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Sousa A, Kulkarni R, Johannessen M, Wohland T, Škalko-Basnet N, Obuobi S. Decoding interactions between biofilms and DNA nanoparticles. Biofilm 2025; 9:100260. [PMID: 40026394 PMCID: PMC11871490 DOI: 10.1016/j.bioflm.2025.100260] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2024] [Revised: 01/20/2025] [Accepted: 02/06/2025] [Indexed: 03/05/2025] Open
Abstract
Biofilms present a great challenge in antimicrobial therapy due to their inherent tolerance to conventional antibiotics, promoting the need for advanced drug delivery strategies that improve therapy. While various nanoparticles (NPs) have been reported for this purpose, DNA-based NPs remain a largely unexploited resource against biofilm-associated infections. To fill this gap and to lay the groundwork for their potential therapeutic exploitation, we investigated the diffusion, penetration, and retention behaviors of three DNA-based nanocarriers -plain or modified-within P. aeruginosa biofilms. Watson-Crick base pairing or hydrophobic interactions mediated the formation of the plain NPs whilst electrostatic interaction enabled optimization of coated NPs via microfluidic mixing. We assessed the interactions of the nanocarriers with biofilm structures via Single Plane Illumination Microscopy - Fluorescence Correlation Spectroscopy (SPIM-FCS) and Confocal Laser Scanning Microscopy (CLSM). We demonstrate the impact of microfluidic parameters on the physicochemical properties of the modified DNA NPs and their subsequent distinct behaviors in the biofilm. Our results show that single stranded DNA micelles (ssDNA micelle) and tetrahedral DNA nanostructures (TDN) had similar diffusion and penetration profiles, whereas chitosan-coated TDN (TDN-Chit) showed reduced diffusion and increased biofilm retention. This is attributable to the relatively larger size and positive surface charge of the TDN-Chit NPs. The study shows first and foremost that DNA can be used as building block in drug delivery for antibiofilm therapeutics. Moreover, the overall behavioral findings are pivotal for the strategic selection of therapeutic agents to be encapsulated within these structures, possibly affecting the treatment efficacy. This research not only highlights the underexplored potential of DNA-based NPs in antibiofilm therapy but also advocates for further studies using different optimization strategies to refine these nanocarrier systems for targeted treatments in biofilm-related infections.
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Affiliation(s)
- Alexandra Sousa
- Drug Transport and Delivery Research Group, Department of Pharmacy, UIT The Arctic University of Norway, Tromsø, Norway
| | - Rutuparna Kulkarni
- Department of Biological Sciences, National University of Singapore, Singapore
- Centre for BioImaging Sciences, National University of Singapore, Singapore
| | - Mona Johannessen
- Host Microbe Interaction Research Group, Department of Medical Biology, UIT The Arctic University of Norway, Tromsø, Norway
| | - Thorsten Wohland
- Department of Biological Sciences, National University of Singapore, Singapore
- Centre for BioImaging Sciences, National University of Singapore, Singapore
| | - Nataša Škalko-Basnet
- Drug Transport and Delivery Research Group, Department of Pharmacy, UIT The Arctic University of Norway, Tromsø, Norway
| | - Sybil Obuobi
- Drug Transport and Delivery Research Group, Department of Pharmacy, UIT The Arctic University of Norway, Tromsø, Norway
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Zeshan M, Amjed N, Ashraf H, Farooq A, Akram N, Zia KM. A review on the application of chitosan-based polymers in liver tissue engineering. Int J Biol Macromol 2024; 262:129350. [PMID: 38242400 DOI: 10.1016/j.ijbiomac.2024.129350] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Revised: 12/29/2023] [Accepted: 01/07/2024] [Indexed: 01/21/2024]
Abstract
Chitosan-based polymers have enormous structural tendencies to build bioactive materials with novel characteristics, functions, and various applications, mainly in liver tissue engineering (LTE). The specific physicochemical, biological, mechanical, and biodegradation properties give the effective ways to blend these biopolymers with synthetic and natural polymers to fabricate scaffolds matrixes, sponges, and complexes. A variety of natural and synthetic biomaterials, including chitosan (CS), alginate (Alg), collagen (CN), gelatin (GL), hyaluronic acid (HA), hydroxyapatite (HAp), polyethylene glycol (PEG), polycaprolactone (PCL), poly(lactic-co-glycolic) acid (PGLA), polylactic acid (PLA), and silk fibroin gained considerable attention due to their structure-properties relationship. The incorporation of CS within the polymer matrix results in increased mechanical strength and also imparts biological behavior to the designed PU formulations. The significant and growing interest in the LTE sector, this review aims to be a detailed exploration of CS-based polymers biomaterials for LTE. A brief explanation of the sources and extraction, properties, structure, and scope of CS is described in the introduction. After that, a full overview of the liver, its anatomy, issues, hepatocyte transplantation, LTE, and CS LTE applications are discussed.
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Affiliation(s)
- Muhammad Zeshan
- Department of Chemistry, University of Agriculture, Faisalabad, Pakistan
| | - Nyla Amjed
- Department of Chemistry, The University of Lahore, Lahore, Pakistan
| | - Humna Ashraf
- Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan
| | - Ariba Farooq
- Department of Chemistry, The University of Lahore, Lahore, Pakistan
| | - Nadia Akram
- Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan
| | - Khalid Mahmood Zia
- Department of Chemistry, Government College University Faisalabad, Faisalabad 38000, Pakistan.
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3
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Jin Y, Guo YH, Li JC, Li Q, Ye D, Zhang XX, Li JT. Vascular endothelial growth factor protein and gene delivery by novel nanomaterials for promoting liver regeneration after partial hepatectomy. World J Gastroenterol 2023; 29:3748-3757. [PMID: 37426320 PMCID: PMC10324527 DOI: 10.3748/wjg.v29.i24.3748] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 05/13/2023] [Accepted: 06/02/2023] [Indexed: 06/28/2023] Open
Abstract
Partial hepatectomy (PH) can lead to severe complications, including liver failure, due to the low regenerative capacity of the remaining liver, especially after extensive hepatectomy. Liver sinusoidal endothelial cells (LSECs), whose proliferation occurs more slowly and later than hepatocytes after PH, compose the lining of the hepatic sinusoids, which are the smallest blood vessels in the liver. Vascular endothelial growth factor (VEGF), secreted by hepatocytes, promotes LSEC proliferation. Supplementation of exogenous VEGF after hepatectomy also increases the number of LSECs in the remaining liver, thus promoting the reestablishment of the hepatic sinusoids and accelerating liver regeneration. At present, some shortcomings exist in the methods of supplementing exogenous VEGF, such as a low drug concentration in the liver and the reaching of other organs. More-over, VEGF should be administered multiple times and in large doses because of its short half-life. This review summarized the most recent findings on liver regeneration and new strategies for the localized delivery VEGF in the liver.
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Affiliation(s)
- Yun Jin
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Ying-Hao Guo
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Jia-Cheng Li
- Department of General Surgery, Yuhuan Second People’s Hospital, Taizhou 317600, Zhejiang Province, China
| | - Qi Li
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Dan Ye
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Xiao-Xiao Zhang
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
| | - Jiang-Tao Li
- Department of Hepatopancreatobiliary Surgery, The Second Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310009, Zhejiang Province, China
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4
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Chung S, Lee CM, Zhang M. Advances in nanoparticle-based mRNA delivery for liver cancer and liver-associated infectious diseases. NANOSCALE HORIZONS 2022; 8:10-28. [PMID: 36260016 PMCID: PMC11144305 DOI: 10.1039/d2nh00289b] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
The liver is a vital organ that functions to detoxify the body. Liver cancer and infectious diseases such as influenza and malaria can fatally compromise liver function. mRNA delivery is a relatively new means of therapeutic treatment which enables expression of tumor or pathogenic antigens, and elicits immune responses for therapeutic or prophylactic effect. Novel nanoparticles with unique biological properties serving as mRNA carriers have allowed mRNA-based therapeutics to become more clinically viable and relevant. In this review, we highlight recent progress in development of nanoparticle-based mRNA delivery systems for treatment of various liver diseases. First, we present developments in nanoparticle systems used to deliver mRNAs, with specific focus on enhanced cellular uptake and endosomal escape achieved through the use of these nanoparticles. To provide context for diseases that target the liver, we provide an overview of the function and structure of the liver, as well as the role of the immune system in the liver. Then, mRNA-based therapeutic approaches for addressing HCC are highlighted. We also discuss nanoparticle-based mRNA vaccines for treating hepatotropic infectious diseases. Finally, we present current challenges in the clinical translation of nanoparticle-based mRNA delivery systems and provide outlooks for their utilization in treating liver-related diseases.
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Affiliation(s)
- Seokhwan Chung
- Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, USA.
| | - Chan Mi Lee
- Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, USA.
| | - Miqin Zhang
- Department of Materials Science and Engineering, University of Washington, Seattle, Washington 98195, USA.
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5
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Chan T, Grisch-Chan HM, Schmierer P, Subotic U, Rimann N, Scherer T, Hetzel U, Bozza M, Harbottle R, Williams JA, Steblaj B, Ringer SK, Häberle J, Sidler X, Thöny B. Delivery of non-viral naked DNA vectors to liver in small weaned pigs by hydrodynamic retrograde intrabiliary injection. Mol Ther Methods Clin Dev 2022; 24:268-279. [PMID: 35211639 PMCID: PMC8829443 DOI: 10.1016/j.omtm.2022.01.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Accepted: 01/16/2022] [Indexed: 11/09/2022]
Abstract
Hepatic gene therapy by delivering non-integrating therapeutic vectors in newborns remains challenging due to the risk of dilution and loss of efficacy in the growing liver. Previously we reported on hepatocyte transfection in piglets by intraportal injection of naked DNA vectors. Here, we established delivery of naked DNA vectors to target periportal hepatocytes in weaned pigs by hydrodynamic retrograde intrabiliary injection (HRII). The surgical procedure involved laparotomy and transient isolation of the liver. For vector delivery, a catheter was placed within the common bile duct by enterotomy. Under optimal conditions, no histological abnormalities were observed in liver tissue upon pressurized injections. The transfection of hepatocytes in all tested liver samples was observed with vectors expressing luciferase from a liver-specific promoter. However, vector copy number and luciferase expression were low compared to hydrodynamic intraportal injection. A 10-fold higher number of vector genomes and luciferase expression was observed in pigs using a non-integrating naked DNA vector with the potential for replication. In summary, the HRII application was less efficient (i.e., lower luciferase activity and vector copy numbers) than the intraportal delivery method but was significantly less distressful for the piglets and has the potential for injection (or re-injection) of vector DNA by endoscopic retrograde cholangiopancreatography.
