Bioresponsive drug delivery systems for the treatment of inflammatory diseases

Abstract

Inflammation is intimately related to the pathogenesis of numerous acute and chronic diseases like cardiovascular disease, inflammatory bowel disease, rheumatoid arthritis, and neurodegenerative diseases. Therefore anti-inflammatory therapy is a very promising strategy for the prevention and treatment of these inflammatory diseases. To overcome the shortcomings of existing anti-inflammatory agents and their traditional formulations, such as nonspecific tissue distribution and uncontrolled drug release, bioresponsive drug delivery systems have received much attention in recent years. In this review, we first provide a brief introduction of the pathogenesis of inflammation, with an emphasis on representative inflammatory cells and mediators in inflammatory microenvironments that serve as pathological fundamentals for rational design of bioresponsive carriers. Then we discuss different materials and delivery systems responsive to inflammation-associated biochemical signals, such as pH, reactive oxygen species, and specific enzymes. Also, applications of various bioresponsive drug delivery systems in the treatment of typical acute and chronic inflammatory diseases are described. Finally, crucial challenges in the future development and clinical translation of bioresponsive anti-inflammatory drug delivery systems are highlighted.

Keywords: Bioresponsive materials; Drug delivery; Hydrogels; Inflammatory diseases; Microparticles; Nanoparticles; Reactive oxygen species.

Graphical abstract

Fig. 1

Inflammation and inflammatory microenvironments. C3a, complement 3a; C5a, complement 5a; CCR, CC-chemokine receptor; CXCR2, CXC-chemokine receptor 2; MCP-1, monocyte chemotactic protein-1; Ox-LDL, oxidized low-density lipoprotein.

Fig. 2

Typical pathological features in inflammatory tissues. (A) Acidosis. (B) Overproduced ROS. ER, endoplasmic reticulum; GLUT, glucose transporter; MCT4, monocarboxylate transport 4; Mito-ETC, mitochondrion-electron transport chain; NOX, NADPH oxidase; NOS, nitric oxide synthetase; OXPHOS, oxidative phosphorylation; SOD1, superoxide dismutase 1; SOD2, superoxide dismutase 2; SOD3, superoxide dismutase 3; TCA, tricarboxylic acid.

Fig. 3

Enzyme-responsive nanoparticles for targeted accumulation and prolonged retention in heart tissue after myocardial infarction (MI). (A) Diagram of a dye-labeled brush peptide-polymer amphiphile (PPA) containing an MMP-2 and MMP-9 specific recognition sequence, shown underlined. PPAs self-assemble into nanoparticles through hydrophobic-hydrophilic interactions when dialyzed into aqueous buffer. (B) Schematic of nanoparticles freely circulating in the bloodstream upon systemic delivery. Nanoparticles enter the infarct tissue through the leaky acute MI vasculature, and up-regulated MMPs within the infarct induce the formation of an aggregate-like scaffold. (C) Responsive nanoparticles are monodisperse micelles with diameters of 15–20 nm. (D) Formation of an aggregate-like scaffold upon activation of responsive nanoparticles. (E) A corresponding image of nanoparticle solutions following activation. (F-H) Retention of responsive nanoparticles upon localized delivery. Particles were injected intramyocardially at day 7 post-MI and assessed at day 6 postinjection. (F) H&E image displays the infarct area. (G) The neighboring fluorescent section. Particles are shown in red and myocardium is shown in green. (H) A selected region from (G) (white outline) was magnified to highlight particle aggregation. Scale bars in (F-H), 100 μm. Reproduced with permission [288]. Copyright 2015, Wiley-VCH.

Fig. 4

Schematic representations of MMP-responsive hydrogel preparation and the process of drug release in the wound bed of MI model rats. (A) Preparation of GST-TIMP-bFGF via a recombinant protein expression method. (B) GSH was loaded into the hydrogel by a chemical crosslinking process to obtain Gel-GSH. (C) GST-TIMP-bFGF was mixed with Gel-GSH, and the two components were linked with a bond between GST and GSH. (D) Intramyocardial injection of the mixed hydrogel to the wound of a rat after MI. (E) In the wound microenvironment, substrate peptides were degraded by MMP-2/9, and specific targeting peptides were released, achieving the dual functions of angiogenesis and MMP inhibition. Reproduced with permission [266]. Copyright 2019, Wiley-VCH.

Fig. 5

Design and preparation of broad-spectrum ROS-scavenging nanoparticles for treatment of acute lung injury (ALI). (A) Schematic illustration of engineering of a broad-spectrum ROS-scavenging material and corresponding nanoparticles. (B) The synthetic route of β-CD conjugated with Tempol (Tpl) and PBAP units (TPCD). (C–F) Comparison of scavenging capabilities of different materials for radical, superoxide anion, H₂O₂, and hypochlorite. (G) SEM image of TPCD NP prepared by nanoprecipitation using methanol as the solvent. (H-I) H&E-stained pathological sections of lung tissues (H) and liver tissues (I) resected from mice subjected to different treatments. Reproduced with permission [298]. Copyright 2018, Wiley-VCH.

