3.4.2. Ocular Drug Delivery
Ophthalmic diseases are generally treated using topical instillation—eye drops of active compounds. However, the method of treatment has been hindered by the inherent defense function of the eye [
11]. The corneal epithelial cells restrict drug proliferation due to blocking the passage of the drug through the cornea. Drugs are degraded by metabolic enzymes in the ocular tissues. Drugs applied to the surface of the eyes are excreted through nasolacrimal ducts. Additionally, spontaneous reject of foreign substances by the oculus also impedes drug transport. Thus, ocular administration remains a clinical challenge [
33]. To increase ocular absorption and improve the drug bioavailability, the research of new drug carriers has become the development trend. CS possesses favorable characteristics such as nontoxicity, biodegradability, and biocompatibility, which make it a suitable choice for ocular drug delivery systems. In addition, it is naturally mucoadhesive, which increases the ocular surface duration of drugs. CS also possesses in situ gelling properties due to which, when it is applied on the ocular surface in liquid form, it gets transformed into gel later. This leads to the improvement of the ocular residence time and therapeutic efficacy of the drug [
52].
Efficient ocular drug delivery to the posterior segment of the eye by topical administration is a great challenge to pharmacologists. Dexamethasone (DEX) is one of the most widely used steroidal agents for the treatment of various inflammatory disorders of the eye with high potency and effectiveness. Yu et al. [
179] prepared a series of dexamethasone-glycol chitosan (DEX-GCS) conjugates. The eye irritation of DEX-GCS NPs was investigated in Japanese white rabbits using a modified Draize test. As shown in
Figure 28A, the eyes treated by DEX-GCS NPs and NS at 2 h did not present any conjunctival congestion, corneal opacity, or iris-inflammatory exudation. Fluorescein staining indicated that there were no ulcers or defects on the corneal epithelial layer of the eyes treated with the DEX-GCS NPs and normal saline after 2 h (
Figure 28B). Moreover, histological observation indicated that there were no obvious morphological or pathological changes to the cornea after treatment with DEX-GCS NPs and normal saline after 24 h (
Figure 28C). Moreover, the intraocular pressure (IOP) did not change obviously for the eyes treated with DEX-GCS NPs during the 3-day study (
Figure 28C) (see Figure 28. (A) Slit-lamp observations of the eyes treated with NS and DEX-GCS NPs at 2 h after administration; (B) fluorescein sodium staining of the cornea treated with NS and DEX-GCS NPs at 2 h after administration; (C) H&E section of the cornea treated with NS and DEX-GCS NPs at 24 h after administration; and (D) the changes in intraocular pressure (IOP) after treatment with Dex-GCS NPs [
179] in our recent paper V. Mikusova, P. Mikus, Int. J. Mol. Sci. 2021, 22, 9652). The proposed NPs showed good ocular tolerance and provided a relatively longer precorneal duration compared with that of the aqueous solution formulation, which suggested that the self-assembled DEX-GCS NP might be a promising candidate for ophthalmic drug delivery.
In another work, Wang et al. [
148] developed a hybrid nanocomposite (layered double hydroxide (LDH)-glutathione-glycylsarcosine (GSH-GlySar)-carboxymethyl chitosan (CMC)) offering a simple and efficient strategy for topically administered dexamethasone disodium phosphate (DEXP) delivery to the posterior segment of the eye. The in vitro experiments on human conjunctival epithelial cells showed no cytotoxicity (LDH concentration ≤100.0 µg/mL) but enhanced permeability for hybrid nanocomposites. Results of the in vivo precorneal retention study showed an 8.35-fold, 2.87-fold, and 2.58-fold increase in AUC 0–6 h, C max and MRT for DEXP-CMC/GSH/GlySar/LDH (10:1) hybrid nanocomposite eye drops, respectively, compared to that of the commercial product. In the evaluation of tissue distribution of rabbit’s eyes, DEXP of the DEXP-CMC/GSH/GS/LDHs (10:1) nanocomposite retained in the target of the choroid-retina for 3 h with final concentration at 120.04 ng/g. Furthermore, the results of fluorescence imaging and tissue distribution suggested that the intraocular transport pathway for the hybrid nanocomposites is the conjunctival-scleral route. Consequently, the developed hybrid nanocomposites offer a simple and efficient strategy for topically administered drug delivery to the posterior segment of the eye.
Liposomes have shown significantly improved penetration potential and compatibility upon comparison with other systems. A coating of liposomes with CS can further improve their availability owing to the mucoadhesive properties which increase the affinity of composite membranes. Khalil et al. [
180] prepared chitosan-coated liposomes (CS/LIP). Conventional liposomes encapsulating triamcinolone acetonide (TA) were compared with their CS-coated counterpart for the drug loading and release studies. CS/LIP showed a higher encapsulation efficiency (74%), and a highly positive surface charge (+41.1 Mv), increased retention time, and sustained release. The results showed successful penetration of the construct via the corneal mucosal barrier and its accumulation in the vitreous body. The analysis shows that this CS-based liposomal construct can be employed as a potential topical delivery system for treating posterior segment diseases.
Levofloxacin (LFX) is a synthetic third generation of fluoroquinolones with a broad spectrum of antibacterial activity. Ameeduzzafar et al. [
181] tried to combine in-situ gel and NPs. They used CS NPs to encapsulate LFX for the treatment of ocular infection. The antimicrobial study revealed that the developed formulation possessed higher antibacterial activity against
P. aeruginosa and
S. aureus. The pharmacoscintigraphic study results revealed the reduced corneal clearance, nasolacrimal drainage as well as higher retention of LFX in comparison to an LFX solution. Thus, the LFX loaded CS NP in situ gel system was found to be efficient for ocular delivery of LFX.
