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Journal International Journal of Nanomedicine

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International Journal of Nanomedicine; doi:10.2147/ijn

Hadeer M. Abdelaziz, Ahmed O. Elzoghby, Maged W. Helmy, Magda W. Samaha, Jia-You Fang, May S. Freag
International Journal of Nanomedicine, Volume 14, pp 499-517; doi:10.2147/ijn.s188335

Abstract:Liquid crystalline assembly for potential combinatorial chemo-herbal drug delivery to lung cancer cells Hadeer M Abdelaziz,1,2 Ahmed O Elzoghby,1,3–5 Maged W Helmy,1,6 Magda W Samaha,1,3 Jia-You Fang,7–9 May S Freag1,4,5,10 1Cancer Nanotechnology Research Laboratory (CNRL), Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt; 2Department of Pharmaceutics, Faculty of Pharmacy, Damanhur University, Damanhur, Egypt; 3Department of Industrial Pharmacy, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt; 4Division of Engineering in Medicine, Department of Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA 02115, USA; 5Harvard-MIT Division of Health Sciences and Technology (HST), Cambridge, MA 02139, USA; 6Department of Pharmacology and Toxicology, Faculty of Pharmacy, Damanhur University, Damanhur, Egypt; 7Pharmaceutics Laboratory, Graduate Institute of Natural Products, Chang Gung University, Taoyuan 333, Taiwan; 8Research Center for Industry of Human Ecology and Research Center for Chinese Herbal Medicine, Chang Gung University of Science and Technology, Kweishan, Taoyuan 333, Taiwan; 9Department of Anesthesiology, Chang Gung Memorial Hospital, Kweishan, Taoyuan 333, Taiwan; 10Department of Pharmaceutics, Faculty of Pharmacy, Alexandria University, Alexandria 21521, Egypt Background: Lung cancer is the most common cancer and the leading cause of total deaths worldwide. Its classified into two major types including non-small cell lung carcinoma (NSCLC) and small cell lung carcinoma (SCLC) based on the origin of abnormal lung cells as well as the smoking status of the patient. NSCLC is the most common and aggressive type of lung cancer representing 80%–85% of all cases. Purpose: The aim of the study was to present lyotropic liquid crystalline nanoparticles (LCNPs) as promising carriers for co-delivery of the chemotherapeutic agent, pemetrexed (PMX) and the herbal drug, resveratrol (RSV) for effective lung cancer management.Methods: The proposed PMX-RSV-LCNPs were prepared by hydrotrope method. Hydrophobic ion pairing with cetyl trimethyl ammonium bromide (CTAB) was implemented to increase the encapsulation efficiency of the hydrophilic PMX up to 95%±3.01%.Results: The tailored PMX-RSV-LCNPs exhibited a particle size of 173±0.26 nm and biphasic release pattern with a relatively initial burst release within first 3–4 hour followed by sustained release up to 24 hours. Moreover, PMX-RSV-LCNPs manifested superior concentration and time dependent cytotoxicity profile against A549 lung cancer cells with IC50 4.0628 µg/mL. Besides, the enhanced cellular uptake profile based on bioadhesive properties of glyceryl monoolein (GMO) as well as energy independent (cholesterol dependent) pattern. In-vivo evaluations against urethane induced lung cancer bearing mice demonstrated the potentiality of PMX-RSV-LCNPs in tumor growth inhibition via inhibition of angiogenesis and induction of...
Yuzhen Hou, Hui Wang, Fan Zhang, Fengyuan Sun, Meng Xin, Mengshuang Li, Jun Li, Xianggen Wu
International Journal of Nanomedicine, Volume 14, pp 557-571; doi:10.2147/ijn.s191337

