Publications by authors named "Caihong Zheng"

39 Publications

Extracellular Matrix: Emerging Roles and Potential Therapeutic Targets for Breast Cancer.

Front Oncol 2021 22;11:650453. Epub 2021 Apr 22.

Department of Pharmacy, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Increasing evidence shows that the extracellular matrix (ECM) is an important regulator of breast cancer (BC). The ECM comprises of highly variable and dynamic components. Compared with normal breast tissue under homeostasis, the ECM undergoes many changes in composition and organization during BC progression. Induced ECM proteins, including fibrinogen, fibronectin, hyaluronic acid, and matricellular proteins, have been identified as important components of BC metastatic cells in recent years. These proteins play major roles in BC progression, invasion, and metastasis. Importantly, several specific ECM molecules, receptors, and remodeling enzymes are involved in promoting resistance to therapeutic intervention. Additional analysis of these ECM proteins and their downstream signaling pathways may reveal promising therapeutic targets against BC. These potential drug targets may be combined with new nanoparticle technologies. This review summarizes recent advances in functional nanoparticles that target the ECM to treat BC. Accurate nanomaterials may offer a new approach to BC treatment.
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http://dx.doi.org/10.3389/fonc.2021.650453DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8100244PMC
April 2021

The Macrophage-Osteoclast Axis in Osteoimmunity and Osteo-Related Diseases.

Front Immunol 2021 31;12:664871. Epub 2021 Mar 31.

Department of Pharmacy, Women's Hospital School of Medicine Zhejiang University, Hangzhou, China.

Osteoimmunity is involved in regulating the balance of bone remodeling and resorption, and is essential for maintaining normal bone morphology. The interaction between immune cells and osteoclasts in the bone marrow or joint cavity is the basis of osteoimmunity, in which the macrophage-osteoclast axis plays a vital role. Monocytes or tissue-specific macrophages (macrophages resident in tissues) are an important origin of osteoclasts in inflammatory and immune environment. Although there are many reports on macrophages and osteoclasts, there is still a lack of systematic reviews on the macrophage-osteoclast axis in osteoimmunity. Elucidating the role of the macrophage-osteoclast axis in osteoimmunity is of great significance for the research or treatment of bone damage caused by inflammation and immune diseases. In this article, we introduced in detail the concept of osteoimmunity and the mechanism and regulators of the differentiation of macrophages into osteoclasts. Furthermore, we described the role of the macrophage-osteoclast axis in typical bone damage caused by inflammation and immune diseases. These provide a clear knowledge framework for studying macrophages and osteoclasts in inflammatory and immune environments. And targeting the macrophage-osteoclast axis may be an effective strategy to treat bone damage caused by inflammation and immune diseases.
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http://dx.doi.org/10.3389/fimmu.2021.664871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8044404PMC
March 2021

Efficacy of phloroglucinol for acceleration of labour: a systematic review and meta‑analysis.

Arch Gynecol Obstet 2021 Apr 17. Epub 2021 Apr 17.

Department of Pharmacy, School of Medicine, Women's Hospital, Zhejiang University, Hangzhou, 310006, China.

Purpose: To assess the efficacy of phloroglucinol for acceleration of labour.

Methods: Randomized controlled trials (RCTs) comparing phloroglucinol with placebo were searched in PubMed, Embase and the Cochrane Library. Literatures were collected up to April 2020. Primary outcomes were the duration of labour and average blood loss. Finally, a total of 4 RCTs, 377 patients were included in this meta-analysis. The included RCTs were analyzed by the software Rev Man 5. 3.

Results: In the phloroglucinol group, the duration of the first stage was reduced by 116.04 min (95% CI 107.71 to 124.68), and the duration of the second stage was reduced by 10.75 min (95% CI 8.79 to 12.70). The average blood loss was reduced by 16.07 ml, which was statistically different from the control group.

Conclusion: The application of phloroglucinol is proved to be effective for accelerating the labour process, reducing the risk of maternal and neonatal complications.
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http://dx.doi.org/10.1007/s00404-021-06043-5DOI Listing
April 2021

Engineering of bioactive metal sulfide nanomaterials for cancer therapy.

J Nanobiotechnology 2021 Mar 31;19(1):93. Epub 2021 Mar 31.

Department of Pharmacy, Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.

Metal sulfide nanomaterials (MeSNs) are a novel class of metal-containing nanomaterials composed of metal ions and sulfur compounds. During the past decade, scientists found that the MeSNs engineered by specific approaches not only had high biocompatibility but also exhibited unique physicochemical properties for cancer therapy, such as Fenton catalysis, light conversion, radiation enhancement, and immune activation. To clarify the development and promote the clinical transformation of MeSNs, the first section of this paper describes the appropriate fabrication approaches of MeSNs for medical science and analyzes the features and limitations of each approach. Secondly, we sort out the mechanisms of functional MeSNs in cancer therapy, including drug delivery, phototherapy, radiotherapy, chemodynamic therapy, gas therapy, and immunotherapy. It is worth noting that the intact MeSNs and the degradation products of MeSNs can exert different types of anti-tumor activities. Thus, MeSNs usually exhibit synergistic antitumor properties. Finally, future expectations and challenges of MeSNs in the research of translational medicine are spotlighted.
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http://dx.doi.org/10.1186/s12951-021-00839-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011210PMC
March 2021

Deciphering the autophagy regulatory network via single-cell transcriptome analysis reveals a requirement for autophagy homeostasis in spermatogenesis.

Theranostics 2021 5;11(10):5010-5027. Epub 2021 Mar 5.

State Key Laboratory of Organ Failure Research, Department of Developmental Biology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China.

