Biomedical Applications of Modified Dextran: History
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Native DEX (Dextran) exhibits low-cell-adhesive properties and in order to obtain hydrogels with controlled cell-scaffold interactions, specific molecules must be incorporated. Many research groups have chemically modified DEX by introducing functional groups into the molecule through cross-linking reactions, therefore improving mechanical strength and drug-loading ability and increasing the number of compound classes that can be obtained. Furthermore, DEX has been shown to have metal chelating activity and antioxidant properties, as well as antitumour activity by regulating apoptosis and autophagy.

  • dextran
  • drug-delivery systems
  • bioactive compounds

1. Acetalated Dextran (Ac-DEX)

The main reason for performing DEX acetylation is to allow solubility of DEX molecules in organic solvents, facilitating the encapsulation of various hydrophilic and hydrophobic active substances, which has always been challenging, and allowing their simultaneous delivery [1]. Ac-DEX is an essential derivative of DEX synthesized in mild conditions, at room temperature, from DEX and 2-methoxypropene in a one-step reaction catalysed by pyridinium p-toluene sulfonate [2]. Ac-DEX contains cyclic and methoxy acyclic acetal moieties and has been shown to be biodegradable at neutral pH, biocompatible and pH-sensitive [1][3]. Because it is an acid-sensitive polymer, Ac-DEX degrades more rapidly at lower pH, for example in the endosome of phagocytic cells, tumours, or in areas with inflammation [4], making it an ideal carrier for a wide range of therapeutics. Ac-DEX has several characteristics that make it a unique biodegradable polymer, such as facile synthesis and degradation rates’ adjustment properties. It is suitable for vaccine applications, targeted host-directed therapies to macrophages, controlled release of drugs, chemotherapeutic delivery and engineered drug-delivery devices [5]. By the simultaneous release of different active substances, synergistic effects, as well as the reduction in side effects and solubility improvement could be achieved at lower concentrations and improved pharmacokinetics [1].
As a therapeutic system, Ac-DEX was used to develop porous microparticles made by single emulsion method in water/oil and loaded with rapamycin [3][6], camptothecin [7], or curcumin [8] in order to be used for pulmonary drug delivery or phagocytes’ passive targeting. The delivery and release tests recorded very good results. These systems are more efficient in drugs’ transport to the alveolar region of the lung, or for immune suppression therapies than other similar systems [3][6][7][8]. At the pulmonary level, after the post-processing of these microparticles, the respirable fraction increased with the improvement of aerosolization and no significant damage was caused by the system to lung epithelial cells either in liquid- or air-exposed conditions [3][6][7][8]. The dry powder aerosol formulations were capable of deep lung delivery of drugs by targeting and releasing the therapeutics to a desired location [3][6][7][8]. By using these systems, a rapid onset of pharmaceutical action was obtained, avoiding hepatic metabolism and decreasing the side effects of the drugs. Resiquimod, a drug with antiviral and antitumour activity, was encapsulated in an electrospun Ac-DEX microparticles’ scaffold and the results were remarkable for tissue engineering, wound healing, immunotherapy and drug-delivery applications [9][10]. Pyraclostrobin, an antifungal agent, was successfully loaded in pH-sensitive Ac-DEX microparticles in order to treat Sclerotinia sclerotiorum plant infections [2]. Konhäuser et al. (2022) [1] developed a DDS system in order to simultaneously release L-asparaginase and etoposide. The active substances have synergistic activity against chronic myeloid leukaemia (CML) K562 cells, but L-asparaginase is hydrophilic and etoposide is hydrophobic [1]. This system has great potential for CML therapy due to its ingenious ability to release both compounds in a pH-dependent manner, leading to synergistic cytotoxicity, increased drug efficacy and reduced side effects [1].

2. Oxidized Dextran (oDEX)

Some research groups have obtained oDEX in order to bind therapeutic active molecules for secure delivery. DEX oxidation using sodium periodate is a catalysis-free aqueous reaction which produces a polyaldehydic DEX that can serve as a macromolecular cross-linker for amino groups-bearing substances.
By using oDEX, different DDS were synthesized, including microspheres, vesicles, hydrogels, NPs. Cortesi et al. (1999) [11] synthesized oDEX gelatine microspheres loaded with TAPP-Br antitumour drug and cromoglycate, obtaining very good results for drug release. Curcio et al. (2020) [12] developed a self-assembling oDEX-based vesicular system loaded with camptothecin, which was determined to be very efficient against MCF-7 and MCF-10A cell lines. The antitumour drugs, such as 5-fluorouracil and methotrexate, were encapsulated in oDEX hydrogels for breast, skin and gastrointestinal tract cancer treatment [13]. The obtained DDS induced faster drug release and had excellent biocompatibility and degradability, therefore being suitable for anticancer therapies [13]. Novel oDEX-based NPs for insulin release [14] or loaded with 5-fluorouracil for colorectal cancer therapies [15] were also obtained and were suitable for further in vivo testing.
Zhou et al. (2022) [16] reported an oDEX-based hydrogel loaded with black phosphorus nanosheets and zinc oxide nanoparticles. This DDS was suggested to be a hopeful approach for chronic wound treatment with bacterial infection through the synergistic effect of photothermal action and immunomodulation [16]. Multiple hydrogels as transdermal DDS loaded with ceftazidime or with collagen and Epidermal Growth Factor were reported for the treatment and healing of diabetic wounds infected with multidrug-resistant bacteria [17][18].

