Publications by authors named "Maling Gou"

98 Publications

Cancer Therapy with Nanoparticle-Medicated Intracellular Expression of Peptide CRM1-Inhibitor.

Int J Nanomedicine 2021 14;16:2833-2847. Epub 2021 Apr 14.

Department of Pathology and State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, and Collaborative Innovation Centre for Biotherapy, Chengdu, 610041, People's Republic of China.

Introduction: Peptides can be rationally designed as non-covalent inhibitors for molecularly targeted therapy. However, it remains challenging to efficiently deliver the peptides into the targeted cells, which often severely affects their therapeutic efficiency.

Methods: Herein, we created a novel non-covalent peptide inhibitor against nuclear export factor CRM1 by a structure-guided drug design method and targetedly delivered the peptide into cancer cells by a nanoparticle-mediated gene expression system for use as a cancer therapy.

Results: The nuclear export signal (NES)-optimized CRM1 peptide inhibitor colocalized with CRM1 to the nuclear envelope and inhibited nuclear export in cancer cell lines in vitro. The crystal structures of the inhibitors complexed with CRM1 were solved. In contrast to the covalent inhibitors, the peptides were similarly effective against cells harboring the CRM1 C528S mutation. Moreover, a plasmid encoding the peptides was delivered by a iRGD-modified nanoparticle to efficiently target and transfect the cancer cells in vivo after intravenous administration. The peptides could be selectively expressed in the tumor, resulting in the efficient inhibition of subcutaneous melanoma xenografts without obvious systemic toxicity.

Discussion: This work provides an effective strategy to design peptide-based molecularly targeted therapeutics, which could lead to the development of future targeted therapy.
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http://dx.doi.org/10.2147/IJN.S266398DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054660PMC
May 2021

Publisher Correction: A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity.

Nature 2021 Feb;590(7844):E23

Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

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http://dx.doi.org/10.1038/s41586-020-03108-4DOI Listing
February 2021

A 3D-Printed Self-Adhesive Bandage with Drug Release for Peripheral Nerve Repair.

Adv Sci (Weinh) 2020 Dec 19;7(23):2002601. Epub 2020 Oct 19.

State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University Chengdu Sichuan 610041 P. R. China.

Peripheral nerve injury is a common disease that often causes disability and challenges surgeons. Drug-releasable biomaterials provide a reliable tool to regulate the nerve healing-associated microenvironment for nerve repair. Here, a self-adhesive bandage is designed that can form a wrap surrounding the injured nerve to promote nerve regeneration and recovery. Via a 3D printing technique, the bandage is prepared with a special structure and made up of two different hydrogel layers that can adhere to each other by a click reaction. The nanodrug is encapsulated in one layer with a grating structure. Wrapping the injured nerve, the grating layer of the bandage is closed to the injured site. The drug can be mainly released to the inner area of the wrap to promote the nerve repair by improving the proliferation and migration of Schwann cells. In this study, the bandage is used to assist the neurorrhaphy for the treatment of complete sciatic nerve transection without obvious defect in rats. Results indicate that the self-adhesive capacity can simplify the installation process and the drug-loaded bandage can promote the repairing of injured nerves. The demonstrated 3D-printed self-adhesive bandage has potential application in assisting the neurorrhaphy for nerve repair.
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http://dx.doi.org/10.1002/advs.202002601DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7709979PMC
December 2020

3D printed titanium scaffolds with homogeneous diamond-like structures mimicking that of the osteocyte microenvironment and its bone regeneration study.

Biofabrication 2020 Oct 12. Epub 2020 Oct 12.

Department of Physics, Sichuan University, Chengdu, CHINA.

Biofabrication of personalized titanium scaffold mimicking that of the osteocyte microenvironment is challenging due to its complex geometrical cues. The effect of scaffolds geometrical cues and implantation sites on osteogenesis is still not clear. In this study, personalized titanium scaffolds with homogeneous diamond-like structures mimicking that of the osteocyte microenvironment were precisely designed and fabricated by selected laser melting method. The effects of different geometric cues, including porosity, pore sizes and interconnection properties, on cellular behavior were investigated. Biomimetic mechanical properties of porous titanium alloy scaffold were predesigned and simulated by finite element analysis. In vitro experiment revealed that homogeneous diamond-like structures mimicking that of the osteocyte microenvironment triggered osteocyte adhesion and migration behavior. Typical implantation sites, including rabbit femur, beagle femur, and beagle skull, were used to study the implantation sites effects on bone regeneration. In vivo experimental results indicated that different implantation sites showed significant differences. This study helps to understand the scaffolds geometrical microenvironment and implantation sites effects on osteogenesis mechanism. And it is beneficial to the development of bone implants with better bone regeneration ability.
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http://dx.doi.org/10.1088/1758-5090/abc060DOI Listing
October 2020

Digital Light Processing Based Three-dimensional Printing for Medical Applications.