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Affiliation(s)
- Tatjana Chan
- Department of Farm Animals, Division of Swine Medicine of the Vetsuisse Faculty University of Zurich, Zurich, Switzerland
| | - Hiu Man Grisch-Chan
- Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Philipp Schmierer
- Department of Small Animal Surgery, Vetsuisse Faculty University of Zurich, Zurich, Switzerland
| | - Ulrike Subotic
- Department of Surgery, University Children's Hospital Basel, Basel, Switzerland
| | - Nicole Rimann
- Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Tanja Scherer
- Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Udo Hetzel
- Department of Pathology, Vetsuisse Faculty University of Zurich, Zurich, Switzerland
| | - Matthias Bozza
- DNA Vector Laboratory, DKFZ Heidelberg, Heidelberg, Germany
| | | | | | - Barbara Steblaj
- Department of Diagnostics and Clinical Services, Section of Anesthesiology, Vetsuisse Faculty University of Zurich, Zurich, Switzerland
| | - Simone K Ringer
- Department of Diagnostics and Clinical Services, Section of Anesthesiology, Vetsuisse Faculty University of Zurich, Zurich, Switzerland
| | - Johannes Häberle
- Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Xaver Sidler
- Department of Farm Animals, Division of Swine Medicine of the Vetsuisse Faculty University of Zurich, Zurich, Switzerland
| | - Beat Thöny
- Division of Metabolism and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
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6
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Pargoo EM, Aghasadeghi MR, Parivar K, Nikbin M, Rahimi P, Ardestani MS. Lamivudine-conjugated and efavirenz-loaded G2 dendrimers: Novel anti-retroviral nano drug delivery systems. IET Nanobiotechnol 2021; 15:627-637. [PMID: 34695297 PMCID: PMC8675833 DOI: 10.1049/nbt2.12060] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2021] [Revised: 04/20/2021] [Accepted: 05/05/2021] [Indexed: 12/19/2022] Open
Abstract
Infection with human immunodeficiency virus (HIV)‐1 causes immunological disorders and death worldwide which needs to be further assisted by novel anti‐retroviral drug delivery systems. Consequently, finding newer anti‐retroviral pharmaceuticals by using biocompatible, biodegradable nanomaterials comprising a nanoparticle as core and a therapeutic agent is of high global interest. In this experiment, a second generation of a negatively charged nano‐biopolymer linear globular G2 dendrimer was carefully conjugated and loaded with well‐known anti‐HIV drugs lamivudine and efavirenz, respectively. They were characterised by a variety of analytical methods such as Zetasizer, Fourier‐transform infrared spectroscopy, elemental analysis and liquid chromatography‐mass spectroscopy. Additionally, conjugated lamivudine and loaded efazirenz with globular PEGylated G2 dendrimer were tested on an HEK293 T cell infected by single‐cycle replicable HIV‐1 virion and evaluated using XTT test and HIV‐1 P24 protein load. The results showed that lamivudine‐conjugated G2 significantly decreased retroviral activity without any cell toxicity. This effect was more or less observed by efavirenz‐loaded G2. These nano‐constructs are strongly suggested for further in vivo anti‐HIV assays.
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Affiliation(s)
| | | | - Kazem Parivar
- Department of Biology, Science and Research Branch, Islamic Azad University, Tehran, Iran
| | - Mehri Nikbin
- Middle East Liver Diseases (MELD) Center, Tehran, Iran
| | - Pooneh Rahimi
- Department of Hepatitis and AIDS, Pasteur Institute of Iran, Tehran, Iran
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7
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Singh U, Morya V, Datta B, Ghoroi C, Bhatia D. Stimuli Responsive, Programmable DNA Nanodevices for Biomedical Applications. Front Chem 2021; 9:704234. [PMID: 34277571 PMCID: PMC8278982 DOI: 10.3389/fchem.2021.704234] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Accepted: 06/18/2021] [Indexed: 12/12/2022] Open
Abstract
Of the multiple areas of applications of DNA nanotechnology, stimuli-responsive nanodevices have emerged as an elite branch of research owing to the advantages of molecular programmability of DNA structures and stimuli-responsiveness of motifs and DNA itself. These classes of devices present multiples areas to explore for basic and applied science using dynamic DNA nanotechnology. Herein, we take the stake in the recent progress of this fast-growing sub-area of DNA nanotechnology. We discuss different stimuli, motifs, scaffolds, and mechanisms of stimuli-responsive behaviours of DNA nanodevices with appropriate examples. Similarly, we present a multitude of biological applications that have been explored using DNA nanodevices, such as biosensing, in vivo pH-mapping, drug delivery, and therapy. We conclude by discussing the challenges and opportunities as well as future prospects of this emerging research area within DNA nanotechnology.
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Affiliation(s)
- Udisha Singh
- Biological Engineering Discipline, Indian Institute of Technology Gandhinagar, Palaj, India
| | - Vinod Morya
- Biological Engineering Discipline, Indian Institute of Technology Gandhinagar, Palaj, India
| | - Bhaskar Datta
- Biological Engineering Discipline, Indian Institute of Technology Gandhinagar, Palaj, India
- Center for Biomedical Engineering, Indian Institute of Technology Gandhinagar, Palaj, India
| | - Chinmay Ghoroi
- Center for Biomedical Engineering, Indian Institute of Technology Gandhinagar, Palaj, India
- Chemical Engineering Discipline, Indian Institute of Technology Gandhinagar, Palaj, India
| | - Dhiraj Bhatia
- Biological Engineering Discipline, Indian Institute of Technology Gandhinagar, Palaj, India
- Center for Biomedical Engineering, Indian Institute of Technology Gandhinagar, Palaj, India
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8
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Nicolle L, Casper J, Willimann M, Journot CMA, Detampel P, Einfalt T, Grisch-Chan HM, Thöny B, Gerber-Lemaire S, Huwyler J. Development of Covalent Chitosan-Polyethylenimine Derivatives as Gene Delivery Vehicle: Synthesis, Characterization, and Evaluation. Int J Mol Sci 2021; 22:ijms22083828. [PMID: 33917124 PMCID: PMC8067803 DOI: 10.3390/ijms22083828] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 03/31/2021] [Accepted: 04/01/2021] [Indexed: 01/03/2023] Open
Abstract
There is an increasing interest in cationic polymers as important constituents of non-viral gene delivery vectors. In the present study, we developed a versatile synthetic route for the production of covalent polymeric conjugates consisting of water-soluble depolymerized chitosan (dCS; MW 6–9 kDa) and low molecular weight polyethylenimine (PEI; 2.5 kDa linear, 1.8 kDa branched). dCS-PEI derivatives were evaluated based on their physicochemical properties, including purity, covalent bonding, solubility in aqueous media, ability for DNA condensation, and colloidal stability of the resulting polyplexes. They were complexed with non-integrating DNA vectors coding for reporter genes by simple admixing and assessed in vitro using liver-derived HuH-7 cells for their transfection efficiency and cytotoxicity. Using a rational screening cascade, a lead compound was selected (dCS-Suc-LPEI-14) displaying the best balance of biocompatibility, cytotoxicity, and transfection efficiency. Scale-up and in vivo evaluation in wild-type mice allowed for a direct comparison with a commercially available non-viral delivery vector (in vivo-jetPEI). Hepatic expression of the reporter gene luciferase resulted in liver-specific bioluminescence, upon intrabiliary infusion of the chitosan-based polyplexes, which exceeded the signal of the in vivo jetPEI reference formulation by a factor of 10. We conclude that the novel chitosan-derivative dCS-Suc-LPEI-14 shows promise and potential as an efficient polymeric conjugate for non-viral in vivo gene therapy.
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Affiliation(s)
- Laura Nicolle
- Group for Functionalized Biomaterials, Institute of Chemical Sciences and Engineering Ecole Polytechnique Fédérale de Lausanne, EPFL SB ISIC SCI-SB-SG, Station 6, CH-1015 Lausanne, Switzerland; (L.N.); (C.M.A.J.)
| | - Jens Casper
- Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland; (J.C.); (P.D.); (T.E.)
| | - Melanie Willimann
- Division of Metabolism and Children’s Research Center, University Children’s Hospital Zürich, CH-8032 Zürich, Switzerland; (M.W.); (H.M.G.-C.); (B.T.)
| | - Céline M. A. Journot
- Group for Functionalized Biomaterials, Institute of Chemical Sciences and Engineering Ecole Polytechnique Fédérale de Lausanne, EPFL SB ISIC SCI-SB-SG, Station 6, CH-1015 Lausanne, Switzerland; (L.N.); (C.M.A.J.)
| | - Pascal Detampel
- Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland; (J.C.); (P.D.); (T.E.)
| | - Tomaž Einfalt
- Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland; (J.C.); (P.D.); (T.E.)
| | - Hiu Man Grisch-Chan
- Division of Metabolism and Children’s Research Center, University Children’s Hospital Zürich, CH-8032 Zürich, Switzerland; (M.W.); (H.M.G.-C.); (B.T.)
| | - Beat Thöny
- Division of Metabolism and Children’s Research Center, University Children’s Hospital Zürich, CH-8032 Zürich, Switzerland; (M.W.); (H.M.G.-C.); (B.T.)
| | - Sandrine Gerber-Lemaire
- Group for Functionalized Biomaterials, Institute of Chemical Sciences and Engineering Ecole Polytechnique Fédérale de Lausanne, EPFL SB ISIC SCI-SB-SG, Station 6, CH-1015 Lausanne, Switzerland; (L.N.); (C.M.A.J.)