Abstract:Novel self-nanomicellizing solid dispersion based on rebaudioside A: a potential nanoplatform for oral delivery of curcumin Yuzhen Hou,1 Hui Wang,1 Fan Zhang,1 Fengyuan Sun,1 Meng Xin,1,2 Mengshuang Li,1,3 Jun Li,4 Xianggen Wu1 1Department of Pharmacy, College of Chemical Engineering, Qingdao University of Science and Technology, Qingdao 266042, China; 2Department of Ophthalmology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai 264100, China; 3Pharmacy Intravenous Admixture Services, Qingdao Women and Children’s Hospital, Qingdao 266034, China; 4Qingdao Eye Hospital, Shandong Eye Institute, Shandong Academy of Medical Sciences, Qingdao 266071, China Purpose: Rebaudioside A (RA) has nanocarrier characteristics that allow it to self-assemble into micelles in aqueous solutions. The purpose of this study was to determine if a self-nanomicellizing solid dispersion based on RA could be utilized as an oral nano-drug delivery system.Materials and methods: Curcumin (Cur) served as a model hydrophobic drug, and a Cur-loaded self-nanomicellizing solid dispersion based on RA (RA-Cur) was formulated. The properties of RA-Cur in the solid state and in aqueous solution were characterized. The antioxidant activity and mechanism of RA-Cur endocytosis were also investigated. The pharmacokinetics, biodistribution in the intestinal tract, and anti-inflammation properties were also evaluated in vivo.Results: RA-Cur could be easily fabricated, and it self-assembled into ultrasmall micelles (particle size ~4 nm) in a homogeneous distribution state (polydispersity index
Yanxiang Xue, Xiaofang Hong, Jie Gao, Renze Shen, Zhanchao Ye
International Journal of Nanomedicine, Volume 14, pp 483-498; doi:10.2147/ijn.s184396

Abstract:Preparation and biological characterization of the mixture of poly(lactic-co-glycolic acid)/chitosan/Ag nanoparticles for periodontal tissue engineering Yanxiang Xue,1,2 Xiaofang Hong,3 Jie Gao,1,2 Renze Shen,3 Zhanchao Ye3 1Department of Stomatology, The Liwan Hospital of The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou 510000, China; 2Department of Stomatology, Southern Medical University Guangzhou, Guangzhou 510515, China; 3Department of Stomatology, Zhongshan Hospital of Xiamen University, Medical College of Xiamen University, Xiamen University, Xiamen 361000, China Objective: This study aims to produce nanoparticles of chitosan (CS), poly(lactic-co-glycolic acid) (PLGA), and silver and investigate the optimal composite ratio of these three materials for periodontal tissue regeneration.Methods: PLGA nanoparticles (nPLGA), CS nanoparticles (nCS), and silver nanoparticles (nAg) were prepared. The antibacterial properties of single nanoparticles and their effects on the proliferation and mineralization of periodontal membrane cells were investigated. Different ratios of nPLGA and nCS were combined, the proliferation and mineralization of periodontal membrane cells were investigated, and based on the results, the optimal ratio was determined. Finally, nPLGA and nCS in optimal ratio were combined with nAg, and the effects of the complex of these three materials on the proliferation and mineralization of periodontal membrane cells were investigated and tested in animals.Results: The single nanoparticles were found to have no cytotoxicity and were able to promote cell mineralization. nCS and nAg in low concentrations showed antibacterial activity; however, nAg inhibited cell proliferation. The nPLGA and nCS complex in 3:7 ratio contributed to cell mineralization and had no cytotoxicity. nPLGA/nCS/nAg complex, which had the optimal proportion of the three materials, showed no cytotoxicity and contributed to cell mineralization.Conclusion: nPLGA/nCS/nAg complex had no cytotoxicity and contributed to cell mineralization. The 3:7 ratio of nPLGA/nCS and 50 µg/mL nAg were found as the optimal proportion of the three materials. Keywords: nanoparticles, bone regeneration, periodontitis
Yeo Jin Kim, Md. Mujibur Rahman, Sang Min Lee, Jung Min Kim, Kwangsik Park, Joo-Hyon Kang, Young Rok Seo
International Journal of Nanomedicine, Volume 14, pp 393-405; doi:10.2147/ijn.s174515