Int J Bioprint 2020 28;6(1):242. Epub 2019 Nov 28.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, Sichuan 610065, China.

An additive manufacturing technology based on projection light, digital light processing (DLP), three-dimensional (3D) printing, has been widely applied in the field of medical products production and development. The precision projection light, reflected by a digital micromirror device of million pixels instead of one focused point, provides this technology both printing accuracy and printing speed. In particular, this printing technology provides a relatively mild condition to cells due to its non-direct contact. This review introduces the DLP-based 3D printing technology and its applications in medicine, including precise medical devices, functionalized artificial tissues, and specific drug delivery systems. The products are particularly discussed for their significance in medicine. This review indicates that the DLP-based 3D printing technology provides a potential tool for biological research and clinical medicine. While, it is faced to the challenges of scale-up of its usage and waiting period of regulatory approval.
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http://dx.doi.org/10.18063/ijb.v6i1.242DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7415858PMC
November 2019

A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity.

Nature 2020 10 29;586(7830):572-577. Epub 2020 Jul 29.

Key Laboratory of Human Disease Comparative Medicine, Chinese Ministry of Health, Beijing Key Laboratory for Animal Models of Emerging and Remerging Infectious Diseases, Institute of Laboratory Animal Science, Chinese Academy of Medical Sciences and Comparative Medicine Center, Peking Union Medical College, Beijing, China.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes a respiratory disease called coronavirus disease 2019 (COVID-19), the spread of which has led to a pandemic. An effective preventive vaccine against this virus is urgently needed. As an essential step during infection, SARS-CoV-2 uses the receptor-binding domain (RBD) of the spike protein to engage with the receptor angiotensin-converting enzyme 2 (ACE2) on host cells. Here we show that a recombinant vaccine that comprises residues 319-545 of the RBD of the spike protein induces a potent functional antibody response in immunized mice, rabbits and non-human primates (Macaca mulatta) as early as 7 or 14 days after the injection of a single vaccine dose. The sera from the immunized animals blocked the binding of the RBD to ACE2, which is expressed on the cell surface, and neutralized infection with a SARS-CoV-2 pseudovirus and live SARS-CoV-2 in vitro. Notably, vaccination also provided protection in non-human primates to an in vivo challenge with SARS-CoV-2. We found increased levels of RBD-specific antibodies in the sera of patients with COVID-19. We show that several immune pathways and CD4 T lymphocytes are involved in the induction of the vaccine antibody response. Our findings highlight the importance of the RBD domain in the design of SARS-CoV-2 vaccines and provide a rationale for the development of a protective vaccine through the induction of antibodies against the RBD domain.
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http://dx.doi.org/10.1038/s41586-020-2599-8DOI Listing
October 2020

Noninvasive in vivo 3D bioprinting.

Sci Adv 2020 Jun 5;6(23):eaba7406. Epub 2020 Jun 5.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, P. R. China.

Three-dimensional (3D) printing technology has great potential in advancing clinical medicine. Currently, the in vivo application strategies for 3D-printed macroscale products are limited to surgical implantation or in situ 3D printing at the exposed trauma, both requiring exposure of the application site. Here, we show a digital near-infrared (NIR) photopolymerization (DNP)-based 3D printing technology that enables the noninvasive in vivo 3D bioprinting of tissue constructs. In this technology, the NIR is modulated into customized pattern by a digital micromirror device, and dynamically projected for spatially inducing the polymerization of monomer solutions. By ex vivo irradiation with the patterned NIR, the subcutaneously injected bioink can be noninvasively printed into customized tissue constructs in situ. Without surgery implantation, a personalized ear-like tissue constructs with chondrification and a muscle tissue repairable cell-laden conformal scaffold were obtained in vivo. This work provides a proof of concept of noninvasive in vivo 3D bioprinting.
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http://dx.doi.org/10.1126/sciadv.aba7406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7269646PMC
June 2020

Modulating physical, chemical, and biological properties in 3D printing for tissue engineering applications.

