Publications by authors named "Zhi-rong Zhang"

182 Publications

Extracorporeal membrane oxygenation treatment for high-risk pulmonary embolism with cardiac arrest in a young adult male.

World J Emerg Med 2021 ;12(4):324-326

Department of Intensive Care Unit, the First Affiliated Rehabilitation Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou 310023, China.

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http://dx.doi.org/10.5847/wjem.j.1920-8642.2021.04.013DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8390356PMC
January 2021

OX40L blockade cellular nanovesicles for autoimmune diseases therapy.

J Control Release 2021 Sep 8;337:557-570. Epub 2021 Aug 8.

College of Polymer Science and Engineering, Key Laboratory of Drug Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, 640041, china. Electronic address:

Current clinical agents for autoimmunity disorders treatment often cause substantial adverse effects and safety concerns, owing to non-specific immune modulation. Due to the prominent contribution of effector T cells in pathogenesis of rheumatoid arthritis (RA) and inflammatory bowel disease (IBD), and preferential location of co-stimulatory receptor-ligand pair OX40-OX40L at the inflamed sites, selectively targeting autoaggressive T cells by blockade OX40-OX40L, might represent an alternative strategy. Herein, we developed a new strategy to antagonize OX40-OX40L interaction by engineering a cell membrane derived nanovesicles (NVs) expressing OX40 receptors (OX40 NVs), and explored their potential for autoimmune disorders therapy. OX40 NVs showed specific binding capability to inflamed HUVECs in vitro, it also possessed distinct arthritic-targeting capacity in RA inflamed joints, and preferential accumulation in IBD inflamed colon. OX40 NVs efficiently suppressed the progression of both RA and IBD diseases through reducing CD4OX40 T cells population, and proinflammatory cytokines (i.e., TNF-α and IL-1β), while reinforcing Tregs immune-suppressive effect, with superior therapeutic efficacy than anti-OX40L. Additionally, dexamethasone (DEX) loading can further enhance the potential of OX40 NVs for RA treatment. Owing to their preferential localization to inflamed sites, and potent immune-suppression ability, targeting OX40-OX40L blockade by OX40 NVs for autoimmune therapy is highly promising.
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http://dx.doi.org/10.1016/j.jconrel.2021.08.008DOI Listing
September 2021

[Preparation and Characterization of Clopidogrel Bisulfate Liposomes].

Sichuan Da Xue Xue Bao Yi Xue Ban 2021 Jul;52(4):630-636

Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.

Objective: To prepare encapsulated clopidogrel bisulfate (CLP) liposomes so as to deal with the poor water solubility of CLP, and to provide the experimental basis for the development of CLP formulations for intravascular injection.

Methods: CLP-loaded liposomes were prepared using thin film hydration/sonication method and pH gradient active drug loading technology. Then, the morphology, particle size, encapsulation efficiency, drug loading capacity, Zeta potentials and release behavior were characterized. Bilateral renal arteries of Sprague-Dawley (SD) rats were clamped with micro-artery clamps to establish the model of renal ischemia-reperfusion injury (IRI) in male SD rats. The study aimed to preliminarily investigate the therapeutic effect of CLP-loaded liposome pretreatment on renal IRI in rats.

Results: It was found that the optimal formulation and preparation technology of CLP liposomes were as follows: the CLP-to-phospholipid weight ratio of 1∶10, phospholipid-to-cholesterol ratio of 6∶1, octadecylamine-to-CLP ratio of 1.2∶1, PEG -to-CLP ratio of 1∶1, and incubation at 50 ℃ for 40 min. Then, following ultrasonication of 100 W efficiency at 5-second intervals for 20 times, CLP loading was conducted using 5 mL of 0.1 mol/L citric acid buffer at pH 3.0. Liposome samples were prepared with the film dispersion method, and the pH value was adjusted to 7.5 through pH gradient active drug loading technology. The CLP-loaded liposomes obtained in this way had a rounded shape, good dispersity, an average particle size of (134.13±2.60) nm, polydispersity index (PDI) of 0.25±0.02, and a Zeta potential of (2.12±0.23) mV. The encapsulation efficiency was found to be (98.66±0.14)%, and the drug loading capacity was (7.47±0.01)%. The release results showed that 66.24% of CLP was released cumulatively within 72 h. Preliminary efficacy experiments showed that animals pretreated with CLP-loaded liposomes had lower serum levels of blood urea nitrogen and creatinine compared to the levels of IRI model rats without any pretreatment.

Conclusion: CLP-loaded liposomes were successfully prepared, which might provide the experimental foundation for the future development of CLP formulations for injection.
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http://dx.doi.org/10.12182/20210760102DOI Listing
July 2021

[Research Development in Transfersome-Based Drug Delivery System].

Sichuan Da Xue Xue Bao Yi Xue Ban 2021 Jul;52(4):543-547

Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.

The transformersome is a new kind of lipoid drug delivery carrier. It has a number of excellent properties, including deformability, pressure permeability, and amphiphilicity. It has been widely used in the field of percutaneous and oral administration of medication. However, due to factors concerning its formulation, the stability and effectiveness of intravenous injection and other systemic routes of administration of transfersomes should be carefully examined. As an alternative, the formulation can be enhanced or improved in order to better exploit the strengths and avoid the weaknesses. Because of its deformability, transfersome may have distinctive potential strengths in the penetration of physiological barriers, for example, the blood-brain barrier, and in the research and development of transdermal immunization vaccines. This review has summarized five aspects of transfersomes, including the main properties, the formulation and process influencing factors, evaluation methods, main administration routes, and problems. Herein, we have given some examples and analysis, summarized the research achievements and assessd prospects for future development.
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http://dx.doi.org/10.12182/20210760203DOI Listing
July 2021

[The Research Status and Future Direction of Pharmaceutical Sciences and Pharmaceutical Materials in China].

