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Chitosan Nanoparticles at the Biological Interface: Implications for Drug Delivery

Aibani, Noorjahan, Rai, Raj, Patel, Parth, Cuddihy, Grace, Wasan, Ellen K.·2021·Pharmaceutics
DOI 10.3390/pharmaceutics13101686PMC PMC8540112
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Abstract

The unique properties of chitosan make it a useful choice for various nanoparticulate drug delivery applications. Although chitosan is biocompatible and enables cellular uptake, its interactions at cellular and systemic levels need to be studied in more depth. This review focuses on the various physical and chemical properties of chitosan that affect its performance in biological systems. We aim to analyze recent research studying interactions of chitosan nanoparticles (NPs) upon their cellular uptake and their journey through the various compartments of the cell. The positive charge of chitosan enables it to efficiently attach to cells, increasing the probability of cellular uptake. Chitosan NPs are taken up by cells via different pathways and escape endosomal degradation due to the proton sponge effect. Furthermore, we have reviewed the interaction of chitosan NPs upon in vivo administration. Chitosan NPs are immediately surrounded by a serum protein corona in systemic circulation upon intravenous administration, and their biodistribution is mainly to the liver and spleen indicating RES uptake. However, the evasion of RES system as well as the targeting ability and bioavailability of chitosan NPs can be improved by utilizing specific routes of administration and covalent modifications of surface properties. Ongoing clinical trials of chitosan formulations for therapeutic applications are paving the way for the introduction of chitosan into the pharmaceutical market and for their toxicological evaluation. Chitosan provides specific biophysical properties for effective and tunable cellular uptake and systemic delivery for a wide range of applications.

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Crossref · 10.3390/pharmaceutics13101686

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Figure 1 Modes of cellular uptake and eventual fate of chitosan in cells.
Figure 1 Modes of cellular uptake and eventual fate of chitosan in cells.CC BY · PubMed Central
Figure 2 Effect of particle size on cellular uptake pathways depicting energy dependent uptake of larger sized NPs and passive uptake of small NPs.
Figure 2 Effect of particle size on cellular uptake pathways depicting energy dependent uptake of larger sized NPs and passive uptake of small NPs.CC BY · PubMed Central
Figure 3 Lifespan of chitosan nanoparticles.
Figure 3 Lifespan of chitosan nanoparticles.CC BY · PubMed Central

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Research works printed but not linked: 175

  1. Calvo, 1997, Novel Hydrophilic Chitosan-Polyethylene Oxide Nanoparticles as Protein Carriers, J. Appl. Polym. Sci., 63, 125, 10.1002/(SICI)1097-4628(19970103)63:1<125::AID-APP13>3.0.CO;2-4 · DOI
  2. Calvo, 1997, Evaluation of Cationic Polymer-Coated Nanocapsules as Ocular Drug Carriers, Int. J. Pharm., 153, 41, 10.1016/S0378-5173(97)00083-5 · DOI
  3. Berthold, 1996, Preparation and Characterization of Chitosan Microspheres as Drug Carrier for Prednisolone Sodium Phosphate as Model for Anti-Inflammatory Drugs, J. Control Release, 39, 17, 10.1016/0168-3659(95)00129-8 · DOI
  4. Ojeda-Hernández, D.D., Canales-Aguirre, A.A., Matias-Guiu, J., Gomez-Pinedo, U., and Mateos-Díaz, J.C. (2020). Potential of Chitosan and Its Derivatives for Biomedical Applications in the Central Nervous System. Front. Bioeng. Biotechnol., 8. · DOI
  5. Wang, W., Meng, Q., Li, Q., Liu, J., Zhou, M., Jin, Z., and Zhao, K. (2020). Chitosan Derivatives and Their Application in Biomedicine. Int. J. Mol. Sci., 21. · DOI
  6. Jhaveri, J., Raichura, Z., Khan, T., Momin, M., and Omri, A. (2021). Chitosan Nanoparticles-Insight into Properties, Functionalization and Applications in Drug Delivery and Theranostics. Molecules, 26. · DOI
  7. Moraru, C., Mincea, M., Menghiu, G., and Ostafe, V. (2020). Understanding the Factors Influencing Chitosan-Based Nanoparticles-Protein Corona Interaction and Drug Delivery Applications. Molecules, 25. · DOI
  8. Sharma, P.D. (2017). Cellular Screening Methods for the Study of Nanoparticle- Induced Lysosomal Damage. Lysosomes—Associated Diseases and Methods to Study Their Function, InTech. · DOI
  9. Jiang, 2017, Intracellular Disposition of Chitosan Nanoparticles in Macrophages: Intracellular Uptake, Exocytosis, and Intercellular Transport, Int. J. Nanomed., 12, 6383, 10.2147/IJN.S142060 · DOI
