Applying nanomedicine in maladaptive inflammation and angiogenesis

Abstract

Inflammation and angiogenesis drive the development and progression of multiple devastating diseases such as atherosclerosis, cancer, rheumatoid arthritis, and inflammatory bowel disease. Though these diseases have very different phenotypic consequences, they possess several common pathophysiological features in which monocyte recruitment, macrophage polarization, and enhanced vascular permeability play critical roles. Thus, developing rational targeting strategies tailored to the different stages of the journey of monocytes, from bone marrow to local lesions, and their extravasation from the vasculature in diseased tissues will advance nanomedicine. The integration of in vivo imaging uniquely allows studying nanoparticle kinetics, accumulation, clearance, and biological activity, at levels ranging from subcellular to an entire organism, and will shed light on the fate of intravenously administered nanomedicines. We anticipate that convergence of nanomedicines, biomedical engineering, and life sciences will help to advance clinically relevant therapeutics and diagnostic agents for patients with chronic inflammatory diseases.

Keywords: Angiogenesis; Atherosclerosis; Cancer; Chronic inflammation; Immunomodulation; Macrophages; Molecular imaging; Monocytes; Nanomedicine; Targeted drug delivery.

Fig. 1. Applying nanomedicine along the journey of monocytes in inflammatory disorders

(A) Several processes that contribute to monocyte/macrophage dynamics in maladaptive inflammation and angiogenesis can be exploited for imaging and therapeutic purposes at the systems level. In A (i) and (ii), tackling hematopoietic stem cell (HSC) proliferation and monocyte migration from the bone marrow and spleen by nanomedicines can be an upstream approach to control inflammation. In A (iii), trafficking of inflammatory monocytes in the circulation and their adhesion to activated endothelial cells can be exploited for cell-mediated therapies and diagnosis. A (iv) Applying nanomedicines at the lesion level can be realized by tackling the enhanced vascular permeability, local macrophage proliferation and activity, and the secretion of proteases or cytokines. Examples of nanomedicines targeting (B) the spleen, (C) tumor-associated macrophages, (D) monocyte migration, and (E) other diseased tissues. Graphs and images in B_i and B_ii are adapted, with permission, from [135]. PET/CT in C_i and histological images in C_ii are reproduced, with permission, from[136]. MRI images in D_i were adapted, with permission, from [137] while histological images in D_ii are adapted, with permission, from [138] (left) and [139] (right). Scintigraphic images of rabbits in E_i and E_ii are reproduced, with permission, from [140] and [141], respectively. MI: myocardial infarction, RA: rheumatoid arthritis, TAM: tumor-associated macrophages.

Fig. 2. Bone marrow activation

Inflammatory disorders are characterized by elevated levels of circulating cytokines, growth factors, and damage-associated molecules. The stress and pain associated with the disease increase sympathetic nervous activity. Both biochemical and neuronal changes increase proliferation and migration of both HSCs and inflammatory monocytes (Ly6C^hi) from bone marrow niches. (A) Nanomedicine can be used to target different features of bone marrow activation, including (i) circulating bone marrow activators, (ii) bone marrow permeability, (iii) HSC proliferation, and (iv) monocyte egress. Combining nanomedicines with molecular imaging at the medullar level can advance our understanding of disease progress. For example, (B) ischemic stroke increases the sympathetic nervous activity, which regulates the proliferation and cell cycle of HSCs, as shown by immunofluorescence staining of tyrosine hydroxylase rich nerve fibers of the sternal bone marrow. (C) Myocardial infarction (MI) increases HSC proliferation in the bone marrow, a process that can be quantified by BrdU staining, and imaged by ¹⁸F-FLT positron emission tomography/computed tomography (PET/CT). Panel B is modified, with permission, from[169]. Panel C is modified, with permission, from [170]. TLR: toll-like receptor, CCL-2: C-C motif chemokine 2, VEGF: vascular endothelial growth factor, GM-CSF: granulocyte-macrophage colony-stimulating factor, HSC: hematopoietic stem cell, MDP: monocyte and dendritic cell progenitor, SUV: standardized uptake value, BrdU: bromodeoxyuridine.

Fig. 3. Monocyte mobilization and recruitment

(A) In response to inflammation, the spleen, in addition to the bone marrow, overproduces monocytes that enter the circulation. The inflammatory monocytes are guided by a gradient of chemokines in their journey to the inflamed lesions. The adhesion and the preferential accumulation of monocytes in lesions are driven by overexpression of certain receptors by the inflamed endothelium, including vascular cell adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1). Nanomedicines can be exploited for imaging and therapeutic purposes at different stages of the monocyte journey in the circulation, starting from (i) monocyte egress from bone marrow, (ii) monocyte production and release from the spleen, (iii) monocyte trafficking in the blood stream, (iv) adhesion of monocytes to the inflamed endothelium, and (v) monocyte accumulation in the lesions. (B) Ischemic myocardial injury induces rapid deployment of splenic monocytes, which can be imaged by intravital microscopy of green fluorescent protein (GFP⁺) monocytes. (C) The preferential uptake of nanoparticles by Ly6C^hi monocytes allows studying both monocyte and nanoparticle trafficking in the circulation using intravital microscopy. (D) Labeling monocytes with a radiotracer (e.g. [¹¹¹Indium] oxyquinoline, ¹¹¹In-oxine) enables noninvasive tracking and visualization of monocyte accumulation in atherosclerotic plaques and other inflammatory lesions using single photon emission/computed tomography (SPECT/CT). Panel B is adapted, with permission, from [175]. Panel C is reproduced, with permission, from[179]. Panel D is adapted, with permission, from[180].

Fig. 4. Enhanced microvascular permeability and local inflammation

(A) Inflammatory monocytes accumulate in inflamed lesions and differentiate into tissue-resident macrophages. A cascade of events ensues such as local macrophage proliferation, the release of proinflammatory cytokines, proteases and cellular vesicles, which can aggravate the inflammatory condition and recruit more inflammatory cells. In addition, the release of vascular endothelial growth factors and other cytokines induce angiogenesis and increase microvascular permeability to macromolecules. Diagnostic and therapeutic nanoparticles can be used to tackle (i) pathological angiogenesis and enhanced permeability, (ii) local cell proliferation, (iii) monocyte differentiation, (iv) cytokine and chemokine release (v) and monocyte infiltration. (B) Cancer-associated angiogenesis and response to anti-angiogenic therapies can be monitored in vivo using optical frequency domain imaging. (C) Anti-inflammatory effect of prednisolone phosphate (PLP) liposomes in rheumatoid arthritis can be noninvasively assessed by ¹⁸F-FDG PET/CT. (D) Protease activity in response to simvastatin rHDL nanoparticles can be monitored in vivo using fluorescence molecular tomography/computed tomography (FMT/CT). Panel B is adapted, with permission, from[211]. Panel C is reproduced, with permission, from[212]. Panel D is adapted, with permission, from[213].

Fig. 5. Considerations for applying and developing nanomedicines for chronic inflammatory diseases

Chronic inflammatory diseases are multifactorial disorders in which genetic background and environmental factors interact and affect different dynamic systems, including genes, signaling pathways, cells, and organs. Nanomedicine should be approached in a holistic way, in which nanodrugs’ systemic interactions are investigated, and can be used to visualize and/or modulate multiple processes. Data acquisition and convergence of nanomedicine with the different biomedical fields and big data (e.g. transcriptomics, proteomics, and genomics) can not only contribute to deciphering these complex diseases but also help to predict the efficacy of nanomedicines and to develop clinically relevant products.