Authors:
Zhi-Rong Zhang

Sichuan Da Xue Xue Bao Yi Xue Ban 2021 Jul;52(4):539-542

Key Laboratory of Drug-Targeting and Drug Delivery System of the Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.

Pharmaceutical sciences and pharmaceutical materials are a discipline that studies drug dosage forms, formulation technology, and drug release patterns and mechanisms. This article briefly discusses the fundamental research and application of pharmaceutical sciences/pharmaceutical materials, summarizes the hot research topics of pharmaceutical sciences/pharmaceutical materials in China over the past 20 years, and analyzes the international status, achievements, and strengths and weaknesses of research in pharmaceutical sciences/pharmaceutical materials in China. Suggestions were made for frontier research directions that should be prioritized in the field of pharmaceutical sciences and pharmaceutical materials in the next decade in China, and potential breakthrough that may be achieved was discussed, which may provide the basis and references for future work in the relevant areas.
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http://dx.doi.org/10.12182/20210760208DOI Listing
July 2021

Extended-release of therapeutic microRNA via a host-guest supramolecular hydrogel to locally alleviate renal interstitial fibrosis.

Biomaterials 2021 08 27;275:120902. Epub 2021 May 27.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China. Electronic address:

Activated fibroblasts are critical contributors to renal interstitial fibrosis thus becoming the cellular target for fibrosis treatment. Previously, microRNA 29 b (miR-29 b) is shown to be down-regulated in various animal models of renal fibrosis. Herein, we describe a facile strategy to achieve localized and sustained delivery of therapeutic microRNA to the kidney via a host-guest supramolecular hydrogel. Specifically, cationic bovine serum albumin is used to complex with miR-29 b to afford nanocomplexes (cBSA/miR-29 b), which is proven to specifically inhibit fibroblast activation in a dose-dependent manner in vitro. Following unilateral ureteral obstruction in mice, a single injection of the hydrogel loaded with cBSA/miR-29 b in vivo, significantly down-regulated proteins and genes related to fibrosis for up to 21 days without affecting the normal liver or kidney functions. Overall, the localized delivery of cBSA/miR-29 b via a host-guest supramolecular hydrogel represents a safe and effective intervention strategy to delay and reverse the progression of interstitial renal fibrosis.
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http://dx.doi.org/10.1016/j.biomaterials.2021.120902DOI Listing
August 2021

Confirmation of biodegradation of low-density polyethylene in dark- versus yellow- mealworms (larvae of Tenebrio obscurus versus Tenebrio molitor) via. gut microbe-independent depolymerization.

Sci Total Environ 2021 Oct 21;789:147915. Epub 2021 May 21.

Department of Civil and Environmental Engineering, Department of Chemistry, William & Cloy Codiga Resource Recovery Center, Center for Sustainable Development & Global Competitiveness, Stanford University, Stanford, CA 94305, USA. Electronic address:

Tenebrio obscurus (Coleoptera: Tenebrionidae) larvae are capable of biodegrading polystyrene (PS) but their capacity for polyethylene (PE) degradation and pattern of depolymerization remains unknown. This study fed the larvae of T. obscurus and Tenebrio molitor, which have PE degrading capacity, two commercial low-density PE (LDPE) foams i.e., PE-1 and PE-2, with respective number-average molecular weights (M) of 28.9 and 27.3 kDa and weight-average molecular weights (M) of 342.0 and 264.1 kDa, over a 36-day period at ambient temperature. The M of residual PE in frass (excrement) of T. obscurus, fed with PE-1 and PE-2, decreased by 45.4 ± 0.4% and 34.8 ± 0.3%, respectively, while the respective decrease in frass of T. molitor was 43.3 ± 0.5% and 31.7 ± 0.5%. Data analysis showed that low molecular weight PE (<5.0 kDa) was rapidly digested while longer chain portions (>10.0 kDa) were broken down or cleaved, indicating a broad depolymerization pattern. Mass balance analysis indicated nearly 40% of ingested LDPE was digested to CO. Antibiotic suppression of gut microbes in T. molitor and T. obscurus larvae with gentamicin obviously reduced their gut microbes on day 15 but did not stop depolymerization because the M, Mw and size- average molecular weight (M) decreased. This confirmed that LDPE biodegradation in T. obscurus was independent of gut microbes as observed during previous PS degradation in T. molitor, suggesting that the intestinal digestive system could perform LDPE depolymerization. High-throughput sequencing revealed significant shifts in the gut microbial community during bran-fed and unfed conditions in response to LDPE feeding in both Tenebrio species. The respective predominant gut genera of Spiroplasma sp. and Enterococcus sp. were observed in LDPE-fed T. molitor and T. obscurus larvae.
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http://dx.doi.org/10.1016/j.scitotenv.2021.147915DOI Listing
October 2021

An injectable micelle-hydrogel hybrid for localized and prolonged drug delivery in the management of renal fibrosis.

