Carbohydrate-based nanoparticles
Introduction
Carbohydrates, which are the most abundant naturally occurring biomolecules, can be classified into two main categories; simple carbohydrates and complex carbohydrates. The widespread applications of carbohydrates within organisms led to their use in the production of nanoparticles.
Nanoparticles are molecules with sizes ranging between 1 and 100 nm, making them undetectable to the naked eye (Mandal, 2019). Although minute, nanoparticles can be engineered to have very significant uses in the medical field. The nanoparticles that result are referred to as ‘carbohydrate-based nanoparticles’ and have been studied for use in drug delivery, immunotherapy, and tissue engineering.
The following shows how certain carbohydrates, namely glycosaminoglycans, cellulose, cyclodextrins, and dextrans have been used in the production of such nanoparticles.
Figure 1: Carbohydrate-based nanoparticles used for biomedical applications.
Glycosaminoglycans
Glycosaminoglycans (GAGs) are linear, negatively-charged polysaccharide compounds that consist of repeating disaccharide units in which one monomer is N-acetyl-glucosamine or N-acetyl-galactosamine, and the other is generally uronic acid, D-glucuronic acid, L-iduronic acid, or galactose. Additionally, some GAGs contain esterified sulphate groups. GAGs, which are found on the cell surface as well as in the extracellular matrix of cells, have a major role in cell signalling and thus help regulate numerous biochemical pathways including cell adhesion, proliferation, anticoagulation and wound healing (Casale & Crane, 2022). These compounds can be classified into seven categories, namely hyaluronic acid, chondroitin sulphate, dermatan sulphate, heparin, heparin-sulphate, keratan sulphate I, and keratan sulphate II (Frevert & Wight, 2006), with each class having its respective nanoparticles.
Nanoparticles that contain GAGs include spherical nanoparticles and novel-redox responsive nanoparticles. Spherical nanoparticles can be prepared using hyaluronic acid and the chelating agent doxorubicin (DOX), a chelating agent. Hyaluronic acid is the simplest GAG and does not require any further modification by the Golgi apparatus once produced in the cytoplasm. It is composed of sequentially bound glucuronic acid and N-acetylglucosamine residues. Liposomal carriers can be formed by combining the spherical nanoparticles, lipoid E80 and cholesterol. Such carriers interact with the CD44+ receptor on tumours. Tumours are then targeted and the drugs are delivered to them via the CD44+ receptor (Li et al., 2016).
Similarly to hyaluronic acid, chondroitin sulphate is a disaccharide consisting of repeated units of glucuronic acid and N-acetylgalactosamine, however, it is bound to a proteoglycan core via a serine residue.(Casale & Crane, 2022). Chondroitin sulphate has been used to fabricate novel-redox responsive nanoparticles that could deliver a chemosensitizer, a photosensitizer, and a chemotherapeutic agent to carry out chemo-photodynamic therapy to overcome multidrug resistance and lung metastasis in breast cancer (Shi et al., 2021).
Figure 2: Structures of the main types of Glycosaminoglycans (Sodhi & Panitch, 2021).
Cellulose
Cellulose is a semicrystalline biopolymer composed of anhydro-D-glucopyranose units (AGU) (monomers) linked to one another via β-1,4-glycosidic bonds to form protofibrils. Every molecule of cellulose contains three hydroxyl groups for each AGU, with the terminal ends being an exception to this (Kamel et al., 2008). Moreover, this molecule is the most abundant polymer on earth, being a major structural component of plants, bacterial sources such as algae, marine animals such as tunicates, fungi, and amoeboid protozoans (Othmer, 1985; Jorfi & Foster, 2014). The source and chemical treatment of cellulose determine the properties of the resulting fibres. Such properties include the crystalline structure, surface chemistry, degree of crystallinity, aspect ratio, and morphology.
Figure 3: Formation of cellulose fibres.
Materials made from cellulose have a strong tendency to self-associate, forming an extended network using intramolecular and intermolecular hydrogen bonds between the hydroxyl groups of protofibrils (Jorfi & Foster, 2014). One of the materials derived from cellulose is nanocellulose (NC), which is further split into three main classes, namely bacterial nanocellulose (BNC), nanofibrillated cellulose (NFC), and cellulose nanocrystals (CNCs).
