Encyclopedia
Please note this is an old version of this entry, which may differ significantly from the current revision.
Subjects:
Medicine, Research & Experimental
Nanosystems-based antifungal agents have emerged as an effective strategy to address issues related to drug resistance, drug release, and toxicity. Among the diverse materials employed for antifungal drug delivery, polymers, including polysaccharides, proteins, and polyesters, have gained significant attention due to their versatility. Considering the complex nature of fungal infections and their varying sites, it is crucial for researchers to carefully select appropriate polymers based on specific scenarios when designing antifungal agent delivery nanosystems.
- antifungal
- drug delivery
- polymers
- nanometer
1. Introduction
Polymers have been extensively studied and applied in biomedicine and are generally divided into two categories: degradable and non-degradable. The degradability of certain polymers can allow for different release requirements of drug delivery systems. Nanopolymer systems offer many advantages in antifungal drug delivery, such as the ability to improve drug loading, the ability to chemically bond drugs to functional groups on the polymer surface, and some polymers even possess inherent antifungal properties [41].
2. Chitosan
CS is a chitin-derived polysaccharide with high biocompatibility and biodegradability [42,43]. Researchers have extensively studied the antibacterial properties of CS due to its amino and positive electrical properties. The antibacterial activity of chitosan and its derivatives may originate from the interaction between positively charged chitosan molecules and negatively charged residues on the surface of fungal cell walls. The methods for preparing CS nanoparticles (CSNPs) include ion crosslinking of low-concentration CS acid solution and tripolyphosphate by ultrasonic and mechanical stirring, 1-(3-Dimethylaminopropyl)-3-ethyl carbodiimide hydrochloride(EDC)/N-Hydroxy succinimide(NHS) crosslinking and redox with metal ions [44]. These methods can be used to prepare antifungal drug delivery nanosystems.
As a drug-releasing nanosystem, CS can deliver a variety of antifungal factors (such as essential oil [45], fluconazole [46], ceftriaxone, imidazolium zinc [47], berberine [48], enzyme, etc.). CS-based nanospheres (CSNPs) can encapsulate poorly water-soluble drugs to improve their solubility. For example, Su Ma et al. encapsulated curcumin (Cur) into CSNPs. Positively charged NPs tend to bind to negatively charged surfaces [49] (such as many biofilms on the surface of microorganisms). Therefore, positively charged CSNPs can deliver Cur to the biofilm and release the drug, thus directly affecting the internal cells. Thus, CSNP-Cur exhibits higher anti-biofilm activity than free Cur and improves its delivery efficiency.
3. Alginate
SA is a widely studied biopolymer with non-toxic, biocompatible, nonimmunogenic, biodegradable, and mucus adhesive properties [52,53,54,55]. SA can be chelated with Ca or other divalent cations to form a gel through the side carboxylic acid part of the G unit. This gel structure is called an ‘egg-box’ structure [56,57]. Therefore, alginate biopolymers can be used to stabilize inorganic metal nanoparticles, and this delivery method is not toxic [58]. That makes SA widely used in antifungal drug delivery nanosystems [57,59].
Abid S et al. prepared SA microspheres with calcium chloride as a crosslinking agent through ion gel technology and used them to coat MgO-CuO nanoparticles loaded with nystatin [60]. Microspheres reduce the specific surface area and reactivity of metal nanoparticles in the human body, providing a safe and improved release mechanism, thereby reducing the toxicity of nanoparticles in direct contact with the human body. At the same time, the nystatin composite loaded microspheres system enables the sustained release of the antifungal agent, which helps to prevent or minimize the occurrence of infection.
The cross-linking properties of SA and divalent cations are commonly used to cross-link with Ca2+ ions to form microspheres. Microspheres of different sizes can be obtained through ultrasound and water/oil (W/O) emulsification. The microspheres are directly used to encapsulate drugs for delivery and release. These microspheres are used to encapsulate drugs for delivery and release directly. For example, María J. Martín et al. used alginate microspheres as nystatin carriers for oral mucosal drug delivery, enabling the microspheres to come into close contact with the mucosal surface [65]. These Nys-loaded microspheres were successfully prepared by emulsification/internal gelation method, showing a significant inhibitory effect on the growth of Candida albicans, indicating its potential clinical use without systemic absorption or tissue damage.
