pH-Responsive Nanoparticles Targeted to Lungs for Improved Therapy of Acute Lung Inflammation/Injury

Abstract

Dysregulated vascular inflammation is the underlying of acute lung inflammation/injury (ALI). Bacterial infections and trauma cause ALI that may rapidly lead to acute respiratory distress syndrome (ARDS). There are no pharmacological therapies available to patients with ALI/ARDS, partially as drugs cannot specifically target the lungs. Herein, we developed a stimuli-responsive nanoparticle to target inflammatory lungs for ALI therapies. The nanoparticle is comprised of a sharp acid-sensitive segment poly(β-amino esters) (PAE) as a core for drug loading and controlled release, and a polyethylene glycol (PEG)-biotin on the particle surface available for bioconjugation enabling lung targeting and extended circulation. The studies on dissipative particle dynamics (DPD) simulation and characteristics of nanoparticles (NPs) suggest that anti-ICAM-1 antibodies can be coated to the particle surface and this coating is required to enhance lung targeting of NPs. A model drug of anti-inflammatory agent TPCA-1 is encapsulated in NPs with high drug loading content at 24 % (w/w). In the mouse ALI model, our TPCA-1-loaded NPs coated with anti-ICAM-1 can target inflamed lungs after intravenous injection, followed by drug release triggered by acid environment, thus mitigating lung inflammation and injury. Our studies reveal the rational design of nanotherapeutics for improved therapy of ALI and it may be applied to treating a wide range of vascular inflammation.

<p>Mitochondria-Modulating Porous Se@SiO₂ Nanoparticles Provide Resistance to Oxidative Injury in Airway Epithelial Cells: Implications for Acute Lung Injury</p>

“…48,49,50,51 Zhang et al prepared an anti-ICAM-1 antibodies-coated stimuliresponsive NP encapsulated with 2-[(Aminocarbonyl) amino]-5-(4-fluorophenyl)-3-thiophenecarboxamide (TPCA-1)] with the ability to target inflammatory endothelia and inhibit neutrophil transmigration, thus restraining the progression of ALI. 48 Recently, another antiinflammatory nanomaterial, the peptide-gold nanoparticle hybrid (P12), has been exploited to specifically target innate immune cells, regulate Toll-like receptor (TLR) signaling and attenuate lung inflammatory responses. 49,51 Current nano-based therapies for ALI mainly aimed to inhibit the activation of inflammatory pathways, such as NF-κB and TLR signal transduction.…”

Co-delivery of resolvin D1 and antibiotics with nanovesicles to lungs resolves inflammation and clears bacteria in mice

“…Infectious microenvironments include pathogens and inflammatory tissues 15,16 . For example, lung infection is a bacterial invasion via the airway.…”

Bioresponsive drug delivery systems for the treatment of inflammatory diseases

“…Considering acidosis and increased expression of lipase and alkaline phosphatase in bacterial-induced ALI [ 299 ], [ 300 ], Wang et al developed pH-responsive nanoparticles for target therapy of ALI [ 301 , 302 ]. To this end, infectious microenvironment-targeting and bioresponsive nanoparticles were assembled using a pH and enzymes multiple-responsive amphiphilic block copolymer consisting of biotinylated PEG-b-poly(β-amino ester)-b-PEG grafted with PEGylated lipid, which were subjected to surface modification with intercellular adhesion molecule-1 (ICAM-1) antibody [ 302 ].…”

“…treatment with the bioresponsive nanotherapy simultaneously eliminated bacteria and alleviated the host inflammatory response, as indicated by the significantly decreased levels of infiltrating leukocytes and proinflammatory cytokines (such as TNF-α, IL-1β, and IL-6) in infected lungs, and therefore it can be further developed as a mechanism-based nanotherapy for infectious diseases. In a most recent study, the same group prepared a nanotherapy assembled by an amphiphilic copolymer of poly(β-amino esters) and PEG, loading an anti-inflammatory agent TPCA-1 in the pH-sensitive core [ 301 ]. Additional decoration using anti-ICAM-1 antibody was carried out for this TPCA-1 nanotherapy to enhance lung targeting capability.…”