NC, which can be extracted from a variety of biosources, has a high surface-to-volume ratio and better solubility than natural cellulose. Moreover, NC can be modified by both physical and chemical means. Materials made from NC have very good biocompatibility and biodegradability as well as low cytotoxicity. Thus, such fibres are used in tissue engineering, drug delivery, medical implants, wound healing, and cardiovascular applications, among others (Jorfi & Foster, 2014).
Figure 4: Various forms of nanocellulose.
Figure 5: Structure of cellulose acetate.
For example, non-steroidal anti-inflammatory drugs (NSAIDs), such as ibuprofen, naproxen, and indomethacin, are incorporated into electrospun cellulose acetate nanofibers and used topically as a new delivery system.
Nanofibres are prepared by electrospinning, a technique that uses an electrical repulsive force to induce electrical stress on the polymer solution, forming conical liquid droplets which are then stretched out into nanofibers (Lee et al., 2018). Furthermore, cellulose acetate nanofibers can also be used as drug delivery systems for anticancer and antioxidant agents, antimicrobial agents, vitamins, amino acids, and hormones (Wsoo et al., 2020).
Ethyl cellulose is a non-ionic, pH-sensitive cellulose ether that is soluble in various polar organic solvents but insoluble in water. Ethyl cellulose serves as a coating agent, binder in dosage processing, filler, flavouring fixative, drug carrier, stabiliser, and film-former in the pharmaceutical industry. The hydrophobic nature and swelling capacity of ethyl cellulose enable it to both modulate and improve the physiological performance of drug dosage forms.
Based on these properties, ethyl cellulose-based nanoparticles have been developed to encapsulate sparingly soluble active pharmaceutical ingredients such as cannabidiol and curcumin (Zamansky et al., 2021). Furthermore, ethyl cellulose-based nanoparticles have been used to reduce ulcerogenicity of Piroxicam, an analgesic, anti-inflammatory, and antipyretic drug, (El-Habashy et al., 2016).
The morphology of BNC is similar to that of collagen. Additionally, it has a high water-holding capacity, making it useful in cellular immobilisation and adhesion. Such properties enable its use in temporary wound healing systems, such as tissue regeneration as well as in drug delivery (Sharma & Bhardwaj, 2019). BNC is used as a cover in micro nerve surgery and as an artificial blood vessel in microsurgery (Klemm et al., 2001).
CNC is extracted from cellulose microcrystals by strong acid hydrolysis. These form a crystalline rod structure composed of cellulose chain segments. CNCs have a high specific strength, high surface area, and liquid crystalline properties. Thus, they are used as drug delivery carriers, in biosensing, and in enzyme immobilisation.
The reaction of cellulose with acetic anhydride and acetic acid in the presence of sulfuric produces cellulose acetate, an ester of cellulose. Nanofibers of cellulose acetate have been widely used in the drug-delivery system, where they carry numerous therapeutic agents based on biodegradability, biocompatibility, thermal constancy, nontoxicity, and chemical persistence.
Cyclodextrins
Cyclodextrins are cyclo-organo compounds that are formed when six to eight glucopyranose units are linked together by α-1,4-glycosidic linkages (Kurkov, 2013). The glucopyranose units making up the structure give cyclodextrins poor water solubility and a hydrophobic core. Cyclodextrins are seen as prime drug delivery candidates because of their chelating properties and hydroxyl groups which allow them to form strong hydrogen bonds with polar chemicals and water. Moreover, cyclodextrins are also favoured for drug delivery because they solve some of the key challenges faced due to low membrane permeability, instability, and short biological half-life (Pandey, 2021).
Figure 6: Cyclodextrin interaction for drug delivery.
Cyclodextrins (CDs) can be classified into three categories; α-cyclodextrins, β-cyclodextrins, and γ-cyclodextrins. The main difference between the categories is the number of subunits they are composed of. The α, β and γ cyclodextrins are made up of six, seven, and eight glucopyranose units, respectively (Haji & Bahtiyari, 2021).
Figure 7: Differences between the three forms of cyclodextrins.
Cyclodextrins can be modified in various ways and hence, the resulting products, which are known as modified nanomaterials, can be classified into five subtypes (Real et al., 2021):
-
Lipid-based nanocarriers
-
Polymeric nanocarriers
-
Polymerised cyclodextrins
-
Surface-modified nanocarriers
-
Other nanosystems
Figure 8: Cyclodextrin-based modified nanomaterials.