- Correspondence: (S.G.-L.); (J.H.); Tel.: +41-21-693-93-72 (S.G.-L.); +41-61-207-15-13 (J.H.)
| | - Jörg Huwyler
- Division of Pharmaceutical Technology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50/70, CH-4056 Basel, Switzerland; (J.C.); (P.D.); (T.E.)
- Correspondence: (S.G.-L.); (J.H.); Tel.: +41-21-693-93-72 (S.G.-L.); +41-61-207-15-13 (J.H.)
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The Effect of Lecithins Coupled Decorin Nanoliposomes on Treatment of Carbon Tetrachloride-Induced Liver Fibrosis. BIOMED RESEARCH INTERNATIONAL 2020; 2020:8815904. [PMID: 33415158 PMCID: PMC7752282 DOI: 10.1155/2020/8815904] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/03/2020] [Revised: 10/26/2020] [Accepted: 11/27/2020] [Indexed: 02/08/2023]
Abstract
This study aimed to investigate the effect of bile duct-targeting lecithins- (PC-) coupled decorin (DCN) (PC-DCN) nanoliposomes against liver fibrosis in vitro and in vivo. We prepared PC-DCN nanoliposomes by using rat astrocytes, HSC-T6, to verify the antifibrosis effect of PC-DCN in vitro. First, we established a rat model of carbon tetrachloride-induced fibrosis. PC-DCN nanoliposomes were then injected into fibrotic rats via the portal vein or bile duct. The EdU assay was performed to analyze cell proliferation. Immunofluorescence staining was used to detect α-smooth muscle actin (α-SMA) expression. Western blot was performed to examine the expression of α-SMA, collagen type I alpha 1 (COL1A1), and transforming growth factor-β (TGF-β) protein. The levels of aspartate transaminase (AST), alanine transaminase (ALT), and total bilirubin (TBIL) were examined by enzyme-linked immunosorbent assay (ELISA) analysis. Hematoxylin and eosin (H&E) staining and Masson trichrome staining were used to determine liver tissue lesions and liver fibrosis. Compared with TGF-β group, PC-DCN treatment could significantly reduce cell proliferation. Western blot analysis indicated that the expression of α-SMA, COL1A1, and TGF-β was downregulated after treatment with PC-DCN in vitro and in vivo. Immunofluorescence staining confirmed that α-SMA expression was reduced by PC-DCN. Furthermore, H&E staining and Masson trichrome staining showed that the administration of PC-DCN nanoliposomes via the bile duct could reduce the extent of liver fibrosis. PCR analysis showed that PC-DCN administration could reduce proinflammatory cytokines IL-6, TNF-α, and IL-1β expression via the bile duct. The administration of PC-DCN nanoliposomes also significantly downregulated liver function indicators ALT, AST, and TBIL. The results of our study indicated that PC-DCN could effectively reduce the extent of liver fibrosis.
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10
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Cai Y, Lapitsky Y. Biomolecular uptake effects on chitosan/tripolyphosphate micro- and nanoparticle stability. Colloids Surf B Biointerfaces 2020; 193:111081. [PMID: 32403037 DOI: 10.1016/j.colsurfb.2020.111081] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2019] [Revised: 04/15/2020] [Accepted: 04/22/2020] [Indexed: 10/24/2022]
Abstract
Colloidal chitosan/tripolyphosphate (TPP) particles have attracted significant attention as potential delivery vehicles for drugs, genes and vaccines. Yet, there have been several fundamental studies that showed these particles to disintegrate at physiological pH and ionic strength levels. To reconcile these findings with the published drug, gene and vaccine delivery research where chitosan/TPP particle disintegration was not reported, it has been postulated that the particles could be stabilized by their bioactive payloads. To test this hypothesis, here we examine whether the association of chitosan/TPP particles with model anionic proteins, α-lactalbumin (α-LA) and bovine serum albumin (BSA), and polynucleotides (DNA) enhances chitosan/TPP particle stability at physiological ionic strengths, using 150 mM NaCl (pH 5.5) and 1× PBS (pH 6.0) as the dissolution media. Light scattering and UV-vis spectroscopy revealed that anionic protein uptake had no impact on particle stability, likely due to the relatively weak protein/particle binding at near-physiological ionic strengths, which caused the protein to be rapidly released. This result occurred regardless of whether the protein was loaded during or after particle formation. Conversely, DNA uptake (at least at some compositions) increased the chitosan fractions persisting in a complexed/particulate form in model dissolution media, with the DNA remaining largely complexed to the chitosan at all investigated conditions. Collectively, these findings suggest that, while most bioactive payloads do not interact with chitosan strongly enough to stabilize chitosan/TPP particles, these chitosan particles can be stabilized to dissolution through the incorporation of polyanions.
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Affiliation(s)
- Yuhang Cai
- Department of Chemical Engineering, University of Toledo, Toledo, Ohio 43606, United States
| | - Yakov Lapitsky
- Department of Chemical Engineering, University of Toledo, Toledo, Ohio 43606, United States.
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11
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Dai C, Wang M, Zhao L, Xu C, Huang J, Fan Z. Liver gene transfection by retrograde intrabiliary infusion facilitated by temporary biliary obstruction. J Gene Med 2020; 22:e3144. [PMID: 31742830 DOI: 10.1002/jgm.3144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2019] [Revised: 11/13/2019] [Accepted: 11/14/2019] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND The hepatobiliary tract may be a valuable administration site for gene delivery. We demonstrated the role of temporary biliary obstruction for gene transfection by retrograde intrabiliary infusion. METHODS Male Sprague-Dawley rats received intrabiliary infusion of luciferase plasmid via an artificial common bile duct, with temporary biliary obstruction for 0 minutes (NO group), 30 minutes (30 min group) and 24 hours (24 h group), respectively (n = 4 for each group). Gene expression levels were evaluated by luciferase bioluminescence on postoperative days (POD) 1, 2 and 7. Serum and livers were collected on POD 1 and 14 for liver biochemistry, hematoxylin and eosin staining, and immunohistochemistry. RESULTS On POD 1, luciferase chemoluminescence was significantly higher in the 24 h group than in the NO group (p = 0.002) and the 30 min group (p = 0.002). However, it decreased rapidly after reversal of the obstruction in the 24 h group (POD 1 versus POD 2, p = 0.002; POD 1 versus POD 7, p = 0.002). Liver biochemistry was changed on POD 1, but no significant differences were detected after 14 days of recovery (p > 0.05). Similar histological changes were found in the three groups, with no unwanted proliferation of biliary epithelial cells. The obstruction did not cause serious liver damage. CONCLUSIONS Temporary biliary obstruction for 24 hours facilitated the safe, feasible and effective transfection of plasmid DNA into the liver via the hepatobiliary tract. In the future, endoscopic retrograde cholangiopancreatography and its dilation balloon could be used to create biliary obstruction and allow the direct gene delivery into the liver. More research is necessary for achieving stable gene expression, as well as in terms of weighing its benefits against potential complications.
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Affiliation(s)
- Chenguang Dai
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
- Digestive Endoscopy Department, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Min Wang
- Digestive Endoscopy Department, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
- Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Lili Zhao
- Digestive Endoscopy Department, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
- Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
| | - Chunfang Xu
- Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China
| | - Jin Huang
- Department of Gastroenterology, The Changzhou Second People's Hospital, Changzhou, China
- Division of Digestive Diseases, the People's Hospital of Ma Anshan, Ma Anshan, China
| | - Zhining Fan
- Digestive Endoscopy Department, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
- Department of General Surgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China
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12
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Chaudhary V, Jangra S, Yadav NR. Nanotechnology based approaches for detection and delivery of microRNA in healthcare and crop protection. J Nanobiotechnology 2018; 16:40. [PMID: 29653577 PMCID: PMC5897953 DOI: 10.1186/s12951-018-0368-8] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2017] [Accepted: 04/07/2018] [Indexed: 12/31/2022] Open
Abstract
Nanobiotechnology has the potential to revolutionize diverse sectors including medicine, agriculture, food, textile and pharmaceuticals. Disease diagnostics, therapeutics and crop protection strategies are fast emerging using nanomaterials preferably nanobiomaterials. It has potential for development of novel nanobiomolecules which offer several advantages over conventional treatment methods. RNA nanoparticles with many unique features are promising candidates in disease treatment. The miRNAs are involved in many biochemical and developmental pathways and their regulation in plants and animals. These appear to be a powerful tool for controlling various pathological diseases in human, plants and animals, however there are challenges associated with miRNA based nanotechnology. Several advancements made in the field of miRNA therapeutics make it an attractive approach, but a lot more has to be explored in nanotechnology assisted miRNA therapy. The miRNA based technologies can be employed for detection and combating crop diseases as well. Despite these potential advantages, nanobiotechnology applications in the agricultural sector are still in its infancy and have not yet made its mark in comparison with healthcare sector. The review provides a platform to discuss nature, role and use of miRNAs in nanobiotechnology applications.