Appl Phys Rev 2018 Dec;5(4)

Department of NanoEngineering, University of California San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.

Over the years, 3D printing technologies have transformed the field of tissue engineering and regenerative medicine by providing a tool that enables unprecedented flexibility, speed, control, and precision over conventional manufacturing methods. As a result, there has been a growing body of research focused on the development of complex biomimetic tissues and organs produced via 3D printing to serve in various applications ranging from models for drug development to translational research and biological studies. With the eventual goal to produce functional tissues, an important feature in 3D printing is the ability to tune and modulate the microenvironment to better mimic conditions to improve tissue maturation and performance. This paper reviews various strategies and techniques employed in 3D printing from the perspective of achieving control over physical, chemical, and biological properties to provide a conducive microenvironment for the development of physiologically relevant tissues. We will also highlight the current limitations associated with attaining each of these properties in addition to introducing challenges that need to be addressed for advancing future 3D printing approaches.
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http://dx.doi.org/10.1063/1.5050245DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6959479PMC
December 2018

3D-engineered GelMA conduit filled with ECM promotes regeneration of peripheral nerve.

J Biomed Mater Res A 2020 03 16;108(3):805-813. Epub 2019 Dec 16.

StemEasy Biotech, Jiangyin, China.

Autologous transplantation remains the golden standard for peripheral nerve repair. However, many drawbacks, such as the risk of reoperation or nerve injury remain associated with this method. To date, commercially available artificial nerve conduits comprise hollow tubes. By providing physical guiding and biological cues, tissue engineered conduits are promising for bridging peripheral nerve defects. The present study focuses on the preparation of artificial composite nerve conduits by 3D bio-printing. 3D-printed molds with a tubular cavity were filled with an Engelbreth-Holm-Swarm (EHS) Hydrogel mimicking the extracellular matrix (ECM) basement membrane. Chemically cross-linked gelatin methacryloyl (GelMA) was used to form the conduit backbone, while EHS Hydrogels improved nerve fiber growth while shortening repair time. Statistical significant difference had been found between the blank conduit and the composite conduit group on compound muscle action potential after 4 months. On the other hand, results between the composite conduit group and the autograft group were of no statistical differences. All results above showed that the composite conduit filled with EHS Hydrogel can promote the repair of peripheral nerve and may become a promising way to treat peripheral nerve defects.
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http://dx.doi.org/10.1002/jbm.a.36859DOI Listing
March 2020

RGD-Modified Nanocarrier-Mediated Targeted Delivery of Plasmid DNA to Cerebrovascular Endothelial Cells for Ischemic Stroke Treatment.

ACS Biomater Sci Eng 2019 Nov 29;5(11):6254-6264. Epub 2019 Oct 29.

Scientific Research Center and Department of Orthopedic, The Seventh Affiliated Hospital, Sun Yat-Sen University, Shenzhen 518107, China.

Studies have shown that the use of proangiogenic genes can improve the prognosis of ischemic stroke by promoting angiogenesis at the injury site. For example, within this study, hypoxia-inducible factor 1-α (HIF-1α) has exhibited an angiogenic effect. Our previous study reported a more stable HIF-1α mutant form (HIF-1α-AA), which was transfected into mesenchymal stem cells to provide neuroprotective effects against ischemic stroke. The safety of nonviral gene vectors has attracted researchers' attention. This study encapsulated the HIF-1α-AA plasmid DNA into a newly synthesized effective nonviral gene vector, a hyperbranched cationic amylopectin derivative (DMAPA-Amyp) nanocarrier. In addition, a targeting strategy was applied to select the RGD peptides and bind to the designed nanocarrier as a molecule targeting endothelial cells. The targeting strategy is used to directly deliver the nanocarriers to the vascular endothelial cells of the brain peri-infarct site. This study emphasizes the targeting ability of nanocarrier and its therapeutic effect on cerebral ischemia. The results showed that RGD-DMAPA-Amyp had good biocompatibility and a high cell uptake rate, indicating that it is a safe nonviral gene vector that can be endocytosed by human cells. In rat models of ischemic stroke, compared with the nontargeted nanocarrier group, more RGD-DMAPA-Amyp nanoparticles aggregated in vascular endothelial cells of the peri-infarct region and significantly improved the recovery of neurological function. It is indicated that the RGD-modified nanomedicine promotes the recovery of nerve function more efficiently. Further study on the mechanism of RGD-DMAPA-Amyp/HIF-1α-AA in the treatment of cerebral ischemia displayed potential to significantly promote the formation of new blood vessels in vivo. Our findings suggest that the RGD-modified nonviral gene vector containing HIF-1α-AA appears to be a safe and promising therapeutic strategy for ischemic stroke gene therapy.
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http://dx.doi.org/10.1021/acsbiomaterials.9b01362DOI Listing
November 2019