Acta Pharm Sin B 2021 Mar 18;11(3):835-847. Epub 2020 Oct 18.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.

Localized delivery, comparing to systemic drug administration, offers a unique alternative to enhance efficacy, lower dosage, and minimize systemic tissue toxicity by releasing therapeutics locally and specifically to the site of interests. Herein, a localized drug delivery platform ("plum‒pudding" structure) with controlled release and long-acting features is developed through an injectable hydrogel ("pudding") crosslinked self-assembled triblock polymeric micelles ("plum") to help reduce renal interstitial fibrosis. This strategy achieves controlled and prolonged release of model therapeutics in the kidney for up to three weeks in mice. Following a single injection, local treatments containing either anti-inflammatory small molecule celastrol or anti-TGF antibody effectively minimize inflammation while alleviating fibrosis inhibiting NF-B signaling pathway or neutralizing TGF-1 locally. Importantly, the micelle-hydrogel hybrid based localized therapy shows enhanced efficacy without local or systemic toxicity, which may represent a clinically relevant delivery platform in the management of renal interstitial fibrosis.
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http://dx.doi.org/10.1016/j.apsb.2020.10.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982499PMC
March 2021

Surface loading of nanoparticles on engineered or natural erythrocytes for prolonged circulation time: strategies and applications.

Acta Pharmacol Sin 2021 Jul 26;42(7):1040-1054. Epub 2021 Mar 26.

West China School of Public Health, College of Polymer Science and Engineering, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.

Nano drug-delivery systems (DDS) may significantly improve efficiency and reduce toxicity of loaded drugs, but a few nano-DDS are highly successful in clinical use. Unprotected nanoparticles in blood flow are often quickly cleared, which could limit their circulation time and drug delivery efficiency. Elongating their blood circulation time may improve their delivery efficiency or grant them new therapeutic possibilities. Erythrocytes are abundant endogenous cells in blood and are continuously renewed, with a long life span of 100-120 days. Hence, loading nanoparticles on the surface of erythrocytes to protect the nanoparticles could be highly effective for enhancing their in vivo circulation time. One of the key questions here is how to properly attach nanoparticles on erythrocytes for different purposes and different types of nanoparticles to achieve ideal results. In this review, we describe various methods to attach nanoparticles and drugs to the erythrocyte surface, and discuss the key factors that influence the stability and circulation properties of the erythrocytes-based delivery system in vivo. These data show that using erythrocytes as a host for nanoparticles possesses great potential for further development.
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http://dx.doi.org/10.1038/s41401-020-00606-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8208981PMC
July 2021

The complete plastid genome of (Nartheciaceae), an endemic species from Yunnan Province of China.

Mitochondrial DNA B Resour 2021 Jan 27;6(1):293-294. Epub 2021 Jan 27.

School of Vocational and Technical Education, Yunnan Normal University, Kunming, China.

F. T. Wang & Tang is an herbal plant species endemic to Yunnan Province of China. Its complete plastid genome sequence was 154,704 bp in length, with a large single-copy (LSC) region of 83,265 bp, a small single-copy (SSC) region of 18,127 bp, and a pair of inverted repeat regions (IRs) of 26,656 bp. The whole plastid genome encoded 132 genes, including 85 protein-coding genes, 38 tRNA genes, and eight rRNA genes. The overall GC content of plastid genome was 37.4%. Maximum likelihood phylogenetic analysis based on 14 taxa indicated that is evolutionarily close to .
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http://dx.doi.org/10.1080/23802359.2020.1866459DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7850363PMC
January 2021

Complete plastome sequence of (Malpighiaceae), a traditional Dai medicinal plant from Xishuangbanna, Yunnan, China.

Mitochondrial DNA B Resour 2020 Oct 9;5(3):3533-3535. Epub 2020 Oct 9.

Center for Integrative Conservation&Southeast Asia Biodiversity Research Institute, Xishuangbanna Tropical Botanical Garden, Chinese Academy of Sciences, Mengla, China.

We reported the first complete plastid genome of (Malpighiaceae) in this study. The complete plastome of is 160,453 bp in length with a base composition of A (31.4%), G (18.5%), C (18.2%), and T (32.0%). Structurally, the genome contains two short inverted repeats (26,905 bp for each), which are separated by a large single copy region (88,491 bp) and a small single copy region (18,152 bp). The plastome contained 113 unique genes, including 79 protein-coding genes, 30 transfer RNAs, and 4 ribosomal RNAs. Phylogenetic analyses showed that was sister to in the monophyletic Malpighiaceae. This study provided a high-quality plastome sequence for future studies in , as well as Malpighiaceae.
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http://dx.doi.org/10.1080/23802359.2020.1827998DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7782151PMC
October 2020

The complete chloroplast genomes of rare medical herb and its relative (Fabaceae).

Mitochondrial DNA B Resour 2019 Nov 18;4(2):4083-4084. Epub 2019 Nov 18.

Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou, China.

is a threatened perennial herb with medicinal value, which restricts in NW China and Mongolia. Its ally species, , is widely distributed from northern China to Turkey. The complete chloroplast genomes were sequenced using the Illumina Hiseq X-Ten platform. Each of the genomes lacks an inverted repeat (IR) region, containing 76 protein-coding genes, 30 tRNAs genes, and 4 rRNAs. The overall GC contents are both 34.3%. A phylogenetic tree based on the whole chloroplast genomes of 15 species indicated that and belonged to a monophyletic , which was nested in IRLC group of the subfamily Papilionoideae (Leguminosae).
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http://dx.doi.org/10.1080/23802359.2019.1691067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707646PMC
November 2019

Reassessment of Oliver (Gesneriaceae) based on molecular and palynological evidence.