For anti-inflammatory ocular treatment, Hanafy et al. [
32] prepared a novel formulation of self-assembled NPs via complexation of CS and, the counter-ion, sodium deoxycholate (SD), loaded with the poorly-water-soluble prednisolone acetate (PA). Drug release of PA as received, in simulated tears fluid (pH 7.4), showed a twofold increase (reaching an average of 98.6% in 24 h) when incorporated into an optimized nanoparticle gel formulation (1:5 CS-SD). The anti-inflammatory effect of PA NPs loaded gel on female guinea pig eyes was significantly superior to that of the micronized drug-loaded gel (
p < 0.05). The prepared ophthalmic NPs loaded gel for delivering PA had the potential at delivery of PA in treating inflammatory ocular diseases.
Baicalein (BAI) is one of the main ingredients of Scutellariae radix. Clinically, it is used to depress apoptosis of retinal ganglion cells which is related to visual decline. Additionally, BAI protects against retinal ischemia by anti-oxidation, anti-apoptosis, and anti-inflammatory. Therefore, BAI has great potential in preventing and treating various ocular diseases such as keratitis and glaucoma. However, molecular dynamics simulation data showed that BAI had a poor membrane permeability, which limited the ocular bioavailability. To improve its ocular bioavailability, Li et al. [
33] prepared and characterized trimethyl chitosan-coated lipid nanoparticles of baicalein (TMC-BAI-LNPs). In vitro drug release revealed that TMC-BAI-LNPs exhibited a sustained-release effect. In vivo studies indicated that TMC-BAI-LNPs had no ocular irritation and the AUC of TMC-BAI-LNPs was 3.17-fold higher than that of the control (
p < 0.01). The results indicated that TMC-BAI-LNPs might open up a new avenue for ocular administration.
Glaucoma is the most common form of optic nerve degeneration that leads to progressive, irreversible blindness. This disease is characterized by increased intraocular pressure (IOP). The main object in the treatment of glaucoma is to reduce IOP to the normal range (16–18 mmHg). Dorzolamide (DRZ), a carbonic anhydrase inhibitor (CAI), is the most common drug used to treat glaucoma by reducing IOP via decreasing aqueous humor secretion (through the inhibition of carbonic anhydrase isoenzyme). Shahab et al. [
82] developed dorzolamide-loaded chitosan-coated polycaprolactone nanoparticles (DRZ-CS-PCL-NPs) for improved ocular delivery. The corneal flux experiment showed many fold enhancement in permeation across goat cornea. DRZ-CS-PCL-NPs exhibited 3.7-fold higher mucoadhesive strength compared to the control. Furthermore, the histopathological assessment and HET-CAM study revealed that the DRZ-CS-PCL-NPs were non-irritant and safe for ocular administration. Therefore, it can be concluded the optimized DRZ-CS-PCL-NPs are safe and have the potential for successful ocular delivery and improved therapeutic efficacy.
Another drug latanoprost reduces IOP by increasing the uveoscleral outflow. Despite its potency, long-term daily application of it may cause undesirable side effects and may require more than one medication for IOP control. Recent studies have suggested that oxidative stress in the trabecular meshwork (TM) plays an important role in the pathogenesis of impaired trabecular outflow facilities. Cheng et al. [
182] combined latanoprost with curcumin, a natural phenolic compound possessing anti-oxidant and anti-inflammation properties. They developed a thermosensitive hydrogel containing latanoprost and curcumin-loaded nanoparticles (CUR-NPs) and evaluated its possible therapeutic effects with cultured human TM cells under oxidative stress. The results demonstrated that 20 μM of CUR-NPs might be the optimal concentration to treat TM cells without causing cytotoxicity.
Intravitreal injections of bevacizumab (BEV) have been used for the treatment of several eye disorders such as diabetic macular edema, central retinal vein occlusion, proliferative diabetic retinopathy, rubeosis iridis, pseudophakia cystoid macular edema, choroid neovascularization, secondary to pathologic myopia. The in vivo studies revealed the absence of ocular toxicity for BEV administered by intravenous injection. Due to its short half-life and the necessity of frequent intravitreal injection, a method for sustained delivery is required. Savin et al. [
48] obtained, for the first time, polymeric nanocarriers based on the chitosan grafted-PEG-methacrylate derivative. They tried to prepare potentially non-toxic micro/nanoparticles (MNPs). The double crosslinking (ionic and covalent) procedure in the reverse emulsion provided the mechanical stability of the polymeric nanocarrier. The potential of MNPs as a drug delivery system was analyzed by loading a full-length monoclonal antibody BEV. The proposed MNPs were found to be suitable from the cytotoxicity and hemocompatibility point of view enabling their potential use as a delivery system for the treatment of a posterior segment of the eye conditions.
3.4.4. Pulmonary Drug Delivery
Drug delivery to the lungs has various advantages such as rapid and sustained drug delivery, high efficacy, no first-pass metabolism, and both local and systemic effects can be achieved. The factors which contribute to the enhanced drug delivery via lungs are the large surface area of lungs, thin absorption barrier, and high vascularity [
52].
NPs can cross the cellular barrier independent of the energy supply. They can be designed to be taken up by macrophages for delivery of drugs directly to bacteria and thus treat diseases such as tuberculosis [
194]. NPs can be used to deliver macromolecular drugs such as peptides and protein through the lung for the treatment of systemic or local diseases. They are effective for lung cancer treatment in association with improved drug accumulation inside the tumors due to facilitating their passive as well as active delivery [
193,
228]. NPs are also used to treat mucus hypersecretion and severe inflammatory lung diseases namely asthma [
196], cystic fibrosis, and chronic obstructive pulmonary disease [
195] due to their ability to provide sustained drug release, overcome airway hypersecretion, and target diseased cells or tissues through matrix decoration with a homing device.
