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  • Review Article
  • OPEN ACCESS

Delivery System for Targeted Drug Therapy in Chronic Diseases

  • Yuan-Qi Jiang1,2,
  • Jin-Peng Chen2,3,4,
  • Yu-Jie Dong1,2,
  • Fu-Jun Zhou2,3,4,
  • Cheng-Wang Tian2,3,4,*  and
  • Chang-Qing Chen2,3,4,* 
 Author information  Cite
Journal of Exploratory Research in Pharmacology   2022;7(2):112-122

doi: 10.14218/JERP.2021.00052

Abstract

Chronic diseases affect many people and have become the leading cause of death and loss of health worldwide. The etiology of chronic diseases is complex. They are usually incurable and require continual medical management. Many chronic diseases deteriorate with time, resulting in an enormous burden on society and patients’ families. During the past years, targeted agents have made improved the management of various chronic diseases. An optimal drug delivery system can improve the therapeutic efficacy of these targeted drugs and reduce systemic adverse effects, bringing benefits to patients with chronic diseases. Here, we highlight recent research progress in the development of targeted therapeutic drugs for chronic diseases and improved delivery systems.

Keywords

Chronic diseases, Targeted drug delivery system, Nano preparation, Targeted therapy

Introduction

Chronic diseases, also known as chronic non-communicable diseases, have complex causes. They are usually incurable, require continual medical management, and often deteriorate with time.1 In recent years, chronic diseases have contributed to 73.4% of all deaths globally, and thus form a substantial medical and economic burden to society. According to data released by the Chinese Resident Nutrition and Chronic Disease Report in December 2020, chronic diseases caused 88.5% of total deaths in China in 2019.2 These data demonstrate that chronic diseases have become the primary threat to human health.

Targeted drug delivery systems can concentrate the active ingredient of a medicine at the site of a lesion or anatomical target, and keep the drug at an effective concentration in the targeted organ for a longer duration of time enabling patients to be prescribed medicines at a lower dose.3 Targeted therapy is a treatment approach that aims to deliver the therapeutic drug to pathogenic organs or sites of required action at a cellular or molecular level. Targeted therapy can help eliminate and reduce drug-related adverse effects, thus improving safety and helping patients to continue taking their prescribed medicines at the prescribed dose and intended dosing frequency without being dissuaded or impeded from doing so by adverse effects. For these reasons, targeted agents are being widely applied in the field of pharmacy. In the past decade, ground-breaking progress has been made in developing targeted therapies for the treatment of chronic diseases. Here, we review research advances in the development of targeted drugs for chronic diseases and their delivery systems.

The role of targeted therapies in metabolic system diseases

Targeted treatment of type 2 diabetes mellitus

Diabetes is mainly divided into four categories: type 1 diabetes, type 2 diabetes, gestational diabetes mellitus, and other specific types of diabetes. Type 2 diabetes is characterized by low degrees of inflammation, insulin resistance, glucose intolerance and an inadequate compensatory insulin secretory response.4 Glucagon-like peptide 1 (GLP-1) is an insulin stimulating hormone that is secreted by intestinal L-cells in the postprandial period. It promotes insulin release, delays gastric emptying, reduces food intake, and thereby helps maintain blood glucose homeostasis.5 However, GLP-1 is easily degraded by diptopeptidase IV (DPP-IV) in vivo, and has a short half-life of about two minutes.6 At present, two types of anti-diabetes drugs targeting GLP-1 receptor (GLP-1R) signaling have been developed, namely, GLP-1R agonists and DPP-IV inhibitors. GLP-1R agonists bind to GLP-1R, acting in a similar manner to GLP-1. Exenatide was the first GLP-1R agonist approved for the treatment of type 2 diabetes, and has been widely used in the clinic. Other GLP-1R agonists includelixisenatide, a short half-life GLP-1R agonist, and the long half-life GLP-1R agonists liraglutide, albiglutide, dulaglutide, and semaglutide. DPP-IV inhibitors increase plasma GLP-1 levels, enhancing insulin secretion. There are currently five approved DPP-IV inhibitors: sitagliptin, vildagliptin, saxagliptin, linagliptin, and alogliptin.7 Targeted therapies based on GLP-1R agonists and DPP-4 inhibitors offer many advantages, including that they:

  • Promote insulin secretion and are associated with reduced risks of hypoglycemia than alternative anti-diabetes medicines such as sulphonylureas.

  • Relieve islet β-cell degradation and delay the deterioration of diabetes.

  • Provide cardiorenal protection.

In addition to GLP-1R agonists and DPP-IV inhibitors, Traditional Chinese Medicine is considered to be effective in the treatment of type 2 diabetes. Some researchers have shown that puerarin, astragalus polysaccharides, and berberine can ameliorate type 2 diabetes, highlighting the potential value of traditional Chinese medicines as anti-diabetic agents.8–10

Targeted treatment of chronic kidney disease

Chronic kidney disease (CKD) is defined as an abnormality of kidney function or structure that lasts for more than three months. It is associated with type 2 diabetes, hypertension, obesity, and age-related degeneration.11 CKD may lead to irreversible renal failure, end-stage renal disease and premature death, and is associated with high rates of incidence and mortality coupled with low rates of awareness.12 In addition, there is currently inadequate implementation of strategies to prevent the development or deterioration of CKD.12 Current therapies for CKD can only delay disease progression, and the cost of treatment can be a substantial economic burden for patients. Therefore, developing new therapies for the treatment of CKD is an area of intense research. Glomerular cells, endothelium cells, podocytes, macrophages, and tubular epithelial cells (TECs) are all involved in the course of CKD, with glomerular cells being particularly affected.13 Gary et al. recently demonstrated that nanoparticles modified with carboxymethyl-terminated poly (20∼200 nm), can deliver drugs to the kidney for treatment of glomerular kidney disease more efficiently, enabling a greater concentration of drug to accumulate in diseased glomeruli.14 Bruni et al. used four-arm star-shaped polymers as raw materials to obtain new drug-loaded ultra-small colloidal nanocarriers with a tunable size of 5–30 nm.15 These drug-loaded ultra-small colloidal nanocarriers can repair podocyte damage and reduce albumin permeability in vitro drug models.15 Tripathy et al. report that kidney-targeted nanoparticle-based transdermal microneedles can target folate receptors on renal epithelial cells in vitro.16