  10. Pilipenko, I., Korzhikov-Vlakh, V., Sharoyko, V., Zhang, N., Schäfer-Korting, M., Rühl, E., Zoschke, C., and Tennikova, T. (2019). PH-Sensitive Chitosan–Heparin Nanoparticles for Effective Delivery of Genetic Drugs into Epithelial Cells. Pharmaceutics, 11. · DOI
  11. Nam, 2016, Target Gene Delivery from Targeting Ligand Conjugated Chitosan–PEI Copolymer for Cancer Therapy, Carbohydr. Polym., 135, 153, 10.1016/j.carbpol.2015.08.053 · DOI
  12. Chen, 2017, Stepwise PH-Responsive Nanoparticles for Enhanced Cellular Uptake and on-Demand Intracellular Release of Doxorubicin, Int. J. Nanomed., 12, 4241, 10.2147/IJN.S129748 · DOI
  13. Chen, 2018, N-Trimethyl Chitosan Nanoparticles and CSKSSDYQC Peptide: N-Trimethyl Chitosan Conjugates Enhance the Oral Bioavailability of Gemcitabine to Treat Breast Cancer, J. Control Release, 277, 142, 10.1016/j.jconrel.2018.03.013 · DOI
  14. Garg, 2019, Current Advances in Chitosan Nanoparticles Based Drug Delivery and Targeting, Adv. Pharm. Bull., 9, 195, 10.15171/apb.2019.023 · DOI · Paper page
  15. Yang, 2015, Getting Across the Cell Membrane: An Overview for Small Molecules, Peptides, and Proteins, Site-Specif. Protein Labeling, 1266, 29, 10.1007/978-1-4939-2272-7_3 · DOI · Paper page
  16. Magalhaes, 2010, Pivotal Advance: Phospholipids Determine Net Membrane Surface Charge Resulting in Differential Localization of Active Rac1 and Rac2, J. Leukoc. Biol., 87, 545, 10.1189/jlb.0609390 · DOI
  17. Schipper, 1996, Chitosans as Absorption Enhancers for Poorly Absorbable Drugs. 1: Influence of Molecular Weight and Degree of Acetylation on Drug Transport Across Human Intestinal Epithelial (Caco-2) Cells, Pharm. Res., 13, 1686, 10.1023/A:1016444808000 · DOI
  18. Verhoef, 1997, Chitosans for Enhanced Delivery of Therapeutic Peptides across Intestinal Epithelia: In Vitro Evaluation in Caco-2 Cell Monolayers, Int. J. Pharm., 159, 243, 10.1016/S0378-5173(97)00287-1 · DOI
  19. Yue, 2011, Surface Charge Affects Cellular Uptake and Intracellular Trafficking of Chitosan-Based Nanoparticles, Biomacromolecules, 12, 2440, 10.1021/bm101482r · DOI · Paper page
  20. Boyles, 2015, Chitosan Functionalisation of Gold Nanoparticles Encourages Particle Uptake and Induces Cytotoxicity and Pro-Inflammatory Conditions in Phagocytic Cells, as Well as Enhancing Particle Interactions with Serum Components, J. Nanobiotechnol., 13, 84, 10.1186/s12951-015-0146-9 · DOI
  21. Hu, 2012, Influence of Charge on FITC-BSA-Loaded Chondroitin Sulfate-Chitosan Nanoparticles upon Cell Uptake in Human Caco-2 Cell Monolayers, Int. J. Nanomed., 7, 4861
  22. Kalliola, 2018, Carboxymethyl Chitosan and Its Hydrophobically Modified Derivative as PH-Switchable Emulsifiers, Langmuir, 34, 2800, 10.1021/acs.langmuir.7b03959 · DOI
  23. Nogueira, 2013, In Vitro Antitumor Activity of Methotrexate via PH-Sensitive Chitosan Nanoparticles, Biomaterials, 34, 2758, 10.1016/j.biomaterials.2013.01.005 · DOI
  24. Amoozgar, 2012, Low Molecular-Weight Chitosan as a PH-Sensitive Stealth Coating for Tumor-Specific Drug Delivery, Mol. Pharm., 9, 1262, 10.1021/mp2005615 · DOI
  25. Khalili, 2015, A Review of Cell Adhesion Studies for Biomedical and Biological Applications, Int. J. Mol. Sci., 16, 18149, 10.3390/ijms160818149 · DOI
  26. Chen, 2012, Control of Cell Attachment on PH-Responsive Chitosan Surface by Precise Adjustment of Medium PH, Biomaterials, 33, 1336, 10.1016/j.biomaterials.2011.10.048 · DOI
  27. Taketa, 2019, Tailored Chitosan/Hyaluronan Coatings for Tumor Cell Adhesion: Effects of Topography, Charge Density and Surface Composition, Appl. Surf. Sci., 486, 508, 10.1016/j.apsusc.2019.04.227 · DOI
  28. Noriega, 2011, Consequences of Neutralization on the Proliferation and Cytoskeletal Organization of Chondrocytes on Chitosan-Based Matrices, Int. J. Carbohydr. Chem., 2011, 1, 10.1155/2011/809743 · DOI
  29. Zhang, 2018, A Proteomics Study to Explore the Role of Adsorbed Serum Proteins for PC12 Cell Adhesion and Growth on Chitosan and Collagen/Chitosan Surfaces, Regen. Biomater., 5, 261, 10.1093/rb/rby017 · DOI
  30. Ibrahim, F., Osman, N.A.A., Usman, J., and Kadri, N.A. (2006, January 11–14). Cell Adhesion and Degradation Behaviors of Acetylated Chitosan Films. Proceedings of the 3rd Kuala Lumpur International Conference on Biomedical Engineering 2006, Kuala Lumpur, Malaysia. · DOI
  31. Foster, L.J.R., Ho, S., Hook, J., Basuki, M., and Marçal, H. (2015). Chitosan as a Biomaterial: Influence of Degree of Deacetylation on Its Physiochemical, Material and Biological Properties. PLoS ONE, 10. · DOI
  32. 2015, Chitosan and Its Potential Use as a Scaffold for Tissue Engineering in Regenerative Medicine, BioMed Res. Int., 2015, 821279
  33. Boecker, A., Daeschler, S.C., Kneser, U., and Harhaus, L. (2019). Relevance and Recent Developments of Chitosan in Peripheral Nerve Surgery. Front. Cell. Neurosci., 13. · DOI