However, NPs are exhaled from the lungs after pulmonary administration. The inhaled particles should have an aerodynamic diameter between 1 and 5 μm to enable the drugs to be deposited in the deep lungs. CS NPs are exhalation prone and agglomerative to pulmonary inhalation. Alhajj et al. [
228] aimed to develop a new NPs lung delivery approach possible for use in lung cancer treatment. They physically blended CS NPs with fine lactose-PEG3000 microparticles, Lac/PEG3000 MPs (~5 μm) to reduce their agglomeration through surface adsorption phenomenon. This carrier exhibited a comparable inhalation performance with the commercial dry powder inhaler products (fine particle fraction between 20% and 30%). Cascade impactor analysis indicated that the aerosolization and inhalation performance of the CS NPs was promoted by their higher zeta potential, circularity, and larger size attributes. These properties led to reduced inter-nanoparticulate aggregation and favored the NPs interacting with the Lac/PEG3000 MPs that aided their delivery into deep and peripheral lungs.
Ahmad et al. [
193] studied possibilities to improve the lungs bioavailability of an anti-lungs cancer drug catechin hydrate (CAT) via the direct nose-to-lungs delivery. For this purpose, they prepared novel chitosan-coated PLGA NPs. SEM (A) and TEM (B) images of CS-coated-CAT-loaded PLGA NPs are illustrated in
Figure 29 (see Figure 29. Scanning electron microscopy (SEM) (
A) and transmission electron microscopy (TEM) (
B) images of CS-coated-CAT-loaded PLGA NPs [
193] in our recent paper V. Mikusova, P. Mikus, Int. J. Mol. Sci. 2021, 22, 9652). Higher entrapment efficiency was observed for the CAT-CS/PLGA NPs. The release pattern of the CAT-CS/PLGA NPs was found to favor the release of entrapped CAT within the cancer microenvironment. The CAT-CS/PLGA NPs exposed on H1299 cancer cells up to 24.0 h were found to exhibit higher cytotoxicity as compared to a CAT-solution. The CAT-CS/PLGA NPs showed higher apoptosis of cancer cells after their exposure as compared to the CAT-solution. The CAT-CS/PLGA NPs showed tremendous mucoadhesive nature as compared to the CAT-solution. The improved Cmax (668.24 ± 29.66 ng/mL) with AUC0–24 (11370.02 ± 191.05 min × ng/mL) was observed extremely significant (
p < 0.001) via i.n. as compared to
oral (Cmax 208.76 ± 17.01 ng/mL, AUC0–24 2223.77 ± 42.08 min × ng/mL) and i.v. (Cmax 469.31 ± 32.96 ng/mL, AUC0–24 6208.00 ± 89.67 min × ng/mL) in the Wistar rat’s lungs. The CS/PLGA NPs system was successfully designed and safely delivered CAT to the lungs without causing any risk. The CAT-CS/PLGA NPs were showed to have a significant role in the enhancement of lungs bioavailability and, thus, represent a promising approach to treat lung cancers.
Tuberculosis is one of the main causes of death worldwide, being the leading cause of a single infectious agent. Rifampicin (RIF) is a drug used in tuberculosis treatment being the first choice in association with other drugs for long periods, resulting in low adherence to the oral conventional treatment. Furthermore, RIF shows a low aqueous solubility, and thus, low bioavailability. Solid lipid nanoparticles (SLNs) can improve the efficacy of antituberculosis drugs and minimize the adverse effects of entrapped drugs. Their association with CS improves the mucoadhesive properties of the NPs. Vieira et al. [
194] developed and characterized SLNs loaded with RIF aiming to enhance mucoadhesion of the SLNs and, consequently, internalization by the alveolar macrophages (AMs). Prepared SLNs coated with CS by the association method (CS SLNs) showed an effective mucoadhesive profile, verified by the turbidimetry and surface loading method, corroborated with the cellular assays. The presence of CS in the CS SLNs promotes not only enhanced mucoadhesive properties of the SLNs but also their higher permeability in the human A549 cell line, suggesting that the safe RIF-CS SLNs can be used as a promising drug delivery system for improving tuberculosis treatment.
Asthma can be well managed with glucocorticoids and long-acting β-agonists. However, higher doses have proved to be both clinically ineffective and potentially detrimental, where poorly treated inflammation causes repeated exacerbations and sudden deaths in severe asthmatic conditions. An alternative anti-inflammatory intervention, capacitated to control airway remodeling and hypersensitivity without the risk of adverse effects, is crucial to achieving effective disease control and prevention of repeated exacerbations. Most of the pulmonary therapeutics suffer from limitations like poor bioavailability and short half-life. The development of new formulations tailored with suitable surface chemistry and actuation technique for effective drug deposition, interaction, and transportation across the mucus layer is crucial to achieving a high therapeutic index. Vibrating mesh nebulizers are recognized as the most efficient actuation technique over conventional inhalers for drug deposition. Dhayanandamoorthy et al. [
196] explored hyaluronic acid (HA) decorated, ferulic acid (FA) loaded chitosan NPs (FA-HA/CS NPs) aerosolized using vibrating mesh nebulizer as a strategic combination of drug, nanocarrier, and delivery device for effective asthma control. In vivo inhalation toxicity assessment confirmed safety, while FA-HA/CS NPs prophylaxis mitigated the inflammation, airway hypersensitivity, and remodeling in OVA-induced mice models of asthma. Thus, the results accentuated the role of pro-pulmonary surface chemistry conferred by HA functionalization that improved (i) thermal stability (as indicated by thermogravimetric analysis) and (ii) therapeutic efficacy of FA, by facilitating better interaction and transportation across mucus barrier (which otherwise suffers from poor bioavailability and rapid metabolism).