Autophagy has been implicated as a crucial component in spermatogenesis, and autophagy dysfunction can lead to reproductive disorders in animal models, including yeast, and mice. However, the sophisticated transcriptional networks of autophagic genes throughout human spermatogenesis and their biological significance remain largely uncharacterized. We profiled the transcriptional signatures of autophagy-related genes during human spermatogenesis by assessing specimens from nine fertile controls (including two normal persons and seven obstructive azoospermia (OA) patients) and one nonobstructive azoospermia (NOA) patient using single-cell RNA sequencing (scRNA-seq) analysis. Dysregulation of autophagy was confirmed in two additional NOA patients by immunofluorescence staining. Gene knockdown was used to identify the role of Cst3 in autophagy during spermatogenesis. Our data uncovered a unique, global stage-specific enrichment of autophagy-related genes. Human-mouse comparison analysis revealed that the stage-specific expression pattern of autophagy-related genes was highly conserved in mammals. More importantly, dysregulation of some clusters of autophagy-related genes was observed in NOA patients, suggesting the association of autophagy with male infertility. Cst3, a human-mouse conserved and autophagy-related gene that is actively expressed in spermatogonia and early spermatocytes, was found to regulate spermatogonial stem cell (SSC) maintenance and subsequent male germ cell development. Knockdown of Cst3 increased autophagic activity in mouse SSCs and subsequently suppressed the transcription of SSC core factors such as Oct4, Id1, and Nanos3, which could be efficiently rescued by manipulating autophagic activity. Our study provides comprehensive insights into the global transcriptional signatures of autophagy-related genes and confirms the importance of autophagy homeostasis in SSC maintenance and normal spermatogenesis, opening new avenues for further dissecting the significance of the autophagy regulatory network in spermatogenesis as well as male infertility.
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http://dx.doi.org/10.7150/thno.55645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7978313PMC
March 2021

Preparation and Biological Property Evaluation of Novel Cationic Lipid-Based Liposomes for Efficient Gene Delivery.

AAPS PharmSciTech 2021 Jan 3;22(1):22. Epub 2021 Jan 3.

Pharmacy Department, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, 310006, China.

Novel cationic lipid-based liposomes prepared using an amphiphilic cationic lipid material, N,N-dimethyl-(N',N'-di-stearoyl-1-ethyl)1,3-diaminopropane (DMSP), have been proposed to enhance the transfection of nucleic acids. Herein, we designed and investigated liposomes prepared using DMSP, soybean phosphatidylcholine, and cholesterol. This novel gene vector has high gene loading capabilities and excellent protection against nuclease degradation. An in vitro study showed that the liposomes had lower toxicity and superior cellular uptake and transfection efficiency compared with Lipofectamine 2000. An endosomal escape study revealed that the liposomes demonstrated high endosomal escape and released their genetic payload in the cytoplasm efficiently. Mechanistic studies indicated that the liposome/nucleic acid complexes entered cells through energy-dependent endocytosis that was mediated by fossa proteins. These results suggest that such cationic lipid-based liposome vectors have potential for clinical gene delivery.
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http://dx.doi.org/10.1208/s12249-020-01868-wDOI Listing
January 2021

Regulating Gut Microbiome: Therapeutic Strategy for Rheumatoid Arthritis During Pregnancy and Lactation.

Front Pharmacol 2020 11;11:594042. Epub 2020 Nov 11.

Department of Pharmacy, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by synovial inflammation and bone destruction. Microbial infection is considered to be the most important inducement of RA. The pregnancy planning of women in childbearing age is seriously affected by the disease activity of RA. Gut microbiome, related to immunity and inflammatory response of the host. At present, emerging evidence suggested there are significant differences in the diversity and abundance of gut microbiome during pregnancy and lactation, which may be associated with the fluctuation of RA disease activity. Based on these research foundations, we pioneer the idea of regulating gut microbiome for the treatment of RA during pregnancy and lactation. In this review, we mainly introduce the potential treatment strategies for controlling the disease activity of RA based on gut microbiome during pregnancy and lactation. Besides, we also briefly generalize the effects of conventional anti-rheumatic drugs on gut microbiome, the effects of metabolic changes during pregnancy on gut microbiome, alteration of gut microbiome during pregnancy and lactation, and the effects of anti-rheumatic drugs commonly used during pregnancy and lactation on gut microbiome. These will provide a clear knowledge framework for researchers in immune-related diseases during pregnancy. Regulating gut microbiome may be a potential and effective treatment to control the disease activity of RA during pregnancy and lactation.
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http://dx.doi.org/10.3389/fphar.2020.594042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748111PMC
November 2020

The role of short-chain fatty acids in immunity, inflammation and metabolism.

Crit Rev Food Sci Nutr 2020 Dec 1:1-12. Epub 2020 Dec 1.

Department of Pharmacy, Women's Hospital School of Medicine Zhejiang University, Hangzhou, China.

Short-chain fatty acids (SCFAs) are carboxylic acids with carbon atom numbers less than 6, which are important metabolites of gut microbiome. Existing research shows that SCFAs play a vital role in the health and disease of the host. First, SCFAs are the key energy source for colon and ileum cells, and affect the intestinal epithelial barrier and defense functions by regulating related gene expression. Second, SCFAs regulate the function of innate immune cells to participate in the immune system, such as macrophages, neutrophils and dendritic cells. Third, SCFAs can also regulate the differentiation of T cells and B cells and the antigen-specific adaptive immunity mediated by them. Besides, SCFAs are raw materials for sugar and lipid synthesis, which provides a theoretical basis for studying the potential role of SCFAs in regulating energy homeostasis and metabolism. There are also studies showing that SCFAs inhibit tumor cell proliferation and promote apoptosis. In this article, we summarized in detail the role of SCFAs in immunity, inflammation and metabolism, and briefly introduced the role of SCFAs in tumor cell survival. It provides a systematic theoretical basis for the study of SCFAs as potential drugs to promote human health.
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http://dx.doi.org/10.1080/10408398.2020.1854675DOI Listing
December 2020

Bioactive metal-containing nanomaterials for ferroptotic cancer therapy.

