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Nanoparticles to Treat Macrophages
Nanoparticles are nanomaterials with three external nanoscale dimensions and an average size ranging from 1 to 1000 nm. Nanoparticles have gained notoriety in technological advances due to their tunable physical, chemical, and biological characteristics. However, the administration of functionalized nanoparticles to living beings is still challenging due to the rapid detection and blood and tissue clearance by the mononuclear phagocytic system. The major exponent of this system is the macrophage. Regardless the nanomaterial composition, macrophages can detect and incorporate foreign bodies by phagocytosis. Therefore, the simplest explanation is that any injected nanoparticle will be probably taken up by macrophages. This explains, in part, the natural accumulation of most nanoparticles in the spleen, lymph nodes, and liver (the main organs of the mononuclear phagocytic system). For this reason, recent investigations are devoted to design nanoparticles for specific macrophage targeting in diseased tissues. The aim of this review is to describe current strategies for the design of nanoparticles to target macrophages and to modulate their immunological function involved in different diseases with special emphasis on chronic inflammation, tissue regeneration, and cancer.
Macrophages are plastic cells from the innate immune system that play different roles in the development, homeostasis, tissue repair, and immune response . The local tissue microenvironment determines the macrophage polarization phenotype, M1-like or M2-like, in such a way that populations of both subsets can be found simultaneously coexisting in the same tissue. Macrophages are classically activated into the pro-inflammatory M1 phenotype in response to inflammatory stimuli such as lipopolysaccharides (LPS) or interferon-γ (IFN-γ). On the other hand, interleukin-4 (IL-4) and IL-13 alternatively activate the macrophage polarization to an anti-inflammatory M2 phenotype . Polarized macrophages can be also reprogrammed by the combination of different agents promoting a phenotype reversion .
Damaged cells release specific molecules known as damage-associated molecular patterns (DAMPs) that activate the immune system in an analogous manner to pathogen-associated molecular patterns (PAMPs), small molecular motifs released from bacteria or viruses . These endogenous molecules display physiological functions in cells, but are recognized as danger signals when released into the extracellular space leading to downstream inflammation. Therefore, tissue-specific macrophage subpopulations detect signals that are not found in healthy tissues following infection or injury and recruit monocytes that differentiate into macrophages . DAMPs, PAMPS, or IFN-γ secreted by lymphocytes induce the pro-inflammatory M1 macrophage phenotype . M1 macrophages secrete a variety of pro-inflammatory mediators such as IL-1 and tumour necrosis factor (TNFα) that stimulate inflammation, and IL-12, which activates T helpers 1 (TH1), initiating the adaptive immune response . M1 macrophages also secrete reactive oxygen species (ROS) and nitrogen species that contribute to the elimination of invading organisms. During this process, they also trigger substantial collateral tissue damage to the host. To prevent further tissue damage due to the inflammatory macrophage response, macrophages undergo apoptosis or polarization to an anti-inflammatory and pro-regenerative phenotype that dampens the pro-inflammatory response and facilitates wound healing . IL-4 and IL-13 alternatively activate the macrophage polarization to an anti-inflammatory M2 phenotype . M2 macrophages secrete anti-inflammatory cytokines such as IL-4, IL-13, or IL-10 to dampen the proinflammatory response  and specific and numerous growth factors such as transforming growth factor (TGFβ1) and vascular endothelial growth factors (VEGFs) to promote cell proliferation and angiogenesis . M2 macrophages can also regulate the proliferation and expansion of neighboring parenchymal and stromal cells and the activation of stem cells and local progenitor cell populations that participate in repair .
The inflammatory and anti-inflammatory responses orchestrated by macrophages need to be accurately regulated to prevent disease. Cytokines are the signals that mediate the coordination between immune cells to harmonize the balance between inflammation and tissue repair . Imbalance of M1/M2 macrophage populations is associated with different diseases . Uncontrolled inflammatory response driven by macrophages leads to chronic inflammation and autoimmune diseases . Similarly, the dysregulation of anti-inflammatory response can contribute to tumour progression and metastasis . In addition, prolonged inflammation and continuous activation of macrophages results in chronic diseases that may lead to the development of pathological fibrosis. In some diseases, extensive fibrosis can ultimately lead to organ failure and death .