PhytoKeys 2020 26;157:27-41. Epub 2020 Aug 26.

CAS Key Laboratory for Plant Diversity and Biogeography of East Asia, Kunming Institute of Botany, Chinese Academy of Sciences, 132 Lanhei Road, Kunming 650201, Yunnan Province, China.

The former genus is endemic to China, including two species, has been under consideration for incorporation into the expanded genus s.l. in Gesneriaceae. The phylogenetic tree inferred from two DNA sequences (L-F and ITS) showed that this genus is deeply nested into s.l. However, the new tree from seven ones (B-L, H-, 132, C-D, L-F, T-L of chloroplast DNA and ITS regions) revealed that is the sister group of other of s.l. Furthermore, is morphologically different from other based on existing data. We suggest keeping as an independent genus in Gesneriaceae.
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http://dx.doi.org/10.3897/phytokeys..55254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7467971PMC
August 2020

Chloroplast Phylogenomics Reveals the Intercontinental Biogeographic History of the Liquorice Genus (Leguminosae: ).

Front Plant Sci 2020 17;11:793. Epub 2020 Jun 17.

Key Laboratory of Plant Resources Conservation and Sustainable Utilization, South China Botanical Garden, Chinese Academy of Sciences, Guangzhou, China.

The liquorice genus, L. (Leguminosae), is a medicinal herb with great economic importance and an intriguing intercontinental disjunct distribution in Eurasia, North Africa, the Americas, and Australia. , along with Boiss. and Fisch. & C.A.Mey., comprise s.l. Here we reconstructed the phylogenetic relationships and biogeographic history in s.l. using sequence data of whole chloroplast genomes. We found that s.l. is sister to the tribe Wisterieae and is divided into four main clades. Clade I, corresponds to and is sister to sensu Meng. is embedded within sensu Meng, and these two genera together form Clades II-IV. Based on biogeographic analyses and divergence time dating, s.l. originated during the late Eocene and its most recent common ancestor (MRCA) was distributed in the interior of Eurasia and the circum-Mediterranean region. A vicariance event, which was possibly a response to the uplifting of the Turkish-Iranian Plateau, may have driven the divergence between sensu Meng and in the Middle Miocene. The third and fourth main uplift events of the Qinghai-Tibetan Plateau may have led to rapid evolutionary diversification within sensu Meng. Subsequently, the MRCA of Clade II might have migrated to North America () via the Bering land bridge during the early Pliocene, and reached temperate South America () by long-distance dispersal (LDD). Within Clade III, the ancestor of arrived at southern Australia through LDD after the late Pliocene, whereas all other species (the SPEY clade) migrated to the interior of Eurasia and the Mediterranean region in the early Pleistocene. The MRCA of Clade IV was restricted in the interior of Eurasia, but its descendants have become widespread in temperate regions of the Old World Northern Hemisphere during the last million years.
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http://dx.doi.org/10.3389/fpls.2020.00793DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7318913PMC
June 2020

[Effect of oral implant restoration on dentition defect patients and its impact on TNF-α and IL-6 levels in gingival crevicular fluid].

Shanghai Kou Qiang Yi Xue 2020 Apr;29(2):217-220

Department of Stomatology, 2.Blood Purification Center, People's Hospital of Shanghai Pudong District. Shanghai 201299, China.

Purpose: To investigate the clinical effects of oral implant restoration in patients with dentition defects and the its impact on tumor necrosis factor-α(TNF-α) and interleukin-6(IL-6) levels in gingival crevicular fluid.

Methods: Eighty-four patients with dentition defects from May 2017 to August 1919 in People's Hospital of Shanghai Pudong District were enrolled and randomly divided into control group (n=42) and experimental group (n=42). Patients in the control group were repaired by routine methods,while those in the experimental group were treated with oral implant restoration. The effect of restoration was evaluated 6 months after treatment. The levels of TNF-α, IL-6 in the gingival crevicular fluid and dental function were compared between the 2 groups. The data were analyzed using SPSS 18.0 software package.

Results: The levels of TNF-α and IL-6 in the experimental group and the control group after treatment were significantly higher than those before treatment (P<0.05). The levels of TNF-α and IL-6 in the experimental group were significantly lower than those in the control group 6 months after treatment (P<0.05). The scores of dental function in the experimental group and the control group were significantly higher than those before treatment (P<0.05). The scores of retention, speech, chewing and aesthetics of the experimental group 6 months after treatment were significantly higher than the control group (P<0.05). The incidence of infection, pricking, post and core loosing and teeth missing in the experimental group was significantly lower than that of the control group (P<0.05).

Conclusions: In the treatment of patients with dentition defects, implant restoration has little effect on the levels of TNF-α and IL-6 in gingival crevicular fluid, which is helpful to improve dental function and reduce the incidence of postoperative complications. Therefore, it is worthwhile to be popularized in clinical application.
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April 2020

Low-dose paclitaxel via hyaluronan-functionalized bovine serum albumin nanoparticulate assembly for metastatic melanoma treatment.

J Mater Chem B 2020 03;8(10):2139-2147

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.