CKD is usually accompanied by renal fibrosis. Celastrol (CEL), a triterpene derived from traditional Chinese medicine, has potent anti-fibrotic activity. However, when administered by common drug delivery mechanisms its use is associated with severe systemic toxicity.17 Li et al. generated a system to deliver CEL specifically to interstitial myofibroblasts that consisted of the pentapeptide Cys-Arg-Glu-Lys-Ala (CREKA) conjugated to PEGylated liposomes (CREKA-Lip), which can specifically bind to fibronectin.18 Systemic administration of CREKA-Lip in mice with unilateral ureteral obstruction led to the accumulation of CREKA-Lip in fibrotic kidneys, effectively alleviating renal fibrosis, injury, and inflammation, with lower toxicity to other major organs than free CEL.18

The role of targeted therapies in chronic respiratory diseases

Targeted treatment of chronic obstructive pulmonary disease (COPD)

COPD is a common severe chronic pulmonary disease that affects over 250 million people around the world, and is the third-leading cause of death in the world.19 COPD, like other respiratory diseases such as acute respiratory distress syndrome, chronic pulmonary fibrosis, and lung cancer is associated with long-term oxidative stress.20 Currently, therapeutic strategies for COPD can only ameliorate symptoms. Targeted therapies could provide new treatment options for patients with COPD, and could form important adjuvant treatments for COPD. New targeted drugs based on the pathogenesis of COPD have been developed, including cytokine inhibitors, chemokine receptor antagonists, phosphodiesterase 4 inhibitors, nuclear factor κB (NF-κB) inhibitors and protease inhibitors.21 Compared with oral administration, lung administration of targeted therapies offers a number of advantages, including a faster absorption rate, a concentrated distribution of metabolic enzymes throughout the lung, and lower rates of degradation of the active ingredient. The manner in which drugs are deposited in the respiratory system is mainly influenced by the diameter of the particles used to deliver the drug (Fig. 1). Studies have found that drug delivery systems that produce a higher proportion of drug particles with a diameter between 1.0 to3.0 µm result in more drug settling in the alveoli and bronchioles, leading to better therapeutic effects.22 New drug delivery systems that could enable this include liposomes, nanoparticles, solid lipid nanoparticles, microspheres and microemulsions (Table 1).23–34

A schematic diagram of particulate deposition in human respiratory system.
Fig. 1  A schematic diagram of particulate deposition in human respiratory system.
Table 1

The potential drugs targeting COPD and their mechanisms

Drug name Method of preparation Size Ref
Liposomal dry powders of N-acetylcysteine (SD-NAC-Lip) Reverse phase evaporation 100 nm23
Budesonide and Colchicine liposomes Thin layer film hydration method 100 nm24
Chitosan or hyaluronan-coated liposomes of curcumin Sonication and stirring 90∼130 nm25
Small Unilamellar Liposomes, Pluronic F127surface modified liposomes and PEG 2000PE-surface modified liposomes of beclomethasone dipropionate Micelle-to-vesicle transition method 40∼65 nm26
Codelivery system using core-shell type lipid-polymer nanoparticles (LPNs) Solvent displacement method 123 ± 31 nm27
PEGylated dextran-coated superparamagnetic iron oxide nanoparticles – 82.7∼133.7 nm28
Chitosan nanoparticles of budesonide Ionotropic gelation technique 363∼543 nm29
Polymeric Nanoparticles of miRNA Oil-in-water single emulsion solvent evaporation method 244.80 ± 4.4 nm30
atRA formulated into solid lipid nanoparticles Emulsification-ultrasonication method 177.3nm ± 29.23 nm31
Mucoadhesive solid lipid microparticles Ethanolic precipitation technique and ultraturrax homogenization 3.5∼4.0 µm32
Chitosan-genipin nanohydrogel Reverse microemulsion method 30∼100 nm33
siRNA-loaded, lipidoid-modified PLGA hybrid nanoparticles Double emulsion solvent evaporation method 200∼260 nm34

atRA, all-trans retinoic acid; COPD, chronic obstructive pulmonary disease; PLGA, poly lactic-co-glycolic acid.

Targeted treatment of bronchial asthma

Bronchial asthma (or asthma for short) is a chronic respiratory inflammatory disease. The main symptoms associated with it are shortness of breath, chest tightness and coughing, often accompanied by hyperventilation. Asthma is also associated with airway remodeling due to smooth muscle cell proliferation. The symptoms of asthma often worsen over time and may lead to respiratory failure during an acute attack.35 In recent years the prevalence of asthma has been increasing, and it is estimated that asthma may affect 400 million people by 2025.36 Asthma may in fact be a collection of different phenotypes rather than a single disease, and can be clinically divided into four broad categories: refractory asthma, environmentally triggered allergic/non-allergic asthma, exercise/aspirin-induced asthma and inflammatory asthma.37 Each of these categories features airway inflammation as a common characteristic, which can be treated with glucocorticoids. Severe asthma is often accompanied by airway mucosal inflammation with neutrophil infiltration, resulting in a poor response to glucocorticoids. Therefore, developing a neutrophil-targeted drug delivery system has become a priority for the treatment of asthma.38 T cells and eosinophils are also important targets for asthma treatment. In recent years, monoclonal antibodies and small molecule chemosynthetic drugs for controlling inflammatory mediators have been the subject of extensive research as targeted therapies for asthma.

