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      pH responsive N-succinyl chitosan/Poly (acrylamide-co-acrylic acid) hydrogels and in vitro release of 5-fluorouracil

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          Abstract

          There has been significant progress in the last few decades in addressing the biomedical applications of polymer hydrogels. Particularly, stimuli responsive hydrogels have been inspected as elegant drug delivery systems capable to deliver at the appropriate site of action within the specific time. The present work describes the synthesis of pH responsive semi-interpenetrating network (semi-IPN) hydrogels of N-succinyl-chitosan (NSC) via Schiff base mechanism using glutaraldehyde as a crosslinking agent and Poly (acrylamide-co-acrylic acid)(Poly (AAm-co-AA)) was embedded within the N-succinyl chitosan network. The physico-chemical interactions were characterized by Fourier transform infrared (FTIR), X-ray diffraction (XRD), thermogravimetric analysis (TGA), and field emission scanning electron microscope (FESEM). The synthesized hydrogels constitute porous structure. The swelling ability was analyzed in physiological mediums of pH 7.4 and pH 1.2 at 37°C. Swelling properties of formulations with various amounts of NSC/ Poly (AAm-co-AA) and crosslinking agent at pH 7.4 and pH 1.2 were investigated. Hydrogels showed higher swelling ratios at pH 7.4 while lower at pH 1.2. Swelling kinetics and diffusion parameters were also determined. Drug loading, encapsulation efficiency, and in vitro release of 5-fluorouracil (5-FU) from the synthesized hydrogels were observed. In vitro release profile revealed the significant influence of pH, amount of NSC, Poly (AAm-co-AA), and crosslinking agent on the release of 5-FU. Accordingly, rapid and large release of drug was observed at pH 7.4 than at pH 1.2. The maximum encapsulation efficiency and release of 5-FU from SP2 were found to be 72.45% and 85.99%, respectively. Kinetics of drug release suggested controlled release mechanism of 5-FU is according to trend of non-Fickian. From the above results, it can be concluded that the synthesized hydrogels have capability to adapt their potential exploitation as targeted oral drug delivery carriers.

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          Hydrogels: from controlled release to pH-responsive drug delivery.

          Hydrogels are one of the upcoming classes of polymer-based controlled-release drug delivery systems. Besides exhibiting swelling-controlled drug release, hydrogels also show stimuli-responsive changes in their structural network and hence, the drug release. Because of large variations in physiological pH at various body sites in normal as well as pathological conditions, pH-responsive polymeric networks have been extensively studied. This review highlights the use of hydrogels (a class of polymeric systems) in controlled drug delivery, and their application in stimuli-responsive, especially pH-responsive, drug release.
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            Dual and multi-stimuli responsive polymeric nanoparticles for programmed site-specific drug delivery.

            In the past decades, polymeric nanoparticles have emerged as a most promising and viable technology platform for targeted and controlled drug delivery. As vehicles, ideal nanoparticles are obliged to possess high drug loading levels, deliver drug to the specific pathological site and/or target cells without drug leakage on the way, while rapidly unload drug at the site of action. To this end, various "intelligent" polymeric nanoparticles that release drugs in response to an internal or external stimulus such as pH, redox, temperature, magnetic and light have been actively pursued. These stimuli-responsive nanoparticles have demonstrated, though to varying degrees, improved in vitro and/or in vivo drug release profiles. In an effort to further improve drug release performances, novel dual and multi-stimuli responsive polymeric nanoparticles that respond to a combination of two or more signals such as pH/temperature, pH/redox, pH/magnetic field, temperature/reduction, double pH, pH and diols, temperature/magnetic field, temperature/enzyme, temperature/pH/redox, temperature/pH/magnetic, pH/redox/magnetic, temperature/redox/guest molecules, and temperature/pH/guest molecules have recently been developed. Notably, these combined responses take place either simultaneously at the pathological site or in a sequential manner from nanoparticle preparation, nanoparticle transporting pathways, to cellular compartments. These dual and multi-stimuli responsive polymeric nanoparticles have shown unprecedented control over drug delivery and release leading to superior in vitro and/or in vivo anti-cancer efficacy. With programmed site-specific drug delivery feature, dual and multi-stimuli responsive nanoparticulate drug formulations have tremendous potential for targeted cancer therapy. In this review paper, we highlight the recent exciting developments in dual and multi-stimuli responsive polymeric nanoparticles for precision drug delivery applications, with a particular focus on their design, drug release performance, and therapeutic benefits. Copyright © 2013 Elsevier Ltd. All rights reserved.
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              pH sensing and regulation in cancer