J Mater Chem B 2020 12;8(46):10461-10473

Department of Pharmacy, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.

The clinical performance of the current cancer therapies is still far from satisfactory. The emerging ferroptosis-driven therapy strategies reignite the hope of chemotherapy in tumor treatment due to their incredible tumor suppression. Among ferroptosis-based cancer therapies, metal elements have attracted remarkable attention due to their inherent physicochemical properties in inducing ferroptosis of tumor cells quickly and strongly without complex cellular signal transduction. Although the discovery and applications of ferroptosis for tumor treatment have been discussed in many reviews, the unique advantages of metal-containing nanomaterials interfering ferroptotic cancer therapies (MIFCT) have seldom been mentioned. Here, we outline the latest advances of MIFCT comprehensively. Firstly, the functions of different kinds of metal elements or their ions are introduced to illustrate their advantages in MIFCT. Secondly, the emerging metal-containing nanomaterials that are designed to achieve ferroptosis-driven therapy are overviewed, including their ability to boost the Fenton or Fenton-like reaction for reactive oxygen species generation, act as hydrogen peroxide self-providers, damage the reducing system, and disturb cellular communication. Moreover, metal-containing nanomaterials with external energy conversion features for MIFCT are discussed. Finally, the future expectations and challenges of MIFCT for clinical cancer therapy are spotlighted.
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http://dx.doi.org/10.1039/d0tb02138eDOI Listing
December 2020

A promising iPS-based single-cell cloning strategy revealing signatures of somatic mutations in heterogeneous normal cells.

Comput Struct Biotechnol J 2020 3;18:2326-2335. Epub 2020 Sep 3.

Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, China National Center for Bioinformation, Beijing 100101, China.

Single-cell genomics has advanced rapidly as trace-DNA amplification technologies evolved. However, current technologies are subject to a variety of pitfalls such as contamination, uneven genomic coverage, and amplification errors. Even for the "golden" strategy of single stem cell-derived clonal formation, high-fidelity amplification is applicable merely to single stem cells. It's still challenging to accurately define somatic mutations of a single cell in various cell types. Herein, we provided evidence, for the first time, to prove that induced pluripotent stem cells (iPS cells or iPSC), being a single somatic cell-derived clone, are recording almost identical (>90%) mutational profile of the initial cell progenitor. This finding demonstrates iPS technique, applicable to any cell type, can be utilized as a cell cloning strategy favorable for single-cell genomic amplification. This novel strategy is not limited by cell-type constraints or amplification artifacts, and thus enables our detailed investigation on the characteristics of somatic mutations in heterogeneous normal cells.
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http://dx.doi.org/10.1016/j.csbj.2020.08.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7493045PMC
September 2020

Identification and rescue of a novel TUBB8 mutation that causes the first mitotic division defects and infertility.

J Assist Reprod Genet 2020 Nov 18;37(11):2713-2722. Epub 2020 Sep 18.

Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai, 200092, China.

Purpose: Tubulin beta eight class VIII (TUBB8) is essential for oogenesis, fertilization, and pre-implantation embryo development in human. Although TUBB8 mutations were recently discovered in meiosis-arrested oocytes of infertile females, there is no effective therapy for this gene mutation caused infertility. Our study aims to further reveal the infertility-causing gene mutations in the patient's family and to explore whether the infertility could be rescued by optimizing the conditions of embryo culture and finally achieve the purpose of making the patient pregnant.

Methods: Whole-exome sequence analysis and Sanger sequencing were performed on patients' family members to screen and identify candidate mutant genes. Construction of plasmids, in vitro transcription, microinjection of disease-causing gene cRNA, and immunofluorescence staining were used to recapitulate the infertility phenotype observed in patients and to understand the pathogenic principles. Simultaneously, overexpression of mutant and wild-type cRNA of the candidate gene in mouse oocytes at either germinal vesicle (GV) or metaphase II (MII) stage was performed in the rescue experiment.

Results: We first identified a novel heritable TUBB8 mutation (c.1041C>A: p.N347K) in the coding region which specifically affects the first mitosis and causes the developmental arrest of early embryos in a three-generation family. We further demonstrated that TUBB8 mutation could lead to abnormal spindle assemble. And moreover, additional expression of wild-type TUBB8 cRNA in the mouse oocytes in which the mutant TUBB8 were expressed can successfully rescue the developmental defects of resulting embryo and produce full-term offspring.

Conclusions: Our study not only defines a novel mutation of TUBB8 causing the early cleavage arrest of embryos, but also provides an important basis for treating such female infertility in the future.
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http://dx.doi.org/10.1007/s10815-020-01945-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7642063PMC
November 2020

Sustained delivery of 17β-estradiol by human amniotic extracellular matrix (HAECM) scaffold integrated with PLGA microspheres for endometrium regeneration.

Drug Deliv 2020 Dec;27(1):1165-1175

Department of Pharmacy, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

The endometrial injury usually results in intrauterine adhesions (IUAs). However, there is no effective treatment to promote the regeneration of the endometrium currently. The decellularized amnion membrane (AM) is a promising material in human tissue repair and regeneration due to its biocompatibility, biodegradability, as well as the preservation of abundant bioactive components. Here, an innovative drug-delivering system based on human amniotic extracellular matrix (HAECM) scaffolds were developed to facilitate endometrium regeneration. The 17β-estradiol (E) loaded PLGA microspheres (E-MS) were well dispersed in the scaffolds without altering their high porosity. E released from E-MS-HAECM scaffolds showed a decreased initial burst release followed with a sustained release for 21 days, which coincided with the female menstrual cycle. Results of cell proliferation suggested E-MS-HAECM scaffolds had good biocompatibility and provided more biologic guidance of endometrial cell proliferation except for mechanical supports. Additionally, the mRNA expression of growth factors in endometrial cells indicated that HAECM scaffolds could upregulate the expression of EGF and IGF-1 to achieve endometrium regeneration. Therefore, these advantages provide the drug-loaded bioactive scaffolds with new choices for the treatments of IUAs.
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http://dx.doi.org/10.1080/10717544.2020.1801891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470125PMC
December 2020

Targeted GSH-exhausting and hydroxyl radical self-producing manganese-silica nanomissiles for MRI guided ferroptotic cancer therapy.