Omalizumab is the first targeted agent for the treatment of asthma.39 It is an anti-IgE monoclonal antibody which has typically been used for the treatment of severe allergic asthma. IgE binds to high-affinity receptors and releases a variety of pro-inflammatory mediators, including leukotrienes and interleukins (IL) such as IL-3, IL-4, and IL-5, which promote the aggregation of eosinophils and other inflammatory cells.40 IL-5 plays a crucial role in the development of type 2 hyperreactivity-dominated asthma. Monoclonal antibodies against IL-5 that are utilized as treatments for asthma include mepolizumab, reslizumab and benralizumab. These can significantly reduce the number of eosinophils in the blood, relieve asthma exacerbations and improve lung function.41 Dupilumab, which targets IL-4 and IL-13, is approved by the US Food and Drug Administration (FDA) for use in patients aged 12 years and over as an adjunct therapy for moderate to severe asthma with a corticosteroid-dependent refractory eosinophils (EOS) phenotype.42 Thymic stromal lymphopoietin (TSLP), a member of the IL-2 cytokine family, acts on dendritic cells, mast cells, type 2 innate lymphocytes (ILC2) and eosinophils, promoting the differentiation of Th2 cells and the secretion of Th2 cytokines, such as IL-4, IL-5, and IL-13.43 Prostaglandin D2 receptor 2 (CRTH2) is expressed on TH2 cells, eosinophils, basophils, epithelial cells and ILC2. CRTH2 expression in patients with severe asthma is higher than that in patients with mild to moderate disease or in healthy subjects without asthma, and is associated with the severity of asthma.44 Chen et al.45 have shown that CRTH2 may be involved in the occurrence and development of bronchial asthma by regulating the function of dendritic cells.45 This suggests that CRTH2 could be a potential target for new therapies for bronchial asthma. Other therapeutic targets for bronchial asthma of interest include IL-17A, KIT, GATA-3, IL-33, IL-25, and significant progress has been made in developing drugs aimed at these targets and other inflammatory cytokines.46

Targeted therapies for cardiovascular diseases

Targeted therapies for pulmonary arterial hypertension (PAH)

PAH is defined as a pulmonary arterial pressure (M PAP) ≥25 mmHg when measuring right cardiac catheterization at rest. PAH is attributed to a variety of factors, particularly an increase in pulmonary vascular resistance that leads to pulmonary arterial remodeling. It is mainly characterized by pulmonary artery smooth muscle cell dysfunction, resulting in right ventricular overload, hypertrophy and dilation, eventually leading to right ventricular failure and even death.47 PAH is associated with a poor prognosis due to the progressive development of these changes or the onset of other complications or syndromes.48 In recent years, the study of PAH therapeutic targets and potential therapeutic strategies has brought new hope for the treatment of PAH. Most therapeutic drugs currently being tested are focused on reducing pulmonary arterial pressure and dilating the pulmonary artery. Three strategies that can regulate pulmonary vasoconstriction or vasodilation and are the target of new therapies for PAH include: nitric oxide-cyclic guanosine monophosphate (NO-cGMP), endothelin receptors and prostacyclin.49 Nitric oxide (NO) is produced by endothelial cells and has a strong vasodilatory effect. Enhancement of NO production can effectively reduce pulmonary artery pressure. Phosphodiesterase 5 (PDE5) is an enzyme that degrades cyclic guanosine, and PDE5 inhibitors or other soluble guanosine cyclase (SGC) activators can enhance the nitric oxide-cyclic guanosine pathway, resulting in blood vessel dilation. The main drugs currently targeting this pathway are tadalafil, vardenafil, sildenafil, and riociguat. Prostacyclin can not only dilate blood vessels, but also inhibit platelet aggregation and have antithrombotic effects. Prostacyclin analogs commonly used in the clinic currently include epoprostenol, iloprost, and prostacyclin receptor agonists such as selexipag.50 Endothelin-1 (ET-1) binds to its receptors A and B, causing vasoconstriction and vascular smooth muscle cell proliferation. Aberrant activation of the endothelin system can lead to continuous vasoconstriction and abnormal vascular smooth muscle cell proliferation. Hence, endothelin receptor antagonists are useful treatments for PAH. Commonly used endothelin receptor antagonists currently in clinical use include bosentan, macitentan, ambrisentan, and ligustrazine, among others.51

In recent years, additional therapeutic targets for PAH have been discovered and tested in animal models. These may lead to a future breakthrough in the treatment of PAH. Endosialin (CD248) is a transmembrane protein and is highly expressed by pericyte cells and fibroblasts. A number of research findings suggest that CD248 could be a useful new target for PAH therapy, including that abnormal levels of CD248 expression have been detected in PAH patients, the degree of CD248 activation in pulmonary smooth muscle cells correlates with the severity of PAH, and that deletion of the CD248 gene in rats can reduce pulmonary vascular remodeling in rat models of PAH.52 The autonomic nervous system is also involved in the pathogenesis of PAH, suggesting that this neurohormonal system can be regulated to treat PAH.53 Besides CD248, there are other potential therapeutic targets for PAH such as miRNAs and spermidine. MiRNAs are non-coding single-stranded RNAs of approximately 22 nucleotides in length. For example, inhibition of the miRNA miR-140-5p promotes pulmonary artery smooth muscle cell (PASMC) proliferation and migration in vitro. In a rat model of PAH, aerosol delivery of miR-140-5p mimics effectively prevents the development of PAH and attenuates the progression of established PAH.54 Using targeted metabolomics, He et al. have found that spermidine can significantly promote the proliferation and migration of human PASMCs induced by platelet-derived growth factor-BB and aggravate arterial remodeling in animal models of PAH.55 Therefore, inhibition of spermine synthesis may be a potential treatment for PAH. Studies have also shown that periosteum protein, hypoxia-inducible factor (HIF), protease-activated receptor 1, and silencing regulatory protein 1 may be therapeutic targets of PAH.56–59

Targeted treatment of coronary atherosclerotic heart disease

The primary pathogenesis of coronary atherosclerotic heart disease (CAHD) is characterized by atherosclerotic lesions in coronary arteries that cause stenosis or obstruction of the vascular lumen, resulting in myocardial ischemia, hypoxia, or necrosis and inducing heart disease.60 The clinical classification of coronary heart disease can be divided into acute coronary syndromes or chronic myocardial ischemia syndromes.61 The incidence and fatality rates of coronary heart disease around the world are increasing yearly, bringing with them substantial economic burdens. The development of coronary atherosclerosis is mainly driven by lipid deposition and macrophage infiltration in the arterial wall, leading to chronic inflammation. Therefore, inflammation is one of the most critical targets for treatment of coronary heart disease. However, at present, drug therapy for the treatment of CAHD is mainly limited to controlling risk factors and providing antithrombotic therapy, and there are currently no specific anti-inflammatory treatments for patients with coronary heart disease. Inflammatory factors involved in the pathogenesis of coronary atherosclerosis include: (1) high sensitivity c-reactive protein (hs-CRP); (2) IL-6, IL-8, IL-18, and other pro-inflammatory interleukins; (3) tumor necrosis factor-α (TNF-α); (4) plasminogen activator inhibitor-1 (PAI-1); and (5) transforming growth factor-β (TGF-β) and others.62 Specific cell types involved in these inflammatory processes or in the release and response to these factors include monocytes, macrophages, lymphocytes, vascular endothelial cells, vascular smooth muscle cells, platelets, and others.62 IL-1β mediates the expression of genes during the process of immune response and inflammation, promoting the adhesion of monocytes and leukocytes to vascular endothelial cells, and inducing the proliferation of vascular smooth muscle cells, the main targets of anti-inflammatory therapy.63 Canakinumab is a monoclonal antibody against IL-1β which can inhibit IL-1-mediated inflammatory responses. The Canakinumab Anti-inflammatory Thrombosis Outcomes Study (CANTOS) trial has demonstrated that inflammation plays a crucial role in atherosclerotic disease.64 In addition, IL-1β can activate downstream IL-6 receptor transduction pathways, resulting in endogenous platelet-derived growth factor (PDGF) production and smooth muscle cell proliferation.65 The IL-6 inhibitor tocilizumab can block this inflammatory cascade and delay the progression of atherosclerosis.