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Affiliation(s)
- Vrantika Chaudhary
- Department of Molecular Biology, Biotechnology and Bioinformatics, CCS Haryana Agricultural University, Hisar, 125004 India
| | - Sumit Jangra
- Department of Molecular Biology, Biotechnology and Bioinformatics, CCS Haryana Agricultural University, Hisar, 125004 India
| | - Neelam R. Yadav
- Department of Molecular Biology, Biotechnology and Bioinformatics, CCS Haryana Agricultural University, Hisar, 125004 India
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13
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14
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Abstract
Drug delivery systems (DDS) are designed to improve the pharmacological and therapeutic effect. In the past few decades, there are some problems that impeded applications of particulate DDS have been resolved, with several DDS formulations of anticancer now approved for clinical use. Liposomal nanoparticles (LNs) encapsulating therapeutic agents have been recognized as one of the most advanced classes of DDS. Liposomal nanoparticles (LNs) could encapsulate both conventional anticancer drugs and the new genetic drugs with several properties such as high drug-to-lipid ratio, excellent retention of drug and a long circulation lifetime. These excellent properties of LNs have the potentials to offer new treatments in area of cancer therapy. Here, we will discuss recent advances in this field involving conventional anticancer drugs as well as the new genetic drugs.
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Affiliation(s)
- J. Zhong
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Huzhou, Zhejiang Province, No. 198, Hongqi Road, China 313000
| | - L. C. Dai
- Huzhou Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Huzhou, Zhejiang Province, No. 198, Hongqi Road, China 313000
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15
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Semnani D, Naghashzargar E, Hadjianfar M, Dehghan Manshadi F, Mohammadi S, Karbasi S, Effaty F. Evaluation of PCL/chitosan electrospun nanofibers for liver tissue engineering. INT J POLYM MATER PO 2016. [DOI: 10.1080/00914037.2016.1190931] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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Poly(lactic-co-glycolic) Acid-Chitosan Dual Loaded Nanoparticles for Antiretroviral Nanoformulations. JOURNAL OF DRUG DELIVERY 2016; 2016:3810175. [PMID: 27190651 PMCID: PMC4852115 DOI: 10.1155/2016/3810175] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2016] [Revised: 03/11/2016] [Accepted: 03/20/2016] [Indexed: 11/17/2022]
Abstract
Poly(lactic-co-glycolic acid) (PLGA) chitosan (CS) coated nanoparticles (NPs) were loaded with two antiretrovirals (ARVs) either lamivudine (LMV) which is hydrophilic or nevirapine (NVP) which is hydrophobic or both LMV and NVP. These ARVs are of importance in resource-limited settings, where they are commonly used in human immunodeficiency virus (HIV-1) treatment due to affordability and accessibility. NPs prepared by a water-oil-water emulsion and reduced pressure solvent evaporation technique were determined to have a positive zeta potential, a capsule-like morphology, and an average hydrodynamic diameter of 240 nm. Entrapment of NVP as a single ARV had a notable increase in NP size compared to LMV alone or in combination with LMV. NPs stored at room temperature in distilled water maintained size, polydispersity (PDI), and zeta potential for one year. No changes in size, PDI, and zeta potential were observed for NPs in 10% sucrose in lyophilized or nonlyophilized states stored at 4°C and -20°C, respectively. Freezing NPs in the absence of sucrose increased NP size. Drug loading, encapsulation efficiency, and kinetic release profiles were quantified by high performance liquid chromatography (HPLC). Our novel nanoformulations have the potential to improve patient outcomes and expand drug access in resource-limited countries for the treatment of HIV-1.
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Surana S, Shenoy AR, Krishnan Y. Designing DNA nanodevices for compatibility with the immune system of higher organisms. NATURE NANOTECHNOLOGY 2015; 10:741-7. [PMID: 26329110 PMCID: PMC4862568 DOI: 10.1038/nnano.2015.180] [Citation(s) in RCA: 169] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2015] [Accepted: 07/17/2015] [Indexed: 05/05/2023]
Abstract
DNA is proving to be a powerful scaffold to construct molecularly precise designer DNA devices. Recent trends reveal their ever-increasing deployment within living systems as delivery devices that not only probe but also program and re-program a cell, or even whole organisms. Given that DNA is highly immunogenic, we outline the molecular, cellular and organismal response pathways that designer nucleic acid nanodevices are likely to elicit in living systems. We address safety issues applicable when such designer DNA nanodevices interact with the immune system. In light of this, we discuss possible molecular programming strategies that could be integrated with such designer nucleic acid scaffolds to either evade or stimulate the host response with a view to optimizing and widening their applications in higher organisms.
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Affiliation(s)
- Sunaina Surana
- Department of Chemistry, University of Chicago, 929 East 57th Street, Chicago, 60637 Illinois, USA
| | - Avinash R. Shenoy
- Section of Microbiology, Medical Research Council Centre for Molecular Bacteriology and Infection, Imperial College London, Armstrong Road, London SW7 2AZ, UK
- ;
| | - Yamuna Krishnan
- Department of Chemistry, University of Chicago, 929 East 57th Street, Chicago, 60637 Illinois, USA
- National Centre for Biological Sciences, Tata Institute of Fundamental Research, GKVK-UAS, Bellary Road, Bangalore 560065, India
- ;
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18
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Ahmed M, Narain R. Carbohydrate-based materials for targeted delivery of drugs and genes to the liver. Nanomedicine (Lond) 2015. [DOI: 10.2217/nnm.15.58] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
The insult to liver by toxic materials leads to cirrhosis, hepatitis and cancer. Upon administration, drugs accumulate in liver, which is systemically cleared by reticuloendothelial system. However, specific targeting of drugs to liver is a serious challenge. Specific delivery of molecules to hepatocytes is accomplished by targeting cell surface lectins, asialoglycoprotein receptors. Asialofetuin, N-acetyl glucosamine and galactose are high-affinity ligands of asialoglycoprotein receptors. The bioconjugation of drugs, fluorescent molecules and gene delivery vectors with lectin-targeting agents, and their delivery in liver hepatocytes, is discussed. Mannose and N-acetyl glucosamine conjugates are evaluated for their delivery to hepatic stellate and kupffer cells. The glycosylated gene and drug delivery vectors in clinical trials are outlined.
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Affiliation(s)
- Marya Ahmed
- Chemical Engineering, California Institute of Technology, 1200 E California Blvd, Pasadena, CA 91125, USA
| | - Ravin Narain
- Chemical & Materials Engineering, University of Alberta, 116 St & 85 Ave, Edmonton, AB T6G 2R3, Canada
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19
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Peng YS, Lai PL, Peng S, Wu HC, Yu S, Tseng TY, Wang LF, Chu IM. Glial cell line-derived neurotrophic factor gene delivery via a polyethylene imine grafted chitosan carrier. Int J Nanomedicine 2014; 9:3163-74. [PMID: 25061293 PMCID: PMC4085318 DOI: 10.2147/ijn.s60465] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Parkinson’s disease is known to result from the loss of dopaminergic neurons. Direct intracerebral injections of high doses of recombinant glial cell line-derived neurotrophic factor (GDNF) have been shown to protect adult nigral dopaminergic neurons. Because GDNF does not cross the blood–brain barrier, intracerebral gene transfer is an ideal option. Chitosan (CHI) is a naturally derived material that has been used for gene transfer. However, the low water solubility often leads to decreased transfection efficiency. Grafting of highly water-soluble polyethylene imines (PEI) and polyethylene glycol onto polymers can increase their solubility. The purpose of this study was to design a non-viral gene carrier with improved water solubility as well as enhanced transfection efficiency for treating Parkinsonism. Two molecular weights (Mw =600 and 1,800 g/mol) of PEI were grafted onto CHI (PEI600-g-CHI and PEI1800-g-CHI, respectively) by opening the epoxide ring of ethylene glycol diglycidyl ether (EX-810). This modification resulted in a non-viral gene carrier with less cytotoxicity. The transfection efficiency of PEI600-g-CHI/deoxyribonucleic acid (DNA) polyplexes was significantly higher than either PEI1800-g-CHI/DNA or CHI/DNA polyplexes. The maximal GDNF expression of PEI600-g-CHI/DNA was at the polymer:DNA weight ratio of 10:1, which was 1.7-fold higher than the maximal GDNF expression of PEI1800-g-CHI/DNA. The low toxicity and high transfection efficiency of PEI600-g-CHI make it ideal for application to GDNF gene therapy, which has potential for the treatment of Parkinson’s disease.
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Affiliation(s)
- Yu-Shiang Peng
- Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan
| | - Po-Liang Lai
- Department of Orthopedic Surgery, Chang Gung Memorial Hospital at Linkou, Chang Gung University College of Medicine, Taoyuan, Taiwan
| | - Sydney Peng
- Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan
| | - His-Chin Wu
- Department of Materials Engineering, Tatung University, Taipei, Taiwan
| | - Siang Yu
- Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan
| | - Tsan-Yun Tseng
- Graduate School of Biotechnology and Bioengineering, College of Engineering, Yuan Ze University, Chung-Li, Taiwan
| | - Li-Fang Wang
- Department of Medicinal and Applied Chemistry, Kaohsiung Medical University, Kaohsiung, Taiwan
| | - I-Ming Chu
- Department of Chemical Engineering, National Tsing Hua University, Hsinchu, Taiwan
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20
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Jin L, Zeng X, Liu M, Deng Y, He N. Current progress in gene delivery technology based on chemical methods and nano-carriers. Am J Cancer Res 2014; 4:240-55. [PMID: 24505233 PMCID: PMC3915088 DOI: 10.7150/thno.6914] [Citation(s) in RCA: 248] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2013] [Accepted: 11/16/2013] [Indexed: 12/21/2022] Open
Abstract
Gene transfer methods are promising in the field of gene therapy. Current methods for gene transfer include three major groups: viral, physical and chemical methods. This review mainly summarizes development of several types of chemical methods for gene transfer in vitro and in vivo by means of nano-carriers like; calcium phosphates, lipids, and cationic polymers including chitosan, polyethylenimine, polyamidoamine dendrimers, and poly(lactide-co-glycolide). This review also briefly introduces applications of these chemical methods for gene delivery.