Abstract:Assessment of in vivo genotoxicity of citrated-coated silver nanoparticles via transcriptomic analysis of rabbit liver tissue Yeo Jin Kim,1,2 Md Mujibur Rahman,1 Sang Min Lee,2 Jung Min Kim,3 Kwangsik Park,4 Joo-Hyon Kang,5 Young Rok Seo1,2 1Institute of Environmental Medicine for Green Chemistry, Dongguk University Biomedi Campus, Ilsandong-gu, Goyang-si, Republic of Korea; 2Department of Life Science, Dongguk University Biomedi Campus, Ilsandong-gu, Goyang-si, Republic of Korea; 3Genoplan Korea, Inc., Seocho-gu, Seoul, Republic of Korea; 4College of Pharmacy, Dongduk Women’s University, Seongbuk-gu, Seoul, Republic of Korea; 5Department of Civil & Environmental Engineering, Dongguk University, Jung-gu, Seoul, Republic of Korea Background: Silver nanoparticles (AgNPs) are widely used in industrial and household applications, arousing concern regarding their safety in humans. The risks posed by stabilizer-coated AgNPs continue to be unclear, and assessing their toxicity is for an understanding of the safety issues involved in their use in various applications. Purpose: We aimed to investigated the long-term toxicity of citrate-coated silver nanoparticles (cAgNPs) in liver tissue using several toxicity tests and transcriptomic analysis at 7 and 28 days after a single intravenous injection into rabbit ear veins (n=4). Materials and methods: The cAgNPs used in this study were in the form of a 20% (w/v) aqueous solution, and their size was 7.9±0.95 nm, measured using transmission electron microscopy. The animal experiments were performed based on the principles of good laboratory practice. Results: Our results showed that the structure and function of liver tissue were disrupted due to a single exposure to cAgNPs. In addition, in vivo comet assay showed unrepaired genotoxicity in liver tissue until 4 weeks after a single injection, suggesting a potential carcinogenic effect of cAgNPs. In our transcriptomic analysis, a total of 244 genes were found to have differential expression at 28 days after a single cAgNP injection. Carefully curated pathway analysis of these genes using Pathway Studio and Ingenuity Pathway Analysis tools revealed major molecular networks responding to cAgNP exposure and indicated a high correlation of the genes with inflammation, hepatotoxicity, and cancer. Molecular validation suggested potential biomarkers for assessing the toxicity of accumulated cAgNPs. Conclusion: Our investigation highlights the risk associated with a single cAgNP exposure with unrepaired damage persisting for at least a month. Keywords: nanotoxicity, liver toxicity, prolonged tissue damage, differentially expressed genes, molecular pathway analysis
Xinxin Yu, Renshu Zhang, Lei Lei, Qianqian Song, Xingyi Li
International Journal of Nanomedicine, Volume 14, pp 591-603; doi:10.2147/ijn.s179118

Abstract:High drug payload nanoparticles formed from dexamethasone-peptide conjugates for the treatment of endotoxin-induced uveitis in rabbit Xinxin Yu, Renshu Zhang, Lei Lei, Qianqian Song, Xingyi Li Institute of Biomedical Engineering, School of Ophthalmology and Optometry and Eye Hospital, Wenzhou Medical University, Wenzhou 325027, People’s Republic of China Purpose: To develop and demonstrate the effectiveness of a novel dexamethasone (Dex) nanoformulation for treating uveitis. Materials and methods: We designed and screened a dexamethasone-peptide conjugate (Dex-SA-FFFE), formed via a biodegradable ester bond linkage, that could spontaneously form high drug payload nanoparticles in aqueous solution for treating uveitis. Results: An in vitro release study indicated that Dex and Dex-SA-FFFE sustainably released from Dex-SA-FFFE nanoparticles over a 48 h study period. Meanwhile, the formed Dex-SA-FFFE nanoparticles hardly caused cytotoxicity in human corneal epithelial cell at drug concentrations up to 1 mM after 24 h of incubation but reduced cell viability after 48 h and 72 h of incubation. An in vitro anti-inflammatory efficacy assay showed that the Dex-SA-FFFE nanoparticles exhibited a comparable anti-inflammatory efficacy to that of Dex in lipopolysaccharide (LPS)-activated RAW264.7 macrophages via significant decreases in the secretion of various pro-inflammatory cytokines (e.g., nitric oxide, tumor necrosis factor-α, interleukin-6). Topical instillation of Dex-SA-FFFE nanoparticles showed good ocular tolerance without causing changes in corneal thickness and intraocular pressure during the entire study period. Furthermore, topical instillation of Dex-SA-FFFE nanoparticles displayed a comparable in vivo therapeutic efficacy to that of dexamethasone sodium phosphate (Dexp) aqueous solutions in an endotoxin-induced uveitis (EIU) rabbit model. Conclusion: Based on these results, it is reasonable to believe that the proposed Dex-SA-FFFE nanoparticles might have great application for the treatment of anterior uveitis. Keywords: drug-peptide conjugate, self-assembly, ocular inflammation, in vivo, nanoparticle
Hanmei Bao, Qing Zhang, Zhao Yan
International Journal of Nanomedicine, Volume 14, pp 383-391; doi:10.2147/ijn.s188984