Tozizumab can reduce IL-6 activity and significantly improve endothelial function in high-risk rheumatoid arthritis, even with elevated levels of total cholesterol and low-density lipoprotein.66 Akitake reported a case of a patient with rheumatoid arthritis that was complicated by three-vessel coronary artery disease and severe heart failure.67 The patient received tocilizumab for five years with no adverse events, suggesting that tocilizumab may be a useful therapeutic option for coronary heart disease and rheumatoid arthritis in the future.

In recent years, research has demonstrated that intestinal flora plays a crucial role in human health and that changes in intestinal flora are closely related to coronary heart disease. The diversity and composition of intestinal flora are different between patients with coronary heart disease and healthy controls, with a decrease in the proportion of Bacteroides and an increase in the proportion of Firmicutes bacteria in patients with coronary heart disease.68 Intestinal flora influence host metabolic pathways through the production of metabolites, one of which is trimethylamine oxide (TMAO). TMAO accelerates atherosclerosis, suggesting that it may be a potential target for predicting and treating coronary heart disease.69,70 Takuo et al.71 have demonstrated that intestinal flora and their metabolites can be used as diagnostic markers for coronary artery disease. The potential relationship between intestinal flora and coronary heart disease has been widely studied, but its application in the diagnosis, treatment, and prevention of coronary heart disease still needs further experimental examination. In the future, the treatment of coronary heart disease by targeting intestinal flora could revolve around the following interventions: adjusting the composition of the diet, regulating the metabolic pathway of intestinal flora, supplementing the diet with probiotics, altering intestinal flora through the transplantation of fecal bacteria, and targeted modification of microorganisms.

Another area of intense research interest is developing targeted treatments for coronary heart disease using new drug delivery systems. Due to their unique size, physical properties and chemical composition, nano agents can flow in blood and tissues without becoming deposited in the endothelial wall, which could enable them to deliver targeted drugs throughout the body while prolonging the length of time those drugs are present in the circulation, which could result in reduced systemic non-targeted cytotoxicity. Nanoparticles prepared by Zang et al. promote the expression of vascular endothelial growth factor (VEGF), dilate coronary arteries, improve cardiac function and reduce the recurrence of angina in patients with coronary heart disease.72 As the development of nanotechnology has progressed, there have been more and more studies into nano-drug targeted treatment of coronary heart disease in recent years (Table 2).73–77

Table 2

Studies on targeted delivery nanomedicine for coronary heart disease

Drug name Method of preparation Therapeutic effect Ref
Polymer nanosystems composed of core-shell nanoparticles of polyethyleneglycol-based block copolymers – Drug were selectively released to the balloon-injured artery73
A novel “nanopolypill” Emulsion- diffusion-evaporation method Has a potential of decreasing pill burden.74
TPCD/TA nanoparticles Polyphenol-assisted nanoprecipitation/self-assembly Effectively protected cells from hypoxic-ischemic injury, by internalization into cardiomyocytes75
Au nanospheres with VCAM-1-binding peptide – Inhibiting the formation of atherosclerotic plaques.76
Rapamycin/Ac-bCD180-derived nanotherapy Oil-in-water (o/w) emulsion solvent evaporation technique Stabilized atherosclerotic plaques compared with free rapamycin, and sustain RAP release in a well-controlled manner both in vitro and in vivo77

The role of targeted therapies in neurological diseases

Targeted treatment of Alzheimer’s disease

Alzheimer’s disease (AD) is a progressive and aggravating degenerative disease of the central nervous system (CNS), with a high incidence in the elderly. The main symptoms include memory loss, disordered thinking, loss of speech, behavioral changes and difficulty eating,78 all of which seriously affect the patients’ daily work, life and social interactions. The pathogenesis of AD is still unclear, although various hypotheses have been pursued, such as the cholinergic hypothesis, the amyloid cascade hypothesis, the excitotoxicity hypothesis, the mitochondrial cascade hypothesis, and the tau hypothesis.79 Currently, there are few medicines available for the prevention and treatment of AD in the clinic and only three FDA-approved drugs for the treatment of AD are available: cholinesterase inhibitors (CHEI), n-methyl-D-aspartate receptor antagonists (NMDA), and both drugs in combination.80 The delivery of drugs across the blood-brain barrier (BBB) to the CNS is a significant obstacle for the treatment of Alzheimer’s disease. In addition, the development of Alzheimer’s-related drugs has been hindered by rapid removal from the circulation and a low bioavailability of candidate treatments.79 As such, the unique size and physicochemical properties of nano-formulations may make them suitable alternatives for the treatment of AD, offering safer treatments than traditional delivery methods.81 Nanoparticles can penetrate the BBB, carry drugs into the brain, and have the advantages of better biocompatibility, easier degradation, and lower toxicity.82 Poly lactic-co-glycolic acid (PLGA) has become one of the most commonly used polymer particles in nanomaterials due to the fact that it readily biodegrades. Yadav et al. have prepared long circulating nanoparticles of etoposide using PLGA, MPEG and PLGA pluronic block copolymers.83 Nanoparticles of these drugs with a particle size of 100 nm can evade metabolism by the liver and improve the aggregation of drugs in the CNS, without the need for surface modification of drug particles to achieve these ends.83 Nanoemulsion is a dispersive system that produces nanoscale oil droplets with a size between 20 and 200 nm. These contain surfactants and are suitable for the delivery of insoluble drugs to the brain. Phenylethanoid glycoside in Cistanche deserticola is the primary pharmacochemical basis for preventing and treating AD, and the traditional way of administration makes it difficult to cross the BBB to play the therapeutic role. Therefore, Hu et al. have prepared nanoemulsions of phenylethanol glycosides.84 Through nasal administration, the absorption of phenethyl alcohol glycosides is significantly improved, helping them to cross the BBB and reach their desired target site and improve bioavailability in vivo.84 Another alternative approach is to use liposomes, which have a diameter of 50 nm to 5 µm and a double-layer structure similar to cell membranes. They are composed of phospholipid and cholesterol molecules, and their hydrophilic and hydrophobic parts can encapsulate water- and fat-soluble drugs, thus improving the stability and biocompatibility of drugs.85 Borneol-modified curcumin cationic liposomes can significantly improve curcumin stability in brain tissue and prolong curcumin circulation time in vivo.86 Other potential nano-targeted drug delivery systems for AD include nanogels, nanosuspensions, dendrimers and micelles, among others.81 Although there have been substantial advancements in the use of nanomedicines in preclinical studies, data from in vivo and clinical studies are limited and the toxicity of these approaches, or side effects associated with them, are not fully understood. Therefore, further research is still needed to validate the potential therapeutic efficacy of nanocarriers for Alzheimer’s disease.