Light-activated drug release from prodrug nanoassemblies by structure destruction.

Chem Commun (Camb) 2019 Oct;55(87):13128-13131

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.

We report here a novel light-triggered nanosystem based on co-assembling nanoaggregates (NAs) of lipophilic photosensitizers and lipophilic prodrugs containing multiple thioethers. Upon laser irradiation, the oxidization of the multiple thioethers by photosensitizer-generated singlet oxygen could rapidly destroy the NA structure, resulting in faster drug release than those containing a single thioether.
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http://dx.doi.org/10.1039/c9cc06673jDOI Listing
October 2019

Improving Mechanical Properties for Extrusion-Based Additive Manufacturing of Poly(Lactic Acid) by Annealing and Blending with Poly(3-Hydroxybutyrate).

Polymers (Basel) 2019 Sep 19;11(9). Epub 2019 Sep 19.

Centre for Polymer and Material Technologies (CPMT), Department of Materials, Textiles and Chemical Engineering, Ghent University, 9052 Zwijnaarde, Belgium.

Based on differential scanning calorimetry (DSC), X-ray diffraction (XRD) analysis, polarizing microscope (POM), and scanning electron microscopy (SEM) analysis, strategies to close the gap on applying conventional processing optimizations for the field of 3D printing and to specifically increase the mechanical performance of extrusion-based additive manufacturing of poly(lactic acid) (PLA) filaments by annealing and/or blending with poly(3-hydroxybutyrate) (PHB) were reported. For filament printing at 210 °C, the PLA crystallinity increased significantly upon annealing. Specifically, for 2 h of annealing at 100 °C, the fracture surface became sufficiently coarse such that the PLA notched impact strength increased significantly (15 kJ m). The Vicat softening temperature (VST) increased to 160 °C, starting from an annealing time of 0.5 h. Similar increases in VST were obtained by blending with PHB (20 wt.%) at a lower printing temperature of 190 °C due to crystallization control. For the blend, the strain at break increased due to the presence of a second phase, with annealing only relevant for enhancing the modulus.
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http://dx.doi.org/10.3390/polym11091529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780387PMC
September 2019

Modular Engineering of Targeted Dual-Drug Nanoassemblies for Cancer Chemoimmunotherapy.

ACS Appl Mater Interfaces 2019 Oct 24;11(40):36371-36382. Epub 2019 Sep 24.

Department of Biomedical Engineering , Southern University of Science and Technology , Shenzhen , Guangdong , 518055 P. R. China.

Combination of chemotherapeutics and immunomodulators can generate synergistic anticancer efficacy, exerting efficient chemoimmunotherapy for cancer treatment. Nanoparticulate delivery systems hold great promise to promote synergistic anticancer efficacy for the codelivery of drugs. However, there remain challenges to precisely coencapsulate and deliver combinational drugs at designed ratios due to the difference of compatibility between drugs and nanocarriers. In this study, coassembled nanoparticles of lipophilic prodrugs (LPs) were designed to codeliver chemotherapeutics and immunomodulators for cancer treatment. Such nanoassemblies (NAs) could act as platforms to ratiometrically coencapsulate chemotherapeutics and immunomodulators. Based on this method, NAs formed by the self-assembly of iRGD peptide derivatives, paclitaxel (PTX) LPs, and imiquimod (R837) LPs were demonstrated to target the tumor at unified pharmacokinetics, further inducing the effective tumor inhibition and tumor recurrence prevention. This work provided an alternative to prepare chemoimmunotherapeutic NAs with advantages of ratiometric drug coencapsulation and unified pharmacokinetics, which may advance the future cancer chemoimmunotherapy.
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http://dx.doi.org/10.1021/acsami.9b11881DOI Listing
October 2019

Kinetic stability-driven cytotoxicity of small-molecule prodrug nanoassemblies.