Fig. 6

A proresolving peptide nanotherapy for site-specific treatment of inflammatory bowel disease. (A-B) Schematic illustration of engineering of a ROS-responsive peptide nanotherapy (AON) (A) and targeted treatment of colitis (B). (C-E) TEM (C) and SEM (D) images as well as size distribution (E) of AON. Scale bars, 200 nm. (F) In vitro release profiles of Ac2-26 nanotherapies AON and APN in 0.01 M PBS at pH 7.4 with or without 1.0 mM H₂O₂. (G) Ac2-26 release in buffers simulating the gastrointestinal pH conditions. (H) Selective accumulation of AON in the inflamed colons of mice with acute colitis. (I-J) Representative digital photos (I) and quantified lengths (J) of colonic tissues isolated from mice after 7 days of treatment. Scale bars, 5 mm. (K) H&E-stained histological sections of colonic tissues. AON, Ac2-26-loaded OxbCD nanoparticles; APN, Ac2-26-loaded PLGA nanoparticles; ON, the blank OxbCD nanoparticles. *p < 0.05, **p < 0.01, ***p < 0.001. Reproduced with permission [321]. Copyright 2019, Wiley-VCH.

Fig. 7

Inflammation-responsive nanotherapies for targeted treatment of atherosclerosis and restenosis. (A) Design of inflammation-triggerable nanoparticles. (B) Representative ex vivo fluorescence images showing retention of Cy7.5/Ac-bCD NP at the injured site of the carotid artery in rats after intravenous injection. (C) H&E stained histological sections of carotid arteries isolated from rats subjected to various treatments. Scale bars, 200 μm (the upper panel), 50 μm (the lower panel). Reproduced with permission [111]. Copyright 2016, Elsevier. (D) Representative ex vivo fluorescence images illustrating accumulation of Cy5 fluorescent signals in the aorta of ApoE^-/- mice at 24 h after intraperitoneal injection of saline, free Cy5, or Cy5/Ac-bCD NP. (E) Representative photographs of en face ORO-stained aortas from each group. (F) Quantitative analysis of the lesion area. **p < 0.01, ***p < 0.001. Reproduced with permission [182]. Copyright 2017, Elsevier. RAP, rapamycin; PLGA, poly(lactide-co-glycolide); Ac-bCD, acetalated β-cyclodextrin; Ox-bCD, oxidation-responsive β-cyclodextrin.

Fig. 8

A targeting nanotherapy for abdominal aortic aneurysms. (A) Schematic (left), TEM image (middle), and size distribution (right) of ROR NP. (B) Ex vivo images (left) and histograms (right) showing accumulated ROCy7.5 NP or OCy7.5 NP in aneurysmal aortas. **p < 0.01, ***p < 0.001. (C) Immunofluorescence analysis of localized ROCy5 NP in aneurysms. Scale bars, 20 μm. (D) H&E, Alizarin Red, or VVG stained histological sections of aneurysmal aortas. (E) Immunohistochemistry analyses of aneurysmal aortas. OR NP, RAP-containing OxbCD nanotherapy; ROR NP, a ROS-responsive, cRGDfK targeting RAP nanotherapy; OCy5 NP, Cy5-labeled OxbCD nanoparticles; ROCy5 NP, Cy5-labeled OxbCD nanoparticles with cRGDfK decoration; OCy7.5 NP, Cy7.5-labeled OxbCD nanoparticles; ROCy7.5 NP, Cy7.5-labeled OxbCD nanoparticles decorated with cRGDfK. Reproduced with permission [329]. Copyright 2018, Elsevier.

Fig. 9

pH-Responsive nanotherapies for targeted treatment of rheumatoid arthritis (RA). (A) Schematic of assembly of pH-sensitive polymeric prodrug micelles for RA. Reproduced with permission [188]. Copyright 2018, Elsevier. (B) Schematic illustration of GDR-improved anti-inflammatory effect of TPT in a mouse model of CIA. GDR improves anti-inflammatory effect of TPT through several mechanisms: (1) GDR itself had anti-inflammatory property via RAR signaling; (2) GDR-mediated macrophage-targeted TPT delivery; (3) pH-sensitive nanoparticle GDR allowed the release of TPT at the intracellular regions of inflamed site, thereby enhancing anti-arthritic effect and improving safety profile of TPT. GDR, all-trans-retinal-dextran conjugate grafted with galactose; RAR, retinoic acid receptor; TPT, triptolide. Reproduced with permission [192]. Copyright 2020, Elsevier.

Fig. 10

A ROS-responsive polymeric micelle system for targeted treatment of Alzheimer’s Disease. (A) The mechanism of ROS-induced self-immolative degradation. (B) Illustration of microglia-induced AD microenvironment and mechanisms of APLB/CUR modulation: 1) Ab peptide modified micelles mimic Aβ transportation from peripheral into brain parenchyma; 2) ROS-responsive release of ROS scavenging polymer and Aβ inhibitive curcumin; and 3) Aβ-mimicked micelle targeting to activated microglia and damaged neurons. Reproduced with permission [342]. Copyright 2019, Wiley-VCH.