Targeted treatment of Parkinson’s disease

Parkinson’s disease (PD) is the second most common neurodegenerative disease after AD.87 PD predominant affects elderly people and seriously reduces their quality of life. The pathogenesis of PD is still unclear. Pathologically, PD is characterized by a loss of dopaminergic neurons in the substantia nigra of the brain. Risk factors for the development and occurrence of PD include aging, exposure to environmental toxins and family genetics. The clinical symptoms of PD are resting tremor, bradykinesia or weakness of movement, a loss of orthodontic reflexes and joint stiffness.88 Currently, the treatment of PD is mainly limited to dopamine-like drugs and anticholinergic agents that aim to improve the balance of neurotransmitters in the brain. These therapeutic drugs can only delay the progression of the disease, but fail to fundamentally improve its prognosis.89 Similar to AD, it is difficult to effectively deliver drugs for the treatment of PD due to the need for those drugs to penetrate the BBB. Interestingly, drug delivery through nasal mucosa can bypass the BBB, allowing direct delivery of drugs into the brain and avoiding hepatic first pass metabolism.90 The neuroactive peptide DNSP-11 is a synthetic 11-position aminated neuroactive peptide. After repeated intranasal administration, DNSP-11 can be detected in the striatum and substantia nigra of the brain within 30 minutes, suggesting that DNSP-11 preferably targets the dopaminergic system.91 Similarly, intranasal administration of dopamine liposomes can promote the entry of dopamine into the CNS and have a significant effect on symptoms of PD.92 Lu et al.93 have reported that cavitation-mediated icariin nanoliposomes with ideal micromorphology and particle size distribution are transferred into the brain through the olfactory area of the nasal cavity. This improves the efficiency of icariin delivery into the brain, thereby enhancing the therapeutic efficacy of icariin for the treatment of PD. The therapeutic effects of this model of delivery have been confirmed in the rat model of PD, with significantly improved motor function and a repair action on the neuronal lesion.94 In addition to these approaches, nanotechnology has been widely used to develop drugs for treatment of PD. For example, some new nanomaterial drug delivery systems have been shown to offer neuroprotective effects, including preventing oxidative stress and interfering with protein aggregation in animal models of PD.95 These systems include the use of fullerenes (C60), magnetic nanoparticles (MNPs) and cerium oxide.95 Thus, in the near future it is possible that the use of nanomaterials will enable improvements in the delivery of drugs for the treatment of PD, enhancing their therapeutic efficacy.

The role of targeted therapies in immune system diseases

Targeted treatment of systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is a complex chronic autoimmune disease that affects multiple organs, including the skin, heart, kidney, joints, and brain. The clinical symptoms of SLE are complex and varied, and the patients are mainly women of childbearing age. The pathogenesis of SLE involves various factors, such as genetics, exposure to the environment and hormonal factors, but the specific mechanisms involved in the development and progression of SLE have not been fully clarified.96 At present, the treatment of SLE mainly consists of glucocorticoids, antimalarials, and immunosuppressants, which can reduce organ injury and mortality. However, these drugs have a wide range of immunosuppressive effects and are associated with varying degrees of adverse reactions. In addition, these therapies do not improve the prognosis of critically ill or refractory patients.97,98 Therefore, more effective immune-targeted drugs are urgently needed. In recent years, biologic agents and small molecule-targeted drugs have emerged which can inhibit B and T lymphocyte activation, block the interaction of different types of immune cells, and reduce cytokine production.99 In 2011, the FDA and European Medicines Agency (EMA) approved belimumab for the treatment of SLE, the first drug to be specifically designed for the treatment of this condition.100 Belimumab is a fully-humanized monoclonal antibody against B cell activator (BAFF) that binds soluble BAFF and inhibits it from binding to the BAFF receptor.101 This leads to autoimmune B cell apoptosis, thereby reducing serum autoantibodies.101 Other recently approved treatment options include blisibimod and talabumab. Unlike belimumab, blisibimod binds to soluble, insoluble, and membranous BAFF, while talabumab binds to soluble and membranous BAFF.99 Other drugs targeting B lymphocytes include atacicept, telitacicept, rituximab, and obinutuzumab. Abatacept is a selective T cell costimulatory modulator that inhibits T cell activation by binding to CD80 and CD86 on antigen-presenting cells. However, a phase II clinical trial for testing the therapeutic efficacy of abatacept failed to meet the primary/secondary endpoints. Although many such targeted treatments have not had their desired effects in initial clinical trials, there are increasing numbers of targeted therapies are undergoing clinical tests and additional targeted drugs may become available for the treatment of SLE in the future.

