Abstract
BackgroundUncontrolled inflammation is a central problem for many respiratory diseases. The development of potent, targeted anti-inflammatory therapies to reduce lung inflammation and re-establish the homeostasis in the respiratory tract is still a challenge. Previously, we developed a unique anti-inflammatory nanodrug, P12 (made of hexapeptides and gold nanoparticles), which can attenuate Toll-like receptor-mediated inflammatory responses in macrophages. However, the effect of the administration route on its therapeutic efficacy and tissue distribution remained to be defined.ResultsIn this study, we systematically compared the effects of three different administration routes [the intratracheal (i.t.), intravenous (i.v.) and intraperitoneal (i.p.)] on the therapeutic activity, biodistribution and pulmonary cell targeting features of P12. Using the LPS-induced ALI mouse model, we found that the local administration route via i.t. instillation was superior in reducing lung inflammation than the other two routes even treated with a lower concentration of P12. Further studies on nanoparticle biodistribution showed that the i.t. administration led to more accumulation of P12 in the lungs but less in the liver and other organs; however, the i.v. and i.p. administration resulted in more nanoparticle accumulation in the liver and lymph nodes, respectively, but less in the lungs. Such a lung favorable distribution was also determined by the unique surface chemistry of P12. Furthermore, the inflammatory condition in the lung could decrease the accumulation of nanoparticles in the lung and liver, while increasing their distribution in the spleen and heart. Interestingly, the i.t. administration route helped the nanoparticles specifically target the lung macrophages, whereas the other two administration routes did not.ConclusionThe i.t. administration is better for treating ALI using nanodevices as it enhances the bioavailability and efficacy of the nanodrugs in the target cells of the lung and reduces the potential systematic side effects.
Highlights
Lung is a unique organ that is continuously exposed to the outside environment
Synthesis and characterization of hexapeptide modified gold nanoparticles (GNPs) Previously, we developed a novel class of anti-inflammatory peptide–GNP hybrids named P12, which was composed of a 13 nm GNP core and a surface coating of hexapeptides (CLPFFD) (Fig. 1a)
Our earlier work demonstrated that i.t. administration of P12 could regulate lung inflammation of LPS-induced acute lung injury (ALI) mice by inhibiting multiple Toll-like receptor (TLR) pathways and promoting the polarization of pulmonary macrophages to M2 phenotype [18, 23]
Summary
Lung is a unique organ that is continuously exposed to the outside environment. A common feature for these respiratory disorders is the uncontrolled inflammatory reaction in the lung [7, 8]. The widely used anti-inflammatory drugs glucocorticoids can reduce inflammation locally and systematically, the long-term use of glucocorticoids is often associated with serious side effects [9,10,11]. There is an urgent need for a potent, targeted anti-inflammatory therapy with minimum side effect to promote the tissue repair and re-establish the homeostasis (i.e., immune balance) in the respiratory tract. The development of potent, targeted anti-inflammatory therapies to reduce lung inflammation and re-establish the homeostasis in the respiratory tract is still a challenge. The effect of the administration route on its therapeutic efficacy and tissue distribution remained to be defined
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