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21
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Isolation, Purification, and Nanotechnological Applications of Chitosan. POLYSACCHARIDES 2014. [DOI: 10.1007/978-3-319-03751-6_45-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
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22
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Narmada BC, Kang Y, Venkatraman L, Peng Q, Sakban RB, Nugraha B, Jiang X, Bunte RM, So PTC, Tucker-Kellogg L, Mao HQ, Yu H. Hepatic stellate cell-targeted delivery of hepatocyte growth factor transgene via bile duct infusion enhances its expression at fibrotic foci to regress dimethylnitrosamine-induced liver fibrosis. Hum Gene Ther 2013; 24:508-19. [PMID: 23527815 DOI: 10.1089/hum.2012.158] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Liver fibrosis generates fibrotic foci with abundant activated hepatic stellate cells and excessive collagen deposition juxtaposed with healthy regions. Targeted delivery of antifibrotic therapeutics to hepatic stellate cells (HSCs) might improve treatment outcomes and reduce adverse effects on healthy tissue. We delivered the hepatocyte growth factor (HGF) gene specifically to activated hepatic stellate cells in fibrotic liver using vitamin A-coupled liposomes by retrograde intrabiliary infusion to bypass capillarized hepatic sinusoids. The antifibrotic effects of DsRed2-HGF vector encapsulated within vitamin A-coupled liposomes were validated by decreases in fibrotic markers in vitro. Fibrotic cultures transfected with the targeted transgene showed a significant decrease in fibrotic markers such as transforming growth factor-β1. In rats, dimethylnitrosamine-induced liver fibrosis is manifested by an increase in collagen deposition and severe defenestration of sinusoidal endothelial cells. The HSC-targeted transgene, administered via retrograde intrabiliary infusion in fibrotic rats, successfully reduced liver fibrosis markers alpha-smooth muscle actin and collagen, accompanied by an increase in the expression of DsRed2-HGF near the fibrotic foci. Thus, targeted delivery of HGF gene to hepatic stellate cells increased the transgene expression at the fibrotic foci and strongly enhanced its antifibrotic effects.
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23
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Molinaro R, Wolfram J, Federico C, Cilurzo F, Di Marzio L, Ventura CA, Carafa M, Celia C, Fresta M. Polyethylenimine and chitosan carriers for the delivery of RNA interference effectors. Expert Opin Drug Deliv 2013; 10:1653-68. [DOI: 10.1517/17425247.2013.840286] [Citation(s) in RCA: 55] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
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24
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Tian H, Chen J, Chen X. Nanoparticles for gene delivery. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2013; 9:2034-2044. [PMID: 23630123 DOI: 10.1002/smll.201202485] [Citation(s) in RCA: 98] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/09/2012] [Revised: 12/21/2012] [Indexed: 05/27/2023]
Abstract
Nanocarriers are a new type of nonviral gene carriers, many of which have demonstrated a broad range of pharmacological and biological properties, such as being biodegradable in the body, stimulus-responsive towards the surrounding environment, and an ability to specifically targeting certain disease sites. By summarizing some main types of nanocarriers, this Concept considers the current status and possible future directions of the potential clinical applications of multifunctional nanocarriers, with primary attention on the combination of such properties as biodegradability, targetability, transfection ability, and stimuli sensitivity.
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Affiliation(s)
- Huayu Tian
- Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences, 5625 Renmin Street, Changchun 130022, China
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25
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Gao L, Xie L, Long X, Wang Z, He CY, Chen ZY, Zhang L, Nan X, Lei H, Liu X, Liu G, Lu J, Qiu B. Efficacy of MRI visible iron oxide nanoparticles in delivering minicircle DNA into liver via intrabiliary infusion. Biomaterials 2013; 34:3688-96. [DOI: 10.1016/j.biomaterials.2013.01.094] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2012] [Accepted: 01/26/2013] [Indexed: 11/15/2022]
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26
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Jiang X, Qu W, Pan D, Ren Y, Williford JM, Cui H, Luijten E, Mao HQ. Plasmid-templated shape control of condensed DNA-block copolymer nanoparticles. ADVANCED MATERIALS (DEERFIELD BEACH, FLA.) 2013; 25:227-32. [PMID: 23055399 PMCID: PMC3918481 DOI: 10.1002/adma.201202932] [Citation(s) in RCA: 93] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/23/2012] [Revised: 09/03/2012] [Indexed: 05/29/2023]
Abstract
DNA-containing micellar nanoparticles with distinctly different and highly uniform morphologies are prepared via condensation of plasmid DNA with a block copolymer of polyethylene glycol and a polycation in solvents of different polarity. Molecular dynamics simulations explain the underlying mechanism.
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Affiliation(s)
- Xuan Jiang
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland 21218; Translational Tissue Engineering Center and Whitaker Biomedical Engineering Institute, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA
| | - Wei Qu
- Department of Materials Science and Engineering, Northwestern University, Evanston, Illinois 60208, USA
| | - Deng Pan
- Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA
| | - Yong Ren
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA
| | - John-Michael Williford
- Department of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, Maryland 21205, USA
| | - Honggang Cui
- Department of Chemical and Biomolecular Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA
| | - Erik Luijten
- Department of Materials Science and Engineering, Northwestern University, Evanston, Illinois 60208; Department of Engineering Sciences and Applied Mathematics, Northwestern University, Evanston, Illinois 60208, USA
| | - Hai-Quan Mao
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland 21218; Translational Tissue Engineering Center and Whitaker Biomedical Engineering Institute, Johns Hopkins School of Medicine, Baltimore, Maryland 21287, USA
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27
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Jiang X, Ren Y, Williford JM, Li Z, Mao HQ. Liver-targeted gene delivery through retrograde intrabiliary infusion. Methods Mol Biol 2013; 948:275-284. [PMID: 23070777 DOI: 10.1007/978-1-62703-140-0_19] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/01/2023]
Abstract
Retrograde intrabiliary infusion (RII) has recently been characterized as a safe and effective administration route for liver-targeted gene delivery. Efficient transgene expression in the liver has been achieved by infusing a variety of gene vectors including adenovirus, retrovirus, lipoplexes, polyplexes, and naked DNA through the common bile duct. Here, we describe the RII technique and key infusion parameters for delivering plasmid DNA and DNA nanoparticles to the rat liver. After RII of plasmid DNA, the level of transgene expression in rat liver is comparable to that achieved by hydrodynamic injection of plasmid DNA, which is considered to be "gold standard" for liver-targeted gene delivery. RII has also been shown to significantly enhance the gene delivery efficiency by polymer/DNA nanoparticles in comparison with intravenous and intraportal infusions. This method induces minimal level of cytotoxicity and damage to the liver and bile duct. Due to these advantages, RII has the potential to be used for delivering various gene vectors in clinical setting through the endoscopic retrograde cholangiopancreatography procedure.
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Affiliation(s)
- Xuan Jiang
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, MD, USA
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28
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Xiao B, Wang X, Qiu Z, Ma J, Zhou L, Wan Y, Zhang S. A dual-functionally modified chitosan derivative for efficient liver-targeted gene delivery. J Biomed Mater Res A 2012. [PMID: 23203540 DOI: 10.1002/jbm.a.34493] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Galactosylated chitosan-hydroxypropyltrimethylammonium (gal-HTCC) was synthesized by galactosylating and quaternizing chitosan to endue chitosan with targeting specificity for potential applications as gene vectors. The composition and physicochemical properties of gal-HTCC were characterized by FT-IR, (1) H NMR, elemental analysis, X-ray diffraction, and turbidity measurement. It was found that water-soluble gal-HTCC showed a more amorphous structure than chitosan, and it also had a much better plasmid condensation capability than galactosylated chitosan. Cytotoxicity measurements revealed that gal-HTCC showed significantly lower cytotoxicity in HepG2 and HeLa cell lines compared to branched polyethylenimine (bPEI, 25 kDa) which was used as a positive control. The nanoparticles (NPs) consisted of gal-HTCC and plasmid DNA had desirable particle size (around 250 nm) with a narrow size distribution. Confocal laser scanning microscopy confirmed that NPs could be internalized and transported to the nucleus efficiently within 6 h. In vitro gene transfection results indicated that gal-HTCC had significantly higher transfection efficiency (7- to 32-fold) compared to chitosan and gal-chitosan for targetable delivery of pGL3 luciferase plasmid to HepG2, and its transfection efficiency was highly inhibited in the presence of galactose (20 mM). All these results suggest that gal-HTCC can function as a promising nonviral gene vector for efficient liver-targeted gene delivery.