Nanoscale 2020 Aug;12(32):16738-16754

Department of Pharmacy, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China.

Ferroptosis, a cell death path induced by the generation of reactive oxygen species (ROS), will cause the accumulation of lipid peroxides (PL-PUFA-OOH) and achieve potent tumor-regression. However, glutathione (GSH)-dependent glutathione peroxidase 4 (GPx4) can reduce PL-PUFA-OOH and antagonize the ferroptosis inducing effect of ROS. Herein, folate-PEG modified dihydroartemisinin (DHA) loaded manganese doped mesoporous silica nanoparticles (described as nanomissiles) were constructed for integrating the effect of GSH exhaustion and ROS generation. After endocytosis by tumor cells, intracellular GSH triggered the degradation of nanomissiles, which allowed the simultaneous release of DHA and Fenton catalytic Mn2+ due to the redox reaction between the manganese-oxygen bonds and GSH. The degradation would lead to GSH exhaustion, activation of Mn2+-based magnetic resonance imaging (MRI), and DHA-driven ˙OH generation. The GSH-free environment inhibited the activity of GPx4 and enhanced the accumulation of PL-PUFA-OOH oxidized by ˙OH. Furthermore, the cooperative effects suppressed tumor metastasis by destroying the structure of polyunsaturated fatty acids in the cell membranes and showed potent antitumor activity. This innovative ferroptotic therapy integrating the GSH exhaustion and ROS generation will be a promising strategy for cancer therapy.
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http://dx.doi.org/10.1039/d0nr02396eDOI Listing
August 2020

The Role of Microbiomes in Pregnant Women and Offspring: Research Progress of Recent Years.

Front Pharmacol 2020 8;11:643. Epub 2020 May 8.

Department of Pharmacy, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, China.

Pregnancy is a complicated and delicate process, the maternal body undergoes changes on hormones, immunity, and metabolism during pregnancy to support fetal development. Microbiomes in the human body mainly live in the intestine, and the human gut microbiomes are complex, which composed of more than 500 to 1500 different bacteria, archaea, fungi, and viruses. Studies have shown that these microbiomes are not only involved in the digestion and absorption of food but also indispensable in regulating host health. In recent years, there has been increasing evidence that microbiomes are important for pregnant women and fetuses. During pregnancy, there will be great changes in gut microbiomes. Regulating gut microbiomes is beneficial to the health of the mother and the fetus. In addition, many complications during pregnancy are related to gut microbiomes, such as gestational diabetes, obesity, preeclampsia, digestive disorders, and autoimmune diseases. Moreover, the microbiomes in mother's milk and vagina are closely related to the colonization of microbiomes in the early life of infants. In this review, we systematically review the role of maternal microbiomes in different gestational complications, and elucidate the function and mechanism of maternal microbiomes in the neural development and immune system of offspring. These will provide a clear knowledge framework or potential research direction for researchers in related fields.
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http://dx.doi.org/10.3389/fphar.2020.00643DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225329PMC
May 2020

Construction of arsenic-metal complexes loaded nanodrugs for solid tumor therapy: A mini review.

Int J Pharm 2020 Jun 4;583:119385. Epub 2020 May 4.

Department of Pharmacy, Women's Hospital, School of Medicine, Zhejiang University, Hangzhou 310006, China. Electronic address:

Arsenic trioxide (AsO), a front-line therapeutic agent against acute promyelocytic leukemia, has a broad spectrum against malignancies. Unfortunately, the clinical application of AsO in treating hematological cancers has not been transformed to solid tumors, for its dose-limited toxicity and undesirable pharmacokinetics. The ordinary AsO loaded nanodrugs (such as liposomes, polymer micelles, albumin-based nanodrugs, and silica-based nanodrugs, etc.) still could not fuel up pharmaceuticals and eradicate toxicity for low delivery efficiency caused by the instability and severe drug leakage of formulations during circulation. Recently, the approach of forming and delivering arsenic-metal complexes which will dissociate in the tumoral environment caught our mind. This is the most effective strategy to reduce drug leakage in circulation and accumulate arsenite ions in tumor sites, therefore promote the anti-tumor effect and lighten the toxicity of the drug. This review aims to explain the formation mechanism of arsenic-metal nanocomposites and summarize the constructing strategies of the arsenic-metal nanocomplexes (arsenic-nickel, arsenic-manganese, arsenic-platinum, arsenic-gadolinium, arsenic-zinc, and arsenic-iron nanobins) loaded nanodrugs for solid tumor therapy. Furthermore, the expectations and challenges of arsenic-metal complexes containing nanodrugs for cancer therapy in the future were discussed.
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http://dx.doi.org/10.1016/j.ijpharm.2020.119385DOI Listing
June 2020

Mannose-Modified PLGA Nanoparticles for Sustained and Targeted Delivery in Hepatitis B Virus Immunoprophylaxis.

AAPS PharmSciTech 2019 Dec 5;21(1):13. Epub 2019 Dec 5.

Women's Hospital, Zhejiang University School of Medicine, Hangzhou, 310006, China.

