Nanotechnology-Based Approaches for Voriconazole Delivery Applied to Invasive Fungal Infections

Nanotechnology-Based Approaches for Voriconazole Delivery Applied to Invasive Fungal Infections

  • Post category:Drug Updates
  • Reading time:9 mins read

Introduction

Fungal infections are a growing threat to global public health, with some species causing life-threatening illnesses. Immunocompromised patients are at higher risk, and systemic fungal infections can be fatal if appropriate therapy is delayed. Mycoses are classified as superficial, cutaneous, subcutaneous, and systemic. Among the most common fungal infections are Cryptococcus, Candida, and Aspergillus. Treatment involves antifungal drugs, but decreased antifungal susceptibility and adverse effects are limitations. Voriconazole (VCZ) is commonly used but has limitations due to inter-individual variation and toxicity. Nanoparticles have been studied for antifungal therapy and can improve drug aspects such as solubility and stability in water, increased bioavailability, and tissue penetration, resulting in increased efficacy and reduced toxicity. Nanoparticles can also maintain drug plasma levels balanced in the therapeutic range and improve the fungal inhibition profile even in lower concentrations compared to plain antifungals. Therefore, nanotechnology-based systems developed for delivering VCZ could be an excellent avenue for treating fungal infections.

Fungal Infections

Pulmonary Aspergillosis

Pulmonary aspergillosis is caused by the Aspergillus fungus and affects immunocompromised or pre-existing lung disease patients. The main types of pulmonary aspergillosis are ABPA, CPA, and IPA. A few species of Aspergillus cause infections, including A. fumigatus, A. flavus, A. niger, A. terreus, A. nidulans, A. calidoustus, A. sydowii, and A. versicolor. A. fumigatus is the most frequently isolated species from CPA patients.

Allergic Bronchopulmonary Aspergillosis
(ABPA)

ABPA is an inflammatory lung disease caused by hypersensitivity to Aspergillus fungus and is commonly found in patients with asthma, cystic fibrosis, tuberculosis, or COPD. The diagnosis is based on skin test or elevated IgE against A. fumigatus, eosinophil count, radiographic characteristics, and serum precipitins or IgG against A. fumigatus. Treatment involves suppressing hyperimmune response and reducing mycological load using glucocorticoids, antifungals, and biologic therapies such as omalizumab and mepolizumab.

Chronic Pulmonary Aspergillosis (CPA)

CPA is a chronic lung disease caused by Aspergillus, affecting immunocompromised patients and those with pre-existing lung disease. Symptoms include chronic cough, weight loss, fever, dyspnea, hemoptysis, and nodules. Diagnosis involves clinical and radiological aspects, immune response, culture, and galactomannan detection. VCZ treatment is the first choice, followed by posaconazole, and antifungal treatment intravenously if needed for at least six months.

Invasive Aspergillosis (IA)

Invasive aspergillosis is a serious fungal infection that can affect various organs and has high mortality, especially in immunocompromised patients. The most severe form is invasive pulmonary aspergillosis (IPA), which is difficult to diagnose and can be confused with bacterial pneumonia. The diagnosis is based on epidemiological, clinical, and radiological data, as well as detection of Aspergillus galactomannan antigen in serum and respiratory specimens. Treatment options include antifungal agents such as VCZ, liposomal amphotericin B, isavuconazole, itraconazole, and echinocandins, and the duration of treatment can be several months. Isavuconazole is a recent therapy with high efficacy and fewer drug interactions than other options.

Candida Infections

Candida infections can have various clinical manifestations, with the most common species being Candida albicans. Invasive candidiasis is one of the most aggressive forms of the disease and has a high mortality rate, particularly in immunocompromised patients. Other common species causing infections are C. glabrata, C. tropicalis, C. parapsilosis, and C. krusei, with C. auris causing concern due to its multidrug resistance properties. Risk factors for candidemia include the use of venous catheters, admission to the intensive care unit, and broad-spectrum antibiotics. Diagnosis is based on culture methods and other tests such as detection of antigens and molecular biology techniques. Treatment involves four different classes of drugs, with echinocandins being the first choice for treating invasive Candida infections.

Cryptococcosis

Cryptococcosis is a systemic fungal infection caused by Cryptococcus spp. that can affect both immunocompetent and immunosuppressed patients. The main species are Cryptococcus neoformans and Cryptococcus gattii, which can cause pulmonary, extrapulmonary, and disseminated forms of the disease. Cryptococcosis is a fungal infection caused by Cryptococcus spp. that can affect both immunocompetent and immunosuppressed patients. Cryptococcal meningitis is a global health concern, with 1 million new infections per year. The first-choice treatment is using Amphotericin B, but it has hepatotoxic and nephrotoxic effects. The search for new treatment alternatives, such as antifungal drug combinations, nanotechnology, and new molecular targets, has grown in recent years.