J Mater Chem B 2019 09;7(36):5563-5572

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.

Nanoassemblies (NAs) of small-molecule lipophilic prodrugs have been widely investigated for efficient drug delivery in cancer therapy, but their kinetic stability has not attracted sufficient attention in the past studies. Herein, we reported that kinetic stability has a great influence on the drug release from the NAs of lipophilic prodrugs in physiologically relevant media. Based on the co-assembled FRET nanosystems of two lipophilic fluorescent prodrugs, we demonstrated that NAs constructed by lipophilic prodrugs containing shorter alkyl chains or those with higher unsaturated degrees displayed poorer kinetic stability, which further resulted in remarkably faster drug release in mouse plasma and various tissue homogenates. More importantly, these kinetically unstable NAs also induced rapid intracellular drug release, resulting in much more potent cytotoxicity. These findings highlight the crucial role of kinetic stability in determining the drug release from the NAs of lipophilic prodrugs, which would effectively guide their rational designs for cancer therapy.
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http://dx.doi.org/10.1039/c9tb01270bDOI Listing
September 2019

An Injectable, Near-Infrared Light-Responsive Click Cross-Linked Azobenzene Hydrogel for Breast Cancer Chemotherapy.

J Biomed Nanotechnol 2019 Sep;15(9):1923-1936

Injectable hydrogels possess huge potential as localized drug carriers in breast cancer chemotherapy, owing to several advantages, including easy target administration, enhanced therapeutic efficiency, and less systemic side effects. Herein, we describe an injectable, near-infrared (NIR) light-responsive click cross-linked azobenzene hydrogel (AzoGel) that displays NIR irradiation-mediated smart drug release. The hydrogel can be formed via click cross-linking by mixing two kinds of gelatin derivatives functioned with dibenzylcyclooctyne (DBCO) and azidated azobenzene (N₃-Azo) respectively. The polyacrylic acid (PAA)-coated upconversion nanoparticles ([email protected])-encapsulated AzoGel has NIR light-responsive characteristics owing to the photoisomerization of azobenzene in the networks. The amount of an anticancer drug doxorubicin (DOX), released from the hydrogel can be efficiently controlled by tuning the exposure time and intensity of 980 nm NIR light. Results of the study using DOX and [email protected] AzoGel controlled by NIR light in the 4T1 breast cancer xenograft mouse model demonstrated an enhanced anti-cancer effect. To conclude, the injectable, NIR light-responsive, click cross-linked AzoGel exhibits a high potential as a localized drug delivery platform for cancer therapy.
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http://dx.doi.org/10.1166/jbn.2019.2821DOI Listing
September 2019

Targeted nanoparticle-mediated LHPP for melanoma treatment.

Int J Nanomedicine 2019 10;14:3455-3468. Epub 2019 May 10.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.

Phospholysine phosphohistidine inorganic pyrophosphate phosphatase (LHPP) is a novel tumor suppressor. However, whether LHPP is effective to melanoma has not been investigated. Gene therapy provides a new strategy for the treatment of melanoma. Currently, it suffers from the lack of safe and effective gene delivery systems. A CRGDKGPDC peptide (iRGD) modified hybrid monomethoxy poly(ethylene glycol)-poly(D,L-lactide) nanoparticle (iDPP) was prepared and complexed with a plasmid, forming an iDPP/ nanocomplex. The iDPP/ nanocomplex was characterized by particle size distribution, zeta potential, morphology, cytotoxicity, and transfection efficiency. The antitumor efficacy of the nanocomplex against melanoma was studied both in vitro and in vivo. Further, the potential epigenetic changes in melanoma induced by iDPP/ nanocomplex were evaluated. The iDPP/ nanocomplex showed high transfection efficiency and low toxicity. Moreover, the nanocomplex displayed a neutral charge that can meet the requirement of intravenous injection for targeted gene therapy. In vitro and in vivo experiments indicated that the iDPP/ nanocomplex significantly inhibited the melanoma growth without causing notable adverse effects. We also found that played an important role in epigenetics. It regulated the expression of genes related to the proliferation and apoptosis chiefly at the level of transcription. This work demonstrates that the iDPP nanoparticle-delivered gene has a potential application in melanoma therapy through regulation of the genes associated with epigenetics.
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http://dx.doi.org/10.2147/IJN.S196374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6516749PMC
August 2019

An evaluation of the wound healing potential of tetrahydrocurcumin-loaded MPEG-PLA nanoparticles.