  34. Dixit, 2017, Immunological Challenges Associated with Artificial Skin Grafts: Available Solutions and Stem Cells in Future Design of Synthetic Skin, J. Biol. Eng., 11, 49, 10.1186/s13036-017-0089-9 · DOI
  35. Salati, 2011, Design and Fabrication of Artificial Skin: Chitosan and Gelatin Immobilization on Silicone by Poly Acrylic Acid Graft Using a Plasma Surface Modification Method, J. Macromol. Sci. Part B, 50, 1972, 10.1080/00222348.2010.549438 · DOI
  36. Vijayan, A., Sabareeswaran, A., and Kumar, G.S.V. (2019). PEG Grafted Chitosan Scaffold for Dual Growth Factor Delivery for Enhanced Wound Healing. Sci. Rep., 9. · DOI
  37. Liu, 2018, A Functional Chitosan-Based Hydrogel as a Wound Dressing and Drug Delivery System in the Treatment of Wound Healing, RSC Adv., 8, 7533, 10.1039/C7RA13510F · DOI
  38. Cho, M.O., Li, Z., Shim, H.-E., Cho, I.-S., Nurunnabi, M., Park, H., Lee, K.Y., Moon, S.-H., Kim, K.-S., and Kang, S.-W. (2016). Bioinspired Tuning of Glycol Chitosan for 3D Cell Culture. NPG Asia Mater., 8. · DOI
  39. Kafi, 2020, Engineered Chitosan for Improved 3D Tissue Growth through Paxillin-FAK-ERK Activation, Regen. Biomater., 7, 141, 10.1093/rb/rbz034 · DOI
  40. Yeh, 2011, Mechanism and Consequence of Chitosan-Mediated Reversible Epithelial Tight Junction Opening, Biomaterials, 32, 6164, 10.1016/j.biomaterials.2011.03.056 · DOI
  41. Sonaje, 2011, Effects of Chitosan-Nanoparticle-Mediated Tight Junction Opening on the Oral Absorption of Endotoxins, Biomaterials, 32, 8712, 10.1016/j.biomaterials.2011.07.086 · DOI
  42. Lee, 2018, Tight Junction in the Intestinal Epithelium: Its Association with Diseases and Regulation by Phytochemicals, J. Immunol. Res., 2018, 1, 10.1155/2018/2645465 · DOI
  43. Bhat, A.A., Uppada, S., Achkar, I.W., Hashem, S., Yadav, S.K., Shanmugakonar, M., Al-Naemi, H.A., Haris, M., and Uddin, S. (2019). Tight Junction Proteins and Signaling Pathways in Cancer and Inflammation: A Functional Crosstalk. Front. Physiol., 9. · DOI
  44. Zihni, 2016, Tight Junctions: From Simple Barriers to Multifunctional Molecular Gates, Nat. Rev. Mol. Cell Biol., 17, 564, 10.1038/nrm.2016.80 · DOI
  45. Wang, 2017, Mechanism of Surface Charge Triggered Intestinal Epithelial Tight Junction Opening upon Chitosan Nanoparticles for Insulin Oral Delivery, Carbohydr. Polym., 157, 596, 10.1016/j.carbpol.2016.10.021 · DOI
  46. Srinivasan, 2015, TEER Measurement Techniques for In Vitro Barrier Model Systems, J. Lab. Autom., 20, 107, 10.1177/2211068214561025 · DOI
  47. Smith, 2004, Effect of Chitosan on Epithelial Cell Tight Junctions, Pharm. Res., 21, 43, 10.1023/B:PHAM.0000012150.60180.e3 · DOI
  48. Vllasaliu, 2010, Tight Junction Modulation by Chitosan Nanoparticles: Comparison with Chitosan Solution, Int. J. Pharm., 400, 183, 10.1016/j.ijpharm.2010.08.020 · DOI
  49. Foroozandeh, 2018, Insight into Cellular Uptake and Intracellular Trafficking of Nanoparticles, Nanoscale Res. Lett., 13, 339, 10.1186/s11671-018-2728-6 · DOI
  50. Li, 2017, Transporting Carriers for Intracellular Targeting Delivery via Non-Endocytic Uptake Pathways, Drug Deliv., 24, 45, 10.1080/10717544.2017.1391889 · DOI
  51. Juliano, 2015, Cellular Uptake and Intracellular Trafficking of Oligonucleotides, Adv. Drug Deliv. Rev., 87, 35, 10.1016/j.addr.2015.04.005 · DOI
  52. Malatesta, M., Grecchi, S., Chiesa, E., Cisterna, B., Costanzo, M., and Zancanaro, C. (2015). Internalized Chitosan Nanoparticles Persist for Long Time in Cultured Cells. Eur. J. Histochem., 59. · DOI
  53. Huang, 2002, Uptake of FITC-Chitosan Nanoparticles by A549 Cells, Pharm. Res., 19, 1488, 10.1023/A:1020404615898 · DOI
  54. Park, 2007, In Vitro Cellular Uptake and Cytotoxicity of Paclitaxel-Loaded Glycol Chitosan Self-Assembled Nanoparticles, Macromol. Res., 15, 513, 10.1007/BF03218824 · DOI
  55. Tahara, 2009, Improved Cellular Uptake of Chitosan-Modified PLGA Nanospheres by A549 Cells, Int. J. Pharm., 382, 198, 10.1016/j.ijpharm.2009.07.023 · DOI
  56. Koppolu, 2013, The Effect of Antigen Encapsulation in Chitosan Particles on Uptake, Activation and Presentation by Antigen Presenting Cells, Biomaterials, 34, 2359, 10.1016/j.biomaterials.2012.11.066 · DOI
  57. Tammam, 2015, Chitosan Nanoparticles for Nuclear Targeting: The Effect of Nanoparticle Size and Nuclear Localization Sequence Density, Mol. Pharm., 12, 4277, 10.1021/acs.molpharmaceut.5b00478 · DOI
  58. 2012, The Role of Surface Charge in Cellular Uptake and Cytotoxicity of Medical Nanoparticles, Int. J. Nanomed., 7, 5577
  59. He, 2010, Effects of Particle Size and Surface Charge on Cellular Uptake and Biodistribution of Polymeric Nanoparticles, Biomaterials, 31, 3657, 10.1016/j.biomaterials.2010.01.065 · DOI · Paper page
