the Complement System and to Improve Vaccine Efficacy in Vivo.

Biomacromolecules 2019 09 28;20(9):3575-3583. Epub 2019 Aug 28.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry , Chinese Academy of Sciences , Changchun 130022 , P. R. China.

Subunit vaccines are safer but often poorly immunogenic in comparison to traditional vaccines, and thus, adjuvants and delivery vehicles are needed to enhance the immune response. The complement system is a part of the innate immune system, which plays an important role in innate and adaptive immunity. Therefore, the activation of the complement system could be utilized as a potential strategy for vaccine applications. Herein, cysteamine hydrochloride was grafted onto a methoxy poly(ethylene glycol)-poly (allyl glycidyl ether)-poly(ε-caprolactone) copolymer to synthesize a triblock polymer mPEG-PAGE15(NH)-PCL(TPCAH) with amino groups on the side chain. The positive charge of the amino groups could bind with the negatively charged protein (like ovalbumin (OVA)) to form a stable complex by electrostatic interaction. The triblock copolymer TPCAH we designed can easily self-assemble into polymer nanomicelles, and the size of the nanoparticles is similar to that of the pathogens, which was beneficial to the uptake by lymphocytes. Furthermore, the amino groups modified on the side chain can not only integrate with proteins but also activate the complement system, thereby enhancing the immune response of subunit vaccines. The results showed that the complex [email protected] could efficiently promote powerful anti-OVA-specific antibody production, enhance CD4 T- and CD8 T-cell activation, improve the lymphocyte proliferation efficiency, and increase the secretion of different cytokines. In addition, the abundant amino groups on the surface of [email protected] could effectively activate the complement system to further enhance adaptive immunity. Overall, these results indicated that the triblock copolymer TPCAH as an adjuvant and carrier can effectively improve the ability of innate and adaptive immune responses to resist pathogens, making it a potential candidate for vaccine applications.
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http://dx.doi.org/10.1021/acs.biomac.9b00887DOI Listing
September 2019

Photostability Highly Improved Nanoparticles Based on IR-780 and Negative Charged Copolymer for Enhanced Photothermal Therapy.

ACS Biomater Sci Eng 2019 Feb 7;5(2):795-804. Epub 2019 Jan 7.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China.

The development of near-infrared (NIR) dyes with desirable photophysical characteristics for tumor therapy is highly expected at present. In this report, IR-780 iodide was loaded by the mercaptopropionic acid grafted poly(ethylene glycol)--poly(ε-caprolactone)--poly(allyl glycidyl ether) [mPEG-PCL-PAGE (MPA)] copolymer to form nanomicelles ([email protected]) in aqueous solution. On account of the hydrophobic and electrostatic interaction between mPEG-PCL-PAGE (MPA) and IR-780, the [email protected] micelle was structurally stable with improved solubility, light stability and biocompatibility. The encapsulation of IR-780 indicated no influence on its original physicochemical property, showing good optical and thermal characteristics. The drug-loaded micelles had appropriate microscopic size for endocytosis, displaying significant cytotoxicity to HeLa cells under NIR laser irradiation. In addition, the phototoxicity generated by photothermal and photodynamic effect of [email protected] under 808 nm laser irradiation was also investigated by reactive oxygen species (ROS) detection and flow cytometry. Furthermore, the superior accumulation of [email protected] in tumor tissues provided sufficient hyperthermia to kill tumor cells, indicating its potential in cancer clinical therapy.
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http://dx.doi.org/10.1021/acsbiomaterials.8b01558DOI Listing
February 2019

Composite PLA/PEG/nHA/Dexamethasone Scaffold Prepared by 3D Printing for Bone Regeneration.

Macromol Biosci 2018 06 24;18(6):e1800068. Epub 2018 Apr 24.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, No. 5625 Renmin Street, Changchun, 130022, P. R. China.