Abstract:The impact of camptothecin-encapsulated poly(lactic-co-glycolic acid) nanoparticles on the activity of cytochrome P450 in vitro Hanmei Bao, Qing Zhang, Zhao Yan Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin’s Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China Background: Poly(lactic-co-glycolic acid) (PLGA) has emerged as a promising anticancer drug delivery scaffold. Camptothecin (CPT) has been fabricated into a variety of nano-sized formulations to improve drug action. We report an experimental study on the effect of CPT-encapsulated PLGA (PLGA-CPT) nanoparticles (NPs) on drug-metabolizing cytochrome P450 enzyme, CYP3A4. Materials and methods: PLGA-CPT NPs were prepared by a single emulsion–solvent evaporation method. Results: Transmission electron micrography showed that the NPs had a round and regular shape with a mean diameter of 94.6±5.7 nm. An in vitro drug release study showed that CPT was continuously released for 48 h. PLGA-CPT NPs showed greater cytotoxic effects on the HepG2 cell line compared with an equal dose of free CPT. Correlation with 4-h uptake data suggested that this was due to a higher cellular uptake amount of CPT from PLGA-CPT NPs than from free CPT. PLGA-CPT NPs tended to inhibit CYP3A4 activity isolated from HepG2 cells. However, PLGA-CPT NPs had no effect on the CYP3A4 mRNA levels. Furthermore, the interaction between PLGA-CPT NPs and CYP3A4 was investigated by ultraviolet–visible absorption spectroscopy and fluorescence spectroscopy. Conclusion: Taken together, the results demonstrate that CYP3A4 may be inhibited by PLGA-CPT NPs and interference with biotransformation should be considered when using NPs as drug delivery vesicles. Keywords: camptothecin, cytochrome P450, nanoparticle, drug delivery
Emre Firlar, Meagan Ouy, Leigha Covnot, Yuan Xing, Daniel Lee, Alessandro Chan, Yi He, Boao Song, Solomon Afelik, Yong Wang, et al.
International Journal of Nanomedicine, Volume 14, pp 371-382; doi:10.2147/ijn.s169506

Abstract:In situ graphene liquid cell-transmission electron microscopy study of insulin secretion in pancreatic islet cells Emre Firlar,1,2 Meagan Ouy,1 Leigha Covnot,1 Yuan Xing,3 Daniel Lee,1,4 Alessandro Chan,1,4 Yi He,3 Boao Song,2 Solomon Afelik,4 Yong Wang,3 Reza Shahbazian-Yassar,2 Jose Oberholzer,1,3 Tolou Shokuhfar1 1Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, USA; 2University of Illinois at Chicago, Department of Mechanical and Industrial Engineering, Chicago, IL, USA; 3University of Virginia, Department of Surgery, Charlottesville, VA, USA; 4University of Illinois at Chicago, Department of Surgery, Chicago, IL, USA Background: Islet cell transplantation is one of the key treatments for type 1 diabetes. Understanding the mechanisms of insulin fusion and exocytosis are of utmost importance for the improvement of the current islet cell transplantation and treatment of diabetes. These phenomena have not been fully evaluated due either to the lack of proper dynamic imaging, or the lack of proper cell preservation during imaging at nanoscales. Methods: By maintaining the native environment of pancreatic β-cells between two graphene monolayer sheets, we were able to monitor the subcellular events using in situ graphene liquid cell (GLC)-transmission electron microscopy (TEM) with both high temporal and high spatial resolution. Results: For the first time, the nucleation and growth of insulin particles until the later stages of fusion were imaged at nanometer scales. The release of insulin from plasma membrane involves the degradation of plasma membrane and drastic reductions in the shorter axis of the insulin particles. Sequential exocytosis results indicated the nucleation, growth and attachment of the new insulin particles to the already anchored ones, which is thermodynamically favorable due to the reduction in total surface, further reducing the Gibbs free energy. The retraction of the already anchored insulin toward the cell is also monitored for the first time live at nanoscale resolution. Conclusion: Investigation of insulin granule dynamics in β-cells can be investigated via GLC-TEM. Our findings with this technology open new realms for the development of novel drugs on pathological pancreatic β-cells, because this approach facilitates observing the effects of the stimuli on the live cells and insulin granules. Keywords: transmission electron microscopy, graphene liquid cell, insulin secretion, exocytosis
Wei Hong, Lipeng Liu, Zehui Zhang, Yining Zhao, Dexian Zhang, Mingchun Liu
International Journal of Nanomedicine, Volume 14, pp 337-338; doi:10.2147/ijn.s197963

