Article

Insight on the Formation of Chitosan Nanoparticles through Ionotropic Gelation with Tripolyphosphate

Laboratory of Molecular Engineering, Department of Physics, University of Patras , Patras GR-26500, Greece.
Molecular Pharmaceutics (Impact Factor: 4.38). 07/2012; 9(10):2856-62. DOI: 10.1021/mp300162j
Source: PubMed

ABSTRACT

This work reports details pertaining to the formation of chitosan nanoparticles that we prepare by the ionic gelation method. The molecular interactions of the ionic cross-linking of chitosan with tripolyphosphate have been investigated and elucidated by means of all-electron density functional theory. Solvent effects have been taken into account using implicit models. We have identified primary-interaction ionic cross-linking configurations that we define as H-link, T-link, and M-link, and we have quantified the corresponding interaction energies. H-links, which display high interaction energies and are also spatially broadly accessible, are the most probable cross-linking configurations. At close range, proton transfer has been identified, with maximum interaction energies ranging from 12.3 up to 68.3 kcal/mol depending on the protonation of the tripolyphosphate polyanion and the relative coordination of chitosan with tripolyphosphate. On the basis of our results for the linking types (interaction energies and torsion bias), we propose a simple mechanism for their impact on the chitosan/TPP nanoparticle formation process. We introduce the β ratio, which is derived from the commonly used α ratio but is more fundamental since it additionally takes into account structural details of the oligomers.

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Available from: Emmanuel N Koukaras
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    • "Thus, for the simplest scenario the corresponding expected weight ratio for the case of CSUS is a CSUC = a CS M CSUC /M CS . Given the well established (Koukaras et al., 2012, 2014; Papadimitriou et al., 2008) optimum CS/TPP weight ratio of 4/1, and the molecular weights M CS = 179.17, and M CSUC = 279.25, the expected optimum weight ratio is a CSUC = 6.2/1. "
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    ABSTRACT: The aim of the present study was to evaluate the effectiveness of neat chitosan (CS) and its derivatives with succinic anhydride (CSUC) and 2-carboxybenzaldehyde (CBCS) as appropriate nanocarriers for ocular release of timolol maleate (Tim). Drug nanoencapsulation was performed via ionic crosslinking gelation of the used carriers and sodium tripolyphosphate (TPP). Nanoparticles with size ranged from about 190 to 525nm were prepared and it was found that the formed size was directly depended on the used carrier and their ratios with TPP. For CS derivatives it was found that as the amount of TPP increased, the particle size increased too, while both derivatives proceeded to nanoparticles with smaller size than thath of neat CS. The interactions between carriers and TPP were studied theoretically using all-electron calculations within the framework of density functional theory (DFT). In most of nanoparticles formulations, Tim was entrapped in amorphous form, while the drug entrapment efficiency was higher in CBCS derivative.It was indicated that Tim release rate depended mainly on the used carrier, particle size of prepared nanocarriers and drug loading. From the theoretical release data analysis, it was found that the Tim release was a stagewise procedure with drug diffusion being the dominant release mechanism for each stage. Copyright © 2015. Published by Elsevier B.V.
    Full-text · Article · Sep 2015 · International Journal of Pharmaceutics
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    • "Thus, for the simplest scenario the corresponding expected weight ratio for the case of CSUS is a CSUC = a CS M CSUC /M CS . Given the well established (Koukaras et al., 2012, 2014; Papadimitriou et al., 2008) optimum CS/TPP weight ratio of 4/1, and the molecular weights M CS = 179.17, and M CSUC = 279.25, the expected optimum weight ratio is a CSUC = 6.2/1. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The aim of the present study was to evaluate the effectiveness of neat chitosan (CS) and its derivatives with succinic anhydride (CSUC) and 2-carboxybenzaldehyde (CBCS) as appropriate nanocarriers for ocular release of timolol maleate (Tim). Drug nanoencapsulation was performed via ionic crosslinking gelation of the used carriers and sodium tripolyphosphate (TPP). Nanoparticles with size ranged from about 190 to 525 nm were prepared and it was found that the formed size was directly depended on the used carrier and their ratios with TPP. For CS derivatives it was found that as the amount of TPP increased, the particle size increased too, while both derivatives proceeded to nanoparticles with smaller size than thath of neat CS. The interactions between carriers and TPP were studied theoretically using all-electron calculations within the framework of density functional theory (DFT). In most of nanoparticles formulations, Tim was entrapped in amorphous form, while the drug entrapment efficiency was higher in CBCS derivative.It was indicated that Tim release rate depended mainly on the used carrier, particle size of prepared nanocarriers and drug loading. From the theoretical release data analysis, it was found that the Tim release was a stagewise procedure with drug diffusion being the dominant release mechanism for each stage.
    Full-text · Article · Sep 2015
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    • "CS-NPs have been investigated as a promising drug carrier for targeted delivery to specific sites. The ionic cross-linking between CS, as the polycation, and TPP, as the polyanionic partner, is a simple production method that avoids the use of organic solvent, while is also an effective way to obtain stable and size-controlled NPs [27]. Moreover, CS-NPs prepared via ionotropic gelation avoid the use of chemical cross-linking or emulsifying agents that can be toxic to cells and affect the biological properties [28] [29]. "
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    ABSTRACT: The pH-responsive delivery systems have brought new advances in the field of functional nanodevices and might allow more accurate and controllable delivery of specific cargoes, which is expected to result in promising applications in different clinical therapies. Here we describe a family of chitosan–TPP (tripolyphosphate) nanoparti-cles (NPs) for intracellular drug delivery, which were designed using two pH-sensitive amino acid-based surfactants from the family N α ,N ε-dioctanoyl lysine as bioactive compounds. Low and medium molecular weight chitosan (LMW-CS and MMW-CS, respectively) were used for NP preparation, and it was observed that the size distribution for NPs with LMW-CS were smaller (~ 168 nm) than that for NPs prepared with MMW-CS (~310 nm). Hemolysis assay demonstrated the pH-dependent biomembrane disruptional capability of the constructed NPs. The nanostructures incorporating the surfactants cause negligible membrane permeabilization at pH 7.4. However, at acidic pH, prevailing in endosomes, membrane-destabilizing activity in an erythrocyte lysis assay became evident. When pH decreased to 6.6 and 5.4, hemolytic capability of chitosan NPs increased along with the raise of concentration. Furthermore, studies with cell culture showed that these pH-responsive NPs displayed low cytotoxic effects against 3T3 fibroblasts. The influence of chitosan molecular weight, chitosan to TPP weight ratio, nanoparticle size and nature of the surfactant counterion on the membrane-disruptive properties of nanoparticles was discussed in detail. Altogether, the results achieved here showed that by inserting the lysine-based amphiphiles into chitosan NPs, pH-sensitive membranolytic and potentially endosomolytic nanocarriers were developed, which, therefore, demonstrated ideal feasibility for intracellular drug delivery.
    Full-text · Article · Aug 2015 · Materials Science and Engineering C
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