3D printing has become an essential part of bone tissue engineering and attracts great attention for the fabrication of bioactive scaffolds. Combining this rapid manufacturing technique with chemical precipitation, biodegradable 3D scaffold composed of polymer matrix (polylactic acid and polyethylene glycol), ceramics (nano hydroxyapatite), and drugs (dexamethasone (Dex)) is prepared. Results of water contact angle, differential scanning calorimeter, and mechanical tests confirm that incorporation of Dex leads to significantly improved wettability, higher crystallinity degree, and tunable degradation rates. In vitro experiment with mouse MC3T3-E1 cells implies that Dex released from scaffolds is not beneficial for early cell proliferation, but it improves late alkaline phosphatase secretion and mineralization significantly. Anti-inflammation assay of murine RAW 264.7 cells proves that Dex released from all the scaffolds successfully suppresses lipopolysaccharide induced interleukin-6 and inducible nitric oxide synthase secretion by M1 macrophages. Further in vivo experiment on rat calvarial defects indicates that scaffolds containing Dex promote osteoinduction and osteogenic response and would be promising candidates for clinical applications.
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http://dx.doi.org/10.1002/mabi.201800068DOI Listing
June 2018

Novel Engineered Microgels with Amphipathic Network Structures for Simultaneous Tumor and Inflammation Depression.

ACS Appl Mater Interfaces 2018 Mar 19;10(12):10501-10512. Epub 2018 Mar 19.

MOE Key Laboratory of Macromolecular Synthesis and Functionalization, Department of Polymer Science & Engineering , Zhejiang University , Hangzhou 310027 , China.

Novel engineered microgels with amphipathic network structures were designed and synthesized by copolymerizing N-isopropylacrylamide, 1-vinylimidazole, and 2-(cinnamoyloxy)ethyl methacrylate in the presence of 1,6-dibromohexane. The engineered microgels possess hydrophilic quaternization cross-linking structures and hydrophobic cross-linking inner nanodomains, which are suitable for loading and simultaneous release of hydrophilic nonsteroidal anti-inflammatory drug diclofenac sodium (DS) and hydrophobic antic cancer drug doxorubicin (DOX), respectively. The engineered microgels exhibited excellent stability, low cytotoxicity, and long blood circulation time and could be uptaken into the cytoplasm of cells, metabolized, and excreted from the living body by the kidney and the liver. In vivo experiments showed that with injection of DS and DOX dual-drug-loaded microgels, simultaneous antitumor treatment and inflammation depression were achieved along with high antitumor efficacy and low drug-related toxicity. Such microgels with amphipathic network structures have promising applications for combination therapy.
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http://dx.doi.org/10.1021/acsami.8b02382DOI Listing
March 2018

Stable amphiphilic supramolecular self-assembly based on cyclodextrin and carborane for the efficient photodynamic therapy.

Chem Commun (Camb) 2017 Mar 17;53(24):3422-3425. Epub 2017 Feb 17.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China.

Novel and stable supramolecular nanoparticles (NP) were prepared based on the high affinity of carboranes to β-cyclodextrin for the efficient photodynamic therapy of porphyrin in vitro.
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http://dx.doi.org/10.1039/c6cc10059gDOI Listing
March 2017

Protein-Cross-Linked Hydrogels with Tailored Swelling and Bioactivity Performance: A Comparative Study.

ACS Appl Mater Interfaces 2016 Nov 8;8(45):30788-30796. Epub 2016 Nov 8.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , 5625 Renmin Street, Changchun 130022, P. R. China.

The design of protein-based hydrogels that include biological activity independent of structural functionality is desirable for many bioengineering applications. Here a general route for construction of protein-based hydrogel is proposed by pretreatment of protein with thiolation agent and succeeding conjugation with 4-arm PEG-acrylate via Michael addition reaction. Different swelling behaviors responding to temperature and ions are comparatively studied for hydrogel cross-linked with hemoglobin (multimeric protein), albumin (monomeric protein), and dithiothreitol (DTT, small molecule). Meanwhile, the microscopic structure change is studied to correlate with the macroscopic hydrogel swelling behavior. Results show that proteins, which function as multisite cross-linkers, affect the gel swelling behaviors, and the effect is more profound for multimeric proteins when exposed to stimulus for protein dissociation. Moreover, the catalytic activity derived from hemoglobin is also preserved in the hydrogel, as demonstrated by the successfully synthesis of the colored product. By taking advantage of each particular protein, a broad range of functional materials can be expected for potential biomedical applications, such as stimuli-responsive hydrogel and immobilized enzyme.
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http://dx.doi.org/10.1021/acsami.6b11287DOI Listing
November 2016

Amphiphilic Polycarbonates from Carborane-Installed Cyclic Carbonates as Potential Agents for Boron Neutron Capture Therapy.