J Biomater Appl 2019 09 19;34(3):315-325. Epub 2019 May 19.

1 Department of Plastic and Burns Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, China.

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http://dx.doi.org/10.1177/0885328219851195DOI Listing
September 2019

Rapid 3D printing of functional nanoparticle-enhanced conduits for effective nerve repair.

Acta Biomater 2019 05 28;90:49-59. Epub 2019 Mar 28.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy, Chengdu, Sichuan 610065, China.

Nerve conduits provide an advanced tool for repairing the injured peripheral nerve that often causes disability and mortality. Currently, the efficiency of conduits in repairing peripheral nerve is unsatisfying. Here, we show a functional nanoparticle-enhanced nerve conduit for promoting the regeneration of peripheral nerves. This conduit, which consists of gelatin-methacryloyl (GelMA) hydrogels with drug loaded poly(ethylene glycol)- poly(3-caprolactone) (MPEG-PCL) nanoparticles dispersed in the hydrogel matrix, is rapidly fabricated by a continuous three-dimensional (3D) printing process. While the 3D-printed hydrogel conduit with customized size, shape and structure provides a physical microenvironment for axonal elongation, the nanoparticles sustained release the drug to facilitate the nerve regeneration. The drug, 4-((5,10-dimethyl-6-oxo-6,10-dihydro-5H-pyrimido[5,4-b]thieno[3,2-e][1,4]diazepin-2-yl)amino) benzenesulfonamide, is a Hippo pathway inhibitor with multiple functions including improving the proliferation and migration of Schwann cells and up-regulating neurotrophic factors genes. The descried functional nerve conduit efficiently induced the recovery of sciatic injuries in morphology, histopathology and functions in vivo, showing the potential clinical application in peripheral nerve repair. STATEMENTS OF SIGNIFICANCE: Functional nerve conduit provides a promising strategy alternative to autografts. In this work, we rapidly customized a nanoparticle-enhanced conduit by the continuous bioprinting process. This nanoparticle in the conduit can release a Hippo pathway inhibitor to facilitate the nerve regeneration and function restoration. The efficacy of the conduits is comparable to that of autograft, suggesting the potential clinical applications.
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http://dx.doi.org/10.1016/j.actbio.2019.03.047DOI Listing
May 2019

3D Printing Enabled Customization of Functional Microgels.

ACS Appl Mater Interfaces 2019 Apr 25;11(13):12209-12215. Epub 2019 Mar 25.

Scientific Research Center , The Seventh Affiliated Hospital of Sun Yat-sen University , Shenzhen 518107 , Guangdong , P. R. China.

Injectable microgels show great promising applications in cell therapy and drug delivery. Currently, there remains a challenge to rapidly and cost-effectively fabricate customized microgels. Here, we present a digital light processing based three-dimensional (3D) printing process to fabricate microgels with tailored shapes and sizes. The microgels are constructed by the digital light controlled polymerization of photopolymerizable monomer solution within 2 s. By mixing nanoparticle-encapsulated drugs into the monomer solution, the microgels with sustained drug release can be readily prepared. Also, cells can be printed into microgels with survival and proliferation. In conclusion, this study provides a 3D printing process for customizing functional microgels containing drugs or cells with potential therapeutic applications.
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http://dx.doi.org/10.1021/acsami.8b18701DOI Listing
April 2019

Prognostic role of early D-dimer level in patients with acute ischemic stroke.

PLoS One 2019 1;14(2):e0211458. Epub 2019 Feb 1.

Department of Neurosurgery and National Clinical Research Center for Geriatrics, West China Hospital, Sichuan University, Chengdu, Sichuan, PR China.

Object: The purpose of our study was to assess the prognostic role of early D-dimer level in patients with acute ischemic stroke (AIS).