Abstract:Insights into the antibacterial mechanism of PEGylated nano-bacitracin A against Streptococcus pneumonia: both penicillin-sensitive and penicillin-resistant strains [Corrigendum] Insights into the antibacterial mechanism of PEG ylated nano-bacitracin A against Streptococcus pneumonia: both penicillin-sensitive and penicillinresistant strains [Corrigendum]Hong W, Liu L, Zhang Z, Zhao Y, Zhang D, Liu M. Int J Nanomedicine. 2018;13:6297–6309.The author wishes to advise that on page 6306, Figure 7 parts A and B are incorrect. The correct figure parts are included below:Read the original article
Xiaoxia Li, Hong Xiao, Caowen Lin, Weitong Sun, Teng Wu, Jin Wang, Bin Chen, Xia Chen, Du Cheng
International Journal of Nanomedicine, Volume 14, pp 649-665; doi:10.2147/ijn.s189819

Abstract:Synergistic effects of liposomes encapsulating atorvastatin calcium and curcumin and targeting dysfunctional endothelial cells in reducing atherosclerosis Xiaoxia Li,1,* Hong Xiao,1,* Chaowen Lin,2,3,* Weitong Sun,1 Teng Wu,1 Jin Wang,4 Bin Chen,3 Xia Chen,2 Du Cheng1 1PCFM Lab of Ministry of Education, School of Materials Science and Engineering, Sun Yat-sen University, Guangzhou 510275, People’s Republic of China; 2Department of Cardiovascular Medicine, The Third Affiliated Hospital, Southern Medical University, Guangzhou 510630, People’s Republic of China; 3Department of Orthopedics and Traumatology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, People’s Republic of China; 4Department of Radiology, The Third Affiliated Hospital, Sun Yat-sen University, Guangzhou 510630, People’s Republic of China *These authors contributed equally to this work Background: Atherosclerosis is a major cardiovascular disease that causes ischemia of the heart, brain, or extremities, and can lead to infarction. The hypolipidemic agent atorvastatin calcium (Ato) alleviates atherosclerosis by reducing plasma lipid and inflammatory factors. However, the low bioavailability of Ato limits its widespread use and clinical effectiveness. Curcumin (Cur), a natural polyphenol with antioxidation and anti-inflammation bioactivities, has potential anti-atherosclerosis activity and may reduce Ato-induced cytotoxicity.Materials and methods: Liposomes modified using a targeting ligand (E-selectin-binding peptide) were prepared to co-deliver Ato and Cur to dysfunctional endothelial cells (ECs) overexpressing E-selectin. Molecules involved in the inhibition of adhesion (E-selectin and intercellular cell adhesion molecule-1 [ICAM-1]) and inflammation (IL-6 and monocyte chemotactic protein 1 [MCP-1]) in human aortic endothelial cells were evaluated using real-time quantitative PCR, flow cytometry, and immunofluorescence staining. The antiatherosclerosis effects of liposomes co-loaded with Ato and Cur in vivo were evaluated using ApoE knockout (ApoE-/-) mice.Results: Targeted liposomes delivered Ato and Cur to dysfunctional ECs, resulting in synergistic suppression of adhesion molecules (E-selectin and ICAM-1) and plasma lipid levels. Moreover, this treatment reduced foam cell formation and the secretion of inflammatory factors (IL-6 and MCP-1) by blocking monocyte migration into the intima. In addition, Cur successfully reduced Ato-inducible cytotoxicity.Conclusion: Both in vitro and in vivo experiments demonstrated that cell-targeted co-delivery of Ato and Cur to dysfunctional ECs drastically reduces atherosclerotic lesions with fewer side effects than either Ato or Cur alone. Keywords: combined therapy, atorvastatin calcium, curcumin, antiatherosclerosis, targeted codelivery
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