Different types of biomaterials such as nanoparticles (NPs) and hydrogels are being extensively developed to target macrophages. Since macrophages are professional phagocytic cells, NPs can be exploited as vehicles that naturally target macrophages. These immune cells can easily incorporate NPs via phagocytosis, macropinocytosis, or receptor-mediated endocytosis . Some types of NPs can interact with macrophages to directly modify their biological functions . In addition, NPs can be used as drug delivery systems to treat macrophages involved in different diseases . Several therapeutic options using functionalized NPs are being explored and developed to modulate macrophages.
This review summarizes the use of NPs to modulate macrophages involved in the initiation and progress of different diseases. We will particularly focus on NPs to target and treat macrophages involved in diseases characterized by chronic inflammation and in tumor-associated macrophages (TAMs).
2. Nanoparticles to Modulate Macrophages in Chronic Inflammation
The persistence of the harmful agent and the propagation of the inflammatory response leads to the imbalance between inflammatory and anti-inflammatory signals. In this scenario, macrophages are potential targets to treat inflammatory disorders such as rheumatoid arthritis, atherosclerosis, and inflammatory bowel disease. Drug-loaded NPs can be used to modulate the immunological activity of the pro-inflammatory M1 macrophages or to switch their phenotype from M1 to M2 . These therapeutic strategies are designed to shift the dynamic balance from pro- to anti-inflammatory signals to mitigate the pathological process .
2.1. NPs Modulating Macrophages in Rheumatoid Arthritis
2.2. NPs Modulating Macrophages in Inflammatory Bowel Disease (IBD)
Inflammatory bowel disease (IBD) is characterized by chronic inflammation of the gastrointestinal (GI) tract. There are two types of IBD: Crohn disease (CD) and ulcerative colitis (UC) . Macrophages are an important source of proinflammatory cytokines (such as TNFα) that play an important role on the pathogenesis of IBD. TNFα has become an attractive target for IBD therapy using NPs. Most studies have investigated the use of different NPs containing TNFα siRNA as an interesting therapeutic strategy. Xiao and colleagues have used mannosylated NPs as delivery vehicles for TNFα siRNA . TNFα siRNA demonstrated an effective activity to drastically reduce the TNFα expression and promoted anti-inflammatory effects in vitro and ex vivo leading to colitis attenuation in a dextran sodium sulfate (DSS)-induced colitis mouse model . Similar results were obtained by H. Laroui and colleagues. They designed NPs with a Fab’ portion of the F4/80 antibody against murine macrophages, which also contained TNFα-siRNA showing high efficiency in the attenuation of colitis . Wilson and colleagues have also encapsulated TNFα siRNA in NPs, but they have designed stimulus-responsive NPs. They have developed thioketal NPs (TKNs) that are reactive to high concentration of ROS . Other strategies have combined the delivery of TNFα siRNA with siRNA against Cyclin D1 . Kriegel and Amiji have used NPs in microsphere oral systems for dual siRNA (TNFα and Cyclin D1) delivery . This dual treatment has shown to be more effective than each agent separately for treating IBD in a DSS-induced mouse model.
2.3. NPs Modulating Macrophages in Atherosclerosis
3. Nanoparticles to Stimulate Tissue Repair and Regeneration
M2 macrophages are actively involved in tissue repair and wound healing. For this reason, many investigations nowadays are dedicated to design NPs to stimulate the M2 macrophage phenotype for tissue or organ regeneration .
3.1. NPs Modulating Macrophages in Myocardial Infarct Repair
Myocardial infarction (MI) is the result of partial or complete coronary artery occlusion that leads to blood flow reduction . The appropriate myocardial healing is guided by macrophages . For this reason, numerous NPs have been developed to target macrophages and achieve myocardial infarct repair.
3.2. NPs Modulating Macrophages in Chronic Liver Injury
4. Nanoparticles to Target and Treat Tumour-Associated Macrophages
4.1. Specific Differential Phenotype of Tumour-Associated Macrophages
4.2. NPs to Target TAM for Cancer Diagnostics and Prognosis
4.3. NPs to Inhibit Macrophage Recruitment and to Deplete TAM in Tumors
4.4. NPs to Block the Macrophage “Do Not Eat Me” Signal
4.5. NPs to Switch TAM to an Antitumor “M1-Like” Phenotype
5. Nanocomposite Hydrogels to Modulate Macrophages
The entry is from 10.3390/pharmaceutics13091340
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