  60. Liu, 2010, Hydrophobic Modifications of Cationic Polymers for Gene Delivery, Prog. Polym. Sci., 35, 1144, 10.1016/j.progpolymsci.2010.04.007 · DOI
  61. Nam, 2009, Cellular Uptake Mechanism and Intracellular Fate of Hydrophobically Modified Glycol Chitosan Nanoparticles, J. Control. Release, 135, 259, 10.1016/j.jconrel.2009.01.018 · DOI
  62. Chiu, 2010, The Characteristics, Cellular Uptake and Intracellular Trafficking of Nanoparticles Made of Hydrophobically-Modified Chitosan, J. Control. Release, 146, 152, 10.1016/j.jconrel.2010.05.023 · DOI
  63. Layek, 2014, Hexanoic Acid and Polyethylene Glycol Double Grafted Amphiphilic Chitosan for Enhanced Gene Delivery: Influence of Hydrophobic and Hydrophilic Substitution Degree, Mol. Pharm., 11, 982, 10.1021/mp400633r · DOI
  64. Wang, 2011, Effects of Hydrophobic and Hydrophilic Modifications on Gene Delivery of Amphiphilic Chitosan Based Nanocarriers, Biomaterials, 32, 4630, 10.1016/j.biomaterials.2011.03.003 · DOI
  65. Zhan, J., Ting, X.L., and Zhu, J. (2017). The Research Progress of Targeted Drug Delivery Systems. IOP Conf. Ser. Mater. Sci. Eng., 207. · DOI
  66. Wang, 2010, Norcantharidin-Associated Galactosylated Chitosan Nanoparticles for Hepatocyte-Targeted Delivery, Nanomed. Nanotechnol. Biol. Med., 6, 371, 10.1016/j.nano.2009.07.006 · DOI
  67. Liu, 2014, TAT-LHRH Conjugated Low Molecular Weight Chitosan as a Gene Carrier Specific for Hepatocellular Carcinoma Cells, Int. J. Nanomed., 9, 2879, 10.2147/IJN.S61392 · DOI
  68. Han, 2015, Dual-Targeting and PH/Redox-Responsive Multi-Layered Nanocomplexes for Smart Co-Delivery of Doxorubicin and SiRNA, Biomaterials, 60, 42, 10.1016/j.biomaterials.2015.05.001 · DOI
  69. Shi, 2017, Enhanced Antitumor Immunity by Targeting Dendritic Cells with Tumor Cell Lysate-Loaded Chitosan Nanoparticles Vaccine, Biomaterials, 113, 191, 10.1016/j.biomaterials.2016.10.047 · DOI
  70. Nascimento, 2017, Overcoming Cisplatin Resistance in Non-Small Cell Lung Cancer with Mad2 Silencing SiRNA Delivered Systemically Using EGFR-Targeted Chitosan Nanoparticles, Acta Biomater., 47, 71, 10.1016/j.actbio.2016.09.045 · DOI
  71. Yang, 2018, Estrone-Modified PH-Sensitive Glycol Chitosan Nanoparticles for Drug Delivery in Breast Cancer, Acta Biomater., 73, 400, 10.1016/j.actbio.2018.04.020 · DOI
  72. Jiang, 2017, A Smart PH-Responsive Nano-Carrier as a Drug Delivery System for the Targeted Delivery of Ursolic Acid: Suppresses Cancer Growth and Metastasis by Modulating P53/MMP-9/PTEN/CD44 Mediated Multiple Signaling Pathways, Nanoscale, 9, 9428, 10.1039/C7NR01677H · DOI
  73. Hefnawy, 2020, Dual-Ligand Functionalized Core-Shell Chitosan-Based Nanocarrier for Hepatocellular Carcinoma-Targeted Drug Delivery, Int. J. Nanomed., 15, 821, 10.2147/IJN.S240359 · DOI
  74. Zhu, 2011, Folate-Modified Chitosan Micelles with Enhanced Tumor Targeting Evaluated by near Infrared Imaging System, Carbohydr. Polym., 86, 1118, 10.1016/j.carbpol.2011.05.061 · DOI
  75. Ramya, A.N., Joseph, M.M., Maniganda, S., Karunakaran, V., Sreelekha, T.T., and Maiti, K.K. (2017). Emergence of Gold-Mesoporous Silica Hybrid Nanotheranostics: Dox-Encoded, Folate Targeted Chemotherapy with Modulation of SERS Fingerprinting for Apoptosis Toward Tumor Eradication. Small, 13. · DOI
  76. Verma, 2016, Vitamin B12 Functionalized Layer by Layer Calcium Phosphate Nanoparticles: A Mucoadhesive and PH Responsive Carrier for Improved Oral Delivery of Insulin, Acta Biomater., 31, 288, 10.1016/j.actbio.2015.12.017 · DOI
  77. Rekha, 2009, Synthesis and Evaluation of Lauryl Succinyl Chitosan Particles towards Oral Insulin Delivery and Absorption, J. Control. Release, 135, 144, 10.1016/j.jconrel.2009.01.011 · DOI
  78. Zhao, 2017, Simultaneous Inhibition of Growth and Metastasis of Hepatocellular Carcinoma by Co-Delivery of Ursolic Acid and Sorafenib Using Lactobionic Acid Modified and PH-Sensitive Chitosan-Conjugated Mesoporous Silica Nanocomplex, Biomaterials, 143, 1, 10.1016/j.biomaterials.2017.07.030 · DOI
  79. Zhu, R., Zhang, C., Liu, Y., Yuan, Z., Chen, W., Yang, S., Li, J., Zhu, W., Zhou, X., and You, B. (2015). CD147 Monoclonal Antibody Mediated by Chitosan Nanoparticles Loaded with α-Hederin Enhances Antineoplastic Activity and Cellular Uptake in Liver Cancer Cells. Sci. Rep., 5. · DOI
  80. Shen, 2012, A Novel Carboxymethyl Chitosan-Based Folate/Fe3O4/CdTe Nanoparticle for Targeted Drug Delivery and Cell Imaging, Carbohydr. Polym., 88, 239, 10.1016/j.carbpol.2011.11.087 · DOI
  81. Mathew, 2010, Folate Conjugated Carboxymethyl Chitosan–Manganese Doped Zinc Sulphide Nanoparticles for Targeted Drug Delivery and Imaging of Cancer Cells, Carbohydr. Polym., 80, 442, 10.1016/j.carbpol.2009.11.047 · DOI
