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Functional Nanocarriers for Delivering Itraconazole Against Fungal Intracellular Infections.

ABSTRACT: Infectious diseases caused by intracellular microorganisms represent a significant challenge in medical care due to interactions among drugs during coinfections and the development of resistance in microorganisms, limiting existing therapies. This work reports on itraconazole (ITZ) encapsulated into functional polymeric nanoparticles for their targeted and controlled release into macrophages to fight intracellular infections. NPs are based on poly (lactic acid-co-glycolic acid) (PLGA) polymers of different compositions, molecular weights, and lactic acid-to-glycolic acid ratios. They were self-assembled using the high-energy nanoemulsion method and characterized by transmission electron microscopy, Fourier transform infrared spectroscopy (FT-IR), and differential scanning calorimetry. It was studied how the polymer-to-drug ratio, changes in the aqueous phase pH, and type and concentration of surfactant affected nanocarriers' formation, drug-loading capacity, and encapsulation efficiency. Results showed that drug-loading capacity and encapsulation efficiency reached 6.7 and 80%, respectively, by lowering the pH to 5.0 and using a mixture of surfactants. Optimized formulation showed an initial immediate ITZ release, followed by a prolonged release phase that fitted better with a Fickian diffusion kinetic model and high stability at 4 and 37°C. NPs functionalized by using the adsorption and carbodiimide methods had different efficiencies, the carbodiimide approach being more efficient, stable, and reproducible. Furthermore, linking F4/80 and mannose to the NPs was demonstrated to increase J774A.1 macrophages' uptake. Overall, in vitro assays showed the nanosystem's efficacy to eliminate the Histoplasma capsulatum fungus and pave the way to design highly efficient nanocarriers for drug delivery against intracellular infections.

SUBMITTER: Mejia SP

PROVIDER: S-EPMC8274696 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Pulmonary intracellular infections, such as tuberculosis, anthrax, and tularemia, have remained a significant challenge to conventional antibiotic therapy. Ineffective antibiotic treatment of these infections can lead not only to undesired side effects, but also to the emergence of antibiotic resistance. Aminoglycosides (e.g., streptomycin) have long been part of the therapeutic regiment for many pulmonary intracellular infections. Their bioavailability for intracellular bacterial pools, however, is limited by poor membrane permeability and rapid elimination. To address this challenge, polymer-augmented liposomes (PALs) were developed to provide improved cytosolic delivery of streptomycin to alveolar macrophages, an important host cell for intracellular pathogens. A multifunctional diblock copolymer was engineered to functionalize PALs with carbohydrate-mediated targeting, pH-responsive drug release, and endosomal release activity with a single functional polymer that replaces the pegylated lipid component to simplify the liposome formulation. The pH-sensing functionality enabled PALs to provide enhanced release of streptomycin under endosomal pH conditions (70% release in 6 hours) with limited release at physiological pH 7.4 (16%). The membrane-destabilizing activity connected to endosomal release was characterized in a hemolysis assay and PALs displayed a sharp pH profile across the endosomal pH development target range. The direct connection of this membrane-destabilizing pH profile to model drug release was demonstrated in an established pyranine/p-xylene bispyridinium dibromide (DPX) fluorescence dequenching assay. PALs displayed similar sharp pH-responsive release, whereas PEGylated control liposomes did not, and similar profiles were then shown for streptomycin release. The mannose-targeting capability of the PALs was also demonstrated with 2.5 times higher internalization compared to non-targeted PEGylated liposomes. Finally, the streptomycin-loaded PALs were shown to have a significantly improved intracellular antibacterial activity in a Francisella-macrophage co-culture model, compared with free streptomycin or streptomycin delivered by control PEGylated liposomes (13× and 16×, respectively). This study suggests the potential of PALs as a useful platform to deliver antibiotics for the treatment of intracellular macrophage infections.

Project description:BackgroundBreast cancer lung metastasis occurs in more than 60% of all patients with breast cancer, and most of those afflicted by it eventually die of recurrence. The tumor microenvironment plays vital roles in metastasis. Modulating the tumor microenvironment via multiple pathways could efficiently prevent or inhibit lung metastasis. Silibinin and cryptotanshinone are natural plant products that demonstrate anti-metastasis effects and modulate the tumor microenvironment via different pathways. However, they have poor aqueous solubility, membrane permeability, and oral bioavailability. Oral drug administration may help improve the quality of life and compliance of patients with breast cancer, primarily under long-term and/or follow-up therapy. Herein, we developed poly-N-(2-hydroxypropyl) methacrylamide (pHPMA)-coated wheat germ agglutinin-modified lipid-polymer hybrid nanoparticles, co-loaded with silibinin and cryptotanshinone (S/C-pW-LPNs). We assessed their oral bioavailability, and evaluated their anti-metastasis efficacy in a 4T1 breast cancer tumor-bearing nude mouse model.ResultsAn in vitro mucus diffusion study revealed that pHPMA enhanced W-LPN mucus penetration. After oral administration, pHPMA enhanced nanoparticle distribution in rat jejunum and substantially augmented oral bioavailability. S/C-W-LPNs markedly increased 4T1 cell toxicity and inhibited cell invasion and migration. Compared to LPNs loaded with either silibinin or cryptotanshinone alone, S/C-pW-LPNs dramatically slowed tumor progression in 4T1 tumor-bearing nude mice. S/C-pW-LPNs presented with the most robust anti-metastasis activity on smooth lung surfaces and mitigated lung metastasis foci. They also downregulated tumor microenvironment biomarkers such as CD31, TGF-?1, and MMP-9 that promote metastasis.ConclusionsSilibinin- and cryptotanshinone-co-loaded pW-LPNs efficiently penetrate intestinal barriers, thereby enhancing the oral bioavailability of the drug loads. These nanoparticles exhibit favorable anti-metastasis effects in breast cancer-bearing nude mice. Hence, S/C-pW-LPNs are promising oral drug nanocarriers that inhibit breast cancer lung metastasis.

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Functional Nanocarriers for Delivering Itraconazole Against Fungal Intracellular Infections.

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