Bioconjug Chem 2016 09 31;27(9):2214-23. Epub 2016 Aug 31.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , Changchun 130022, PR China.

Carboranes with rich boron content have showed significant applications in the field of boron neutron capture therapy. Biodegradable derivatives of carborane-conjugated polymers with well-defined structure and tunable loading of boron atoms are far less explored. Herein, a new family of amphiphilic carborane-conjugated polycarbonates was synthesized by ring-opening polymerization of a carborane-installed cyclic carbonate monomer. Catalyzed by TBD from a poly(ethylene glycol) macroinitiator, the polymerization proceeded to relatively high conversions (>65%), with low polydispersity in a certain range of molecular weight. The boron content was readily tuned by the feed ratio of the monomer and initiator. The resultant amphiphilic polycarbonates self-assembled in water into spherical nanoparticles of different sizes depending on the hydrophilic-to-hydrophobic ratio. It was demonstrated that larger nanoparticles (PN150) were more easily subjected to protein adsorption and captured by the liver, and smaller nanoparticles (PN50) were more likely to enter cancer cells and accumulate at the tumor site. PN50 with thermal neutron irradiation exhibited the highest therapeutic efficacy in vivo. The new synthetic method utilizing amphiphilic biodegradable boron-enriched polymers is useful for developing more-selective and -effective boron delivery systems for BNCT.
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http://dx.doi.org/10.1021/acs.bioconjchem.6b00454DOI Listing
September 2016

Time-programmed DCA and oxaliplatin release by multilayered nanofiber mats in prevention of local cancer recurrence following surgery.

J Control Release 2016 08 21;235:125-133. Epub 2016 May 21.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, People's Republic of China. Electronic address:

Local recurrence following surgery in cancer treatment remains a major clinical challenge. To increase antitumor activity but maintain toxicity in an acceptable level in prevention of local cancer recurrence, we demonstrated a dual drug-loaded multilayered fiber mats strategy, in which DCA and oxaliplatin were co-electrospun into the distinct layer of resultant fabrics and the oxaliplatin-loaded fibers layer was sealed between the basement film layer and other two fibers layers. The dual drug-loaded multilayered fiber mats exhibit time-programmed dual release behavior and synergistic effect upon cancer cells. Nontoxic DCA selectively promotes apoptosis of cancer cells through modulating cellular metabolism, and oxaliplatin subsequently kills the remained cancer cells in a low concentration. After implantation on the resection margin of cervical carcinoma on a murine model, the dual drug-loaded multilayered fiber mats displayed enhanced anti-recurrence efficacy and decreased side toxic effects over 30days compared with drug-loaded monolayered fiber mats. The time-programmed combination of DCA and oxaliplatin within multilayered nanofiber mats appears to be a promising strategy for local cancer treatment following resection.
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http://dx.doi.org/10.1016/j.jconrel.2016.05.046DOI Listing
August 2016

Single-Stimulus Dual-Drug Sensitive Nanoplatform for Enhanced Photoactivated Therapy.

Biomacromolecules 2016 06 24;17(6):2120-7. Epub 2016 May 24.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , Changchun 130022, PR China.

Photoactivated therapy has become a complementary and attractive modality for traditional cancer treatment. Herein, we demonstrated a novel single-stimulus dual-drug sensitive nanoplatform, Cur-loaded Dex-Pt(N3) nanoparticles ([email protected]) for enhanced photoactivated therapy. The developed [email protected] could be photoactivated by UVA light to simultaneously generate instant reactive oxygen species from Cur for fast photodynamic therapy and release lasting Pt(II) from Pt(N3) for long-acting photochemotherapy. Compared with small free drugs and individual photoactivated therapy, [email protected] exhibited enhanced photoactivated cytotoxicity and in vivo antitumor efficacy with low systemic toxicity accompanied. Therefore, the single-stimulus dual-drug sensitive nanoplatform is convinced to be a promising strategy for multidrug delivery, site-selective and combinational photoactivated therapy in the near future.
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http://dx.doi.org/10.1021/acs.biomac.6b00353DOI Listing
June 2016

Borane-conjugated poly(ester-carbonate) amphiphilic block copolymers as potential agents for boron neutron capture therapy.