  82. Guan, 2012, N-Trimethyl Chitosan Nanoparticle-Encapsulated Lactosyl-Norcantharidin for Liver Cancer Therapy with High Targeting Efficacy, Nanomed. Nanotechnol. Biol. Med., 8, 1172, 10.1016/j.nano.2012.01.009 · DOI
  83. Zhu, 2014, Low-Density Lipoprotein-Coupled N-Succinyl Chitosan Nanoparticles Co-Delivering SiRNA and Doxorubicin for Hepatocyte-Targeted Therapy, Biomaterials, 35, 5965, 10.1016/j.biomaterials.2014.03.088 · DOI
  84. Chou, 2011, Strategies for the Intracellular Delivery of Nanoparticles, Chem. Soc. Rev., 40, 233, 10.1039/C0CS00003E · DOI
  85. Cao, Y., Tan, Y.F., Wong, Y.S., Liew, M.W.J., and Venkatraman, S. (2019). Recent Advances in Chitosan-Based Carriers for Gene Delivery. Mar. Drugs, 17. · DOI
  86. Lai, 2018, Design of Polymeric Gene Carriers for Effective Intracellular Delivery, Trends Biotechnol., 36, 713, 10.1016/j.tibtech.2018.02.006 · DOI
  87. Zhang, 2018, Convenient Preparation of Charge-Adaptive Chitosan Nanomedicines for Extended Blood Circulation and Accelerated Endosomal Escape, Nano Res., 11, 4278, 10.1007/s12274-018-2014-z · DOI
  88. Moreira, 2009, Improving Chitosan-Mediated Gene Transfer by the Introduction of Intracellular Buffering Moieties into the Chitosan Backbone, Acta Biomater., 5, 2995, 10.1016/j.actbio.2009.04.021 · DOI
  89. Chang, 2010, Efficient Gene Transfection by Histidine-Modified Chitosan through Enhancement of Endosomal Escape, Bioconj. Chem., 21, 1087, 10.1021/bc1000609 · DOI
  90. Huang, G., Chen, Q., Wu, W., Wang, J., Chu, P.K., Bai, H., and Tang, G. (2020). Reconstructed Chitosan with Alkylamine for Enhanced Gene Delivery by Promoting Endosomal Escape. Carbohydr. Polym., 227. · DOI
  91. Rathore, 2019, Nanomaterial Designing Strategies Related to Cell Lysosome and Their Biomedical Applications: A Review, Biomaterials, 211, 25, 10.1016/j.biomaterials.2019.05.002 · DOI
  92. Manshian, 2018, The Impact of Nanoparticle-Driven Lysosomal Alkalinization on Cellular Functionality, J. Nanobiotechnol., 16, 85, 10.1186/s12951-018-0413-7 · DOI
  93. Fong, 2017, Lysosomal Rupture Induced by Structurally Distinct Chitosans Either Promotes a Type 1 IFN Response or Activates the Inflammasome in Macrophages, Biomaterials, 129, 127, 10.1016/j.biomaterials.2017.03.022 · DOI
  94. Thibault, 2011, Excess Polycation Mediates Efficient Chitosan-Based Gene Transfer by Promoting Lysosomal Release of the Polyplexes, Biomaterials, 32, 4639, 10.1016/j.biomaterials.2011.03.010 · DOI
  95. Seijo, 2011, Intracellular Trafficking of Hyaluronic Acid-Chitosan Oligomer-Based Nanoparticles in Cultured Human Ocular Surface Cells, Mol. Vis., 17, 279
  96. Yameen, 2014, Insight into Nanoparticle Cellular Uptake and Intracellular Targeting, J. Control Release, 190, 485, 10.1016/j.jconrel.2014.06.038 · DOI
  97. Tammam, 2016, How Successful Is Nuclear Targeting by Nanocarriers?, J. Control Release, 229, 140, 10.1016/j.jconrel.2016.03.022 · DOI
  98. Opanasopit, 2009, Nuclear Localization Signal Peptides Enhance Transfection Efficiency of Chitosan/DNA Complexes, Int. J. Pharm., 382, 291, 10.1016/j.ijpharm.2009.08.029 · DOI
  99. Barbieri, 2013, Lecithin/Chitosan Controlled Release Nanopreparations of Tamoxifen Citrate: Loading, Enzyme-Trigger Release and Cell Uptake, J. Control Release, 167, 276, 10.1016/j.jconrel.2013.02.009 · DOI
  100. Lee, 2009, Tumor Specificity and Therapeutic Efficacy of Photosensitizer-Encapsulated Glycol Chitosan-Based Nanoparticles in Tumor-Bearing Mice, Biomaterials, 30, 2929, 10.1016/j.biomaterials.2009.01.058 · DOI
  101. Zorova, 2018, Functional Significance of the Mitochondrial Membrane Potential, Biochem. Mosc. Suppl. Ser. Membr. Cell Biol., 12, 20
  102. Qi, 2005, In Vitro Effects of Chitosan Nanoparticles on Proliferation of Human Gastric Carcinoma Cell Line MGC803 Cells, World J. Gastroenterol., 11, 5136
  103. Jiang, 2019, Chitosan Nanoparticles Induced the Antitumor Effect in Hepatocellular Carcinoma Cells by Regulating ROS-Mediated Mitochondrial Damage and Endoplasmic Reticulum Stress, Artif. Cells Nanomed. Biotechnol., 47, 747, 10.1080/21691401.2019.1577876 · DOI
  104. Chen, 2015, Hierarchical Targeted Hepatocyte Mitochondrial Multifunctional Chitosan Nanoparticles for Anticancer Drug Delivery, Biomaterials, 52, 240, 10.1016/j.biomaterials.2015.02.001 · DOI
  105. Hou, 2017, Triphenyl Phosphine-Functionalized Chitosan Nanoparticles Enhanced Antitumor Efficiency Through Targeted Delivery of Doxorubicin to Mitochondria, Nanoscale Res. Lett., 12, 158, 10.1186/s11671-017-1931-1 · DOI
  106. Wang, 2017, Hyaluronic Acid-Coated Chitosan Nanoparticles Induce ROS-Mediated Tumor Cell Apoptosis and Enhance Antitumor Efficiency by Targeted Drug Delivery via CD44, J. Nanobiotechnol., 15, 7, 10.1186/s12951-016-0245-2 · DOI
  107. Mallick, 2019, Self-Assembled Nanoparticles Composed of Glycol Chitosan-Dequalinium for Mitochondria-Targeted Drug Delivery, Int. J. Biol. Macromol., 132, 451, 10.1016/j.ijbiomac.2019.03.215 · DOI