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Affiliation(s)
- Bo Xiao
- Advanced Biomaterials and Tissue Engineering Center, Huazhong University of Science and Technology, Wuhan 430074, People's Republic of China
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29
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Hsieh WH, Chang SF, Chen HM, Chen JH, Liaw J. Oral gene delivery with cyclo-(D-Trp-Tyr) peptide nanotubes. Mol Pharm 2012; 9:1231-49. [PMID: 22480317 DOI: 10.1021/mp200523n] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The feasibility of cyclo-(D-Trp-Tyr) peptide nanotubes (PNTs) as oral gene delivery carriers was investigated in nude mice with eight 40 μg doses of pCMV-lacZ in 2 days at 3 h intervals. The association between DNA and PNTs, the DNase I stability of PNTs-associated DNA, and in vitro permeability of DNA were estimated. The results showed that the cyclo-(D-Trp-Tyr) PNTs self-associated at concentrations above 0.01 mg/mL. Plasmid DNA associated with PNTs with a binding constant of 3.2 × 10(8) M(-1) calculated by a fluorescence quenching assay. PNTs were able to protect DNA from DNase I, acid, and bile digestion for 50 min, 60 min, and 180 min, respectively. The in vitro duodenal apparent permeability coefficient of pCMV-lacZ calculated from a steady state flux was increased from 49.2 ± 21.6 × 10(-10) cm/s of naked DNA to 395.6 ± 142.2 × 10(-10) cm/s of pCMV-lacZ/PNT formulation. The permeation of pCMV-lacZ formulated with PNTs was found in an energy-dependent process. Furthermore, β-galatosidase (β-Gal) activity in tissues was quantitatively assessed using chlorophenol red-β-D-galactopyranoside (CPRG) and was significantly increased by 41% in the kidneys at 48 h and by 49, 63, and 46% in the stomach, duodenum, and liver, respectively, at 72 h after the first dose of oral delivery of pCMV-lacZ/PNT formulation. The organs with β-Gal activity were confirmed for the presence of pCMV-lacZ DNA with Southern blotting analysis and intracellular tracing the TM-rhodamine-labeled DNA and the presence of mRNA by reverse transcription-real time quantitative PCR (RT-qPCR). Another plasmid (pCMV-hRluc) encoding Renilla reniformis luciferase was used to confirm the results. An increased hRluc mRNA and luciferase in stomach, duodenum, liver, and kidney were detected by RT-qPCR, ex vivo bioluminescence imaging, luciferase activity quantification, and immunostaining, respectively.
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Affiliation(s)
- Wei-Hsien Hsieh
- College of Pharmacy, Taipei Medical University, 250 Wu Hsing Street, Taipei 110, Taiwan
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Tseng MT, Lu X, Duan X, Hardas SS, Sultana R, Wu P, Unrine JM, Graham U, Butterfield DA, Grulke EA, Yokel RA. Alteration of hepatic structure and oxidative stress induced by intravenous nanoceria. Toxicol Appl Pharmacol 2012; 260:173-82. [PMID: 22373796 DOI: 10.1016/j.taap.2012.02.008] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2011] [Revised: 02/08/2012] [Accepted: 02/13/2012] [Indexed: 01/18/2023]
Abstract
Beyond the traditional use of ceria as an abrasive, the scope of nanoceria applications now extends into fuel cell manufacturing, diesel fuel additives, and for therapeutic intervention as a putative antioxidant. However, the biological effects of nanoceria exposure have yet to be fully defined, which gave us the impetus to examine its systemic biodistribution and biological responses. An extensively characterized nanoceria (5 nm) dispersion was vascularly infused into rats, which were terminated 1 h, 20 h or 30 days later. Light and electron microscopic tissue characterization was conducted and hepatic oxidative stress parameters determined. We observed acute ceria nanoparticle sequestration by Kupffer cells with subsequent bioretention in parenchymal cells as well. The internalized ceria nanoparticles appeared as spherical agglomerates of varying dimension without specific organelle penetration. In hepatocytes, the agglomerated nanoceria frequently localized to the plasma membrane facing bile canaliculi. Hepatic stellate cells also sequestered nanoceria. Within the sinusoids, sustained nanoceria bioretention was associated with granuloma formations comprised of Kupffer cells and intermingling CD3⁺ T cells. A statistically significant elevation of serum aspartate aminotransferase (AST) level was seen at 1 and 20 h, but subsided by 30 days after ceria administration. Further, elevated apoptosis was observed on day 30. These findings, together with increased hepatic protein carbonyl levels on day 30, indicate ceria-induced hepatic injury and oxidative stress, respectively. Such observations suggest a single vascular infusion of nanoceria can lead to persistent hepatic retention of particles with possible implications for occupational and therapeutic exposures.
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Affiliation(s)
- Michael T Tseng
- Dept of Anatomical Sciences & Neurobiology, University of Louisville, Louisville, Kentucky, USA.
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Galvin P, Thompson D, Ryan KB, McCarthy A, Moore AC, Burke CS, Dyson M, Maccraith BD, Gun'ko YK, Byrne MT, Volkov Y, Keely C, Keehan E, Howe M, Duffy C, MacLoughlin R. Nanoparticle-based drug delivery: case studies for cancer and cardiovascular applications. Cell Mol Life Sci 2012; 69:389-404. [PMID: 22015612 PMCID: PMC11115117 DOI: 10.1007/s00018-011-0856-6] [Citation(s) in RCA: 66] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2011] [Revised: 09/29/2011] [Accepted: 09/29/2011] [Indexed: 11/25/2022]
Abstract
Nanoparticles (NPs) comprised of nanoengineered complexes are providing new opportunities for enabling targeted delivery of a range of therapeutics and combinations. A range of functionalities can be included within a nanoparticle complex, including surface chemistry that allows attachment of cell-specific ligands for targeted delivery, surface coatings to increase circulation times for enhanced bioavailability, specific materials on the surface or in the nanoparticle core that enable storage of a therapeutic cargo until the target site is reached, and materials sensitive to local or remote actuation cues that allow controlled delivery of therapeutics to the target cells. However, despite the potential benefits of NPs as smart drug delivery and diagnostic systems, much research is still required to evaluate potential toxicity issues related to the chemical properties of NP materials, as well as their size and shape. The need to validate each NP for safety and efficacy with each therapeutic compound or combination of therapeutics is an enormous challenge, which forces industry to focus mainly on those nanoparticle materials where data on safety and efficacy already exists, i.e., predominantly polymer NPs. However, the enhanced functionality affordable by inclusion of metallic materials as part of nanoengineered particles provides a wealth of new opportunity for innovation and new, more effective, and safer therapeutics for applications such as cancer and cardiovascular diseases, which require selective targeting of the therapeutic to maximize effectiveness while avoiding adverse effects on non-target tissues.
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Affiliation(s)
- Paul Galvin
- Tyndall National Institute, University College Cork, Cork, Ireland.
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Fernandez-Fernandez A, Manchanda R, McGoron AJ. Theranostic applications of nanomaterials in cancer: drug delivery, image-guided therapy, and multifunctional platforms. Appl Biochem Biotechnol 2011; 165:1628-51. [PMID: 21947761 PMCID: PMC3239222 DOI: 10.1007/s12010-011-9383-z] [Citation(s) in RCA: 186] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2011] [Accepted: 09/07/2011] [Indexed: 12/18/2022]
Abstract
Successful cancer management depends on accurate diagnostics along with specific treatment protocols. Current diagnostic techniques need to be improved to provide earlier detection capabilities, and traditional chemotherapy approaches to cancer treatment are limited by lack of specificity and systemic toxicity. This review highlights advances in nanotechnology that have allowed the development of multifunctional platforms for cancer detection, therapy, and monitoring. Nanomaterials can be used as MRI, optical imaging, and photoacoustic imaging contrast agents. When used as drug carriers, nanoformulations can increase tumor exposure to therapeutic agents and result in improved treatment effects by prolonging circulation times, protecting entrapped drugs from degradation, and enhancing tumor uptake through the enhanced permeability and retention effect as well as receptor-mediated endocytosis. Multiple therapeutic agents such as chemotherapy, antiangiogenic, or gene therapy agents can be simultaneously delivered by nanocarriers to tumor sites to enhance the effectiveness of therapy. Additionally, imaging and therapy agents can be co-delivered to provide seamless integration of diagnostics, therapy, and follow-up, and different therapeutic modalities such as chemotherapy and hyperthermia can be co-administered to take advantage of synergistic effects. Liposomes, metallic nanoparticles, polymeric nanoparticles, dendrimers, carbon nanotubes, and quantum dots are examples of nanoformulations that can be used as multifunctional platforms for cancer theranostics. Nanomedicine approaches in cancer have great potential for clinically translatable advances that can positively impact the overall diagnostic and therapeutic process and result in enhanced quality of life for cancer patients. However, a concerted scientific effort is still necessary to fully explore long-term risks, effects, and precautions for safe human use.
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Affiliation(s)
- Alicia Fernandez-Fernandez
- Department of Biomedical Engineering, Florida International University, 10555 West Flagler Street, Miami, FL 33174, USA
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Dash M, Chiellini F, Ottenbrite R, Chiellini E. Chitosan—A versatile semi-synthetic polymer in biomedical applications. Prog Polym Sci 2011. [DOI: 10.1016/j.progpolymsci.2011.02.001] [Citation(s) in RCA: 1932] [Impact Index Per Article: 138.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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Patil RR, Yu J, Banerjee SR, Ren Y, Leong D, Jiang X, Pomper M, Tsui B, Kraitchman DL, Mao HQ. Probing in vivo trafficking of polymer/DNA micellar nanoparticles using SPECT/CT imaging. Mol Ther 2011; 19:1626-35. [PMID: 21750533 DOI: 10.1038/mt.2011.128] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
Successful translation of nonviral gene delivery to therapeutic applications requires detailed understanding of in vivo trafficking of the vehicles. This report compares the pharmacokinetic and biodistribution profiles of polyethylene glycol-b-polyphosphoramidate (PEG-b-PPA)/DNA micellar nanoparticles after administration through intravenous infusion, intrabiliary infusion, and hydrodynamic injection using single photon emission computed tomography/computed tomography (SPECT/CT) imaging. Nanoparticles were labeled with (111)In using an optimized protocol to retain their favorable physicochemical properties. Quantitative imaging analysis revealed different in vivo trafficking kinetics for PEG-b-PPA/DNA nanoparticles after different routes of administration. The intrabiliary infusion resulted in the highest liver uptake of micelles compared with the other two routes. Analysis of intrabiliary infusion by the two-compartment pharmacokinetic modeling revealed efficient retention of micelles in the liver and minimal micelle leakage from the liver to the blood stream. This study demonstrates the utility of SPECT/CT as an effective noninvasive imaging modality for the characterization of nanoparticle trafficking in vivo and confirms that intrabiliary infusion is an effective route for liver-targeted delivery of DNA-containing nanoparticles.