J Control Release 2015 Sep 19;213:e39-40. Epub 2015 Aug 19.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China. Electronic address:

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http://dx.doi.org/10.1016/j.jconrel.2015.05.063DOI Listing
September 2015

Synthesis of the Hemoglobin-Conjugated Polymer Micelles by Thiol Michael Addition Reactions.

Macromol Biosci 2016 06 3;16(6):906-13. Epub 2016 Mar 3.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P. R. China.

Amphiphilic triblock copolymers mPEG-b-PMAC-b-PCL are synthesized using methoxyl poly(ethylene glycol), cyclic carbonic ester monomer including acryloyl group, and ε-caprolactone. Copolymers are self-assembled into core-shell micelles in aqueous solution. Thiolated hemoglobin (Hb) is conjugated with micelles sufficiently through thiol Michael addition reaction to form hemoglobin nanoparticles (HbNs) with 200 nm in diameter. The conjugation of Hb onto the micelle surface is further confirmed by X-ray photoelectron spectroscopy. Feeding ratio of copolymer micelles to Hb at 1:3 would lead to the highest hemoglobin loading efficiency 36.7 wt%. The UV results demonstrate that the gas transporting capacity of HbNs is well remained after Hb is conjugated with polymeric micelles. Furthermore, the obtained HbNs have no obvious detrimental effects on blood components in vitro. This system may thus have great potential as one of the candidates to be developed as oxygen carriers and provide a reference for the modification of protein drugs.
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http://dx.doi.org/10.1002/mabi.201500460DOI Listing
June 2016

Doxorubicin-Loaded Carborane-Conjugated Polymeric Nanoparticles as Delivery System for Combination Cancer Therapy.

Biomacromolecules 2015 Dec 23;16(12):3980-8. Epub 2015 Nov 23.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , Changchun 130022, P. R. China.

Carborane-conjugated amphiphilic copolymer nanoparticles were designed to deliver anticancer drugs for the combination of chemotherapy and boron neutron capture therapy (BNCT). Poly(ethylene glycol)-b-poly(L-lactide-co-2-methyl-2(2-dicarba-closo-dodecarborane)propyloxycarbonyl-propyne carbonate) (PLMB) was synthesized via the versatile reaction between decaborane and side alkynyl groups, and self-assembled with doxorubicin (DOX) to form drug-loaded nanoparticles. These [email protected] nanoparticles could not only suppress the leakage of the boron compounds into the bloodstream due to the covalent bonds between carborane and polymer main chains, but also protect DOX from initial burst release at physiological conditions because of the dihydrogen bonds between DOX and carborane. It was demonstrated that [email protected] nanoparticles could selectively deliver boron atoms and DOX to the tumor site simultaneously in vivo. Under the combination of chemotherapy and BNCT, the highest tumor suppression efficiency without reduction of body weight was achieved. This polymeric nanoparticles delivery system could be very useful in future chemoradiotherapy to obtain improved therapeutic effect with reduced systemic toxicity.
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http://dx.doi.org/10.1021/acs.biomac.5b01311DOI Listing
December 2015

Overcoming tumor resistance to cisplatin through micelle-mediated combination chemotherapy.

Biomater Sci 2015 Jan 24;3(1):182-91. Epub 2014 Sep 24.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, PR China.