The launched hepatitis B vaccine could induce powerful antibodies, whereas it failed to improve potent cellular immune responses due to that the Th2-type response-induced aluminum adjuvant was adopted. Here, to target antigen-presenting cells under the epidermis and induce potent cellular and humoral immune responses, mannose-modified poly D,L-lactide-co-glycolic acid (PLGA) was synthesized and nanoparticle (MNP)-loaded hepatitis B surface antigen (HBsAg) protein was prepared. HBsAg could be slowly released and highly presented to lymphocytes which facilitated to produce long-lasting immunity based on characters of PLGA. In vitro uptake test results showed that MNPs could enhance internalization in bone marrow-derived dendritic cells (BMDCs) and RAW 264.7 cells. Subcutaneous delivery of MNPs into mice kept humoral immune and strengthened cellular immune responses. Experimental results indicated that MNPs showed significantly modified properties compared with parental PLGA nanoparticles. Thus, the obtained MNPs could be a promising vehicle for hepatitis B vaccine delivery.
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http://dx.doi.org/10.1208/s12249-019-1526-5DOI Listing
December 2019

Dual GSH-exhausting sorafenib loaded manganese-silica nanodrugs for inducing the ferroptosis of hepatocellular carcinoma cells.

Int J Pharm 2019 Dec 31;572:118782. Epub 2019 Oct 31.

Department of Pharmacy, Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310006, China. Electronic address:

Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths. Unfortunately, there is still no completely effective treatment. Ferroptosis could affect the development of HCC by regulating the level of glutathione (GSH), intracellular lipid peroxidation, and other related substances. This paper introduced a new one-pot reaction for the synthesis of manganese doped mesoporous silica nanoparticles (manganese-silica nanoparticles, MMSNs) which could induce ferroptosis of the tumor cells through the consumption of intracellular GSH caused by the degradation of MMSNs. The more amount of MnCl added during the preparation, the larger doping amount of manganese presented in MMSNs. When the molar ratio of TEOS to MnCl was 5:1, the prepared MMSNs had a small size (102.6 ± 3.06 nm), uniform structure (pore sizes of 3.67 nm) and large pore volume. Manganese-oxidation bonds of MMSNs could break in high GSH concentration, which in turn consume GSH in the environment rapidly. Sorafenib (SO), an inhibitor of X transport system was loaded in the MMSNs ([email protected]) with a drug loading rate of 2.68 ± 0.32%. [email protected] achieved on-demand drug release in the tumor microenvironment due to the degradation of MMSNs. Subsequently, a significant tumor cell (HepG2) suppression effect of [email protected] was achieved through the consumption of GSH and synthesis inhibition of intracellular GSH. The depletion of GSH led to the inactivity of glutathione peroxidase 4 and increase of intracellular lipid peroxide, which could induce the ferroptosis of HCC cells. In summary, such dual GSH-exhausting nanodrugs have a great potential to induce ferroptosis of HCC cells.
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http://dx.doi.org/10.1016/j.ijpharm.2019.118782DOI Listing
December 2019

Multiple Drug Transporters Contribute to the Placental Transfer of Emtricitabine.

Antimicrob Agents Chemother 2019 08 25;63(8). Epub 2019 Jul 25.

Women's Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

Emtricitabine (FTC) is a first-line antiviral drug recommended for the treatment of AIDS during pregnancy. We hypothesized that transporters located in the placenta contribute to FTC transfer across the blood-placenta barrier. BeWo cells, cell models with stable or transient expression of transporter genes, primary human trophoblast cells (PHTCs), and small interfering RNAs (siRNAs) were applied to demonstrate which transporters were involved. FTC accumulation in BeWo cells was reduced markedly by inhibitors of equilibrative nucleoside transporters (ENTs), concentrative nucleoside transporters (CNTs), organic cation transporters (OCTs), and organic cation/carnitine transporter 1 (OCTN1) and increased by inhibitors of breast cancer resistance protein (BCRP) and multidrug resistance-associated proteins (MRPs). ENT1, CNT1, OCTN1, MRP1/2/3, and BCRP, but not ENT2, CNT3, OCTN2, or multidrug resistance protein 1 (MDR1), were found to transport FTC. FTC accumulation in PHTCs was decreased significantly by inhibitors of ENTs and OCTN1. These results suggest that ENT1, CNT1, and OCTN1 probably contribute to FTC uptake from maternal circulation to trophoblasts and that ENT1, CNT1, and MRP1 are likely involved in FTC transport between trophoblasts and fetal blood, whereas BCRP and MRP1/2/3 facilitate FTC transport from trophoblasts to maternal circulation. Coexistence of tenofovir or efavirenz with FTC in the cell medium did not influence FTC accumulation in BeWo cells or PHTCs.
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http://dx.doi.org/10.1128/AAC.00199-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6658773PMC
August 2019

Maternal Plasma l-Carnitine Reduction During Pregnancy Is Mainly Attributed to OCTN2-Mediated Placental Uptake and Does Not Result in Maternal Hepatic Fatty Acid -Oxidation Decline.

Drug Metab Dispos 2019 06 27;47(6):582-591. Epub 2019 Mar 27.

Laboratory of Pharmaceutical Analysis and Drug Metabolism, College of Pharmaceutical Sciences (M.B., Y.C., M.C., P.L., Z.M., H.Z., S.Z., H.J.) and Women's Hospital, School of Medicine (Q.Z., D.S., C.Z.), Zhejiang University, Hangzhou, People's Republic of China