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Affiliation(s)
- Rajesh R Patil
- Department of Materials Science and Engineering, Whiting School of Engineering, Johns Hopkins University, Baltimore, Maryland 21218, USA
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String-like micellar nanoparticles formed by complexation of PEG-b-PPA and plasmid DNA and their transfection efficiency. Pharm Res 2011; 28:1317-27. [PMID: 21499836 DOI: 10.1007/s11095-011-0436-3] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2010] [Accepted: 03/18/2011] [Indexed: 10/18/2022]
Abstract
PURPOSE To investigate the gene delivery efficiency of string-like PEG-b-PPA/DNA micellar nanoparticles in the liver after intravenous injection and intrabiliary infusion. METHODS PEG-b-PPA/DNA micellar nanoparticles were prepared in aqueous solution through spontaneous self-assembly between plasmid DNA and PEG(10K)-b-PPA(4K) or PEG(10K)-b-PP(13K) polymer. The stability of these micellar nanoparticles in different physiological media was evaluated by monitoring the particle size change of micellar nanoparticles with dynamic light scattering (DLS). The transfection efficiency of string-like PEG-b-PPA/DNA micellar nanoparticles in the liver was examined and compared with that of PPA/DNA nanoparticles after intravenous and intrabiliary infusion. RESULTS These PEG-b-PPA/DNA micellar nanoparticles exhibited unique string-like morphology under TEM. The stability of these string-like nanoparticles in salt-, serum- or bile- containing media was significantly improved compared with PPA/DNA nanoparticles. More importantly, these PEG-b-PPA/DNA nanoparticles mediated 10-fold higher transfection efficiency than PPA/DNA nanoparticles in rat liver when delivered via intrabiliary infusion. In addition, histopathological data revealed that the PEG-b-PPA/DNA nanoparticles induced minimal level of liver toxicity or damage. CONCLUSIONS These string-like PEG-b-PPA/DNA micelles can mediate efficient transgene expression in the liver after bile duct infusion, and they have great potential to be used as effective gene carriers for liver-targeted gene delivery.
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Zhai X, Sun P, Luo Y, Ma C, Xu J, Liu W. Guanidinylation: A simple way to fabricate cell penetrating peptide analogue-modified chitosan vector for enhanced gene delivery. J Appl Polym Sci 2011. [DOI: 10.1002/app.34156] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023]
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Chaudhury A, Das S. Recent advancement of chitosan-based nanoparticles for oral controlled delivery of insulin and other therapeutic agents. AAPS PharmSciTech 2011; 12:10-20. [PMID: 21153572 DOI: 10.1208/s12249-010-9561-2] [Citation(s) in RCA: 107] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2010] [Accepted: 11/30/2010] [Indexed: 01/04/2023] Open
Abstract
Nanoparticles composed of naturally occurring biodegradable polymers have emerged as potential carriers of various therapeutic agents for controlled drug delivery through the oral route. Chitosan, a cationic polysaccharide, is one of such biodegradable polymers, which has been extensively exploited for the preparation of nanoparticles for oral controlled delivery of several therapeutic agents. In recent years, the area of focus has shifted from chitosan to chitosan derivatized polymers for the preparation of oral nanoparticles due to its vastly improved properties, such as better drug retention capability, improved permeation, enhanced mucoadhesion and sustained release of therapeutic agents. Chitosan derivatized polymers are primarily the quaternized chitosan derivatives, chitosan cyclodextrin complexes, thiolated chitosan, pegylated chitosan and chitosan combined with other peptides. The current review focuses on the recent advancements in the field of oral controlled release via chitosan nanoparticles and discusses about its in vitro and in vivo implications.
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Dai H, Jiang X, Leong KW, Mao HQ. Transient depletion of kupffer cells leads to enhanced transgene expression in rat liver following retrograde intrabiliary infusion of plasmid DNA and DNA nanoparticles. Hum Gene Ther 2010; 22:873-8. [PMID: 21091274 DOI: 10.1089/hum.2010.146] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023] Open
Abstract
In this report, we have demonstrated that by temporarily removing Kupffer cells (KCs), the transgene expression levels mediated by retrograde intrabiliary infusion (RII) of plasmid DNA, polyethylenimine-DNA, and chitosan nanoparticles were enhanced by 1,927-, 131-, and 23,450-fold, respectively, in comparison with the respective groups without KC removal. KC removal also led to significantly prolonged transgene expression in the liver that received all three carriers. This increased transgene expression was correlated with significantly reduced serum tumor necrosis factor-α level as an indicator for KC activation. These results suggest that KC activation is a significant contributing factor to the lowered transgene expression by polycation-DNA nanoparticles delivered by RII. More importantly, the combination of RII and transient removal of KCs may be adopted as an effective approach to achieving high and persistent transgene expression in the liver mediated by nonviral nanoparticles.
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Affiliation(s)
- Hui Dai
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, MD 21205, USA
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Tajdini F, Amini MA, Nafissi-Varcheh N, Faramarzi MA. Production, physiochemical and antimicrobial properties of fungal chitosan from Rhizomucor miehei and Mucor racemosus. Int J Biol Macromol 2010; 47:180-3. [DOI: 10.1016/j.ijbiomac.2010.05.002] [Citation(s) in RCA: 62] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2010] [Revised: 05/03/2010] [Accepted: 05/05/2010] [Indexed: 11/16/2022]
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Abstract
Ultrafine particles and engineered nanoparticles have unique aerodynamic and biochemical properties that affect the immune system and human health in ways that are different from or exceed those seen with gases or larger particulates. These effects result from a unique set of physical characteristics and surface moieties, which generate an ability of UFPs to enter tissues and cells, interact with proteins and DNA at a molecular level and directly and indirectly modulate the immune system by novel mechanisms. In recent years, a new field known as nanotechnology has impacted multiple industries by taking advantage of the special qualities of these small "atomic-sized" particles. Nanomedicine has already opened up a new avenue of research in cancer therapy, drug delivery and immune regulation. While the benefits of this new science to human civilization are seemingly immeasurable, it is also important to appreciate that these particles can also lead to harmful effects on human health. In vitro and animal studies are showing that nanoparticles and UFPs are capable of activating proinflammatory cytokines, chemokines and adhesion molecules, with recruitment of inflammatory cells including basophils, macrophages, dendritic cells, T cells, neutrophils and eosinophils. These changes may have an impact on immune defense, but also on the Th1/Th2 balance, and even on non-immunologic function. Resulting immune system derangement can lead to increases in incidence of autoimmune, allergic and even neoplastic diseases. Cardiorespiratory effects have been observed to occur in humans. Much further research is needed to establish safe exposure levels for this important new class of particulates.
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Affiliation(s)
- Christopher Chang
- Division of Rheumatology, Allergy and Clinical Immunology, University of California at Davis School of Medicine, 451 Health Sciences Drive, Suite 6510, Davis, CA 95616, USA.
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42
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Ding XQ, Quiambao AB, Fitzgerald JB, Cooper MJ, Conley SM, Naash MI. Ocular delivery of compacted DNA-nanoparticles does not elicit toxicity in the mouse retina. PLoS One 2009; 4:e7410. [PMID: 19823583 PMCID: PMC2756629 DOI: 10.1371/journal.pone.0007410] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2009] [Accepted: 09/10/2009] [Indexed: 12/14/2022] Open
Abstract
Subretinal delivery of polyethylene glycol-substituted lysine peptide (CK30PEG)-compacted DNA nanoparticles results in efficient gene expression in retinal cells. This work evaluates the ocular safety of compacted DNA nanoparticles. CK30PEG-compacted nanoparticles containing an EGFP expression plasmid were subretinally injected in adult mice (1 µl at 0.3, 1.0 and 3.0 µg/µl). Retinas were examined for signs of inflammation at 1, 2, 4 and 7 days post-injection. Neither infiltration of polymorphonuclear neutrophils or lymphocytes was detected in retinas. In addition, elevation of macrophage marker F4/80 or myeloid marker myeloperoxidase was not detected in the injected eyes. The chemokine KC mRNA increased 3–4 fold in eyes injected with either nanoparticles or saline at 1 day post-injection, but returned to control levels at 2 days post-injection. No elevation of KC protein was observed in these mice. The monocyte chemotactic protein-1, increased 3–4 fold at 1 day post-injection for both nanoparticle and saline injected eyes, but also returned to control levels at 2 days. No elevations of tumor necrosis factor alpha mRNA or protein were detected. These investigations show no signs of local inflammatory responses associated with subretinal injection of compacted DNA nanoparticles, indicating that the retina may be a suitable target for clinical nanoparticle-based interventions.
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Affiliation(s)
- Xi-Qin Ding
- The Department of Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, United States of America.
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Peng L, Cheng X, Zhuo R, Lan J, Wang Y, Shi B, Li S. Novel gene-activated matrix with embedded chitosan/plasmid DNA nanoparticles encoding PDGF for periodontal tissue engineering. J Biomed Mater Res A 2009; 90:564-76. [DOI: 10.1002/jbm.a.32117] [Citation(s) in RCA: 60] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022]
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Casé AH, Picola IPD, Zaniquelli MED, Fernandes JC, Taboga SR, Winnik FM, Tiera MJ. Physicochemical characterization of nanoparticles formed between DNA and phosphorylcholine substituted chitosans. J Colloid Interface Sci 2009; 336:125-33. [DOI: 10.1016/j.jcis.2009.02.069] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2008] [Revised: 02/25/2009] [Accepted: 02/27/2009] [Indexed: 10/20/2022]
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Dai LC, Yao X, Wang X, Niu SQ, Zhou LF, Fu FF, Yang SX, Ping JL. In vitro and in vivo suppression of hepatocellular carcinoma growth by midkine-antisense oligonucleotide-loaded nanoparticles. World J Gastroenterol 2009; 15:1966-72. [PMID: 19399928 PMCID: PMC2675086 DOI: 10.3748/wjg.15.1966] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To synthesize antisense oligonucleotides (ASODNs) of midkine (MK), package the ASODNs with nanoparticles, and to inhibit hepatocellular carcinoma (HCC) growth using these nanoparticles.