Due to the critical role of CD44 in mediating cell adhesion and migration, CD44-targeted drug delivery via hyaluronan has been extensively explored. Herein, cationic bovine serum albumin nanoparticles were assembled with hyaluronan (HA) of various molecular weights via simple electrostatic interaction to afford hierarchical nanoparticles (HNPs) with various size distributions and structures. Next, HNPs obtained using 49 kDa HA have been used to encapsulate paclitaxel (PTX-HNPs), which demonstrated selective lung accumulation due to both size effect and CD44-mediated targetability. Biodistribution studies showed that HNPs enhanced the lung specific accumulation of HNPs in the C57BL/6 mice melanoma lung metastasis model. In the antitumor studies, compared with the Taxol or bovine serum albumin nanoparticle (NP) groups, PTX-HNPs significantly inhibited B16F10 lung metastasis at a relatively low dose. Additionally, cell migration and invasion experiments in vitro further confirmed that PTX-HNPs significantly inhibited the migration of B16F10 cells compared to Taxol or paclitaxel-loaded NP groups. Overall, our results suggest that PTX-HNPs represent a highly promising strategy for the treatment of lung metastatic melanoma.
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http://dx.doi.org/10.1039/c9tb02780gDOI Listing
March 2020

[Preliminary Investigation on Difference of Protein Compositions Between DC2.4 Cells and Their Derived Exosomes by nanoLC-MS/MS].

Sichuan Da Xue Xue Bao Yi Xue Ban 2020 Jan;51(1):81-86

College of Polymer Science and Engineering, Sichuan University, Chengdu 610065, China.

Objective: To preliminarily investigate the differences of protein composition between immature dendritic cells (DC2.4) and their derived exosomes (DC-Exo) using a relatively rapid and sample-saving method based on nano-flow liquid chromatography tandem mass spectrometry (nanoLC-MS/MS).

Methods: The supernatant of DC2.4 cells culture medium was collected and gradient centrifugation was applied to primarily extract and isolate DC-Exo; then sucrose density gradient ultracentrifugation was adopted to purify the DC-Exo. Bradford protein assay was used to determine the total protein content of the purified DC-Exo, and dynamic light scattering and transmission electron microscope were conducted to characterize the morphology and size distribution of the DC-Exo. Afterwards, protein samples including DC2.4 cells and DC-Exo were prepared by FASP enzymolysis method. Samples were performed nanoLC-MS/MS assay. The μLPickUp sample loading mode was used and only 1 μg of protein sample was required for each assay. The phase of Transport liquid and Micro A were both 0.05% trifluoroacetic acid-2% acetonitrile (ACN) . ( / ). Acclaim PepMap RSLC column was used to separate sample compositions and the gradient elute was adopted where the mobile phase consisted of (A) 0.1% formic acid (FA) and (B) 0.08% FA-80% ACN . ( / ) with flow rate of 0.3 μL/min. Positive APCI nanospray interface was used and "one-drive-ten" schema was set to collect primary information. The collected data was then searched and matched based on Uniport Mouse Fasta file as protein database in this case, and the re-annotated data was further sorted out and analyzed.

Results: In the current study, relatively high yield of DC-Exo samples with sizes of 40-200 nm were obtained. The lyophilized protein samples prepared by FASP method could be loaded directly after redissolution, and only 1 μg of protein sample is required. The annotated results showed that DC2.4 cells contained 998 kinds of proteins, among which 227 were highly expressed and 535 were unique; while DC-Exo contained only 348 types of proteins, among which 18 were uniquely and highly expressed. There were 306 kinds of consensus proteins in both DC2.4 cells and DC-Exo, among them 7 kinds were highly expressed.

Conclusion: The nanoLC-MS/MS method developed in this study only requires very small amount of protein samples, and it could primarily differentiate the protein compositions between DC2.4 cells and their derived exosomes rapidly.
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http://dx.doi.org/10.12182/20200160103DOI Listing
January 2020

Correction: A fast-dissolving microneedle array loaded with chitosan nanoparticles to evoke systemic immune responses in mice.

J Mater Chem B 2020 Jan;8(3):578-579

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu 610041, China.

Correction for 'A fast-dissolving microneedle array loaded with chitosan nanoparticles to evoke systemic immune responses in mice' by Zhilin Li et al., J. Mater. Chem. B, 2020, DOI: 10.1039/c9tb02061f.
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http://dx.doi.org/10.1039/c9tb90179eDOI Listing
January 2020

A fast-dissolving microneedle array loaded with chitosan nanoparticles to evoke systemic immune responses in mice.

J Mater Chem B 2020 01 5;8(2):216-225. Epub 2019 Dec 5.

Department of Pharmacy, West China Second University Hospital and Evidence-Based Pharmacy Center and Key Laboratory of Birth Defects and Related Diseases of Woman and Children, Sichuan University, Chengdu 610041, China.