3. Carboxymethyl Dextran (CMD)

CMD, a polyanionic polysaccharide, was considered as a DDS constituent since it was discovered that its functional groups facilitate chemical conjugation and ionic complexation with various drugs. Its hydrophilic characteristics facilitate prolonged drug circulation improving its tumour-targeting efficiency [19]. By itself, CMD has high antioxidant properties [20].
CMD was used as a nanocomposite hydrophilic shell in order to be loaded with glutathione as an inhibitor of reactive oxygen species’ cytotoxic effects associated with tumour apoptosis [21].
Magnetic NPs were coated with CMD in order to be used as contrast agents for magnetic resonance molecular imaging (MRI) [22][23]. Several research groups used CMD-coated magnetic NPs loaded with antibodies [24], peptides [25] and enzymes [26] for different medical applications.

4. Dextran Sulphate Sodium (DSS)

Certain types of dextran functionalization can lead to very toxic compounds, which can, however, be useful for particular applications. DSS is a polyanionic derivative of dextran with high-water solubility properties containing approximately 17% sulphur with up to three sulphate groups (-OSO3Na) per glucose molecule [27]. DSS has found wide utilization in the food, biotechnology, cosmetic and pharmaceutical industries [28]. In proper concentrations, it exhibits positive effects as an anticoagulant and antiviral agent or has the properties of lowering blood lipid and glucose levels in clinical studies [29]. Despite DSS promising application prospects and biological properties, its application is limited due to its harmful effects on the gastrointestinal tract [29].
Different research groups use DSS to induce colitis, thus creating artificial conditions for studying inflammatory bowel diseases, such as ulcerative colitis and Crohn’s disease. The colitogenic potential of DSS depends on its molecular weight which must be between 36–50 kDa. DSS produces manifestations associated with inflammatory bowel disease, such as submucosal erosions, ulceration, inflammatory cell infiltration, crypt abscesses, as well as epithelioglandular hyperplasia [27]. It also determines the shrinkage of colon length and increases the relative colon weight/length ratio accompanied by mucosal oedema and bloody stools [27]. The DSS colitis paradigm is the most appropriate model for the human phenotype, from many points of view. For this injury, many drugs were tested as treatment, including curcumin [30], garlic oil (which has antioxidant, anti-inflammatory and immunomodulatory effects) [31], carvacrol (a phenolic monoterpene extracted from Oreganum vulgarea sp. essential oils with antioxidant, anti-inflammatory and anticancer properties) [32], resveratrol [33], glucose-lysine Maillard reaction products [34], liquorice (a Glycyrrhiza uralensis rhizome-derived product with anti-inflammatory activity) [35], Lactobacillus sakei K040706 (with immuno-stimulatory effects) [36] and Polygonum tinctorium leaves extract (by enhancing the mRNA expression of interleukin-10 and decreasing expression of tumour necrosis factor in colon tissues) [37].
DSS has also been used for film coatings with biological and biomedical applications [38]. Mixed DSS-based systems were developed, such as eco-friendly PVA/DSS nanofibers loaded with ciprofloxacin [39] or chitosan-DSS microparticles loaded with a hydrophilic peptide used as immunity-enhancing adjuvant or considered as vaccine electuary [40].
An antibacterial biocapsule system obtained from multilayer self-assembled diethylaminoethyl (DEAE)-DEX hydrochloride and DSS was developed as a DDS for kanamycin-resistant Escherichia coli treatment. The system manifested an inhibitory effect during bacterial growth having high potential as an antimicrobial agent in future treatments against infection [41].
Wang et al. (2020) [42] developed a dual DDS for paclitaxel and 5-fluorouracil. The pH-sensitive system exhibited a controlled release profile based on a mechanism following a two-phase kinetic model [42]. The system’s efficiency was investigated on HepG2 cells, resulting in synergistic effects between the two drugs and enhanced inhibition of cancer cells, presenting a good potential for biomedical delivery applications [42].

5. Diethylaminoethyl-Dextran (DEAE-DEX)

DEAE-DEX was the very first chemical vector used for DNA delivery, reported by Vaheri and Pagano in 1965 as DEAE-DEX used to enhance the cells’ viral infectivity. The DEAE-DEX-mediated transfection method gained attention in the early 1980s because of the simplicity, efficiency and reproducibility of the procedure. DEAE-DEX forms electrostatic interaction complexes with DNA, exhibiting higher transfection efficiency, but at high concentrations, it is toxic to cells [43]. Recently, it was used to develop carrier polyplex nanoparticles with luciferase coding mRNA [44] or used for β-interferon production enhancement [45].

This entry is adapted from the peer-reviewed paper 10.3390/molecules28031086

References

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