l-Carnitine (l-Car) plays a crucial role in fatty acid -oxidation. However, the plasma l-Car concentration in women markedly declines during pregnancy, but the underlying mechanism and its consequences on maternal hepatic -oxidation have not yet been clarified. Our results showed that the plasma l-Car level in mice at gestation day (GD) 18 was significantly lower than that in nonpregnant mice, and the mean fetal-to-maternal plasma l-Car ratio in GD 18 mice was 3.0. Carnitine/organic cation transporter 2 (OCTN2) was highly expressed in mouse and human placenta and upregulated as gestation proceeds in human placenta, whereas expressions of carnitine transporter (CT) 1, CT2, and amino acid transporter B were extremely low. Further study revealed that renal peroxisome proliferator-activated receptor (PPAR) and OCTN2 were downregulated and the renal l-Car level was reduced, whereas the urinary excretion of l-Car was lower in late pregnant mice than in nonpregnant mice. Meanwhile, progesterone (pregnancy-related hormone) downregulated the expression of renal OCTN2 via PPAR-mediated pathway, and inhibited the activity of OCTN2, but estradiol, corticosterone, and cortisol did not. Unexpectedly, the maternal hepatic level of l-Car and -hydroxybutyrate (an indicator of mitochondrial -oxidation), and mRNA levels of several enzymes involved in fatty acid -oxidation in GD 18 mice were higher than that in nonpregnant mice. In conclusion, OCTN2 mediated l-Car transfer across the placenta played a major role in maternal plasma l-Car reduction during pregnancy, which did not subsequently result in maternal hepatic fatty acid -oxidation decrease.
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http://dx.doi.org/10.1124/dmd.119.086439DOI Listing
June 2019

DSMNC: a database of somatic mutations in normal cells.

Nucleic Acids Res 2019 01;47(D1):D971-D975

Key Laboratory of Genomic and Precision Medicine, Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China.

Numerous non-inherited somatic mutations, distinct from those of germ-line origin, occur in somatic cells during DNA replication per cell-division. The somatic mutations, recording the unique genetic cell-lineage 'history' of each proliferating normal cell, are important but remain to be investigated because of their ultra-low frequency hidden in the genetic background of heterogeneous cells. Luckily, the recent development of single-cell genomics biotechnologies enables the screening and collection of the somatic mutations, especial single nucleotide variations (SNVs), occurring in normal cells. Here, we established DSMNC: a database of somatic mutations in normal cells (http://dsmnc.big.ac.cn/), which provides most comprehensive catalogue of somatic SNVs in single cells from various normal tissues. In the current version, the database collected ∼0.8 million SNVs accumulated in ∼600 single normal cells (579 human cells and 39 mouse cells). The database interface supports the user-friendly capability of browsing and searching the SNVs and their annotation information. DSMNC, which serves as a timely and valuable collection of somatic mutations in individual normal cells, has made it possible to analyze the burdens and signatures of somatic mutations in various types of heterogeneous normal cells. Therefore, DSMNC will significantly improve our understanding of the characteristics of somatic mutations in normal cells.
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http://dx.doi.org/10.1093/nar/gky1045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6323907PMC
January 2019

Histone arginine methylation by Prmt5 is required for lung branching morphogenesis through repression of BMP signaling.

J Cell Sci 2018 07 25;131(14). Epub 2018 Jul 25.

State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, People's Republic of China

Branching morphogenesis is essential for the successful development of a functional lung to accomplish its gas exchange function. Although many studies have highlighted requirements for the bone morphogenetic protein (BMP) signaling pathway during branching morphogenesis, little is known about how BMP signaling is regulated. Here, we report that the protein arginine methyltransferase 5 (Prmt5) and symmetric dimethylation at histone H4 arginine 3 (H4R3sme2) directly associate with chromatin of to suppress its transcription. Inactivation of in the lung epithelium results in halted branching morphogenesis, altered epithelial cell differentiation and neonatal lethality. These defects are accompanied by increased apoptosis and reduced proliferation of lung epithelium, as a consequence of elevated canonical BMP-Smad1/5/9 signaling. Inhibition of BMP signaling by Noggin rescues the lung branching defects of mutant Taken together, our results identify a novel mechanism through which Prmt5-mediated histone arginine methylation represses canonical BMP signaling to regulate lung branching morphogenesis.
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http://dx.doi.org/10.1242/jcs.217406DOI Listing
July 2018

Copper-catalyzed selective radical-radical cross-coupling for C-S bond formation: an access to α-alkylthionitriles.

Chem Commun (Camb) 2018 May;54(44):5574-5577

National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, Jiangxi, P. R. China.

A new protocol for C-S bond formation was developed by selective cross-coupling between a thiyl radical and an isobutyronitrile radical. Using this strategy, a series of valuable α-alkylthionitrile derivatives were synthesized from basic starting materials. Preliminary mechanistic investigation was performed by EPR and XAFS, revealing that the transient thiyl radical could be stabilized by a copper catalyst to a persistent one. Therefore, on the basis of the persistent radical effect, selective radical-radical cross-coupling between the thiyl radical and the isobutyronitrile radical was achieved successfully in this work.
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http://dx.doi.org/10.1039/c8cc02371aDOI Listing
May 2018

Taxanes in combination with platinum derivatives for the treatment of ovarian cancer during pregnancy: A literature review
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Int J Clin Pharmacol Ther 2017 Sep;55(9):753-760

Ovarian cancer is one of the most common types of solid carcinoma diagnosed during pregnancy. Taxane plus a platinum derivative is a combination therapy that is predominantly used in the treatment of ovarian cancer in non-pregnant women. Pregnancy adds various complexities to a course of treatment. In pregnant patients diagnosed with cancer during the first trimester, the risks of fetal malformations and fetal loss increase following the administration of cytotoxic drugs, and this is higher with multi-agent vs. single-agent chemotherapy (~ 25 vs. 10%). Exposure during the second and third trimester has little influence on teratogenic effects but increases the risk of intrauterine growth retardation, prematurity, low birth weight, and bone marrow toxicity. The present study aimed to review the maternal and fetal safety of treatment with taxane plus platinum derivatives for ovarian cancer during pregnancy. Relevant literature was retrieved from the Embase and PubMed databases using the search terms "ovarian cancer", "pregnancy", "taxane", "paclitaxel", "docetaxel", "platinum", "cisplatin", and "carboplatin". All available data up until September 2016 was synthesized, with no language restrictions. A total of 11 articles (including 13 pregnancies and 14 newborns) were retrieved that reported on the use of standard-dose taxane and platinum chemotherapy, including 9 cases treated with paclitaxel and carboplatin, 3 cases treated with paclitaxel and cisplatin, and 1 case treated with docetaxel and cisplatin. In 13 of the 14 (92.9%) births included, a healthy neonate was born, with follow-up ranging from 2 to 160 months. The average weight of the neonates at the time of delivery was 2,442.1 g. In 7 of 9 the case reports that provided survival data, the mother was alive and disease-free at the end of follow-up (ranging from 2 to 40 months). In conclusion, combination therapy with taxanes and a platinum derivative may play a significant role in the management of pregnant patients with ovarian cancer during the second and third trimester. Exposure to this combination of agents during the second and third trimester does not appear to have a significant bearing on fetal mortality and abortion.
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http://dx.doi.org/10.5414/CP202995DOI Listing
September 2017