The main obstacles to cancer therapy are the inability to target cancer cells and the acquired drug resistance after a period of chemotherapy. Reduced drug uptake and DNA repair are the two main mechanisms involved in cisplatin resistance. In the present investigation, canthaplatin, a Pt(iv) pro-drug of cisplatin and a protein phosphatase 2A (PP2A) inhibitor (4-(3-carboxy-7-oxa-bicyclo[2.2.1]heptane-2-carbonyl)piperazine-1-carboxylic acid tert-butyl ester), was designed and delivered using PEG-b-PLGA micelles for combination chemotherapy. Polymer/canthaplatin micelles facilitated the delivery of the drug into cancer cells through endocytosis and diminished DNA repair by PP2A inhibition, resulting in enhanced anti-tumor efficiency and excellent reversal ability of tumor resistance to cisplatin both in vitro and in vivo. Additionally, the polymer/canthaplatin micelles could prolong drug residence in the blood and decrease the side effects when compared to cisplatin.
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http://dx.doi.org/10.1039/c4bm00305eDOI Listing
January 2015

Protein-Resistant Biodegradable Amphiphilic Graft Copolymer Vesicles as Protein Carriers.

Macromol Biosci 2015 Sep 2;15(9):1304-13. Epub 2015 Jun 2.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, ChangChun, 130022, People's Republic of China.

The protein adsorption and self-assembly behavior of biocompatible graft copolymer, poly(lactide-co-diazidomethyl trimethylene carbonate)-g-poly(ethylene glycol) [P(LA-co-DAC)-g-PEG], were systematically studied. The graft copolymers showed enhanced resistance to non-specific protein adsorption compared with their block copolymer counterparts, indicative of the increased effect of PEG density beyond PEG length. Diverse nanostructures including vesicles can be assembled from the amphiphilic graft copolymers with well-defined nano-sizes. Hemoglobin (Hb), as a model protein, can be entrapped in the formed vesicles and keep the gas-binding capacity. The reduced release rate of Hb from graft copolymer vesicles indicated the relatively stable membrane packing compared with block copolymer counterpart.
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http://dx.doi.org/10.1002/mabi.201500096DOI Listing
September 2015

Asymmetric copolymer vesicles to serve as a hemoglobin vector for ischemia therapy.

Biomater Sci 2014 Sep 17;2(9):1254-1261. Epub 2014 Jun 17.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, P. R. China.

Self-aggregated vesicles have been considered to be promising candidates for hemoglobin-based oxygen carriers. Here, amphiphilic hetero-triblock copolymers are designed and synthesized with the capacity to self-assemble into polymer vesicles (polymersomes). Conceivably, vesicles are formed with asymmetric membranes, which achieve enhanced encapsulation efficiency of hemoglobin (Hb) beyond the diblock counterpart. Furthermore, hemoglobin-loaded vesicles (HbV) are fabricated with high Hb content and submicron particle sizes. The gas-binding capability, oxygen affinity and methemoglobin (metHb) level of the HbV dispersions are all comparable to the natural erythrocytes. In vitro HbV stability studies further reveal that the encapsulation of Hb within vesicles can greatly avoid the existence of free Hb and shows no interference with cells, especially for blood components. To evaluate the efficacy on ischemia reperfusion, HbV suspended in a plasma expander is transfused as a resuscitation fluid into an acute anemia rat model. Results demonstrate that the combined infusion of the plasma expander with HbV effectively ameliorates the lethal shock symptom and reduces short-term mortality. Concurrently, rats transfused with HbV are void of the acute tubular necrosis caused by the filtration of dissociated Hb dimers from glomeruli. We envision that the oxygen carriers derived from polymer self-assembly technology will become an alternative strategy for future development of blood substitutes.
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http://dx.doi.org/10.1039/c4bm00123kDOI Listing
September 2014

Preclinical pharmacology and toxicology study of Ad-hTERT-E1a-Apoptin, a novel dual cancer-specific oncolytic adenovirus.

Toxicol Appl Pharmacol 2014 Oct 20;280(2):362-9. Epub 2014 Aug 20.

Institute of Military Veterinary, Academy of Military Medical Sciences of PLA, Changchun 130122, PR China; The Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122, PR China. Electronic address:

Clinical studies have demonstrated that conditionally replicating adenovirus is safe. We constructed an oncolytic adenovirus, Ad-hTERT-E1a-Apoptin, using a cancer-specific promoter (human telomerase reverse transcriptase promoter, hTERTp) and a cancer cell-selective apoptosis-inducing gene (Apoptin). Ad-hTERT-E1a-Apoptin was proven effective both in vitro and in vivo in our previous study. In this study, the preclinical safety profiles of Ad-hTERT-E1a-Apoptin in animal models were investigated. At doses of 5.0×10(8), 2.5×10(9), and 1.25×10(10) viral particles (VP)/kg, Ad-hTERT-E1a-Apoptin had no adverse effects on mouse behavior, muscle cooperation, sedative effect, digestive system, and nervous systems, or on beagle cardiovascular and respiratory systems at 5.0×10(8), 2.5×10(9), and 1.25×10(10) VP/kg doses. In acute toxicity tests in mice, the maximum tolerated dose>5×10(10) VP/kg. There was no inflammation or ulceration at the injection sites within two weeks. In repeat-dose toxicological studies, the no observable adverse effect levels of Ad-hTERT-E1a-Apoptin in rats (1.25×10(10) VP/kg) and beagles (2.5×10(9) VP/kg) were 62.5- and 12.5-fold of the proposed clinical dose, respectively. The anti-virus antibody was produced in animal sera. Bone marrow examination revealed no histopathological changes. Guinea pigs sensitized by three repeated intraperitoneal injections of 1.35×10(10) VP/mL Ad-hTERT-E1a-Apoptin each and challenged by one intravenous injection of 1.67×10(8) VP/kg Ad-hTERT-E1a-Apoptin did not exhibit any sign of systemic anaphylaxis. Our data from different animal models suggest that Ad-hTERT-E1a-Apoptin is a safe anti-tumor therapeutic agent.
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http://dx.doi.org/10.1016/j.taap.2014.08.008DOI Listing
October 2014

Insight into the fabrication of polymeric particle based oxygen carriers.

Int J Pharm 2014 Jul 5;468(1-2):75-82. Epub 2014 Apr 5.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun 130022, China. Electronic address:

For the sake of protein stability and targeted application as blood substitutes, formulation customization of hemoglobin-loaded polymeric particles (HbP) was conducted via a double emulsion method. Screening of the emulsification parameters was firstly performed for the stability of Hb, and the structure and functions of recovered Hb could be well preserved via CD and UV-vis spectroscopy investigation. In the optimized conditions, Hb was loaded into the polymeric matrix formed of three material compositions. They were poly(ϵ-caprolactone)(PCL), poly(ethylene glycol)-block-poly(allyl glycidyl ether) (functionalized with mercaptopropionic acid)-block-poly(ϵ-caprolactone) (PEG-PAGE(MPA)-PCL), and the blend of the two polymers. The morphology, internal structure, in vitro leakage and hemocompatibility of the HbP products were characterized in detail, and the encapsulation mechanism was explored by the combined analysis of the encapsulation efficiency, non-specific protein adsorption and in vitro leakage studies. Results showed that the burst release effect found in homopolymers could be alleviated by use of block copolymers due to the reduced protein adsorption, and completely avoided by further cross-linking of particles through carbonyl-amino condensation reactions. The amphiphilic copolymers showed relatively high stability in blood and no interference with blood components compared with hydrophobic PCL. These results suggest that both the optimization of emulsion formation and material composition are prerequisite for stable formulations of Hb encapsulated in polymeric particles.
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http://dx.doi.org/10.1016/j.ijpharm.2014.04.004DOI Listing
July 2014

Generation of an attenuated Tiantan vaccinia virus by deletion of the ribonucleotide reductase large subunit.

Arch Virol 2014 Sep 28;159(9):2223-31. Epub 2014 Mar 28.

Institute of Military Veterinary Medicine, Academy of Military Medical Sciences of PLA, Jilin, People's Republic of China,

Attenuation of the virulence of vaccinia Tiantan virus (VTT) underlies the strategy adopted for mass vaccination campaigns. This strategy provides advantages of safety and efficacy over traditional vaccines and is aimed at minimization of adverse health effects. In this study, a mutant form of the virus, MVTT was derived from VTT by deletion of the ribonucleotide reductase large subunit (R1) (TI4L). Compared to wild-type parental (VTT) and revertant (VTT-rev) viruses, virulence of the mutant MVTT was reduced by 100-fold based on body weight reduction and by 3,200-fold based on determination of the intracranial 50% lethal infectious dose. However, the immunogenicity of MVTT was equivalent to that of the parental VTT. We also demonstrated that the TI4L gene is not required for efficient replication. These data support the conclusion that MVTT can be used as a replicating virus vector or as a platform for the development of vaccines against infectious diseases and for cancer therapy.
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http://dx.doi.org/10.1007/s00705-014-2057-8DOI Listing
September 2014

Injectable and biodegradable supramolecular hydrogels formed by nucleobase-terminated poly(ethylene oxide)s and α-cyclodextrin.