Microneedle (MN) arrays offer an alternative approach to hypodermic injection via syringe needles. In this work, polyvinylpyrrolidone (PVP)-based fast dissolving MN arrays were developed in which the needle tips were loaded with chitosan nanoparticles (NPs) for coencapsulation of a model antigen, ovalbumin (OVA), and an adjuvant, CpG oligodeoxynucleotides (CpG). After insertion into the skin, these MN arrays fully dissolved within 3 min to release antigen and adjuvant co-loaded NPs rapidly in the epidermal layer. Positively charged chitosan was proven to be an excellent carrier for negatively charged OVA and CpG, which formed nanocomplexes via simple electrostatic interactions and greatly enhanced the uptake efficiency of OVA in DC2.4 dendritic cells. Vaccination studies in mice further demonstrated that chitosan NPs effectively accumulated in peripheral lymph nodes, thus inducing greatly enhanced immune responses compared to those of free OVA. The antibody dose-response curve further demonstrated that MN immunization achieved comparable levels of immune responses as compared to conventional subcutaneous injections in a more convenient and less invasive way. Overall, a PVP-based fast dissolving MN array with chitosan NPs represents a promising and robust platform system for efficient transcutaneous vaccine delivery.
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http://dx.doi.org/10.1039/c9tb02061fDOI Listing
January 2020

, a new species of (Gentianaceae) from Xinjiang, China.

PhytoKeys 2019 29;130:59-73. Epub 2019 Aug 29.

Center for Integrative Conservation, Xishuangbanna Tropical Botanical Garden, Chinese Academy of Sciences, Mengla 666303, Yunnan, China Xishuangbanna Tropical Botanical Garden Mengla China.

Ma ex H.F. Cao, J.D. Ya & Q.R. Zhang, a new species of Gentianaceae from Xinjiang, Northwest China is described and illustrated. This new species is unique in having equal length of corolla lobe and corolla tube, nectaries located at the throat of the corolla tube and large seeds up to 1.6 mm in diameter. In addition, an updated identification key to the Chinese species of is provided.
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http://dx.doi.org/10.3897/phytokeys.130.35476DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6728362PMC
August 2019

Current status and future direction of lymph node dissection in radical surgery for esophageal cancer.

J Thorac Dis 2019 Aug;11(Suppl 13):S1678-S1682

Department of Thoracic Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020, China.

Surgical resection is the main treatment for esophageal cancer. Lymph node dissection is an essential part of radical surgery for esophageal cancer. However, the extent of dissection, numbers of lymph nodes, and sentinel lymph nodes in lymphadenectomy are still under debate. However, a clinical practice consensus has gradually formed despite this dispute.
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http://dx.doi.org/10.21037/jtd.2019.05.51DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6706621PMC
August 2019

Hierarchical assembly of hyaluronan coated albumin nanoparticles for pancreatic cancer chemoimmunotherapy.

Nanoscale 2019 Sep 27;11(35):16476-16487. Epub 2019 Aug 27.

Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, 610041, China.

Pancreatic cancer is a highly malignant carcinoma with limited effective treatment options, resulting in a poor patient survival rate of less than 5%. In this study, cationic albumin nanoparticles were assembled with negatively charged hyaluronic acid (HA) to achieve a hierarchical nanostructure and efficient delivery of small molecule drugs to the tumor site in the pancreas. A combination of chemotherapy with indoleamine-2,3-dioxygenase (IDO) inhibition was explored to enhance the chemotherapeutic efficacy in vivo. Hydrophobic celastrol (CLT) and hydrophilic 1-methyltryptophan (MT) were concurrently loaded in HA coated cationic albumin nanoparticles (HNPs) with an average size of ∼300 nm. The size of HNPs was reduced in the presence of hyaluronidase to facilitate penetration into deep tumor tissues. Also, the biodistribution study in the C57BL/6 mice xenograft model showed enhanced tumor accumulation and prolonged circulation of HNPs. Compared with CLT solution, the combination of CLT with MT showed significantly enhanced tumor inhibition in both xenograft and orthotopic pancreatic cancer mice models via downregulating the immunosuppressive tumor microenvironment. Taken together, the combination of CLT with MT administered via HNPs represents a highly promising strategy for targeted pancreatic cancer therapy.
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http://dx.doi.org/10.1039/c9nr03684aDOI Listing
September 2019

Chondroitin Sulfate-Linked Prodrug Nanoparticles Target the Golgi Apparatus for Cancer Metastasis Treatment.

ACS Nano 2019 08 6;13(8):9386-9396. Epub 2019 Aug 6.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy , Sichuan University , Chengdu 610064 , China.

Metastasis is a multistep biological process regulated by multiple signaling pathways. The integrity of the Golgi apparatus plays an important role in these signaling pathways. Inspired by the mechanism and our previous finding about accumulation of chondroitin sulfate in Golgi apparatus in hepatic stellate cells, we developed a Golgi apparatus-targeting prodrug nanoparticle system by synthesizing retinoic acid (RA)-conjugated chondroitin sulfate (CS) (CS-RA). The prodrug nanoparticles appeared to accumulate in the Golgi apparatus in cancer cells and realized RA release under an acidic environment. We confirmed that CS-RA exhibited successful inhibition of multiple metastasis-associated proteins expression and by disruption of the Golgi apparatus structure. Following loading with paclitaxel (PTX), the CS-RA based nanoformulation (PTX-CS-RA) inhibited migration, invasion, and angiogenesis and suppressed tumor growth and metastasis in 4T1-Luc bearing mice. This multistep targeted nanoparticle system potentially enhanced the effect of antimetastasis combined with chemotherapy.
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http://dx.doi.org/10.1021/acsnano.9b04166DOI Listing
August 2019

Origin of angiosperms and the puzzle of the Jurassic gap.

Nat Plants 2019 05 6;5(5):461-470. Epub 2019 May 6.

Germplasm Bank of Wild Species, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, China.