Methods: The included patients' D-dimer levels have to be tested within 24 hours from stroke onset. Poor functional outcome was defined as modified Rankin Scale (mRS) ≥3. The endpoints included recurrence on 5-day diffusion-weighted imaging, 30-day mRS ≥3, 30-day mortality and 90-day mRS ≥3. Regarding to each endpoint, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to assess the prognostic role of D-dimer in patients with AIS.

Results: A total of 2,479 patients were included. The results showed that elevated D-dimer levels were associated with recurrence on 5-day diffusion-weighted imaging (OR = 2.28, 95% CI = 1.32-3.95), 30-day mRS≥3 (OR = 1.59, 95% CI = 1.37-1.85), 30-day mortality (OR = 1.92, 95% CI = 1.27-2.90) and 90-day mRS≥3 (OR = 1.61, 95% CI = 1.05-2.46).

Conclusions: In conclusion, for patients with AIS, higher D-dimer level within 24 hours from stroke onset was associated with recurrence on 5-day diffusion-weighted imaging, mortality at 30 days, and poor functional outcome at both 30 days and 90 days. However, more studies are warranted to clarify this issue.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211458PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6358072PMC
November 2019

Self-Assembled Nanoparticle Mediated for Ovarian Cancer Therapy.

J Biomed Nanotechnol 2018 Dec;14(12):2092-2101

Gene therapy is emerging as a promising tool for cancer treatment. Down-regulation of gene can lead to the cancer inhibition. However, the lack of efficient and safe gene delivery system is still a critical obstacle to clinical gene therapy. In this study, we use a biodegradable nanoparticle to deliver human () to dominant-negatively regulate gene for ovarian cancer therapy. This nanoparticle, self-assembled from monomethoxy poly(ethylene glycol)-poly(D,L-lactide) (MPEG-PLA) copolymer and -[1-(2,3-dioleoyloxy) propyl]-,,-trimethylammonium chloride (DOTAP), has high transfection capability and negligible cytotoxicity. The nanoparticle-delivered gene can efficiently inhibit the growth of SKOV3 ovarian cancer cells through induction of apoptosis . After intraperitoneal injection, the nanoparticle-delivered gene significantly inhibited the growth of intraperitoneal metastasis of SKOV3 ovarian cancer, with no obvious adverse effects. Our data suggest that the nanoparticle-delivered gene has promising clinical applications in ovarian cancer treatment.
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http://dx.doi.org/10.1166/jbn.2018.2641DOI Listing
December 2018

Co-assembling FRET nanomedicine with self-indicating drug release.

Chem Commun (Camb) 2018 Oct;54(82):11618-11621

Department of Biotherapy, State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, 610041, China.

Two lipophilic fluorescent prodrugs co-assembled into nanoaggregates with the ability to release FRET-indicated drugs, which was used to investigate the role of reduction-responsive linkers on drug release kinetics in the cytoplasm and physiologically relevant media in a visualized, noninvasive manner.
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http://dx.doi.org/10.1039/c8cc06792aDOI Listing
October 2018

3D bioprinting of functional tissue models for personalized drug screening and in vitro disease modeling.

Adv Drug Deliv Rev 2018 07 21;132:235-251. Epub 2018 Jun 21.

Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Materials Science and Engineering Program, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; Department of NanoEngineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093, USA; State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University and Collaborative Innovation Center of Biotherapy, Chengdu, PR China. Electronic address:

3D bioprinting is emerging as a promising technology for fabricating complex tissue constructs with tailored biological components and mechanical properties. Recent advances have enabled scientists to precisely position materials and cells to build functional tissue models for in vitro drug screening and disease modeling. This review presents state-of-the-art 3D bioprinting techniques and discusses the choice of cell source and biomaterials for building functional tissue models that can be used for personalized drug screening and disease modeling. In particular, we focus on 3D-bioprinted liver models, cardiac tissues, vascularized constructs, and cancer models for their promising applications in medical research, drug discovery, toxicology, and other pre-clinical studies.
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http://dx.doi.org/10.1016/j.addr.2018.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6226327PMC
July 2018

A biomimetic nanoparticle-enabled toxoid vaccine against melittin.

Int J Nanomedicine 2018 1;13:3251-3261. Epub 2018 Jun 1.

State Key Laboratory of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, People's Republic of China.