Targeted treatment of rheumatoid arthritis

Rheumatoid arthritis (RA) is a common systemic immune disease with an incidence rate of 0.5∼1.0%, particularly in women of the age of thirty to fifty years. RA is characterized by chronic synovitis with inflammatory infiltrates, which produces a variety of clinical symptoms. The main clinical manifestations of RA are symmetric joint swelling, morning stiffness, and a continuous decline in activity levels. Continual progression of RA may cause joint deformity or even disability.102 It is generally believed that RA involves genetic and environmental factors which activate immune cells that attack the synovial membrane, leading to inflammation and joint injury.103 At present, the preferred drugs for the treatment of RA mainly include non-steroidal anti-inflammatory drugs, glucocorticoids, anti-rheumatism drugs, and biological agents. However, these drugs usually require high doses, frequent administration, and have severe adverse reactions, limiting their clinical application.104 These barriers have encouraged the development of nano-targeted drug delivery systems for the treatment of RA. A recent study in arthritic mice has shown that nanoparticles can deliver these drugs in such a way that they selectively accumulate in inflammatory synovial tissues with high vascular permeability.105 Researchers have also designed and developed four nano agents which are targeted either passively, actively, in response to the cellular micro-environment responsive, or via bionic targeting.104 For example, Yang et al. have designed a passive targeting agent—consisting of folic acid-modified silver nanoparticles (FA-AGNPs), which accumulate in inflamed joints by binding to folic acid receptors that are highly expressed on M1 macrophages. This results in greater M2 maturation and inhibits inflammation in animals with RA without long-term toxicity. Hence, using techniques such as these to rebalance pro-inflammatory M1 and anti-inflammatory M2 macrophages can alleviate synovial inflammation. Furthermore, metabolites of this drug are cleared through feces and do not accumulate in other organs.106 Oxidative stress in the synovium of the RA joint can promote the generation of reactive oxygen species (ROS) and aggravate synovitis. The manganese ferrite and ceria nanoparticle-anchored Mesoporous silica nanoparticles (MFC-MSNs) can synergistically remove ROS and produce O2 to rebalance M1 and M2 macrophages for RA treatment.

Meanwhile, methotrexate-based MFC-MSNs enable continuous release of the anti-rheumatism drug to enhance its therapeutic effect.107 Bionic targeting of nano agents utilizes endogenous proteins, viruses, and cells gathering to the inflammatory site to inhibit inflammation.104 As an example, An et al.108 have developed a cell-carrier nanoparticle as an anti-inflammatory platform to inhibit the inflammatory response of LPS-induced RAW264.7 cells. In an inflammatory animal model, administration of these nanoparticles resulted in accumulation of inflammatory lesions, inhibiting signaling through Notch1 and NF-κB pathways, reducing clinical symptoms, inflammatory infiltration, bone erosion, and serum inflammatory factors.

Targeted treatment of psoriasis

Psoriasis is a chronic inflammatory skin disease with a global prevalence of about 2%. Its main symptoms are well-defined plaques on the trunk, limbs, and scalp that are accompanied by itching, burning, and pain. Continuous inflammation leads to uncontrolled keratinocyte proliferation and dysfunctional differentiation, which triggers psoriasis.109 Psoriasis can be associated with various complications, such as arthritis, coronary artery disease, hyperlipidemia, obesity, and depression.110 In recent years, molecular targeted therapies for the treatment of psoriasis have been developed that can be divided into three main categories: 1) targeted cytokines, 2) receptors involved in the pathogenesis of psoriasis, and 3) small molecule inhibitors targeting intracellular signaling molecules.111 Given that Th17 cells and the IL-23/Th17 signaling axis is crucial for the pathogenesis of psoriasis, targeted agents currently being developed for the treatment of psoriasis have mainly been focused on Th17-related cytokines, such as TNF, IL-23, and IL-17.112 IL-23 inhibitors are safe and effective in treating psoriasis and psoriatic arthritis without obvious adverse effects. Since 2004, the U.S. FDA has approved 11 biologically-targeted agents to treat plaque psoriasis, including etanercept, infliximab, adalimumab, ustekinumab, secukinumab, ixekizumab, brodalumab, guselkumab, tildrakizumab, certolizumab, and risankizumab.113 In the future, biologically-targeted drugs may be an effective alternative to treat psoriasis.

Targeted therapies for other Chronic Diseases

Targeted treatment of chronic myelogenous leukemia

Chronic myelogenous leukemia (CML) is a malignant disease originating from bone marrow hematopoietic stem cells with chromosomal abnormalities. It results from the ABL proto-oncogene on chromosome 9 joining the BCR gene on chromosome 22 to form the BCR-ABL fusion gene, resulting in the expression of a BCR-ABL fusion protein with high tyrosine kinase activity.114 Prior to 2000, the treatment of CML relied on non-specific drugs, such as busulfan, hydroxyurea, and interferon-α (IFN-α).115 However, more recently, the development of tyrosine kinase inhibitors (TKIs) has changed the history of CML therapy. TKIs can effectively inhibit the phosphorylation of tyrosine residues and inactivate this enzyme, inhibiting the excessive proliferation of white blood cells and achieving targeted treatment of CML. One such treatment, imatinib, has a potent effect on the early chronic stage of CML in children, with mild adverse reactions and a good tolerance and safety profile.116 However, many patients with CML develop resistance to imatinib. Subsequently, drugs based on other targets have been developed, including tipifarnib and lonafarnib. These are two selective farnesyltransferase inhibitors with potential anti-leukemia activity in patients with CML. Studies have demonstrated the safety of lonafarnib combined with imatinib in the treatment of chronic myelogenous leukemia. Another treatment approach is the use of histone deacetylase inhibitors, which can reduce levels of BCR-ABL protein expression and induce apoptosis of imatinib mesylate-resistant BCR-ABL positive cells, potentially forming useful treatments for CML.117 Another approach is the use of aurora kinase inhibitors (AURK-IS), which inhibit the activity of the AURK family of serine kinases that regulate cell mitosis and are potential therapeutic targets for anticancer drug development.118

Future directions

Targeted therapies for many chronic diseases are currently being tested in clinical trials, with many displaying beneficial effects. However, developing appropriate delivery systems for targeted drugs has proven to be difficult because the pathogenesis of many chronic diseases remains unclear. Several questions need to be addressed urgently. At present, the pathogenesis of many chronic diseases is not entirely understood, but uncovering the molecular mechanisms underlying the pathogenesis of individual chronic diseases will help to identify disease-related targets for developing targeted drugs. The ability to develop appropriate delivery systems for targeted drugs in the future will undoubtedly enhance the treatment of various chronic diseases.