The (1–4)-linked β-d-mannuronic acid (M Unit) and α-l-glucuronic acid (G unit) of SA exhibit anionic properties. They provide mucus penetration for nanoparticles through repulsive interactions with negatively charged sialic acid in the mucosal layer [66]. Vaishnavi et al. coated CS nanospheres with SA, enabling nanoparticles to exhibit better retention efficiency, loading capacity, release kinetics, and corneal permeability [67]. Due to changes in the particle size and surface energy of nanoparticles, they can effectively penetrate the thick mucin layer, which can effectively treat fungal keratitis and deep corneal ulcers.
4. Gelatin
Gelatin is a product of incomplete hydrolysis of collagen extracted from animals. However, the hydrolyzed polypeptides have different lengths and usually have a certain width of molecular weight distribution. Gelatin is easily absorbed by the human body due to its hydrolysate being amino acids, resulting in nutritional value. However, gelatin nanomaterials themselves are not antibacterial, and the solubility of gelatin in water is not stable, which is easily affected by temperature. Therefore, gelatin and its modified products are often used as carriers of antibacterial drugs. Compared to synthetic polymer materials, gelatin nanomaterials have lower biological toxicity in terms of antifungal activity. The abundant active groups in gelatin make it easy for nanomaterials to improve their mechanical and rheological properties through crosslinking and chemical modification [72].
In the nanoscale range, gelatin can be made into nanoparticles and nanofibers as carriers of antifungal drugs (such as amp B, Daptomycin [73], Polymyxin B [74], Tobramycin, Vancomycin, etc. [75]).
Hassan M et al. synthesized gelatin nanoparticles by dissolvent method and loaded them with chidamycin and chloramphenicol to improve the antifungal properties of external gauze [76]. The two-step solvent removal method creates gelatin nanoparticles (GNPs) with a low aggregation trend within a limited size range. GNPs contain spectinomycin and chloramphenicol to enhance the treatment of bacterial and fungal infections. The results showed that gelatin nanoparticles loaded with research antibiotics and cellulose cotton gauze treated with these particles exhibited higher antibacterial activity against the bacteria and fungi studied. This is due to the presence of drugs, the safety of nanostructures, and their biocompatibility with skin cells.
V. Aparna et al. innovatively used AutoDock software to calculate and select modified gelatin A nanoparticles to deliver Amp B [77]. Under the action of cross-linking agents, modified gelatin nanoparticles were prepared and delivered to macrophages to treat intracellular fungal infections. Amp B Loaded Gelatin A NPs and Carboxymethylated ι-Carrageenan are combined to achieve the treatment of intracellular Clostridium smooth infection. CMC-Amp B-GNP exhibits appropriate stability, cell compatibility, and blood compatibility.
Although gelatin cannot maintain structural stability in an aqueous environment, some researchers have also achieved the preparation of nanoscale fibers using an electrospinning process. Chetna Dhand et al. used drugs rich in hydroxyl groups to improve the water stability of gelatin nanofibers and prepared polydopamine crosslinked gelatin nanofibers as scald wound dressings [75]. The method can be extended to impart broad-spectrum antibacterial activity by binding to an antibiotic mixture and retaining long-term antibacterial activity. It was further demonstrated that the electrospun gelatin loaded with vancomycin was directly electrospun onto the bandage gauze, then cross-linked, and its efficacy was examined in an animal model simulating the pathophysiology of human burn wounds. The results confirmed that polydopamine cross-linking did not interfere with wound healing; however, the incorporation of vancomycin enhances wound closure and reduces inflammation. In addition to delivering drugs, researchers have also used polyvinyl alcohol and gelatin blends to improve the properties of gelatin nanofibers [78]. This preparation method makes the selection of gelatin nanofibers for drug delivery more extensive.
5. Dextran
Dextran is a non-toxic, biocompatible, biodegradable, and hydrophilic natural polysaccharide [81,82]. Dextran can enhance the stability of the drug delivery system and avoid accumulation in blood circulation. Activating macrophages and neutrophils can increase the content of leukocytes, cytokinins, and special antibodies, comprehensively stimulating the immune system of the body. Due to the rich hydroxyl groups in dextran, it can directly bind to biologically active molecules [83,84,85]. In addition, dextran acts as a nanosystem and can form hydrogels [86], films [87], and other systems for drug release. Dextran is easily modified by chemical means and can be derived and modified by etherification, esterification, amidation, and oxidation. The chemical modification rate is as high as 30%, which can also maintain the biodegradability of the skeleton [88,89]. These advantages provide a basis for designing and preparing antifungal drug delivery nanosystems [90,91].
