Therapeutic Fluorescent Hybrid Nanoparticles for Traceable Delivery of Glucocorticoids to Inflammatory Sites

Abstract

Treatment of inflammatory disorders with glucocorticoids (GCs) is often accompanied by severe adverse effects. Application of GCs via nanoparticles (NPs), especially those using simple formulations, could possibly improve their delivery to sites of inflammation and therefore their efficacy, minimising the required dose and thus reducing side effects. Here, we present the evaluation of NPs composed of GC betamethasone phosphate (BMP) and the fluorescent dye DY-647 (BMP-IOH-NPs) for improved treatment of inflammation with simultaneous in vivo monitoring of NP delivery.Methods: BMP-IOH-NP uptake by MH-S macrophages was analysed by fluorescence and electron microscopy. Lipopolysaccharide (LPS)-stimulated cells were treated for 48 h with BMP-IOH-NPs (1×10-5-1×10-9 M), BMP or dexamethasone (Dexa). Drug efficacy was assessed by measurement of interleukin 6. Mice with Zymosan-A-induced paw inflammation were intraperitoneally treated with BMP-IOH-NPs (10 mg/kg) and mice with ovalbumin (OVA)-induced allergic airway inflammation (AAI) were treated intranasally with BMP-IOH-NPs, BMP or Dexa (each 2.5 mg/kg). Efficacy was assessed in vivo by paw volume measurements with µCT and ex vivo by measurement of paw weight for Zymosan-A-treated mice, or in the AAI model by in vivo x-ray-based lung function assessment and by cell counts in the bronchoalveolar lavage (BAL) fluid and histology. Delivery of BMP-IOH-NPs to the lungs of AAI mice was monitored by in vivo optical imaging and by fluorescence microscopy.Results: Uptake of BMP-IOH-NPs by MH-S cells was observed during the first 10 min of incubation, with the NP load increasing over time. The anti-inflammatory effect of BMP-IOH-NPs in vitro was dose dependent and higher than that of Dexa or free BMP, confirming efficient release of the drug. In vivo, Zymosan-A-induced paw inflammation was significantly reduced in mice treated with BMP-IOH-NPs. AAI mice that received BMP-IOH-NPs or Dexa but not BMP revealed significantly decreased eosinophil numbers in BALs and reduced immune cell infiltration in lungs. Correspondingly, lung function parameters, which were strongly affected in non-treated AAI mice, were unaffected in AAI mice treated with BMP-IOH-NPs and resembled those of healthy animals. Accumulation of BMP-IOH-NPs within the lungs of AAI mice was detectable by optical imaging for at least 4 h in vivo, where they were preferentially taken up by peribronchial and alveolar M2 macrophages.Conclusion: Our results show that BMP-IOH-NPs can effectively be applied in therapy of inflammatory diseases with at least equal efficacy as the gold standard Dexa, while their delivery can be simultaneously tracked in vivo by fluorescence imaging. BMP-IOH-NPs thus have the potential to reach clinical applications.

Controlling protein interactions in blood for effective liver immunosuppressive therapy by silica nanocapsules

“…5 Water-soluble polymers and nanoparticles have been used as drug carriers for increasing the solubility of hydrophobic drugs. 10 Because large quantities of nanoparticles translocate to the liver by passive targeting upon parenteral administration, [11][12][13] nanocarriermediated drug delivery represents a promising strategy for combatting liver diseases. 14 There are two main strategies for the controlled delivery of DXM.…”

“…Alternatively, DXM compounds can be directly loaded in nanoparticles. A variety of nanoparticles prepared from biodegradable polymers such as PLGA, [28][29][30][31][32][33][34][35][36][37] PLLA, 38 PCL, 38 cellulose, 39 cyclodextrin, 40 chitosan, 41 polyglutamic acid, 42 or lipids 43 and inorganic materials, 10,44 as well as polymer micelles, 45 liposomes, [46][47][48][49] and carbon nanotubes 50 have been used to transport DXM. Entrapment of DXM in nanoparticles led usually to a prolonged and sustained release of DXM.…”

“…Entrapment of DXM in nanoparticles led usually to a prolonged and sustained release of DXM. 10,[30][31][32][33][34][35][36][37][38][39][40]44,50 Nevertheless, premature release of DXM before reaching the targeting tissues is still an issue. In order to minimize side effects due to leakage of drug and increase its bioavailability, an efficient encapsulation and a selective release drug delivery system are needed.…”

“…Furthermore, most of the DXM nano-formulations were developed for topical therapies, e.g. the treatment of ophthalmic, 30,42,45,51 dermal, 10,39 respiratory, 32,52 bowel, 43,53 brain, 36,41 and joint diseases 18,24,28,29,[54][55][56] by local administration. In this case, the nanoencapsulation is mainly used for increasing local concentration of drugs and controlling their release kinetics.…”

Recent Progress of Nanomedicine in the Treatment of Central Nervous System Diseases

“…As the research has progressed, a number of NPs have been successfully introduced into routine clinical application. Most of them are simple formulations based on clinically approved materials in order to improve the rate and specificity of current therapeutics …”