Etophylline (ETO), a bronchodilator used to treat airway diseases like asthma, chronic bronchitis, and chronic obstructive pulmonary disease (COPD), works by relaxing the smooth muscles of the lungs and dilating the bronchioles. Currently, tablet and injection dosage forms are commercially available. However, poor bioavailability with oral dose (owing to ETO incomplete absorption and high first-pass effect) and patient’s discomfort with painful injectable administration calls for the alternative formulation approach. Pardeshi et al. [
195] fabricated the ETO encapsulated mannose-anchored N,N,N-trimethyl chitosan nanoparticles (Mn-TMC NPs). The prominent characteristics like biocompatibility, controlled release, targeted delivery, high penetrability, enhanced physical stability, and scalability marked the Mn-TMC NPs as a viable alternative to various nanoplatform technologies for effective drug delivery. Mannosylation of TMC NPs led to the evolution of a new drug delivery vehicle with gratifying characteristics, and potential benefits at efficient drug therapy. It is widely accepted that following pulmonary administration, i.e., the introduction of mannose to the surface of drug nanocarriers, provides selective macrophage targeting via receptor-mediated endocytosis. The in vivo pharmacokinetic studies in a Wistar rat model revealed a significant improvement in the therapeutic efficacy of ETO, illustrating mannosylation of CS NPs as a promising approach for efficient therapy of airway diseases following pulmonary administration
Tobacco smoking and nicotine addiction are common public health problems all over the world causing to death of more than 6 million people per year. The harmful effects of tobacco smoking are primarily due to the other by-products of tobacco combustion such as tar constituents and carbon monoxide rather than nicotine. It is of interest to determine if there is an opportunity to develop a dry powder form of inhalable nicotine formulation and assess its applicability in reducing the health problems associated with smoking. The pulmonary route of nicotine delivery would be expected to mimic the effects of tobacco smoking and would significantly reduce cravings and withdrawal symptoms. Wang et al. [
192] built a nose-only inhalation device for pulmonary administration of nicotine to mice and determined the optimal operational parameters. They used the locomotor activity test to compare the effects of the inhaled nicotine hydrogen tartrate-loaded chitosan nanoparticles (NHT-CS NPs) with an inhaled and subcutaneously injected NHT in C57BL/6 mice. A minimum of 0.88 mg inhaled of NHT-CS NPs or 0.59 mg inhaled of NHT was required to alter locomotor activity similarly to injection of 0.50 mg/kg nicotine, suggesting the reformulation process did not alter the activity of NHT-CS NPs. No differences between untreated and NHT-CS NPs treated lung tissue upon histological examination were observed. The results indicated the inhaled NHT-CS NPs represent a viable preclinical option for developing novel inhalation formulations as a potential anti-smoking therapeutic.
3.4.8. Wound Healing
In recent years, a growing deal of attention has been attracted to develop and promoting wound healing agents. Injured skin can be infected and colonization by a diverse population of microbes, which can facilitate their access to the underlying tissues. Infection is considered a significant factor that prolongs the wound healing process. Wound dressing should protect the wound from microorganisms, provide a moist environment to hinder the wound dryness, decline the wound surface necrosis, be oxygen permeable without dehydrating the wound, plus should be comfortable, and avoid mechanical trauma. Moreover, low toxicity, biodegradability, and biocompatibility are some remarkable criteria for a material employed for the fabrication of wound dressing. It is proved that N-acetyl glucosamine as a monomer unit of CS stimulates hemostasis, encourages cell proliferation, and subsequently accelerates wound healing. As a biocompatibility aspect, CS does not lead to adverse reactions in contact with human cells. Furthermore, by binding to red blood cells CS causes rapid blood clotting. CS is also utilized to improve the stability of the drugs by producing CS NPs and resulting in drug accumulation increment [
206].
Fahimirad et al. [
206] fabricated the electrospun poly(ε-caprolactone) (PCL)/Chitosan (CS)/curcumin (CUR) nanofiber (CUR-PCL/CS NFs) with CUR loaded CS nano-encapsulated particles (CUR-CS NPs). The electrospraying of CUR-CS NPs on the surface of CUR-PCL/CS NFs resulted in enhanced antibacterial, antioxidant, cell proliferation efficiencies, and higher swelling and water vapor transition rates. In vivo examination and histological analysis showed CUR-PCL/CS NFs electrosprayed with CUR-PCL/CS NFs led to a significant improvement of the complete well-organized wound healing process in MRSA (methicillin-resistant
Staphylococcus aureus) infected wounds. These results suggest that the application of CUR-PCL/CS NFs electrosprayed with CUR-CS NPs as a wound dressing significantly facilitates wound healing with notable antibacterial, antioxidant, and cell proliferation properties.
Antibiotic-loaded nanofibrous-delivery systems offer an advanced approach to overcome several limitations associated with antibiotic therapy; the benefits include high surface-area-to-volume ratios, high porosity, high loading capacity, high encapsulation efficiency, minimum systemic toxicity, and the possibility of controlling the release from immediate to controlled release. Antibiotic-loaded NFs can be applied topically for skin and wound healing, post-operation implants for the prevention of abdominal adhesion, and prophylaxis and treatment of infections in orthopedic surgery. Amiri et al. [
67] developed a local antibiotic delivery system using polyethylene oxide/chitosan nanofibers (PEO/CS NFs) prepared via electrospinning for delivery of teicoplanin. The PEO/CS NFs were able to release teicoplanin for up to 12 days. An antibacterial test and time-kill study on
Staphylococcus aureus also demonstrated that loading teicoplanin in the PEO/CS NFs not only kept the antibacterial activity of antibiotic but also enhanced it up to 1.5- to 2-fold. The teicoplanin-loaded NFs did not show any cytotoxicity to human fibroblast. Moreover, in vivo study on a rat full-thickness wound model confirmed the safety and efficacy of applying the teicoplanin-loaded PEO/CS NFs; a significant improvement in wound closure was observed especially with the NFs containing 4% teicoplanin. The sustained release profile, enhanced drug activity, cytocompatibility, and significant wound healing activity affirm the potential applications of the teicoplanin-loaded PEO/CS NFs in wound healing and local antibiotic delivery.