Cristina et al. found in their research that, although dextran itself does not possess antifungal properties, it significantly enhances the stability, magnetic behavior, and biocompatibility of inorganic nanoparticles when coated with dextran on the surface of iron oxide nanoparticles [92]. In addition, by utilizing the drug-loading properties of dextran to load curcumin onto nanoparticles, the antifungal properties of the oxidized nanoparticles were synthesized to enhance the antibacterial activity of cerium dioxide nanoparticles by changing the pH value (i.e., ion balance) of the local environment. In addition, dextran-coated cerium dioxide nanoparticles can enhance the antibacterial activity of nano-ceria by changing the pH value of the local environment (ion balance). In addition to being used as a coating material for nanoparticles, dextran can also be used to synthesize stable silver nanoparticles through chemical reduction and other methods. The reduced silver nanoparticles have good antibacterial properties. Milorad et al. synthesized dextran sulfate stabilized silver nanoparticles (AgNPs-DSS) using a chemical reduction green synthesis method [93]. DS provides structural stability for AgNPs-DSS as a capping agent. Although there are uncertainties in organisms and other factors, AgNPs-DSS have an inhibitory effect on fungi at low concentrations.
6. Cellulose
Cellulose, the major component that makes up the cell walls of plants and algae and part of the microbial capsule [101,102], can be obtained by cellulose extraction and artificial synthesis [103,104]. Cellulose can be prepared into cellulose nanoparticles and nanofibers [105,106]. However, cellulose itself is not anti-fungal, and it is often necessary to synergize it with other antibacterial drugs or antibacterial polymers [107,108,109]. Cellulose units contain three hydroxyl groups. These groups can also be transformed into various functionalities without affecting cellulose structure [107,110]. Cellulose has been widely studied due to its wide source and simplicity of preparation [111,112,113]. Therefore, nano cellulose is widely used in antifungal applications, such as wound dressings and drug carriers [114].
Carla Vilela X et al. combined bacterial nanocellulose (BNC) with monomers of antibacterial polymers (poly[2-(methacryloyloxy)ethyl] trimethyl ammonium chloride, PMETAC) to prepare layered nanofilms for the treatment of fungal infections [115]. These cationic nanocomposite PMETAC/BN materials have UV-blocking properties, high water absorption capacity, thermal stability up to 200 °C, and good mechanical properties. PMETAC/BN has no cytotoxicity to HaCaT cells and can inactivate Candida albicans.
Researchers have extensively studied modified cellulose derivatives. Rimpy et al. prepared fluconazole containing 3D scaffolds by modifying plant-derived nanocellulose with tetraethyl orthosilicate (TEOS) [116]. The swelling, porosity, and tensile strength of TEOS-modified nanocellulose scaffolds were significantly improved. Silica groups added to nanocellulose enhanced mucoadhesive strength, antifungal properties, and ex vivo vaginal penetration ability of lyophilized scaffolds. TEOS-modified nanocellulose scaffolds also exhibited prolonged drug release behavior in SVF buffer up to 24 h, being histologically safe and less cytotoxic to Vero cell lines. Therefore fluconazole loaded TEOS modified cellulose scaffolds have great potential for vaginal drug delivery applications.
7. Polyesters
Polyester materials are the most widely used biodegradable synthetic polymer materials [124,125,126]. Among them, hydroxy acids and lactone polymers represented by polylactic acid (PLA) were first used in the biomedical field and have been certified by the US Food and Drug Administration (FDA) [127]. Polyester-based materials are more hydrophobic in molecular structure and more stable in structure than hydrophilic macromolecules like polysaccharides, giving them unique advantages for applications as drug delivery nanosystems [128,129,130]. The development of electrospinning technology has made up for the shortcomings of polyesters in poor thermal stability during processing [131,132]. Therefore, polyester materials and their copolymers have been widely studied in antifungal applications [133,134,135]. In terms of antifungal applications, polyesters can be applied in the biomedical field as antibacterial drug dressings by preparing nanofibrous membranes using electrospinning technology [136,137,138].
Raul Machado et al. made bovine lactoferrin (bLF) and PLA form uniform, smooth nanofibers (fiber minimum diameter of 380 nm) by electrospinning technique [139]. The final formed nanofibrous membranes had porosity up to 80%. The high porosity and uniform fibers enabled a slow and uniform release of bLF mixed in PLA at 60 days. bLF-PLLA membranes did not induce cytotoxicity in human fibroblasts, and 20 wt% of bLF-PLLA membranes were able to induce cell proliferation even after 24 h of indirect contact. The composite membranes showed very potent antifungal activity against the filamentous fungus A.nidulans. Polylactic acid nanofibers can also be given more possibilities by more complex coaxial electrospinning. B. Jalvo et al. prepared a core–shell nanocomposite membrane with polylactic acid as the core [140]. Chitosan on the fiber surface makes the nanofibers positively charged and not prone to microbial colonization. Such that bacteria in contact with the chitosan membrane surface undergo cellular damage.