Voriconazole

VCZ is an antifungal drug derived from fluconazole and approved by FDA in 2002. It belongs to the azole class and inhibits the ergosterol synthesis by inhibiting cytochrome P450 (CYP 450)-dependent 14-lanosterol demethylation. It is fungicidal against most molds, except Mucorales. VCZ is fungistatic against Candida spp. and other yeasts. It is active against Blastomyces dermatitidis, Coccidioides spp., Histoplasma capsulatum and Paracoccidioides brasiliensis. The non-linear pharmacokinetics of VCZ, which presents wide inter-individual variability according to cytochrome P450 polymorphisms, is one of its main limitations. Its absorption varies from 35% to 83% due to CYP2C19 enzyme activity, and it is rapidly absorbed, reaching maximum plasma concentration in 1-2 h. VCZ is extensively metabolized in the liver by enzymes of cytochrome P450, which can result in dose-dependent auto-inhibition and saturation of metabolism. Only 2% of VCZ is excreted unchanged in the urine, with an elimination half-life of approximately six hours. Therapeutic monitoring has been suggested in clinical practice to reduce adverse effects and increase the therapeutic efficacy and safety of VCZ.

Nanotechnology-Based Voriconazole
Delivery Systems

Considering all limitations regarding the use of VCZ, nanotechnology-based delivery systems represent an excellent approach. Furthermore, the loading of VCZ in nanoparticles, in addition to improving the physicochemical and biological aspects of the drug in the conventional routes of administration (oral and parenteral), could propose alternative routes (topical, intranasal, pulmonary, ocular, vaginal, and others), as can be represented in Figure 1.


Lipid Nanoparticles

The article discusses the potential of lipid nanocarriers as drug delivery systems due to their controlled and specific target release capabilities. The main lipid nanocarriers discussed are liposomes, solid lipid nanoparticles (SLNs), and nanostructured lipid carriers (NLCs). SLNs have limitations such as low physical stability and limited encapsulation efficiency, which have been addressed by the development of NLCs. SLNs and NLCs have been used to improve drug solubility and reduce adverse effects of antifungals, specifically voriconazole (VCZ). Lipid nanoparticles containing VCZ have been developed mainly for ocular delivery and have shown increased permeation and sustained release, increasing their therapeutic efficacy. Studies have shown that liposomes and SLNs are effective in improving the pharmacokinetic characteristics of antifungals and reducing their adverse effects.

Polymeric Nanoparticles

Polymeric nanoparticles are a promising drug delivery system due to their controlled release and interaction with pharmacokinetic parameters. Two types of biodegradable polymers, synthetic and natural, are used to create these nanoparticles through dispersion and polymerization techniques. Despite challenges, diseases including cancer, neurodegenerative, and cardiovascular diseases have been effectively treated with these nanoparticles. Chitosan-coated PLGA and chitosan nanoparticles have been developed for VCZ delivery with high encapsulation efficiency and sustained release, providing protection against degradation and enabling surface modification with ligands. Mucoadhesive chitosan increases VCZ delivery in target tissues.

Protein Nanocarriers

Protein nanoparticles, derived from animal or plant proteins using various techniques, have various applications including drug delivery, gene delivery, and cosmetics. Human serum albumin nanoparticles containing voriconazole have been successfully developed, with promising results for parenteral administration. The physicochemical characteristics of nanoparticles are important for improving the treatment of fungal infections, allowing for better interaction with the fungus. Using nanotechnology for voriconazole encapsulation and release is a promising strategy to increase therapeutic activity and improve solubility and bioavailability, but further comprehensive studies are needed regarding cytotoxicity and antifungal potential, especially in in vivo studies.

Other Systems for Voriconazole Delivery

Cubosomes are liquid crystalline nanoparticles composed of a lipid and surfactant/stabilizer that can efficiently transport and release drugs at specific target sites. They have been studied for ocular delivery of VCZ and demonstrated prolonged release and increased permeation when coated with chitosan. Cyclodextrins, cyclic oligosaccharides, are used to improve drug solubility and stability, and were used to produce thermosensitive gels for vaginal and ophthalmic application of VCZ with improved drug uptake and residence time.

Conclusions

Therapeutic management of fungal infections is challenging due to limitations of antifungals. VCZ has pharmacokinetic and toxicity limitations. Nanocarrier systems loaded with VCZ offer advantages such as improved solubility and dissolution rate, sustained release, and improved pharmacokinetic parameters for topical applications.

 

Source:  de Almeida Campos, L.; Fin, M.T.; Santos, K.S.; de Lima Gualque, M.W.; Freire Cabral, A.K.L.; Khalil, N.M.; Fusco-Almeida, A.M.; Mainardes, R.M.; Mendes-Giannini, M.J.S. Nanotechnology-Based Approaches for Voriconazole Delivery Applied to Invasive Fungal Infections. Pharmaceutics 2023, 15, 266. https://- doi.org/10.3390/pharmaceutics15010266.