Conclusions

Chronic diseases have seriously affected human life and health and their incidence is increasing, including in younger people.119 Given the chronic nature of these conditions, patients with chronic diseases depend on continual drug treatment, which is associated with an ongoing risk of adverse effects. Developing appropriate delivery systems for targeted drugs can promote the accumulation of targeted drugs in pathogenic lesions, reducing systemic adverse effects and improving patient outcomes. In addition, targeted delivery systems can help deliver drugs to specific immune-privileged tissues by passing through the BBB and other similar barriers. This technology provides many promising avenues for the future treatment of chronic diseases.

Abbreviations

AD: 

alzheimer’s disease

AURK-IS: 

aurora kinase inhibitors

BAFF: 

cell activating factor

BBB: 

blood-brain barrier

CAHD: 

coronary atherosclerotic heart disease

CANTOS: 

Canakinumab Anti-inflammatory Thrombosis Outcomes Study

CEL: 

celastrol

CHEI: 

cholinesterase inhibitors

CKD: 

chronic kidney disease

CML: 

chronic myelogenous leukemia

CNS: 

central nervous system

COPD: 

chronic obstructive pulmonary disease

NF-κB: 

nuclear factor κB

CREKA: 

Cys-Arg-Glu-Lys-Ala

CREKA-Lip: 

Cys-Arg-Glu-Lys-Ala liposomes

DA: 

dopamine

DPP-IV: 

Diptopeptidase

EMA: 

European Medicines Agency

ET-1: 

endothelin-1

FA-AGNPs: 

folic acid-modified silver nanoparticles

FDA: 

Food and Drug Administration

EOS: 

eosinophils

GLP-1: 

Glucagon-like peptide 1

GLP-1R: 

GLP-1 receptor

HIF: 

hypoxia-inducible factor

hs-CRP: 

high sensitivity c-reactive protein

IFN-α: 

interferon-α

IL: 

interleukins

LPNs: 

lipid-polymer nanoparticles

MFC-MSNs: 

Mesoporous silica nanoparticles

MNPs: 

magnetic nanoparticles

NMDA: 

n-methyl-D-aspartate receptor antagonists

NO: 

nitric oxide

NO-cGMP: 

nitric oxide-cyclic guanosine monophosphate

PAH: 

pulmonary arterial hypertension

PAI-1: 

plasminogen activator inhibitor-1

PD: 

parkinson’s disease

PDE5: 

phosphodiesterase 5

PDGF: 

platelet-derived growth factor

PLGA: 

poly lactic-co-glycolic acid

RA: 

rheumatoid arthritis

ROS: 

reactive oxygen species

SD-NAC-Lip: 

liposomal dry powders of N-acetylcysteine

SGC: 

soluble guanosine cyclase

SLE: 

systemic lupus erythematosus

TGF-β: 

transforming growth factor-β

TKIs: 

tyrosine kinase inhibitors

TMAO: 

trimethylamine oxide

TNF-α: 

tumor necrosis factor-α

VEGF: 

vascular endothelial growth factor

Declarations

Acknowledgement

None.

Funding

This work was supported by a grant from International Cooperation Project of Traditional Chinese Medicine (0610-2140NF020630).

Conflict of interest

The authors declare no conflicts of interest.

Authors’ contributions

Manuscript writing (JYQ, CJP), literature search (ZFJ, DYJ), review and editing (CJP, TCW), supervision (TCW, CCQ). All authors have read and agreed to submit the manuscript.