Nanofibrous membranes can be used for antifungal drug delivery in superficial layers, such as the oral cavity and skin. Copolymers of polylactic acid can also be used for drug delivery by forming nanoparticles that are more widely applied. A novel nanoantibiotic system based on mesoporous silica encapsulated in PLA nanoflowers (PLA-NFs) was developed by Mostafa F. Abdelbar et al. [141]. This mesoporous silicate has a two-dimensional hexagonal porous array and high surface area sensitivity. Such mesoporous silicates exhibit 2D porous hexagonal arrays and high sensitivity of the surface area. The nanoantibiotic system combines polylactic acid nanoflowers with mesoporous silica, which enables the antimicrobial drug (levofloxacin) to be released in a controlled manner under a pH environment. PLA-NFs exhibited a rather fast degradation rate during hydrolysis under an acidic environment, allowing the drug (Levofloxacin; LVX) in the delivery system to be released under controlled conditions.
Due to the limitations of polylactic acid in mechanical properties, current research on polylactic acid nanoscale antifungal is mostly synergistic with other polymers. Polylactic acid glycolic acid (PLGA) exhibits excellent drug loading and antifungal properties. Researchers have characterized the drug-loading properties of PLGA nanoparticles for antifungal drugs, such as butenolone (BT) and Amp B [133,142,144]. In addition, Some researchers explored the enhancement of oral absorption of Amp B by PLGA-PEG nanoparticles [143]. Due to the excellent degradation properties of PLA and PLGA, they are metabolized in the human body within a few weeks and are likely not to cause significant environmental residues [155].
Besides PLA, PCL has also been used by researchers to design antifungal drug delivery nanosystems. Vanessa et al. loaded 4-Neroliyl chloride methanol (4-NC) with PCL, which showed high encapsulation efficiency (100%) for 4-NC [149]. PCL nanoparticles, while retaining 4-NC antifungal activity, also reduced cytotoxicity, increased the stability and solubility of the substance, and increased the efficacy of 4-NC.
Compared to conventional drug delivery systems, nanosystems exhibit significantly high specific surface areas, which are advantageous for drug loading and release. The antifungal nanosystems based on polymer matrices discussed herein can be primarily classified into two categories: nanoparticles and nanofibers.
Nanoparticles can be classified into two categories based on their morphological characteristics: nanocapsules and nanospheres. Nanocapsules are composed of a core, which can be oil-based or water-based, encapsulated by a polymer shell. This dual-layer structure allows for the drug to be dissolved in the internal oil-based or water-based phase of the capsule, facilitating drug loading and release. The polymer shell provides protection for the internal drug while maintaining the nanosize of the system, preventing aggregation and fusion of the internal nanophase from forming larger particles. Additionally, the polymer shell can control the release rate of the drug, reducing drug inactivation. On the other hand, nanospheres are composed of a continuous polymer network and can retain the drug internally or adsorb it on the surface through physical adsorption and chemical interactions. Due to their larger specific surface area, nanospheres provide more contact between the drug and the release environment, enabling drug loading and release. Nanocapsules offer controlled release capabilities, while nanospheres, due to their internal continuous polymer network, exhibit higher contact areas for drug interaction.
Compared to nanoparticles, nanofibers exhibit unique characteristics for drug delivery. Nanoparticles are typically employed as drug carriers and require a combination with liquid dispersion systems or solid carriers, such as incorporation into dressings, injectables, or gels, for application. In contrast, nanofibers can directly form fibrous membranes, providing both mechanical strength and drug-loading capability. Due to their porous structure, nanofibers can be utilized as the surface layer of antifungal dressings while maintaining breathability. The development of electrospinning techniques has enabled researchers to fabricate nanofibers using coaxial electrospinning, wherein different drugs are loaded in the core and shell layers to achieve sequential drug release. Furthermore, precise control over the diameter and morphology of nanofibers can be achieved by adjusting process parameters during electrospinning, enabling accurate modulation of drug delivery. Nanoparticle size control is relatively challenging, particularly when compared to nanofiber diameter.
This entry is adapted from the peer-reviewed paper 10.3390/pharmaceutics15071866
This entry is offline, you can click here to edit this entry!