  108. He, 2018, Carboxymethylated Chitosan Protects Schwann Cells against Hydrogen Peroxide-Induced Apoptosis by Inhibiting Oxidative Stress and Mitochondria Dependent Pathway, Eur. J. Pharmacol., 825, 48, 10.1016/j.ejphar.2018.02.024 · DOI
  109. Shukla, 2015, In Vitro Toxicity Assessment of Chitosan Oligosaccharide Coated Iron Oxide Nanoparticles, Toxicol. Rep., 2, 27, 10.1016/j.toxrep.2014.11.002 · DOI
  110. Park, 2014, Endocytosis and Exocytosis of Nanoparticles in Mammalian Cells, Int. J. Nanomed., 9, 51, 10.2147/IJN.S26592 · DOI
  111. Sakhtianchi, 2013, Exocytosis of Nanoparticles from Cells: Role in Cellular Retention and Toxicity, Adv. Colloid Interface Sci., 201–202, 18, 10.1016/j.cis.2013.10.013 · DOI
  112. Park, 2006, N-Acetyl Histidine-Conjugated Glycol Chitosan Self-Assembled Nanoparticles for Intracytoplasmic Delivery of Drugs: Endocytosis, Exocytosis and Drug Release, J. Control Release, 115, 37, 10.1016/j.jconrel.2006.07.011 · DOI
  113. Tahara, 2012, The Suppression of IgE-Mediated Histamine Release from Mast Cells Following Exocytic Exclusion of Biodegradable Polymeric Nanoparticles, Biomaterials, 33, 343, 10.1016/j.biomaterials.2011.09.043 · DOI
  114. Bakhru, 2012, Enhanced Cellular Uptake and Long-Term Retention of Chitosan-Modified Iron-Oxide Nanoparticles for MRI-Based Cell Tracking, Int. J. Nanomed., 7, 4613, 10.2147/IJN.S28294 · DOI
  115. Jin, 2012, PH-Sensitive Chitosan-Derived Nanoparticles as Doxorubicin Carriers for Effective Anti-Tumor Activity: Preparation and in Vitro Evaluation, Colloids Surf. B Biointerfaces, 94, 184, 10.1016/j.colsurfb.2012.01.032 · DOI
  116. Trif, 2015, Cytotoxicity and Intracellular Fate of PLGA and Chitosan-Coated PLGA Nanoparticles in Madin-Darby Bovine Kidney (MDBK) and Human Colorectal Adenocarcinoma (Colo 205) Cells, J. Biomed. Mater. Res. A, 103, 3599, 10.1002/jbm.a.35498 · DOI
  117. Durán, V., Yasar, H., Becker, J., Thiyagarajan, D., Loretz, B., Kalinke, U., and Lehr, C.-M. (2019). Preferential Uptake of Chitosan-Coated PLGA Nanoparticles by Primary Human Antigen Presenting Cells. Nanomed. Nanotechnol. Biol. Med., 21. · DOI
  118. Grenha, 2007, Chitosan Nanoparticles Are Compatible with Respiratory Epithelial Cells in Vitro, Eur. J. Pharm. Sci., 31, 73, 10.1016/j.ejps.2007.02.008 · DOI
  119. Rajam, 2011, Chitosan Nanoparticles as a Dual Growth Factor Delivery System for Tissue Engineering Applications, Int. J. Pharm., 410, 145, 10.1016/j.ijpharm.2011.02.065 · DOI
  120. Zhang, 2017, Amino Acid-Modified Chitosan Nanoparticles for Cu2+ Chelation to Suppress CuO Nanoparticle Cytotoxicity, J. Mater. Chem. B, 5, 3521, 10.1039/C7TB00344G · DOI
  121. Nafee, 2009, Relevance of the Colloidal Stability of Chitosan/PLGA Nanoparticles on Their Cytotoxicity Profile, Int. J. Pharm., 381, 130, 10.1016/j.ijpharm.2009.04.049 · DOI
  122. Sarangapani, 2018, Chitosan Nanoparticles’ Functionality as Redox Active Drugs through Cytotoxicity, Radical Scavenging and Cellular Behaviour, Integr. Biol., 10, 313, 10.1039/C8IB00038G · DOI
  123. Lin, 2019, Chitosan Nanoparticles Strengthen Vγ9Vδ2 T-Cell Cytotoxicity through Upregulation of Killing Molecules and Cytoskeleton Polarization, Int. J. Nanomed., 14, 9325, 10.2147/IJN.S212898 · DOI
  124. Richardson, 1999, Potential of Low Molecular Mass Chitosan as a DNA Delivery System: Biocompatibility, Body Distribution and Ability to Complex and Protect DNA, Int. J. Pharm., 178, 231, 10.1016/S0378-5173(98)00378-0 · DOI
  125. Suzuki, 1998, Biodistribution and Kinetics of Holmium-166-Chitosan Complex (DW-166HC) in Rats and Mice, J. Nucl. Med., 39, 2161
  126. Onishi, 1999, Biodegradation and Distribution of Water-Soluble Chitosan in Mice, Biomaterials, 20, 175, 10.1016/S0142-9612(98)00159-8 · DOI
  127. Banerjee, 2002, Preparation, Characterization and Biodistribution of Ultrafine Chitosan Nanoparticles, Int. J. Pharm., 243, 93, 10.1016/S0378-5173(02)00267-3 · DOI
  128. Kean, 2010, Biodegradation, Biodistribution and Toxicity of Chitosan, Adv. Drug Deliv. Rev., 62, 3, 10.1016/j.addr.2009.09.004 · DOI · Paper page
  129. Kadam, 2012, Nano-Advantage in Enhanced Drug Delivery with Biodegradable Nanoparticles: Contribution of Reduced Clearance, Drug Metab. Dispos., 40, 1380, 10.1124/dmd.112.044925 · DOI
  130. Termsarasab, 2014, Polyethylene Glycol-Modified Arachidyl Chitosan-Based Nanoparticles for Prolonged Blood Circulation of Doxorubicin, Int. J. Pharm., 464, 127, 10.1016/j.ijpharm.2014.01.015 · DOI
  131. Wu, 2017, Facile Fabrication of Poly(Acrylic Acid) Coated Chitosan Nanoparticles with Improved Stability in Biological Environments, Eur. J. Pharm. Biopharm., 112, 148, 10.1016/j.ejpb.2016.11.020 · DOI