              Cells maintain intracellular pH (pHi) within a narrow range (7.1–7.2) by controlling membrane proton pumps and transporters whose activity is set by intra-cytoplasmic pH sensors. These sensors have the ability to recognize and induce cellular responses to maintain the pHi, often at the expense of acidifying the extracellular pH. In turn, extracellular acidification impacts cells via specific acid-sensing ion channels (ASICs) and proton-sensing G-protein coupled receptors (GPCRs). In this review, we will discuss some of the major players in proton sensing at the plasma membrane and their downstream consequences in cancer cells and how these pH-mediated changes affect processes such as migration and metastasis. The complex mechanisms by which they transduce acid pH signals to the cytoplasm and nucleus are not well understood. However, there is evidence that expression of proton-sensing GPCRs such as GPR4, TDAG8, and OGR1 can regulate aspects of tumorigenesis and invasion, including cofilin and talin regulated actin (de-)polymerization. Major mechanisms for maintenance of pHi homeostasis include monocarboxylate, bicarbonate, and proton transporters. Notably, there is little evidence suggesting a link between their activities and those of the extracellular H+-sensors, suggesting a mechanistic disconnect between intra- and extracellular pH. Understanding the mechanisms of pH sensing and regulation may lead to novel and informed therapeutic strategies that can target acidosis, a common physical hallmark of solid tumors.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing – original draftRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: Formal analysisRole: InvestigationRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                5 July 2017
                2017
                : 12
                : 7
                : e0179250
                Affiliations
                [1 ]Department of Chemistry, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia
                [2 ]Centre of Ionics University of Malaya, Department of Physics, Faculty of Science, University of Malaya, Kuala Lumpur, Malaysia
                Kyoto Daigaku, JAPAN
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Article
                PONE-D-16-33838
                10.1371/journal.pone.0179250
                5497947
                28678803
                de98662a-7efd-4cae-a081-74c8216abc82
                © 2017 Bashir et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 24 August 2016
                : 28 May 2017
                Page count
                Figures: 8, Tables: 6, Pages: 24
                Funding
                Funded by: funder-id http://dx.doi.org/10.13039/501100004386, Universiti Malaya;
                Award ID: H21001-F000046
                Award Recipient :
                This work was supported by the High Impact Research Grant (H21001-F000046) from the Ministry of Education, Malaysia, and University of Malaya Research Grants (RP025A- 14 AFR and RP017C-14AFR).
                Categories
                Research Article
                Physical Sciences
                Materials Science
                Materials by Structure
                Amorphous Solids
                Gels
                Physical Sciences
                Materials Science
                Materials by Structure
                Mixtures
                Gels
                Physical Sciences
                Chemistry
                Polymer Chemistry
                Macromolecules
                Polymers
                Physical Sciences
                Materials Science
                Materials by Structure
                Polymers
                Physical Sciences
                Chemistry
                Physical Chemistry
                Chemical Bonding
                Cross-Linking
                Medicine and Health Sciences
                Pharmaceutics
                Pharmaceutical Processing Technology
                Drug Synthesis
                Medicine and Health Sciences
                Pharmaceutics
                Drug Delivery
                Research and analysis methods
                Spectrum analysis techniques
                NMR spectroscopy
                Medicine and Health Sciences
                Pharmacology
                Drug Research and Development
                Drug Regulation
                Physical Sciences
                Chemistry
                Polymer Chemistry
                Macromolecules
                Polymers
                Acrylics
                Physical Sciences
                Materials Science
                Materials by Structure
                Polymers
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