Wounds are often recalcitrant to traditional wound dressings and a bioactive and biodegradable wound dressing using hydrogel membranes can be a promising approach for wound healing applications. Shafique et al. [
207] designed hydrogel membranes based on hyaluronic acid, pullulan, and polyvinyl alcohol and loaded with chitosan-based cefepime nanoparticles (CEF-CS NPs) for potential use in cutaneous wound healing. The results indicated the novel crosslinking and thermal stability of the fabricated hydrogel membrane. The in vitro analysis demonstrated that the developed membrane had water vapors transmission rate (WVTR) between 2000 and 2500 g/m
2/day and oxygen permeability between 7 and 14 mg/L, which laid in the range of an ideal dressing. The swelling capacity and surface porosity to liberate encapsulated drug (CEF) in a sustained manner and 88% of drug release was observed. The CEF-loaded hydrogel membrane demonstrated a higher zone of inhibition against
Staphylococcus aureus,
Pseudomonas aeruginosa, and
Escherichia coli and the excisional rat model exhibited an expeditious recovery rate. The developed hydrogel membrane loaded with CEF-CS NPs is a promising approach for topical application and has a great potential for an accelerated wound healing process.
The application of modern nanomedicines to enhance wound healing is growing due to their simplicity for topical organization and fast flexibility with molecules that can boost and reinforce the process of healing even in patients with diabetes. Manne et al. [
208] prepared an effective
Pterocarpus marsupium heartwood extract-chitosan nanoparticles (PMH-CS NPs) loaded carbopol hydrogel and evaluated its drug release efficiency, in vitro antimicrobial activity, and wound healing action in streptozotocin administered diabetic rat models. In vivo rats treated with such hydrogel displayed significantly much quicker healing of wounds in both diabetic and non-diabetic rats. Photographs of wound areas of the diabetic group of rats on 1, 9, and 18th day after treatment with Control, Standard, and PM-CS NPs H-1 (test treated) are shown in
Figure 32. (see Figure 32. Photographs of wound areas of the diabetic group of rats on 1, 9, and 18th days after treatment with Control, Standard, and PM-CS NPs H-1 (test treated) [
208] in our recent paper V. Mikusova, P. Mikus, Int. J. Mol. Sci. 2021, 22, 9652). The histological examination revealed re-epithelization and growth of granular tissue and an improvement in collagen deposition. These results indicated the effectiveness of optimized CS nanocomposites as a potential treatment for curing diabetic wounds.
3.4.9. Vaginal Drug Delivery
Vaginal delivery is very attractive for both local and systemic administration of drugs. For the latest purpose, it shows several advantages concerning conventional oral or parenteral ways, such as the avoidance of the stomach acidic pH, the hepatic first-pass effect, or the needle-based formulations uncomfortable for the patients. The vaginal mucosa is characterized by high robustness, ease of accessibility, and rich blood supply. The effectiveness of typical vaginal formulations (creams, foams, gels, tablets, films, rings, and suppositories) can be limited by their low active residence time due to the washing-effect of the vaginal physiological fluids, small absorption area, barrier properties of the mucosa, and inadequate spreading of the formulation on vaginal surfaces. Pharmaceutical nanocarriers provide several advantages such as a high surface area and great carrier capacity, improved stability of the therapeutic agents against chemical/enzymatic degradation, enhanced bioavailability, longer drug effect in the target tissue, and drug targeting upon inclusion of specific ligands. The development of NP-based vaginal drug delivery formulations has largely been focused on biological vaccine or microbicide delivery for prevention or treatment of sexually transmitted diseases such as human immunodeficiency virus (HIV), herpes simplex virus (HSV), or human papillomavirus (HPV). The vaginal route allows a localized delivery of peptide-based vaccines/microbicides close to both the site of infection and infectible cells. An opportune vaginal drug delivery system should provide mucosal interactions that facilitate bioadhesion with mucosa increasing drug residence time at the mucosal surface, and penetration enhancement properties to allow penetration into vaginal tissue cells. In the last years, many authors have studied the mucoadhesive and penetration enhancement properties of CS in this area [11,52].
Marciello et al. [211] proposed a straightforward and efficient strategy for the vaginal application and release of peptide-loaded mucoadhesive CS NPs. The CS NPs, responsible for carrying the peptide drug and allowing adhesion to the vaginal mucosal epithelium, were encapsulated in suitable hydrophilic freeze-dried cylinders. The hydrophilic freeze-dried cylinders facilitated the application and quick release of the CS NPs to the vaginal zone. Upon contact with the aqueous vaginal medium, the excipients constituting these sponge-like systems were quickly dissolved enabling the release of their content. In vitro release studies showed the ability of the sponge-like systems and the CS NPs to deliver the mucoadhesive NPs and peptides, respectively. CLSM (confocal laser scanning microscopy) micrographs proved the CS NPs ability to promote the peptide penetration inside the vaginal mucosa.
To prime adaptive immune responses from the female reproductive tract (FRT), particulate antigens must be transported to draining lymph nodes (dLNs) since no local organized lymphoid structures are being equivalent to those found in the respiratory or gastrointestinal tracts. Therefore, it is a challenge to find how to safely and effectively navigate successive barriers to transport such as crossing the epithelium and gaining access to migratory cells and lymphatic drainage that provide entry into dLNs. Park et al. [235] demonstrated that an intravaginal pretreatment with CS significantly facilitated the translocation of NPs across the multilayered vaginal epithelium to target dLNs. In addition, the CS pretreatment was found to enhance the NP associations with immunogenic antigen-presenting cells in the vaginal submucosa. These observations indicate that CS may have great potential as an adjuvant for both local and systemic protective immunity against viral infections in the FRT.