  132. Zhang, 2009, O-Carboxymethyl-Chitosan/Organosilica Hybrid Nanoparticles as Non-Viral Vectors for Gene Delivery, Mater. Sci. Eng. C, 29, 2045, 10.1016/j.msec.2009.04.003 · DOI
  133. Katas, 2006, Development and Characterisation of Chitosan Nanoparticles for SiRNA Delivery, J. Control Release, 115, 216, 10.1016/j.jconrel.2006.07.021 · DOI
  134. Shi, S., Zhang, Z., Luo, Z., Yu, J., Liang, R., Li, X., and Chen, H. (2015). Chitosan Grafted Methoxy Poly(Ethylene Glycol)-Poly(ε-Caprolactone) Nanosuspension for Ocular Delivery of Hydrophobic Diclofenac. Sci. Rep., 5. · DOI
  135. Sun, 2014, Biocompatible Glycol Chitosan-Coated Gold Nanoparticles for Tumor-Targeting CT Imaging, Pharm. Res., 31, 1418, 10.1007/s11095-013-1142-0 · DOI
  136. Duan, 2018, Chitosan-Stabilized Self-Assembled Fluorescent Gold Nanoclusters for Cell Imaging and Biodistribution In Vivo, ACS Biomater. Sci. Eng., 4, 1055, 10.1021/acsbiomaterials.7b00975 · DOI
  137. Mahmoudi, 2016, Emerging Understanding of the Protein Corona at the Nano-Bio Interfaces, Nano Today, 11, 817, 10.1016/j.nantod.2016.10.005 · DOI · Paper page
  138. Forest, 2017, Preferential Binding of Positive Nanoparticles on Cell Membranes Is Due to Electrostatic Interactions: A Too Simplistic Explanation That Does Not Take into Account the Nanoparticle Protein Corona, Mater. Sci. Eng. C, 70, 889, 10.1016/j.msec.2016.09.016 · DOI
  139. Almalik, 2013, Hyaluronic Acid-Coated Chitosan Nanoparticles: Molecular Weight-Dependent Effects on Morphology and Hyaluronic Acid Presentation, J. Control Release, 172, 1142, 10.1016/j.jconrel.2013.09.032 · DOI
  140. Almalik, A., Benabdelkamel, H., Masood, A., Alanazi, I.O., Alradwan, I., Majrashi, M.A., Alfadda, A.A., Alghamdi, W.M., Alrabiah, H., and Tirelli, N. (2017). Hyaluronic Acid Coated Chitosan Nanoparticles Reduced the Immunogenicity of the Formed Protein Corona. Sci. Rep., 7. · DOI
  141. Basu, 2019, Biopolymer Nanoparticle Surface Chemistry Dictates the Nature and Extent of Protein Hard Corona, J. Mol. Liq., 282, 169, 10.1016/j.molliq.2019.03.016 · DOI
  142. Abouelmagd, 2015, Low Molecular Weight Chitosan-Coated Polymeric Nanoparticles for Sustained and PH-Sensitive Delivery of Paclitaxel, J. Drug Target., 23, 725, 10.3109/1061186X.2015.1054829 · DOI
  143. Tekie, 2020, Controlling Evolution of Protein Corona: A Prosperous Approach to Improve Chitosan-Based Nanoparticle Biodistribution and Half-Life, Sci. Rep., 10, 9664, 10.1038/s41598-020-66572-y · DOI
  144. Chen, 2009, The Characteristics, Biodistribution and Bioavailability of a Chitosan-Based Nanoparticulate System for the Oral Delivery of Heparin, Biomaterials, 30, 6629, 10.1016/j.biomaterials.2009.08.030 · DOI
  145. Raj, 2018, Biodistribution and Targeting Potential Assessment of Mucoadhesive Chitosan Nanoparticles Designed for Ulcerative Colitis via Scintigraphy, RSC Adv., 8, 20809, 10.1039/C8RA01898G · DOI
  146. Navarro, 2014, Biodistribution of PLGA and PLGA/Chitosan Nanoparticles after Repeat-Dose Oral Delivery in F344 Rats for 7 Days, Ther. Deliv., 5, 1191, 10.4155/tde.14.79 · DOI
  147. Gartziandia, 2015, Chitosan Coated Nanostructured Lipid Carriers for Brain Delivery of Proteins by Intranasal Administration, Colloids Surf. B Biointerfaces, 134, 304, 10.1016/j.colsurfb.2015.06.054 · DOI
  148. Yousfan, 2020, Preparation and Characterisation of PHT-Loaded Chitosan Lecithin Nanoparticles for Intranasal Drug Delivery to the Brain, RSC Adv., 10, 28992, 10.1039/D0RA04890A · DOI
  149. Franca, J.R., Foureaux, G., Fuscaldi, L.L., Ribeiro, T.G., Rodrigues, L.B., Bravo, R., Castilho, R.O., Yoshida, M.I., Cardoso, V.N., and Fernandes, S.O. (2014). Bimatoprost-Loaded Ocular Inserts as Sustained Release Drug Delivery Systems for Glaucoma Treatment: In Vitro and In Vivo Evaluation. PLoS ONE, 9. · DOI
  150. Franca, 2020, Use of Chitosan as Pharmaceutical Excipient in Ocular Drug Delivery Systems: Sterilization and Pharmacokinetics, J. Biomed. Mater. Res. B Appl. Biomater., 108, 2227, 10.1002/jbm.b.34560 · DOI
  151. Kamiyama, 1999, Biodisposition Characteristics of N-Succinyl-Chitosan and Glycol-Chitosan in Normal and Tumor-Bearing Mice, Biol. Pharm. Bull., 22, 179, 10.1248/bpb.22.179 · DOI
  152. Li, 2020, Biodistribution and Biocompatibility of Glycyrrhetinic Acid and Galactose-Modified Chitosan Nanoparticles as a Novel Targeting Vehicle for Hepatocellular Carcinoma, Nanomedicine, 15, 145, 10.2217/nnm-2018-0455 · DOI
  153. Niu, 2019, A Chitosan-Based Cascade-Responsive Drug Delivery System for Triple-Negative Breast Cancer Therapy, J. Nanobiotechnol., 17, 95, 10.1186/s12951-019-0529-4 · DOI
  154. Cordeiro, 2021, Carboxymethyl-β-Glucan/Chitosan Nanoparticles: New Thermostable and Efficient Carriers for Antigen Delivery, Drug Deliv. Transl. Res., 11, 1689, 10.1007/s13346-021-00968-9 · DOI