Angiosperms are by far the most species-rich clade of land plants, but their origin and early evolutionary history remain poorly understood. We reconstructed angiosperm phylogeny based on 80 genes from 2,881 plastid genomes representing 85% of extant families and all orders. With a well-resolved plastid tree and 62 fossil calibrations, we dated the origin of the crown angiosperms to the Upper Triassic, with major angiosperm radiations occurring in the Jurassic and Lower Cretaceous. This estimated crown age is substantially earlier than that of unequivocal angiosperm fossils, and the difference is here termed the 'Jurassic angiosperm gap'. Our time-calibrated plastid phylogenomic tree provides a highly relevant framework for future comparative studies of flowering plant evolution.
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http://dx.doi.org/10.1038/s41477-019-0421-0DOI Listing
May 2019

A novel gemcitabine derivative-loaded liposome with great pancreas-targeting ability.

Acta Pharmacol Sin 2019 Nov 23;40(11):1448-1456. Epub 2019 Apr 23.

School of Pharmacy, Chengdu Medical College, Chengdu 610500, China.

Gemcitabine (Gem) is a standard first-line treatment for pancreatic cancer (PC). However, its chemotherapeutic efficacy is hampered by various limitations such as short half-life, metabolic inactivation, and lack of tumor localizing. We previously synthesized a lipophilic Gem derivative (Gem formyl hexadecyl ester, GemC16) that exhibited improved antitumor activity in vitro. In this study, a target ligand N,N-dimethyl-1,3-propanediamine was conjugated to 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[hydroxyl succinimidyl (polyethylene glycol-2000)] (DSPE-PEG-NHS) to form DSPE-PEG-2N. Then, pancreas-targeting liposomes (2N-LPs) were prepared using the film dispersion-ultrasonic method. GemC16-loaded 2N-LPs displayed near-spherical shapes with an average size distribution of 157.2 nm (polydispersity index (PDI) = 0.201). The encapsulation efficiency of GemC16 was up to 97.3% with a loading capacity of 8.9%. In human PC cell line (BxPC-3) and rat pancreatic acinar cell line (AR42J), cellular uptake of 2N-LPs was significantly enhanced compared with that of unmodified PEG-LPs. 2N-LPs exhibited more potent in vitro cytotoxicity against BxPC-3 and AR42J cell lines than PEG-LPs. After systemic administration in mice, 2N-LPs remarkably increased drug distribution in the pancreas. In an orthotopic tumor mouse model of PC, GemC16-bearing liposomes were more effective in preventing tumor growth than free GemC16. Among these treatments, 2N-LPs showed the best curative effect. Together, 2N-LPs represent a promising nanocarrier to achieve pancreas-targeting drug delivery, and this work would provide new ideas for the chemotherapy of PC.
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http://dx.doi.org/10.1038/s41401-019-0227-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6888841PMC
November 2019

Golgi Apparatus-Targeted Chondroitin-Modified Nanomicelles Suppress Hepatic Stellate Cell Activation for the Management of Liver Fibrosis.

ACS Nano 2019 04 4;13(4):3910-3923. Epub 2019 Apr 4.

Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy , Sichuan University , Chengdu 610064 , China.

Liver fibrosis is a serious liver disease associated with high morbidity and mortality. The activation of hepatic stellate cells (HSCs) and the overproduction of extracellular matrix proteins are key features during disease progression. In this work, chondroitin sulfate nanomicelles (CSmicelles) were developed as a delivery system targeting HSCs for the treatment of liver fibrosis. CS-deoxycholic acid conjugates (CS-DOCA) were synthesized via amide bond formation. Next, retinoic acid (RA) and doxorubicin (DOX) were encapsulated into CSmicells to afford a DOX+RA-CSmicelles codelivery system. CSmicelles were selectively taken up in activated HSCs and hepatoma (HepG2) cells other than in normal hepatocytes (LO2), the internalization of which was proven to be mediated by CD44 receptors. Interestingly, DOX+RA-CSmicelles preferentially accumulated in the Golgi apparatus, destroyed the Golgi structure, and ultimately downregulated collagen I production. Following tail-vein injection, DOX+RA-CSmicelles were delivered to the cirrhotic liver and showed synergistic antifibrosis effects in the CCl-induced fibrotic rat model. Further, immunofluorescence staining of dissected liver tissues revealed CD44-specific delivery of CS derivatives to activated HSCs. Together, our results demonstrate the great potential of CS based carrier systems for the targeted treatment of chronic liver diseases.
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http://dx.doi.org/10.1021/acsnano.8b06924DOI Listing
April 2019

Bio-Mimicking Nanoparticles for Targeted Therapy of Malignant Melanoma.