Vaginal candidiasis is a common genital tract infection caused by dimorphic fungi of the genus Candida. Sustained delivery systems prepared using biodegradable polymers, such as CS, are interesting because they may promote a slow release of the drug by controlled rates of their degradation. CS itself can reduce the microbial population. Hence, a nanoparticulate system based on CS can represent an alternative and promising therapy for the treatment of vulvovaginal candidiasis. Amaral et al. [210] fabricated polymeric NPs based on CS incorporating the common antifungal miconazole nitrate and tested them in vivo using murine vulvovaginal candidiasis (VVC). The treatment using the CS NPs with miconazole nitrate provided the same therapeutic efficacy as miconazole nitrate in a commercial cream formulation but using the antifungal content about seven-fold lower. In another work, Arumugam et al. [212] studied the killing effects of seaweed-derived metabolite Callophycin A (Cal) loaded in both chitosan (Cal-CS) and marine sponge-derived spicules (Cal-Spi) NPs. Vaginal candidiasis-induced animal model experiments confirmed that the candidicidal activity of Cal-CS NPs resulted in a significant reduction in the fungal burden of vaginal lavage. The histo-morphological alterations also evidenced that the protective role of Cal-CS NPs in the VVC model. The Cal-CS NPs could be used as an alternative strategy for the development of novel marine natural product-based topical applications.
3.4.10. Vaccine Delivery
Vaccine refers to biological products applied to prevent or control the occurrence and spread of infectious diseases. As for nature, the vaccines may be microbes or their toxins, enzymes, human or animal serum, and cells. The emergence of vaccines has made a significant contribution to the prevention and control of diseases. However, many problems are affecting the quality of the vaccines during their preparation, storage, and administration The major hurdle associated with oral mucosal immunization is enzymatic degradation of antigen at the stomach and low uptake of antigen sampling cells through the intestine. Hence, the vaccine administered through the oral route (less through the nasal route) requires the use of NPs. Nanomaterial-encapsulated vaccines have been proved effective in the delivery of antigens to immune cells. Such encapsulation can help in promoting immune responses and represents a promising vaccine transport vehicle. In oral vaccine delivery, the main target is Peyer’s patches. Due to the nanoparticle system, the vaccine is protected from enzymatic degradation while going to the mucosal tissue and taken up by the M-cells. CS is a particularly attractive choice for vaccine delivery because of its low immunogenicity, low toxicity, biocompatibility, and biodegradability. It has been widely used for mucosal but also systemic vaccine delivery and even in the preparation of DNA mucosal vaccines [11,52]. For novel, recently published oral and nasal CS NP-based vaccine delivery systems see Sections 3.4.1.6 and 3.4.3.2, respectively.
In systemic vaccine delivery, CS acts as an adjuvant. Activation of macrophages occurs after the uptake of CS [52]. CS exhibited good tolerability and excellent immune stimulation. The numerous recent hepatitis A outbreaks emphasize the need for vaccination; despite the effectiveness of the current vaccination, further development is needed to overcome its high cost plus some immune response limitations. AbdelaAllah et al. [213] evaluated the use of CS and ALG-coated CS NPs as an adjuvant/carrier for the hepatitis A (HA) vaccine against the traditional adjuvant alum (AL). Immune responses towards the HA-AL, HA-CS, and HA-ALG/CS NPs were assessed in mice. The HA-ALG/CS NPs significantly improved the immunogenicity by increasing the seroconversion rate, the hepatitis A antibodies level, and the splenocytes proliferation. Thus, the HA-ALG/CS NPs adjuvant was superior to the other classes in IFN-γ (interferon-gamma) and IL-10 (interleukin 10) development. The solution formula of the HA vaccine with CS showed comparable humoral and cellular immune responses to AL-adjuvanted suspension with a balanced Th1/Th2 immune pathway. The study demonstrated the potential of the ALG-coated CS NPs as an effective carrier for an HA vaccine.
3.4.11. Gene Delivery
Genes encoded specific proteins are essential for various physiological processes of the body and their mutations often result in disease. Gene therapy is a promising strategy to treat genetic diseases via the introduction of a foreign gene into a target cell which is then transcribed, and the genetic information is finally translated into the corresponding protein. The aim is to correct a damaged gene. For this process to be completed, the gene delivery system has to overcome several hurdles. The factors affecting transfection include targeting the delivery system to the target cell, uptake, and degradation in the endolysosomes, transport through the cell membrane, and intracellular transfer of plasmid DNA to the nucleus. Thus, DNA and RNA molecules can be destroyed by harsh acids and enzymes that are produced in the body. DNA and RNA are anionic polymers that have a good affinity with cationic polymers such as CS. CS can protect the DNA or RNA against nuclease degradation by forming a polyelectrolyte complex with negatively charged DNA or RNA. This protection can improve the transfection efficiency [11,52].
There are two main approaches for gene delivery systems, i.e., viral and nonviral ones. Considering efficiency and safety issues, polymeric vehicles would seem more convenient than other gene delivery approaches. Because of its positive charge and the small size of CS NPs (below 100 nm), endocytosis can be achieved. CS NP is therefore a promising excipient for non-viral gene delivery. In addition, chitosan–DNA-based drug complexes protect at least to some extent against degradation by DNAses in this way improving the bioavailability of DNA-based drugs delivered into the body [8]. Rahmani et al. [217] investigated in vitro DNA transfection efficiency of three CS derivatives, namely trimethyl chitosan thiolated with cysteine (CysTMC), methylated 4-N,N-dimethyl aminobenzyl N,O carboxymethyl chitosan (MABCMC), and trimethyl aminobenzyl chitosan thiolated with cysteine (CysMABC). The results showed that all the polymers could condense DNA plasmid strongly from N/P 2 and nanocomplexes had eligible sizes and zeta potentials. Moreover, the nanocomplexes had negligible cytotoxicity and CysMABC was the most effective vehicle for gene delivery in HEK-293T cells. In the two other cell lines, SKOV-3 and MCF-7, CysTMC exhibited the highest transfection efficiency.