An example of such modified nanomaterials is lipid nanocarriers that are produced by combining liposomes and cyclodextrins. This allows for the inclusion of complexes within the aqueous nucleus of liposomes which provides ‘drug-in CD-in liposomes systems’. Such systems have been successfully applied to ovarian cancer, in which the Pin1 inhibitor was encapsulated in modified cyclodextrins and remotely loaded onto liposomes. This led to the accumulation of the liposomal formulation in the tumour and the subsequent proteasome-dependent degradation of Pin1. The final result was the suppression of tumour growth in vivo (Russo, Spena et al., 2018).
Figure 9: Tumour suppression via modified cyclodextrin nanoparticles.
Dextrans
Dextran forms part of a family of neutral polysaccharides made up of an α-1,6-linked D-glucose main chain with various proportions of links and branches. It is the most significant polysaccharide generated by bacterial strains for medicinal and industrial uses. α-1,6 connections make up between 50 and 97% of the total glycosidic links of dextran. The figure below shows the difference between dextran and dextrin, with the former containing α-1,2, α-1,3, and α-1,4 linkages, and the latter only containing α-1,4-glycosidic linkages. (Taylor et al., 1985).
Figure 10: Differences between the structures of Dextran and Dextrin.
In order to form nanoparticles from dextrans, researchers bound hydrophobic amines, which serve as coiling agents, to the aldehyde groups on dextran that are formed upon oxidation. Nanoparticles can also be formed by self-assembly in an aqueous environment. Such dextran nanoparticles were used for the delivery of drugs such as doxorubicin. Dextran nanoparticles have pH-dependent bonds which accelerate drug release at lower pH levels (Wasiak et al., 2016).
Figure 11: An example of a dextran nanoparticle.
Another example of dextran nanoparticles is dextran-coated iron oxide nanoparticles, which have been used as anti-biofilm agents. A biofilm is an assembly of microbial cells such as bacteria, which are encapsulated within extracellular matrices of macromolecules; these bacterial cells are therefore protected against the external environment and can cause diseases such as tooth decay. Dextran-coated iron oxide nanoparticles have been used as a treatment for biofilm because in acidic environments, they show peroxidase-like activity which hinders dental cavity development, in the presence of low concentrations of hydrogen peroxide (Naha et al., 2019).
Figure 12: Biofilm treatment using dextran-coated iron oxide nanoparticles.
Moreover, dextran nanoparticles have recently been used as injectable antibacterial agents. Dextran sodium sulphate (DSS) nanoparticles, which are formed via a gelation technique using sodium sulphate as a polymeric carrier and tripolyphosphate as a stabiliser, were shown to have antibacterial properties on both Gram-positive and Gram-negative bacterial strains (Madkhali et al., 2021).
Figure 13: DSS nanoparticles used as injectable antibacterial agents.
Conclusion
From the in-depth evaluation of glycosaminoglycans, cellulose, cyclodextrins, and dextrans as carbohydrates in the production of nanoparticles, the importance of these molecules can be better understood and appreciated. Chitosan, alginate, and ulvin among many others are possible alternatives. Research in the field is still ongoing and new research and findings are continuously being published.
References
Casale, J., & Crane, J. S. (2022). Biochemistry, Glycosaminoglycans. PubMed; StatPearls Publishing.
https://pubmed.ncbi.nlm.nih.gov/31335015/
El-Habashy, S. E., Allam, A. N., & El-Kamel, A. H. (2016). Ethyl cellulose nanoparticles as a platform to decrease ulcerogenic potential of piroxicam: formulation and in vitro/in vivo evaluation. International Journal of Nanomedicine, 11, 2369-2380.
https://doi.org/10.2147/IJN.S93354
Haji, A., & Bahtiyari, M. B. (2021). Natural compounds in sustainable dyeing and functional finishing of textiles. Green Chemistry for Sustainable Textiles, 191–203.
https://doi.org/10.1016/b978-0-323-85204-3.00004-x
Klemm, D., Schumann, D., Udhardt, U., & Marsch, S. (2001). Bacterial synthesized cellulose — artificial blood vessels for microsurgery. Progress in Polymer Science, 26(9), 1561-1603.
https://doi.org/10.1016/S0079-6700(01)00021-1
Kurkov, S. V., & Loftsson, T. (2013). Cyclodextrins. International Journal of Pharmaceutics, 453(1), 167–180.
https://doi.org/10.1016/j.ijpharm.2012.06.055
Lee, H., Nishino, M., Sohn, D., Lee, J. S., & Kim, I. S. (2018). Control of the morphology of cellulose acetate nanofibers via electrospinning. Cellulose (London), 25(5), 2829-2837.
https://doi.org/10.1007/s10570-018-1744-0
Li, W., Yi, X., Liu, X., Zhang, Z., Fu, Y., & Gong, T. (2016). Hyaluronic acid ion-pairing nanoparticles for targeted tumour therapy. Journal of Controlled Release, 225, 170-182.