METHODS: HepG2 cell proliferation was analyzed in vitro using the 3-(4,5-dimethythiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2Htetrazolium, inner salt assay. The in vivo activity of nanoparticles delivering the MK-ASODNs was analyzed by histopathological and immunohistochemical staining and quantitative real time polymerase chain reaction (PCR).
RESULTS: The in vitro proliferation of HepG2 cells was significantly inhibited by the nanoparticles packaged with MK-ASODNs (NANO-ASODNs). Furthermore, the NANO-ASODNs significantly inhibited the growth of HCC in the mouse model.
CONCLUSION: NANO-ASODNs can significantly suppress the growth of HCC in vitro and in vivo.
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Yang Y, Wang Z, Li M, Lu S. Chitosan/pshRNA plasmid nanoparticles targeting MDR1 gene reverse paclitaxel resistance in ovarian cancer cells. ACTA ACUST UNITED AC 2009; 29:239-42. [PMID: 19399413 DOI: 10.1007/s11596-009-0221-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2008] [Indexed: 11/28/2022]
Abstract
In order to investigate the effect of chitosan/pshRNA plasmid nanoparticles targeting MDR1 genes on the resistance of A2780/TS cells to paclitaxel, chitosan/pshRNA plasmid nanoparticles were synthesized by means of a complex coacervation technique and transfected into A2780/TS cells. The cells transfected with MDR1-targeted chitosan/pshRNA plasmid nanoparticles were experimental cells and the cells transfected with chitosan/pGPU6/GFP/Neo no-load plasmid nanoparticles served as negative control cells. Morphological features of the nanoparticles were observed under transmission electron microscope (TEM). MDR1 mRNA expression was assessed by RT-PCR. Half-inhibitory concentration (IC50) of paclitaxel for A2780/TS cells was determined by MTT method. TEM showed that the nanoparticles were round-shaped, smooth in surface and the diameters varied from 80 to 120 nm. The MDR1 mRNA in the transfected cells was significantly decreased by 17.6%, 27.8% and 52.6% on the post-transfection day 2, 4 and 7 when compared with that in A2780/TS cells control (P<0.05). MTT assay revealed that the relative reversal efficiency was increased over time and was 29.6%, 51.2% and 61.3% respectively in the transfected cells 2, 4, 7 days after transfection and IC50 (0.197+/-0.003, 0.144+/-0.001, 0.120+/-0.004) were decreased with difference being significant when compared with that in A2780/TS (0.269+/-0.003) cells control (P<0.05). It was concluded that chitosan/pshRNA plasmid nanoparticles targeting MDR1 can effectively reverse the paclitaxel resistance in A2780/TS cells in a time-dependent manner.
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Affiliation(s)
- Yan Yang
- Department of Obstetrics and Gynecology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
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Chen HH, Ho YP, Jiang X, Mao HQ, Wang TH, Leong KW. Simultaneous Non-invasive Analysis of DNA Condensation and Stability by Two-step QD-FRET. NANO TODAY 2009; 4:125-134. [PMID: 20161048 PMCID: PMC2746678 DOI: 10.1016/j.nantod.2009.02.008] [Citation(s) in RCA: 39] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
Nanoscale vectors comprised of cationic polymers that condense DNA to form nanocomplexes are promising options for gene transfer. The rational design of more efficient nonviral gene carriers will be possible only with better mechanistic understanding of the critical rate-limiting steps, such as nanocomplex unpacking to release DNA and degradation by nucleases. We present a two-step quantum dot fluorescence resonance energy transfer (two-step QD-FRET) approach to simultaneously and non-invasively analyze DNA condensation and stability. Plasmid DNA, double-labeled with QD (525 nm emission) and nucleic acid dyes, were complexed with Cy5-labeled cationic gene carriers. The QD donor drives energy transfer stepwise through the intermediate nucleic acid dye to the final acceptor Cy5. At least three distinct states of DNA condensation and integrity were distinguished in single particle manner and within cells by quantitative ratiometric analysis of energy transfer efficiencies. This novel two-step QD-FRET method allows for more detailed assessment of the onset of DNA release and degradation simultaneously.
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Affiliation(s)
- Hunter H. Chen
- Dept. of Biomedical Engineering, Johns Hopkins School of Medicine, Baltimore, MD
- Dept. of Biomedical Engineering, Duke University, Durham, NC
| | - Yi-Ping Ho
- Dept. of Mechanical Engineering, Johns Hopkins University, Baltimore, MD
- Dept. of Biomedical Engineering, Duke University, Durham, NC
| | - Xuan Jiang
- Dept. of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD
| | - Hai-Quan Mao
- Dept. of Materials Science and Engineering, Johns Hopkins University, Baltimore, MD
| | - Tza-Huei Wang
- Dept. of Mechanical Engineering, Johns Hopkins University, Baltimore, MD
| | - Kam W. Leong
- Dept. of Biomedical Engineering, Duke University, Durham, NC
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48
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Velasco D, Elvira C, San Román J. New stimuli-responsive polymers derived from morpholine and pyrrolidine. JOURNAL OF MATERIALS SCIENCE. MATERIALS IN MEDICINE 2008; 19:1453-1458. [PMID: 18046630 DOI: 10.1007/s10856-007-3315-z] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/07/2007] [Accepted: 10/16/2007] [Indexed: 05/25/2023]
Abstract
The preparation of three new ionizable monomers: N-ethyl morpholine metacrylate (EMM), N-ethyl morpholine methacrylamide (EMA) and N-ethyl pyrrolidine metacrylamide (EPA) and their respective homopolymers poly-EMM, poly-EMA and poly-EPA prepared by radical polymerization in solution, is described. The systems have been characterized by NMR and FTIR spectroscopic techniques, determined their glass transition temperatures by DSC and their respective pKs. Moreover, crosslinked samples were prepared by bulk polymerization using N,N-methylene bisacrylamide (BAam) and the trifunctional 1,3,5-triacryloylhexa-hydro-1,3,5-triazine (135-T) as crosslinkers. The studies of swelling kinetics were carried out in different pH buffer solutions (2, 7.4 and 10) in a thermostatic bath at 37 degrees C showing hydration degrees that go from 2,600% to about 200% depending on the pH and on the crosslinker used. The systems seem to be suitable for the preparation of smart hydrogels for drug delivery and Tissue Engineering.
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Affiliation(s)
- Diego Velasco
- Department of Biomaterials, Institute of Polymer Science and Technology, CSIC, Juan de la Cierva 3, 28006 Madrid, Spain
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49
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Pathak A, Vyas SP, Gupta KC. Nano-vectors for efficient liver specific gene transfer. Int J Nanomedicine 2008; 3:31-49. [PMID: 18488414 PMCID: PMC2526359] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Recent progress in nanotechnology has triggered the site specific drug/gene delivery research and gained wide acknowledgment in contemporary DNA therapeutics. Amongst various organs, liver plays a crucial role in various body functions and in addition, the site is a primary location of metastatic tumor growth. In past few years, a plethora of nano-vectors have been developed and investigated to target liver associated cells through receptor mediated endocytosis. This emerging paradigm in cellular drug/gene delivery provides promising approach to eradicate genetic as well as acquired diseases affecting the liver. The present review provides a comprehensive overview of potential of various delivery systems, viz., lipoplexes, liposomes, polyplexes, nanoparticles and so forth to selectively relocate foreign therapeutic DNA into liver specific cell type via the receptor mediated endocytosis. Various receptors like asialoglycoprotein receptors (ASGP-R) provide unique opportunity to target liver parenchymal cells. The results obtained so far reveal tremendous promise and offer enormous options to develop novel DNA-based pharmaceuticals for liver disorders in near future.
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Affiliation(s)
- Atul Pathak
- Nucleic Acids Research Laboratory, Institute of Genomics and Integrative Biology, Delhi University CampusDelhi, India
| | - Suresh P Vyas
- Department of Pharmaceutical Sciences, Dr. Harisingh Gour VishwavidyalayaSagar, (M.P.), India
| | - Kailash C Gupta
- Nucleic Acids Research Laboratory, Institute of Genomics and Integrative Biology, Delhi University CampusDelhi, India
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Masotti A, Bordi F, Ortaggi G, Marino F, Palocci C. A novel method to obtain chitosan/DNA nanospheres and a study of their release properties. NANOTECHNOLOGY 2008; 19:055302. [PMID: 21817607 DOI: 10.1088/0957-4484/19/05/055302] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/31/2023]
Abstract
Polysaccharides and other cationic polymers have recently been used in pharmaceutical research and industry for their properties to control the release of antibiotics, DNA, proteins, peptide drugs or vaccines, and they have also been extensively studied as non-viral DNA carriers for gene delivery and therapy. Among them, chitosan is the most used since it can promote long-term release of incorporated drugs. This work is focused on the preparation of chitosan and chitosan/DNA nanospheres by using a novel and simple osmosis-based method, recently patented. The morphology of chitosan/DNA particles is spherical (as observed by scanning electron microscopy, SEM) and the nanospheres' average diameter is 38 ± 4 nm (obtained by dynamic light scattering, DLS). With this method, DNA is incorporated with high yield (up to 30%) and the release process is gradual and prolonged in time. The novelty of the reported method resides in the general applicability to various synthetic or natural biopolymers. Solvent, temperature and membrane cut-off are the physicochemical parameters that one is able to use to control the overall osmotic process, leading to several nanostructured systems with different size and shape that may be used in several biotechnological applications.
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Affiliation(s)
- Andrea Masotti
- Dipartimento di Chimica, SAPIENZA Università di Roma, Piazzale Aldo Moro 5, 00185 Rome, Italy
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