Among several types of non-viral vectors, cell-penetrating peptides (CPPs), short peptides with 30 amino acids, are promising. CPPs show high biocompatibility and offer the potential for large-scale production. However, CPPs exhibit low transfection efficiency. Hybrid conjugation of CPPs with inorganic nanomaterials improved their efficiency and may open new venues for multifunctional treatment. Abdelhamid et al. [215] synthesized hierarchical mesoporous carbon (MPC) nanomaterials derived from the carbonized chitosan (CTS) encapsulated zeolitic imidazolate frameworks-8 (ZIF-8) and applied them for gene delivery. The MPC materials were applied as a non-viral vector for gene delivery using two oligonucleotides (ONs) called luciferase-expressing plasmid (pGL3), and splice correction oligonucleotides (SCO). The materials were biocompatible and showed insignificant toxicity. The MPC improved the transfection efficiency of cell-penetrating peptides (CPPs) (PepFect 14 (PF-14), and PF-221) by 10-fold compared to commercial vector Lipofectamine™2000 due to the synergistic effect of their action. This may be due to the positive charge of CPPs that ensure higher interactions with the negative charge of the cells.
Small interfering RNA (siRNA) is a double-stranded RNA of 20 to 25 nucleotides in length and has many important functions in biology. It primarily plays a unique role in the RNA interference events which regulates gene expression in a specific manner. siRNA-based therapies have great potential in the modulation of a large number of target mRNA molecule silencing, which ultimately decreased levels of the targeted protein. Nevertheless, there are challenges that applications of this gene silencing technology need to overcome, including rapid degradation of siRNA under physiological conditions and the difficulty of passing the cytoplasmic membrane of negatively charged siRNA. The key challenge in realizing the therapeutic potency of siRNA is the development and design of a novel degradable vector with safe and sufficient gene delivery efficacy. To improve the transfection efficiency, new safe vehicles for cancer gene delivery based on NPs have been developed. Recently some different modifications of CS have been used to produce these NPs, for example, a polyelectrolyte complex containing trimethyl chitosan (TMC) as the positive and, dextran sulfate, and alginate as the negative part [219], guanidinylated O-carboxymethyl chitosan (GOCMCS) along with poly-β-amino ester (PBAE) for siRNA delivery [221].
Yan et al. [220] fabricated the NPs of carboxymethyl chitosan (CMC) and labeled fluorescein isothiocyanate (FITC)-chitosan hydrochloride (FITCCS) as carriers for ultrasound-triggered drug delivery to treat colon cancer. The results showed the FITCCS/CMC NPs could effectively encapsulate anti-β-catenin siRNA through ionic gelation self-assembly to improve the stability of siRNA. The FITCCS/CMC NP-based pH-sensitive delivery system provided a controlled release of siRNA through responding to external stimulus (ultrasound) under favorable pH conditions. Following the transfection of anti-β-catenin siRNA for 48 h, the β-catenin protein expression of the colon cancer cells was reduced to about 40.10%, indicating the effective reduction of the protein that promotes colon cancer proliferation.
CS as a promising polysaccharide for gene/siRNA delivery requires some additional treatments to modify CS NPs. Mobarakeh et al. [218] modified CS NPs to introduce anti-HIV siRNA into two mammalian cell lines, macrophage RAW264.7, and HEK293. The CS NPs were prepared by using different concentrations of CS, polyethyleneimine (PEI), and carboxymethyl dextran (CMD) in various formulations. The results indicated that the combination of CS with both CMD and PEI significantly improved both cell viability and siRNA delivery. In the studied cell types, the NPs noticeably increased siRNA delivery efficiency with no significant cytotoxicity or apoptosis-inducing effects compared to the control cells. In addition, the NPs significantly reduced the RNA and protein expression of HIV-1 tat in both stable cells.
Induction of Hypoxia Inducible Factor (HIF) as a direct consequence of oxygen deficiency in tumor tissues is a potent stimulus of CD73 (ecto-5′nucleotidase) expression. Hypoxic environment and CD73 overexpression are associated with altered metabolism, elevated cancer cell proliferation, and tumor vascularization. Hajizadeh et al. [222] developed a delivery system for silencing CD73 and HIF-1α gene using siRNA-loaded superparamagnetic iron oxide (SPION) nanocarriers for cancer treatment. The SPIONs were encapsulated with thiolated chitosan (TC) and trimethyl chitosan (TMC) for improving their stabilization and functionalization. The produced NPs were efficiently accumulated in the tumor site, indicating their stability and targeting ability in reaching the tumor region. TAT-conjugated TMC/TC/SPIONs containing siRNAs significantly reduced the HIF-1α and CD73 expression levels in cancer cells. Moreover, siRNA-loaded NPs effectively reduced tumor growth and angiogenesis as is illustrated by CAM (cell angiogenesis) assay in Figure 33 (see Figure 33. CAM assay of HIF-1α/CD73 siRNA loaded TAT-TMC/TC/SPION nanocarriers suppressed in vivo tumor development and angiogenesis [222] in our recent paper V. Mikusova, P. Mikus, Int. J. Mol. Sci. 2021, 22, 9652). Hence, the co-silencing of CD73 and HIF-1α can be assumed as a novel anti-cancer treatment strategy with a high tumor suppression potential.
Some researchers focused on the development of delivery systems that combine silencing of inhibitor of apoptosis (IAP) genes BV6 (their increased expression is associated with cancer progression and chemoresistance) and interleukin (IL)-6, as a new promising anti-tumor treatment strategy. For this purpose, Salimifar et al. [223] prepared hyaluronate/PEGylated chitosan lactate HA/PCL) NPs to simultaneously deliver IL6-specific siRNA and BV6 to 4T1 (breast cancer) and CT26 (colon cancer) cells. They investigated the anti-tumor properties of this combined therapy both in vitro and in vivo. Such therapy synergistically increased apoptosis and decreased cell migration, proliferation, colony formation, and angiogenesis in both 4T1 and CT26 cell lines and, by that, suppressed cancer progression in tumor-bearing mice that was associated with enhanced survival time.