Background: Melittin, the main active peptide ingredient of bee venom, can cause severe cell membrane lysis due to its robust interaction with negatively charged phospholipids. So far, no effective anti-melittin vaccine has been developed to protect people from undesired melittin intoxication.

Methods: Herein, we prepared a polydiacetylene (PDA) nanoparticle with cell membrane-mimic surface to complex melittin, forming an anti-melittin vaccine (PDA-melittin).

Results: PDA nanoparticles could effectively combine with melittin and neutralize its toxicity. PDA-melittin nanocomplex is demonstrated to enhance melittin uptake by DCs and stimulate strong melittin-specific immunity. Mice immunized with PDA-melittin nanocomplex showed higher survival rate after exposion to melittin than untreated mice.

Conclusion: The PDA-melittin nanocomplex can efficiently and safely generate a specific immunity against melittin to protect body from melittin intoxication, providing a new method with potential clinical application for the treatment of melittin intoxication.
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http://dx.doi.org/10.2147/IJN.S156346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5987856PMC
July 2018

A Vesicular Stomatitis Virus-Inspired DNA Nanocomplex for Ovarian Cancer Therapy.

Adv Sci (Weinh) 2018 03 29;5(3):1700263. Epub 2017 Dec 29.

State Key Laboratory of Biotherapy and Cancer Center West China Hospital Sichuan University, and Collaborative Innovation Center for Biotherapy Chengdu 610041 P. R. China.

Gene therapy provides a novel method for cancer therapy. This study shows a DNA nanocomplex that is inspired from vesicular stomatitis virus (VSV) for ovarian cancer therapy. This DNA nanocomplex consists of a cationized monomethoxy poly (ethylene glycol)-poly (d,l-lactide) (MPEG-PLA) nanoparticle and a plasmid encoding the matrix protein of vesicular stomatitis virus (VSVMP) that plays a critical role in the VSV-induced apoptosis of cancer cells. The cationized MPEG-PLA nanoparticle that is self-assembled by MPEG-PLA copolymer and -[1-(2,3-dioleoyloxy) propyl]--trimethylammonium chloride (DOTAP) has low cytotoxicity and high transfection efficiency (>80%). Intraperitoneal administration of the p nanocomplex remarkably inhibits the intraperitoneal metastasis of ovarian cancer and does not cause significant systemic toxicity. The apoptosis induction and anti-angiogenesis are involved in the anticancer mechanism. This work demonstrates a VSV-inspired DNA nanocomplex that has potential application for the treatment of intraperitoneal metastasis of ovarian cancer.
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http://dx.doi.org/10.1002/advs.201700263DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5867128PMC
March 2018

Carbonate esters turn camptothecin-unsaturated fatty acid prodrugs into nanomedicines for cancer therapy.

Chem Commun (Camb) 2018 Feb;54(16):1996-1999

West China Medical School of Si Chuan University, Chengdu, China.

We report that carbonate esters could turn hydrophobic camptothecin (CPT)-unsaturated fatty acid prodrugs into nanoaggregates in aqueous solution. The active CPT could be rapidly released once triggered by a reductive stimulus when a carbonate ester was combined with a disulfide bond, resulting in a potent in vivo antitumor activity.
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http://dx.doi.org/10.1039/c8cc00639cDOI Listing
February 2018

Bioprinting of skin constructs for wound healing.

Burns Trauma 2018 23;6. Epub 2018 Jan 23.

1The Affiliated Hospital of Southwest Medical University, the department of Plastic & Burns Surgery, Tai Ping Street, Luzhou, 646000 People's Republic of China.

Extensive burns and full-thickness skin wounds are difficult to repair. Autologous split-thickness skin graft (ASSG) is still used as the gold standard in the clinic. However, the shortage of donor skin tissues is a serious problem. A potential solution to this problem is to fabricate skin constructs using biomaterial scaffolds with or without cells. Bioprinting is being applied to address the need for skin tissues suitable for transplantation, and can lead to the development of skin equivalents for wound healing therapy. Here, we summarize strategies of bioprinting and review current advances of bioprinting of skin constructs. There will be challenges on the way of 3D bioprinting for skin regeneration, but we still believe bioprinting will be potential skills for wounds healing in the foreseeable future.
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http://dx.doi.org/10.1186/s41038-017-0104-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5778803PMC
January 2018