  155. Zhang, 2008, Nasal Absorption Enhancement of Insulin Using PEG-Grafted Chitosan Nanoparticles, Eur. J. Pharm. Biopharm., 68, 526, 10.1016/j.ejpb.2007.08.009 · DOI
  156. Zu, 2016, Preparation and In Vitro/In Vivo Evaluation of Resveratrol-Loaded Carboxymethyl Chitosan Nanoparticles, Drug Deliv., 23, 971, 10.3109/10717544.2014.924167 · DOI
  157. Wang, 2014, In Vitro and In Vivo Evaluation of Chitosan Graft Glyceryl Monooleate as Peroral Delivery Carrier of Enoxaparin, Int. J. Pharm., 471, 391, 10.1016/j.ijpharm.2014.05.050 · DOI
  158. Asasutjarit, 2015, Development and Evaluation of Diclofenac Sodium Loaded-N-Trimethyl Chitosan Nanoparticles for Ophthalmic Use, AAPS PharmSciTech, 16, 1013, 10.1208/s12249-015-0290-4 · DOI
  159. Narayanan, 2013, In Vitro and In Vivo Evaluation of Osteoporosis Therapeutic Peptide PTH 1–34 Loaded PEGylated Chitosan Nanoparticles, Mol. Pharm., 10, 4159, 10.1021/mp400184v · DOI
  160. Feng, 2013, Chitosan/o-Carboxymethyl Chitosan Nanoparticles for Efficient and Safe Oral Anticancer Drug Delivery: In Vitro and In Vivo Evaluation, Int. J. Pharm., 457, 158, 10.1016/j.ijpharm.2013.07.079 · DOI
  161. Liu, 2011, In Vivo Evaluation of Novel Chitosan Graft Polymeric Micelles for Delivery of Paclitaxel, Drug Deliv., 18, 181, 10.3109/10717544.2010.520355 · DOI
  162. Braz, 2017, Chitosan/Sulfated Locust Bean Gum Nanoparticles: In Vitro and In Vivo Evaluation towards an Application in Oral Immunization, Int. J. Biol. Macromol., 96, 786, 10.1016/j.ijbiomac.2016.12.076 · DOI
  163. Yu, 2009, Polymeric Nanoparticles of Cholesterol-Modified Glycol Chitosan for Doxorubicin Delivery: Preparation and in-Vitro and in-Vivo Characterization, J. Pharm. Pharmacol., 61, 713, 10.1211/jpp.61.06.0003 · DOI
  164. Zhang, 2008, Pharmacokinetics, Biodistribution, Efficacy and Safety of N-Octyl-O-Sulfate Chitosan Micelles Loaded with Paclitaxel, Biomaterials, 29, 1233, 10.1016/j.biomaterials.2007.11.029 · DOI
  165. Bachir, 2018, Effects of PEG Surface Density and Chain Length on the Pharmacokinetics and Biodistribution of Methotrexate-Loaded Chitosan Nanoparticles, Int. J. Nanomed., 13, 5657, 10.2147/IJN.S167443 · DOI
  166. Dong, 2010, Pharmacokinetics and Biodegradation Mechanisms of a Versatile Carboxymethyl Derivative of Chitosan in Rats: In Vivo and In Vitro Evaluation, Biomacromolecules, 11, 1527, 10.1021/bm100158p · DOI
  167. Sonin, D., Pochkaeva, E., Zhuravskii, S., Postnov, V., Korolev, D., Vasina, L., Kostina, D., Mukhametdinova, D., Zelinskaya, I., and Skorik, Y. (2020). Biological Safety and Biodistribution of Chitosan Nanoparticles. Nanomaterials, 10. · DOI
  168. Nadesh, 2013, Hematotoxicological Analysis of Surface-Modified and -Unmodified Chitosan Nanoparticles, J. Biomed. Mater. Res. A, 101, 2957, 10.1002/jbm.a.34591 · DOI
  169. Sonaje, 2009, In Vivo Evaluation of Safety and Efficacy of Self-Assembled Nanoparticles for Oral Insulin Delivery, Biomaterials, 30, 2329, 10.1016/j.biomaterials.2008.12.066 · DOI
  170. Shan, 2017, Safety and Toxicology of the Intravenous Administration of Ang2-SiRNA Plasmid Chitosan Magnetic Nanoparticles, Mol. Med. Rep., 15, 736, 10.3892/mmr.2016.6090 · DOI
  171. Islam, N., Dmour, I., and Taha, M.O. (2019). Degradability of Chitosan Micro/Nanoparticles for Pulmonary Drug Delivery. Heliyon, 5. · DOI
  172. Lichtfouse, 2019, Applications of Chitosan in Food, Pharmaceuticals, Medicine, Cosmetics, Agriculture, Textiles, Pulp and Paper, Biotechnology, and Environmental Chemistry, Environ. Chem. Lett., 17, 1667, 10.1007/s10311-019-00904-x · DOI
  173. Marques, C., Som, C., Schmutz, M., Borges, O., and Borchard, G. (2020). How the Lack of Chitosan Characterization Precludes Implementation of the Safe-by-Design Concept. Front. Bioeng. Biotechnol., 8. · DOI
  174. Pasetti, 2010, Adjuvanted Intranasal Norwalk Virus-Like Particle Vaccine Elicits Antibodies and Antibody-Secreting Cells That Express Homing Receptors for Mucosal and Peripheral Lymphoid Tissues, J. Infect. Dis., 202, 1649, 10.1086/657087 · DOI
  175. Mann, A.J., Noulin, N., Catchpole, A., Stittelaar, K.J., de Waal, L., Kroeze, E.J.B.V., Hinchcliffe, M., Smith, A., Montomoli, E., and Piccirella, S. (2014). Intranasal H5N1 Vaccines, Adjuvanted with Chitosan Derivatives, Protect Ferrets against Highly Pathogenic Influenza Intranasal and Intratracheal Challenge. PLoS ONE, 9. · DOI

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Metadata

Authors
Aibani, N., Rai, R., Patel, P., Cuddihy, G., & Wasan, E. K.
Venue
Pharmaceutics
Publisher
MDPI AG
Published
2021-10-14
Volume
13
Issue
10
Pages
1686
ISSN
1999-4923
DOI
10.3390/pharmaceutics13101686
PMC
PMC8540112
Cited by
419
References
2
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)

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