Another strategy is to use BV6 along with inhibition of signal transducer and activator of transcription 3 (STAT3), which is an important factor in the survival of tumor cells, and NIK as a mediator of BV6 unpredicted side effects. This combination has the potential to induce effective apoptosis in tumor cells. Nikhoo et al. [224] used carboxymethyl dextran-conjugated trimethyl chitosan (CMD/TMC) NPs loaded with NIK/STAT3-specific siRNA and BV6 to synergistically induce apoptosis in the breast, colorectal, and melanoma cancer cell lines. Their results showed that in addition to enhanced pro-apoptotic effects, this combined therapy reduced proliferation, cell migration, colony formation, and angiogenesis, along with the expression of factors including IL-10 and HIF in the tumor cells. Masjedi et al. [225] generated the active-targeted hyaluronate (HA) recoated N, N, N-trimethyl chitosan (TMC) NPs to deliver IL-6- and STAT3-specific siRNAs to the CD44-expressing cancer cells. The results showed that the synthesized NPs had high transfection efficiency, low toxicity, and controlled siRNA release. The siRNA-loaded NPs significantly inhibited the IL-6/STAT3 expression, which was associated with blockade of proliferation, colony formation, migration, and angiogenesis in the cancer cells.
A co-delivery of chemotherapeutic drugs and siRNA has gained increasing attention owing to the enhanced antitumor efficacy over the single administration. Studies in this field showed that simultaneous delivery of chemotherapeutic drugs and siRNA via a single targeted vector was more effective in treating some cancers than a sequential administration of two separate vectors with one drug in each. Yan et al. [226] developed a CS-based pH-responsive prodrug vector for the co-delivery of doxorubicin (DOX) and Bcl-2 siRNA. The accumulation of fabricated NPs in hepatoma cells was enhanced by glycyrrhetinic acid receptor-mediated endocytosis. This nanoplatform can efficiently integrate gene- and chemotherapies with a dramatically enhanced tumor inhibitory rate (88.0%) in vivo.
Gene therapy treatment strategies for Parkinson’s disease (PD) have recently come into prominence. Here, gene therapy has potential advantages to increase pre-cursor cells to synthesize dopamine and could repair or prevent degeneration of dopaminergic neurons. Gene therapy could correct a specific genetic defect by increasing, decreasing, or silencing the expression of target genes, or induce the endogenous production of a therapeutic protein. Xue et al. [227] proposed drug-loaded chitosan nanoparticles (pDNA-NGF-ActPP/CS NPs as novel candidates for the design of anti-PD drugs. They investigated the effects of chitosan polyethylene glycol-poly lactic acid (PP/CS) NPs conjugated with nerve growth factor (NGF), acteoside (Act), and plasmid DNA (pDNA) (pDNA-NGF-ActPP/CS NPs) for PD therapy using in vitro and in vivo models. Using PD cell models, they demonstrated that pDNA-NGF-ActPP/CS NPs had good neuroprotective effects. More significantly, experiments using a mouse PD model showed that pDNA-NGF-ActPP/CS NPs could ameliorate the behavioral disorders of sick mice. Immunohistochemical and Western blot (WB) analyses revealed that pDNA-NGF-ActPP/CS NPs could significantly reverse dopaminergic (DA) neuron loss in the substantia nigra and striatum of sick mice. This study opens up a novel avenue to develop anti-PD drugs.
4. Concluding Remarks
The recent review and research papers indicate CS NPs play a vital role in biomedical applications such as drug/vaccine/gene delivery, bioimaging, wound healing, tissue engineering, etc. They highlighted an outstanding position of CS as a polysaccharide able to form NPs favorable for various drug delivery purposes because of its many beneficial properties, such as mucoadhesion, controlled drug release, transfection, permeation enhancement, in situ gelation, efflux pump inhibitory properties, and stimuli-responsive properties. Many works demonstrated, via in vitro and in vivo experiments, CS NPs designed for controlled drug delivery may improve the stability of the drug and increase the efficacy of therapeutic agents. The other advantages of CS NPs DDS, presented in recent works, involved reduced therapeutical doses leading to reduced possible side effects, better bioavailability, and finally better patient compliance.
Nevertheless, the current research is still oriented towards an additional improvement of the chitosan properties. There are efforts to enhance its low solubility in physiological pH, stimuli-responsive properties, and specificity towards complex biological systems by chemical modifications of pure CS or by blending CS with other polymers or inorganic materials. In this way, new modified CS-based nanoparticles and nanocomposites possessing more or less enhanced properties were developed. Such innovative CS particulate systems provided, to a more/less extent, non-toxic, biocompatible, stable, target-specific, and biodegradable delivery devices. In addition, the systems with a proper label (e.g., metal-based nanocomposites) enabled target-specific diagnostics (due to easy dual introduction of an imaging agent together with a therapeutic agent) along with a target-specific therapy (due to a stimulus-responsive matrix). Recent newly developed native CS NPs, modified CS NPs, or CS nanocomposites were applied as potential drug carriers for many drugs and various routes of administrations. They were mainly studied for anticancer agents, proteins, vaccines, and genetic material. For example, in oral DD, new CS NPs enhanced the absorption of the drugs through the opening of tight junctions of the mucosal membrane. In ocular DD, in situ gelling properties and mucoadhesive character of CS enabled prolonging drug release. In nasal delivery, CS NPs increased the permeability of the drugs. In vaccine delivery, CS NPs enabled to formulate oral vaccines providing enhanced absorption of these hydrophilic biomolecules.
Despite apparent current progress, safety and targeting specificity are remaining among the main challenges in the future development of CS-based nanoparticulate DDSs. Therefore, systematic studies on biodistribution, in vitro and in vivo toxicity, and selectivity will further continue with newly developed CS derivatives and their NPs and nanocomposites for various administration routes.
Acknowledgments: work was supported by the projects APVV-15-0585, VEGA 1/0463/18, KEGA 027UK-4/2020, and the Toxicological and Antidoping Center at the Faculty of Pharmacy, Comenius University in Bratislava.
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