J Mater Chem B 2014 Feb 12;2(6):659-667. Epub 2013 Dec 12.

State Key Laboratory of Polymer Physics and Chemistry, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, Changchun, 130022, P.R. China.

Injectable and biodegradable supramolecular hydrogels were prepared by nucleobase (adenine/thymine)-terminated poly(ethylene oxide)s (A-PEG-A/T-PEG-T) and α-cyclodextrin (α-CD). The supramolecular hydrogels were thoroughly characterized by WXRD, rheometer, and SEM. The gelation time depended on the molecular weight of PEG and the concentration of polymer precursors. The rheological studies showed enhanced elastic modulus (G') of hydrogels, because of the hydrogen-bonding between A and T acting as additional network junctions. In vitro evaluation showed that the supramolecular hydrogels have acceptable biocompatibility, and are suitable for sustained and controlled release of loaded antitumor drugs. Gel formation was also confirmed when the supramolecular hydrogels were subcutaneously injected into rats. In addition, in vivo experiments employing U14 cancer cell xenograft-bearing mice showed that the intratumoral injection of a DOX-loaded A-PEG-A/T-PEG-T/α-CD gel inhibited tumor growth more effectively than that of free DOX, DOX-loaded PEG/α-CD gel, saline or gel alone. Hence, such a simple and convenient anti-cancer drug delivery system of a A-PEG-A/T-PEG-T/α-CD supramolecular hydrogel would be a promising candidate for many biomedical applications, especially in the area of the chemotherapy of solid tumors.
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http://dx.doi.org/10.1039/c3tb21475cDOI Listing
February 2014

Characterization of an attenuated TE3L-deficient vaccinia virus Tian Tan strain.

Antiviral Res 2012 Dec 17;96(3):324-32. Epub 2012 Oct 17.

Institute of Military Veterinary Medicine, Academy of Military Medical Sciences of PLA, Key Laboratory of Jilin Province for Zoonosis Prevention and Control, Changchun 130122, PR China.

An attenuated vaccinia virus (VACV), TE3L(-)VTT, was evaluated for virulence and safety to determine its potential use as a vaccine or as a recombinant virus vector to express foreign genes. The virulence of TE3L(-)VTT was compared with that of the wild-type VTT both in vivo and in vitro. The humoral and cellular immune responses were detected in a mouse model to test the vaccine efficacy of the TE3L mutant. The results suggested that deletion of the TE3L gene decreased the virulence and neurovirulence significantly in mice and rabbit models, yet retained the immunogenicity. Thus, the deletion of TE3L improved the safety of the VTT vector; this approach may yield a valuable resource for studies of recombinant VACV-vectored vaccines.
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http://dx.doi.org/10.1016/j.antiviral.2012.10.002DOI Listing
December 2012

Attenuation of vaccinia Tian Tan strain by removal of viral TC7L-TK2L and TA35R genes.

PLoS One 2012 21;7(2):e31979. Epub 2012 Feb 21.

College of Animal Science and Veterinary Medicine, Jilin University, Jilin, People's Republic of China.

Vaccinia Tian Tan (VTT) was attenuated by deletion of the TC7L-TK2L and TA35R genes to generate MVTT3. The mutant was generated by replacing the open reading frames by a gene encoding enhanced green fluorescent protein (EGFP) flanked by loxP sites. Viruses expressing EGFP were then screened for and purified by serial plaque formation. In a second step the marker EGFP gene was removed by transfecting cells with a plasmid encoding cre recombinase and selecting for viruses that had lost the EGFP phenotype. The MVTT3 mutant was shown to be avirulent and immunogenic. These results support the conclusion that TC7L-TK2L and TA35R deletion mutants can be used as safe viral vectors or as platform for vaccines.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0031979PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3283712PMC
June 2012