J Biomed Nanotechnol 2019 May;15(5):993-1004

Polyethylene glycol-poly(lactic-co-glycolic acid) (PEG-PLGA) nanoparticles coated with neutrophil membranes were fabricated to afford a bio-mimicking delivery system and achieve targeted delivery of chemotherapeutics towards malignant melanoma via systemic administration. Using celastrol as the model compound, celastrol-loaded PEG-PLGA nanoparticles coated with neutrophil membranes displayed significantly enhanced cytotoxicity and apoptosis rate in a murine melanoma cell line B16F10 compared to celastrol-loaded PEG-PLGA nanoparticles. Moreover, PEG-PLGA nanoparticles coated with neutrophil membranes exhibited significantly higher internalization efficiency in B16F10 cells than nanoparticles without membrane coating. Next, a B16F10 tumor xenograft mice model was established to explore the biodistribution profiles of PEG-PLGA nanoparticles coated with neutrophil membranes which showed remarkably prolonged blood circulation and more selective accumulation at the tumor site. Celastrol-loaded PEG-PLGA nanoparticles coated with neutrophil membranes also demonstrated greatly improved antitumor efficacy in B16F10 tumor bearing mice xenografts. Taken together, PEG-PLGA nanoparticles coated with neutrophil membranes represent a highly promising nanoscale delivery system to achieve tumor-targeted therapy following systemic administration.
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http://dx.doi.org/10.1166/jbn.2019.2739DOI Listing
May 2019

A Density-Changing Centrifugation Method for Efficient Separation of Free Drugs from Drug-Loaded Particulate Delivery Systems.

AAPS J 2019 02 25;21(3):33. Epub 2019 Feb 25.

Key Laboratory of Drug Targeting and Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, No 17, Section 3, Southern Remin Rd, Chengdu, 610041, China.

Commonly used separation techniques, such as ultracentrifugation, chromatography, and membrane separation, have inherent drawbacks that limit their usage. Herein, we introduced a new separation method, density-changing centrifugation (DCC), which is based on trisodium citrate (TC) and ultracentrifugation. Paclitaxel-loaded cationic solid lipid nanoparticles (SLNs/PTX) and doxorubicin-loaded PEGylated liposomes (Lipo/Dox) were prepared as model drug delivery particulates. After optimizing TC concentration and centrifugal conditions, DCC showed superior separation efficiency and accuracy over common ultracentrifugation and ultrafiltration methods and displayed comparable or even better separation efficiency compared with size-exclusion chromatography, as demonstrated by the determination of encapsulation efficiency, Tyndall effect, transmittance, and drug recovery. DCC was also proven to minimally impact the size distribution, surface morphology, and thermal properties of the nanoparticles and liposomes, and moreover, it did not affect the determination of drug concentrations. Together, DCC has been demonstrated as a neat and effective method for the separation of free drugs from drug-loaded SLNs and liposomes, which shall be of great benefit for the development of particulate based delivery systems.
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http://dx.doi.org/10.1208/s12248-019-0306-1DOI Listing
February 2019

Inflammation-Targeted Delivery of Celastrol via Neutrophil Membrane-Coated Nanoparticles in the Management of Acute Pancreatitis.

Mol Pharm 2019 03 21;16(3):1397-1405. Epub 2019 Feb 21.

Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy , Sichuan University , Chengdu 610041 , China.

Celastrol (CLT)-loaded PEG-PLGA nanoparticles (NPs/CLT) coated with neutrophil membranes (NNPs/CLT) were explored for the management of acute pancreatitis (AP). PEG-PLGA nanoparticles sized around 150 nm were proven to selectively accumulate in the pancreas in rats with AP. NNPs were found to overcome the blood-pancreas barrier and specifically distributed to the pancreatic tissues. Moreover, NNPs showed more selective accumulation in the pancreas than nanoparticles without any membrane coating in AP rats. Compared to CLT solution and the NPs/CLT group, NNPs/CLT significantly downregulated the levels of serum amylase and pancreatic myeloperoxidase in AP rats. Also, using NNPs as the delivery vehicle significantly reduced the systemic toxicity of CLT in AP rats. Together, these results suggest that NNPs/CLT represent a highly promising delivery vehicle for the targeted therapy of AP.
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http://dx.doi.org/10.1021/acs.molpharmaceut.8b01342DOI Listing
March 2019

Acetyl-macrocalin B suppresses tumor growth in esophageal squamous cell carcinoma and exhibits synergistic anti-cancer effects with the Chk1/2 inhibitor AZD7762.

Toxicol Appl Pharmacol 2019 02 8;365:71-83. Epub 2019 Jan 8.

Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Electronic address:

Natural products derived from herbal medicines have become a major focus of anti-cancer drug discovery studies. Acetyl-macrocalin B (A-macB) is an ent-diterpenoid isolated from Isodon silvatica. This study aimed to examine the effect and molecular action of A-macB in esophageal squamous cell carcinoma (ESCC) and explore possible drug synergistic modalities. A-macB induced cellular reactive oxygen species (ROS) generation, initiated the p38 mitogen-activated protein kinase (MAPK) signaling pathway, and triggered the caspase-9-dependent apoptosis cascade in ESCC cells. The ROS scavenger N-acetylcysteine (NAC) and the specific p38 inhibitor SB203580 reversed the effects of A-macB on the p38 network and thus rescued ESCC cells from apoptosis. The cellular ROS increase was at least partially due to the suppression of glutathione-S-transferase P1 (GSTP1) by A-macB. A-macB also upregulated the Chk1/Chk2-Cdc25C/Cdc2/Cyclin B1 axis to induce G2/M phase arrest. The cell growth inhibition induced by A-macB was further enhanced by AZD7762, a specific Chk1/Chk2 inhibitor, with a combination index (CI) of <1. Moreover, A-macB efficiently suppressed xenograft growth without inducing significant toxicity, and AZD7762 potentiated the effects of A-macB in the suppression of tumor growth in vivo. Taken together, A-macB is a promising lead compound for ESCC and exerts synergistic anti-cancer effects with AZD7762.
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http://dx.doi.org/10.1016/j.taap.2019.01.005DOI Listing
February 2019
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