Tumor diversity and evolution revealed through RADseq.

Oncotarget 2017 Jun;8(26):41792-41805

Cancer Biology & Genetics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

Cancer is an evolutionary disease, and there is increasing interest in applying tools from evolutionary biology to understand cancer progression. Restriction-site associated DNA sequencing (RADseq) was developed for the field of evolutionary genetics to study adaptation and identify evolutionary relationships among populations. Here we apply RADseq to study tumor evolution, which allows for unbiased sampling of any desired frequency of the genome, overcoming the selection bias and cost limitations inherent to exome or whole-genome sequencing. We apply RADseq to both human pancreatic cancer and zebrafish melanoma samples. Using either a low-frequency (SbfI, 0.4% of the genome) or high-frequency (NsiI, 6-9% of the genome) cutter, we successfully identify single nucleotide substitutions and copy number alterations in tumors, which can be augmented by performing RADseq on sublineages within the tumor. We are able to infer phylogenetic relationships between primary tumors and metastases. These same methods can be used to identify somatic mosaicism in seemingly normal, non-cancerous tissues. Evolutionary studies of cancer that focus on rates of tumor evolution and evolutionary relationships among tumor lineages will benefit from the flexibility and efficiency of restriction-site associated DNA sequencing.
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http://dx.doi.org/10.18632/oncotarget.18355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5522028PMC
June 2017

Multiple drug transporters mediate the placental transport of sulpiride.

Arch Toxicol 2017 Dec 9;91(12):3873-3884. Epub 2017 Jun 9.

Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, 866 Yuhangtang Road, Hangzhou, 310058, China.

Sulpiride is a typical antipsychotic drug for the treatment of schizophrenia, depression and other psychological disorders. It has been proven that a small amount of sulpiride could cross the human placenta using an ex vivo placental perfusion model. However, the placental transfer mechanism has not been elucidated. Considering the structure of sulpiride, we speculated that the transporters expressed in placenta might be involved in sulpiride uptake across the blood-placenta barrier. The aim of our study was to determine which transporters contributed to the placental transfer of sulpiride. Our results revealed that sulpiride was a substrate of human organic cation transporter (hOCT) 3, human multidrug resistance protein (hMDR) 1 and human breast cancer resistance protein (hBCRP) using transfected cells expressing respective transporters. In addition, the accumulation of sulpiride in BeWo cells (a human choriocarcinoma cell line) was obviously affected by inhibitors of carnitine/organic cation transporter (OCTN) 2, MDR1 and BCRP. The accumulation of sulpiride in primary human trophoblast cells was obviously affected by inhibitors of OCT3, OCTN1 and OCTN2. The above results indicate that hOCTN1 and hOCTN2 likely contribute to the sulpiride uptake from maternal circulation to trophoblast cells, while hMDR1 and hBCRP mediate the efflux from trophoblast cells to maternal circulation, and hOCT3 probably is involved in the bidirectional transport of sulpiride between the placenta and fetal blood.
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http://dx.doi.org/10.1007/s00204-017-2008-8DOI Listing
December 2017

Multiple SLC and ABC Transporters Contribute to the Placental Transfer of Entecavir.

Drug Metab Dispos 2017 03 6;45(3):269-278. Epub 2017 Jan 6.

Laboratory of Pharmaceutical Analysis and Drug Metabolism, Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, Zhejiang, China (Z.M., X.Y., T.J., M.B., S.Z., H.J.); and Women's Hospital School of Medicine Zhejiang University, Hangzhou, China (C.Z., D.S.)

Entecavir (ETV), a nucleoside analog with high efficacy against hepatitis B virus, is recommended as a first-line antiviral drug for the treatment of chronic hepatitis B. However, scant information is available on the use of ETV in pregnancy. To better understand the safety of ETV in pregnant women, we aimed to demonstrate whether ETV could permeate placental barrier and the underlying mechanism. Our study showed that small amount of ETV could permeate across placenta in mice. ETV accumulation in activated or nonactivated BeWo cells (treated with or without forskolin) was sharply reduced in the presence of 100 µM of adenosine, cytidine, and in Na free medium, indicating that nucleoside transporters possibly mediate the uptake of ETV. Furthermore, ETV was proved to be a substrate of concentrative nucleoside transporter (CNT) 2 and CNT3, of organic cation transporter (OCT) 3, and of breast cancer resistance protein (BCRP) using transfected cells expressing respective transporters. The inhibition of ETV uptake in primary human trophoblast cells further confirmed that equilibrative nucleoside transporter (ENT) 1/2, CNT2/3, OCT3, and organic cation/carnitine transporter (OCTN) 2 might be involved in ETV transfer in human placenta. Therefore, ETV uptake from maternal circulation to trophoblast cells was possibly transported by CNT2/3, ENT1/2, and OCTN2, whereas ETV efflux from trophoblast cells to fetal circulation was mediated by OCT3, and efflux from trophoblast cells to maternal circulation might be mediated by BCRP, multidrug resistance-associated protein 2, and P-glycoprotein. The information obtained in the present study may provide a basis for the use of ETV in pregnancy.
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http://dx.doi.org/10.1124/dmd.116.073304DOI Listing
March 2017

3D nest-shaped SbO/RGO composite based high-performance lithium-ion batteries.

