Self-assembled polymeric micelles for combined delivery of anti-inflammatory gene and drug to the lungs by inhalation

Abstract

Acute lung injury (ALI) is a lung inflammatory disease for which pulmonary delivery of drug and gene could be a useful strategy. In this study, cholesterol-conjugated polyamidoamine (PAM-Chol) was synthesized and characterized as a carrier for combined delivery of anti-inflammatory gene and drug into the lungs by inhalation. The PAM-Chol formed self-assembled micelles in an aqueous solution with a critical micelle concentration of 0.22 mg ml-1. An in vitro transfection assay to L2 lung epithelial cells showed that the PAM-Chol micelle had higher transfection efficiency than lipofectamine and polyethylenimine (25 kDa, PEI25k). As the anti-inflammatory drug, resveratrol was loaded into the cores of the PAM-Chol micelles using the oil-in-water emulsion/solvent evaporation method. In lipopolysaccharide (LPS)-activated macrophage cells, resveratrol-loaded PAM-Chol (PAM-Chol/Res) reduced pro-inflammatory cytokines, confirming the anti-inflammatory effects of resveratrol. In in vitro transfection assays to L2 cells, the PAM-Chol/Res micelles had transfection efficiency similar to that of PAM-Chol. The delivery of resveratrol or the heme oxygenase-1 gene (pHO-1) by inhalation was evaluated in an ALI animal model. Resveratrol delivery using the PAM-Chol/Res micelles inhibited the nuclear translocation of nuclear factor-κB (NF-κB) and reduced pro-inflammatory cytokines in the lungs. pHO-1 delivery using PAM-Chol induced HO-1 expression and reduced pro-inflammatory cytokines. However, the highest anti-inflammatory effects were obtained with combined delivery of pHO-1 and resveratrol using the pHO-1/PAM-Chol/Res complex, as demonstrated in cytokine assays and immunohistochemical studies. Therefore, the PAM-Chol micelle is an efficient carrier of resveratrol and pHO-1 into the lungs and could be useful for the treatment of ALI by inhalation.

Nanoformulations to Enhance the Bioavailability and Physiological Functions of Polyphenols

“…In another study, resveratrol was loaded into cholesterol-polyamide micelles by solvent evaporation. The micelles reduced the production of pro-inflammatory factors in the lungs by the inhibiting nuclear transposition of NF-κB, demonstrating the anti-inflammatory effect of resveratrol ( Figure 9 ) [ 269 ]. Washington et al [ 270 ] used poly(ethylene glycol)-b-poly(ε-caprolactone) (PEG-b-PCL) and poly(ethylene glycol)-b-poly(γ-benzyl-ε-caprolactone) (PEG-b-PBCL) amphiphilic copolymer micelles loaded with doxorubicin and resveratrol.…”

“…The heme oxygenase-1 gene (pHO-1). Adapted from reference [ 269 ]. Copyright 2018 Royal Society of Chemistry.…”

Novel drug delivery systems and significance in respiratory diseases

“…Several micellar systems are being evaluated for their potential in pulmonary drug delivery. The study by Kim et al [48] presented the formulation and characterization of coencapsulated antiinflammatory drug resveratrol and gene into cholesterol-conjugated polyamidoamine (Chol-PAM)-based polymeric micelles. Resveratrol-loaded Chol-PAM micelles exhibited antiinflammatory effects in the in vitro evaluations.…”

Poly(Ethylene Glycol) Crosslinked Multi-Armed Poly(l-Lysine) with Encapsulating Capacity and Antimicrobial Activity for the Potential Treatment of Infection-Involved Multifactorial Diseases

“…In the past decades, nanotechnology has been well developed to construct drug delivery systems, including but not limited to micelles, liposomes, and nanoparticles [1][2][3][4][5][6][7][8][9][10]. Compared with conventional formulations, these nanoscaled drug delivery systems (DDS) exhibit great potential in improving drug stability, preventing premature drug release, altering drug distribution, and prolonging the half-life of drugs [11].…”

“…Compared with conventional formulations, these nanoscaled drug delivery systems (DDS) exhibit great potential in improving drug stability, preventing premature drug release, altering drug distribution, and prolonging the half-life of drugs [11]. Therefore, they are widely applied in the delivery of a great variety of drugs including anticancer drugs [1,2], antimicrobial agents [3,4], and anti-inflammatory drugs [5,6], among others.…”