Fluorescent PLGA Nanocarriers for Pulmonary Administration: Influence of the Surface Charge

Abstract

Nearly four million yearly deaths can be attributed to respiratory diseases, prompting a huge worldwide health emergency. Additionally, the COVID-19 pandemic’s death toll has surpassed six million, significantly increasing respiratory disease morbidity and mortality rates. Despite recent advances, it is still challenging for many drugs to be homogeneously distributed throughout the lungs, and specifically to reach the lower respiratory tract with an accurate sustained dose and minimal systemic side effects. Engineered nanocarriers can provide increased therapeutic efficacy while lessening potential biochemical adverse reactions. Poly(lactic-co-glycolic acid) (PLGA), a biodegradable polymer, has attracted significant interest as an inhalable drug delivery system. However, the influence of the nanocarrier surface charge and its intratracheal instillation has not been addressed so far. In this study, we fabricated red fluorescent PLGA nanocapsules (NCs)—Cy5/PLGA—with either positive (Cy5/PLGA+) or negative surface charge (Cy5/PLGA-). We report here on their excellent colloidal stability in culture and biological media, and after cryo-storage. Their lack of cytotoxicity in two relevant lung cell types, even for concentrations as high as 10 mg/mL, is also reported. More importantly, differences in the NCs’ cell uptake rates and internalization capacity were identified. The uptake of the anionic system was faster and in much higher amounts—10-fold and 2.5-fold in macrophages and epithelial alveolar cells, respectively. The in vivo study demonstrated that anionic PLGA NCs were retained in all lung lobules after 1 h of being intratracheally instilled, and were found to accumulate in lung macrophages after 24 h, making those nanocarriers especially suitable as a pulmonary immunomodulatory delivery system with a marked translational character.

Nebulized Inhalation of Peptide-Modified DNA Origami To Alleviate Acute Lung Injury

“…The administration of drugs to the lungs faces challenges in passing through the airway and crossing the mucus barrier. Specifically, tDONs-R9 possess the characteristics of nanomedicines that are more likely to penetrate the mucus network. − We were further inspired to investigate the tissue distribution, alveolar deposition effect, and cellular uptake fate of inhaled tDONs-R9 in ALI mice.…”

“…DNA origami nanostructure (DON) is an emerging drug platform for the treatment of diseases with the advantage of biocompatibility, biostability, and programmability. − Previously, we reported that DON based on efficient self-assembly, well-defined, uniform size, and spatially addressability is a powerful nanomedicine vehicle for cancer therapy. − Recent studies have reported the ROS-scavenging capability of DONs and their potential for the treatment of inflammatory injury-related diseases, such as acute kidney injury and rheumatoid arthritis. − However, no studies have explored the therapeutic possibility of DONs in lung inflammatory diseases, especially the potential of inhaled therapeutic. According to the studies of drug delivery to lung inflammatory diseases, − hydrophilic nanoparticles with a size of 60–300 nm and neutral/negative charge are more likely to penetrate the mucus barrier and deposit to the alveolar region. Notably, DON is not only a ROS scavenger but also a negatively charged hydrophilic nanostructure with a uniform size, which makes it advantageous and promising for inhalation therapy in ALI.…”

Bioactive Materials for Disease Diagnosis and Therapy

“…Both methods to diagnose in vivo (Ximendes et al, 2021), (Ximendes et al, 2017), (Pellico et al, 2021), (Santos et al, 2020) and ex vivo (Pelaez et al, 2018), (Litti et al, 2021), (Enshaei et al, 2021) enabled by several nanoformulations have revolutionized current medical practices and will continue to improve the crucial ability to diagnose diseases efficiently. In addition, the continuous effort of researchers to understand and exquisitely characterize the fate of NPs in biological system is a crucial foundation for all this work (Carregal-Romero et al, 2021;Areny-Balaguero et al, 2022).…”

Bioengineered extracellular vesicles: future of precision medicine for sepsis

“…Furthermore, biodegradable polymers, such as poly(lactic-co-glycolic acid) (PLGA), have also been used to develop nanocarriers that resemble EVs in size and morphology. PLGA nanocarriers have been proposed as a potential pulmonary drug delivery system, since they did not exhibit signs of cytotoxicity and showed and excellent lung biodistribution after intratracheal instillation, offering a suitable tool for the treatment of sepsis-induced acute lung injury [126]. Below, several studies are shown that demonstrate the efficacy of this type of nanocarriers for the treatment of sepsis-induced ARDS.…”