Nanoscale 2016 Oct;8(39):17131-17135

College of Chemistry and Environment, Beihang University, Beijing 100191, P. R. China.

A SbO/graphene composite with nest-shaped architecture has been successfully prepared. Compared with pure SbO materials, the SbO/graphene composite exhibits superior electrochemical performance as an anode material in lithium-ion batteries, and this should be attributed to the synergistic effects of the high conductivity of graphene and the novel nest-shaped structure of the composite.
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http://dx.doi.org/10.1039/c6nr06454jDOI Listing
October 2016

Unique features of mutations revealed by sequentially reprogrammed induced pluripotent stem cells.

Nat Commun 2015 Feb 18;6:6318. Epub 2015 Feb 18.

1] National Institute of Biological Sciences, NIBS, Beijing 102206, China [2] Clinical and Translational Research Center of Shanghai First Maternity &Infant Hospital, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.

Although viable mice can be generated from induced pluripotent stem cells (iPSCs), the impact of accumulated mutations on the developmental potential of the resulting iPSCs remains to be determined. Here, we demonstrate that all-iPSC mice generated through tetraploid blastocysts complementation can tolerate the accumulation of somatic mutations for up to six generations using a Tet-on inducible reprogramming system. But, the viability of the all-iPS mice decreased with increasing generations. A whole-genome sequencing survey revealed that thousands of single-nucleotide variations (SNVs), including 44 non-synonymous ones, accumulated throughout the sequential reprogramming process. Subsequent analysis provides evidence that these accumulated SNVs account for the gradual reduction in viability of the resultant all-iPSC mice. Unexpectedly, our present reprogramming system revealed that pluripotent stem cells are heterogeneous in terms of possessing a set of copy-number alterations (CNAs). These CNAs are unique for pluripotent cells and subsequently disappear in the differentiating progenies.
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http://dx.doi.org/10.1038/ncomms7318DOI Listing
February 2015

Knockdown of STAT3 expression in SKOV3 cells by biodegradable siRNA-PLGA/CSO conjugate micelles.

Colloids Surf B Biointerfaces 2015 Mar 28;127:155-63. Epub 2015 Jan 28.

Women's Hospital, Medicine of School, Zhejiang University, Hangzhou 310006, China.

Biodegradable and biocompatible poly(d,l-lactic-co-glycolic acid) (PLGA)was conjugated to the 5'-thiol end of signal transducer and activator of transcription 3 (STAT3) small interfering RNA (STAT3-siRNA) via a disulfide bond. In aqueous environments, these siRNA-PLGA conjugates can spontaneously form core/shell type spherical micelles with a particle size of about 200 nm. A biodegradable, low molecular weight cationic polymer, chitosan oligosaccharide (CSO), was added to the siRNA-PLGA micelles at different nitrogen to phosphate (N/P) ratios to form stable, spherical siRNA-PLGA/CSO micelles with sizes of 150-180 nm. The siRNA-PLGA/CSO micelles were produced via ionic complexation between negatively charged siRNA and positively charged CSO on the outer shell of the micelles. The siRNA-PLGA/CSO micelles exhibited superior cellular uptake and STAT3 gene silencing efficiency in SKOV3 ovarian cancer cells when compared with siRNA/CSO complexes at the same N/P ratios with no significant differences with lipofectamine 2000. Furthermore, the siRNA-PLGA/CSO micelles showed that the efficiencies of cellular uptake and STAT3 gene silencing gradually increased with increasing N/P ratios. The siRNA-PLGA/CSO micelles also inhibited the growth of SKOV3 cells, as well as, promoted apoptosis of the cells. These results indicate that siRNA-PLGA/CSO micelles can be utilized as a novel and efficient siRNA carrier to treat a variety of diseases.
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http://dx.doi.org/10.1016/j.colsurfb.2015.01.034DOI Listing
March 2015

[Preparation of microspheres of superoxide dismutase and their activities].

Zhejiang Da Xue Xue Bao Yi Xue Ban 2013 Nov;42(6):666-70

Women's Hospital, School of Medicine,Zhejiang University, Hangzhou 310006, China.

Objective: To prepare the poly(lactic-co-glycolic acid) (PLGA) microspheres and composite alginate-chitosan-PLGA microspheres containing superoxide dismutase (SOD) and to evaluate their SOD activities.

Methods: The SOD-PLGA microspheres were prepared by W/O/W emulsification method, and the composite microspheres were prepared by two steps:alginate-chitosan microcapsules were first prepared by a modified emulsification and ion crosslinking method, and then they were further dispersed in PLGA to form the composite microspheres. The SOD concentration was determined by Coomassie method, its activity was measured by xanthine oxidase system.

Results: The SOD activity was less sensitive to temperature and sensitive to pH, organic solvents, ultrasound and vigorous stir without iced bath. The entrapment efficiencies of SOD in PLGA (50:50) microspheres, PLGA (70:30) microspheres, alginate-chitosan microcapsules, the composite PLGA (50:50) microspheres and the composite PLGA (70:30) microspheres were 36.42%±1.81%, 66.18%±0.05%, 91.08%±1.28%, 87.30%±3.89% and 83.19%±3.48%, respectively. In vitro release tests demonstrated that the SOD activities in 50:50 composite microspheres were higher than that in the PLGA ones at 1 h, 8 h and 1 w.

Conclusion: The composite alginate-chitosan-PLGA microspheres for SOD sustained release can significantly improve the protein entrapment efficiency and maintain its protein activity.
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November 2013