Madkhali, O. A., Sivagurunathan Moni, S., Sultan, M. H., Bukhary, H. A., Ghazwani, M., Alhakamy, N. A., Meraya, A. M., Alshahrani, S., Alqahtani, S. S., Bakkari, M. A., Alam, M. I., & Elmobark, M. E. (2021). Formulation and evaluation of injectable dextran sulfate sodium nanoparticles as a potent antibacterial agent. Scientific Reports, 11(1), 9914.
https://doi.org/10.1038/s41598-021-89330-0
Mandal, A., MD. (2019, February 26). What are Nanoparticles? News-Medical.net.
https://www.news-medical.net/life-sciences/What-are-Nanoparticles.aspx
Naha, P. C., Liu, Y., Hwang, G., Huang, Y., Gubara, S., Jonnakuti, V., Simon-Soro, A., Kim, D., Gao, L., Koo, H., & Cormode, D. P. (2019). Dextran-Coated Iron Oxide Nanoparticles as Biomimetic Catalysts for Localized and pH-Activated Biofilm Disruption. ACS Nano, 13(5), 4960-4971.
https://doi.org/10.1021/acsnano.8b08702
Pandey, A. (2021). Cyclodextrin-based nanoparticles for pharmaceutical applications: a review. Environmental Chemistry Letters, 19(6), 4297–4310.
https://doi.org/10.1007/s10311-021-01275-y
Russo Spena, C., De Stefano, L., Palazzolo, S., Salis, B., Granchi, C., Minutolo, F., Tuccinardi, T., Fratamico, R., Crotti, S., D’Aronco, S., Agostini, M., Corona, G., Caligiuri, I., Canzonieri, V., & Rizzolio, F. (2018). Liposomal delivery of a Pin1 inhibitor complexed with cyclodextrins as new therapy for high-grade serous ovarian cancer. Journal of Controlled Release, 281, 1–10.
https://doi.org/10.1016/j.jconrel.2018.04.055
Santos, R. F., Ribeiro, J. C. L., Franco de Carvalho, J. M., Magalhães, W. L. E., Pedroti, L. G., Nalon, G. H., & Lima, G. E. S. d. (2021). Nanofibrillated cellulose and its applications in cement-based composites: A review. Construction & Building Materials, 288, 123122.
https://doi.org/10.1016/j.conbuildmat.2021.123122
Sharma, C., & Bhardwaj, N. K. (2019). Bacterial nanocellulose: Present status, biomedical applications and future perspectives. Materials Science & Engineering C, 104, 109963.
https://doi.org/10.1016/j.msec.2019.109963
Shi, X., Yang, X., Liu, M., Wang, R., Qiu, N., Liu, Y., Yang, H., Ji, J., & Zhai, G. (2021). Chondroitin sulfate-based nanoparticles for enhanced chemo-photodynamic therapy overcoming multidrug resistance and lung metastasis of breast cancer. Carbohydrate Polymers, 254, 117459.
https://doi.org/10.1016/j.carbpol.2020.117459
Sodhi, H., & Panitch, A. (2021, November). Structures of the main types of Glycosaminoglycans (Sodhi & Panitch, 2021).
https://www.mdpi.com/2218-273X/11/1/29/html
Wasiak, I., Kulikowska, A., Janczewska, M., Michalak, M., Cymerman, I. A., Nagalski, A., Kallinger, P., Szymanski, W. W., & Ciach, T. (2016). Dextran Nanoparticle Synthesis and Properties. PLoS ONE, 11(1), e0146237.
https://doi.org/10.1371/journal.pone.0146237
Zamansky, M., Zehavi, N., Ben-Shabat, S., & Sintov, A. C. (2021). Corrigendum to “Characterization of nanoparticles made of ethyl cellulose and stabilizing lipids: Mode of manufacturing, size modulation, and study of their effect on keratinocytes” [Int. J. Pharm. 607 (2021) 121003]. International Journal of Pharmaceutics, 609, 121177.