References

  1. Li P, Wang L. Current situation of burden of major chronic diseases in Chinese population (in Chinese). Journal of Baotou Medical College 2017;33(7):138-141 View Article
  2. Li XM, Xia YJ. Research on chronic disease prevention and control strategies at home and abroad (in Chinese). J Pub Health Prev Med 2021;32(3):117-121 View Article
  3. Zhang N, Zhang H. Advances of targeted drug delivery system (in Chinese). Journal of Liaoning University of Traditional Chinese Medicine 2017;19(2):218-221 View Article
  4. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 2014;37(Suppl1):S81-90 View Article PubMed/NCBI
  5. Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev 2007;87(4):1409-1439 View Article PubMed/NCBI
  6. Zhou YH, Huang WL, Zhang HB, Chi YS. Progress in the investigation of GLP-1 receptor agonists and DPP-IV inhibitors (in Chinese). Journal of China Pharmaceutical University 2008;39(5):385-391
  7. Gupta A, Jelinek HF, Al-Aubaidy H. Glucagon like peptide-1 and its receptor agonists: Their roles in management of Type 2 diabetes mellitus. Diabetes Metab Syndr 2017;11(3):225-230 View Article PubMed/NCBI
  8. Wang C, Yao J, Ju L, Wen X, Shu L. Puerarin ameliorates hyperglycemia in HFD diabetic mice by promoting β-cell neogenesis via GLP-1R signaling activation. Phytomedicine 2020;70:153222 View Article PubMed/NCBI
  9. Chen X, Qian L, Wang B, Zhang Z, Liu H, Zhang Y, et al. Synergistic hypoglycemic effects of pumpkin polysaccharides and puerarin on Type II diabetes mellitus mice. Molecules 2019;24(5):955 View Article PubMed/NCBI
  10. Wei Z, Weng S, Wang L, Mao Z. Mechanism of Astragalus polysaccharides in attenuating insulin resistance in Rats with type 2 diabetes mellitus via the regulation of liver microRNA-203a-3p. Mol Med Rep 2018;17(1):1617-1624 View Article PubMed/NCBI
  11. Parrish AR. Advances in chronic kidney disease. Int J Mol Sci 2016;17(8):1314 View Article PubMed/NCBI
  12. Ruiz-Ortega M, Rayego-Mateos S, Lamas S, Ortiz A, Rodrigues-Diez RR. Targeting the progression of chronic kidney disease. Nat Rev Nephrol 2020;16(5):269-288 View Article PubMed/NCBI
  13. Liu D, Du Y, Jin FY, Xu XL, Du YZ. Renal cell-targeted drug delivery strategy for acute kidney injury and chronic kidney disease: A mini-review. Mol Pharm 2021;18(9):3206-3222 View Article PubMed/NCBI
  14. Liu GW, Pippin JW, Eng DG, Lv S, Shankland SJ, Pun SH. Nanoparticles exhibit greater accumulation in kidney glomeruli during experimental glomerular kidney disease. Physiol Rep 2020;8(15):e14545 View Article PubMed/NCBI
  15. Bruni R, Possenti P, Bordignon C, Li M, Ordanini S, Messa P, et al. Ultrasmall polymeric nanocarriers for drug delivery to podocytes in kidney glomerulus. J Control Release 2017;255:94-107 View Article PubMed/NCBI
  16. Tripathy N, Wang J, Tung M, Conway C, Chung EJ. Transdermal delivery of kidney-targeting nanoparticles using dissolvable microneedles. Cell Mol Bioeng 2020;13(5):475-486 View Article PubMed/NCBI
  17. Tang M, Cao X, Zhang K, Li Y, Zheng QY, Li GQ, et al. Celastrol alleviates renal fibrosis by upregulating cannabinoid receptor 2 expression. Cell Death Dis 2018;9(6):601 View Article PubMed/NCBI
  18. Li R, Li Y, Zhang J, Liu Q, Wu T, Zhou J, et al. Targeted delivery of celastrol to renal interstitial myofibroblasts using fibronectin-binding liposomes attenuates renal fibrosis and reduces systemic toxicity. J Control Release 2020;320:32-44 View Article PubMed/NCBI
  19. Conde-Sampayo A, Lorenzo-González M, Fernández-Villar A, Barros-Dios JM, Ruano-Ravina A. Exposure to residential radon and COPD: A systematic review. Int J Chron Obstruct Pulmon Dis 2020;15:939-948 View Article PubMed/NCBI
  20. Park HS, Kim SR, Lee YC. Impact of oxidative stress on lung diseases. Respirology 2009;14(1):27-38 View Article PubMed/NCBI
  21. Bai Y, Tao XN. Targeted drugs in research status in chronic obstructive pulmonary disease treatment (in Chinese). Journal of Clinical Pulmonary Medicine 2019;24(11):2107-2112
  22. Wan N, Chen B, Li H, Ye W, Wang H. Research progress in pulmonary inhalation drug delivery system (in Chinese). Chinese Journal of New Drugs 2021;30(15):1386-1395
  23. Ourique AF, Chaves Pdos S, Souto GD, Pohlmann AR, Guterres SS, Beck RC. Redispersible liposomal-N-acetylcysteine powder for pulmonary administration: development, in vitro characterization and antioxidant activity. Eur J Pharm Sci 2014;65:174-182 View Article PubMed/NCBI
  24. Chennakesavulu S, Mishra A, Sudheer A, Sowmya C, Suryaprakash Reddy C, Bhargav E. Pulmonary delivery of liposomal dry powder inhaler formulation for effective treatment of idiopathic pulmonary fibrosis. Asian J Pharm Sci 2018;13(1):91-100 View Article PubMed/NCBI
  25. Manconi M, Manca ML, Valenti D, Escribano E, Hillaireau H, Fadda AM, et al. Chitosan and hyaluronan coated liposomes for pulmonary administration of curcumin. Int J Pharm 2017;525(1):203-210 View Article PubMed/NCBI
  26. De Leo V, Ruscigno S, Trapani A, Di Gioia S, Milano F, Mandracchia D, et al. Preparation of drug-loaded small unilamellar liposomes and evaluation of their potential for the treatment of chronic respiratory diseases. Int J Pharm 2018;545(1-2):378-388 View Article PubMed/NCBI
  27. Chikuma K, Arima K, Asaba Y, Kubota R, Asayama S, Sato K, et al. The potential of lipid-polymer nanoparticles as epigenetic and ROS control approaches for COPD. Free Radic Res 2020;54(11-12):829-840 View Article PubMed/NCBI
  28. Al Faraj A, Shaik AS, Afzal S, Al Sayed B, Halwani R. MR imaging and targeting of a specific alveolar macrophage subpopulation in LPS-induced COPD animal model using antibody-conjugated magnetic nanoparticles. Int J Nanomedicine 2014;9:1491-1503 View Article PubMed/NCBI
  29. Michailidou G, Ainali NM, Xanthopoulou E, Nanaki S, Kostoglou M, Koukaras EN, et al. Effect of Poly(vinyl alcohol) on nanoencapsulation of budesonide in chitosan nanoparticles via ionic gelation and its improved bioavailability. Polymers (Basel) 2020;12(5):E1101 View Article PubMed/NCBI
  30. Mohamed A, Kunda NK, Ross K, Hutcheon GA, Saleem IY. Polymeric nanoparticles for the delivery of miRNA to treat Chronic Obstructive Pulmonary Disease (COPD). Eur J Pharm Biopharm 2019;136:1-8 View Article PubMed/NCBI
  31. Payne CM, Burke LP, Cavanagh B, O’Toole D, Cryan SA, Kelly HM. Evaluation of the immunomodulatory effects of all-trans retinoic acid solid lipid nanoparticles and human mesenchymal stem cells in an A549 epithelial cell line model. Pharm Res 2019;36(4):50 View Article PubMed/NCBI
  32. Amore E, Ferraro M, Manca ML, Gjomarkaj M, Giammona G, Pace E, et al. Mucoadhesive solid lipid microparticles for controlled release of a corticosteroid in the chronic obstructive pulmonary disease treatment. Nanomedicine (Lond) 2017;12(19):2287-2302 View Article PubMed/NCBI
  33. Ghasemi A, Mohtashami M, Sheijani SS, Aliakbari K. Chitosan-genipin nanohydrogel as a vehicle for sustained delivery of alpha-1 antitrypsin. Res Pharm Sci 2015;10(6):523-34 PubMed/NCBI
  34. Thanki K, Zeng X, Justesen S, Tejlmann S, Falkenberg E, Van Driessche E, et al. Engineering of small interfering RNA-loaded lipidoid-poly(DL-lactic-co-glycolic acid) hybrid nanoparticles for highly efficient and safe gene silencing: A quality by design-based approach. Eur J Pharm Biopharm 2017;120:22-33 View Article PubMed/NCBI
  35. Lambrecht BN, Hammad H, Fahy JV. The cytokines of asthma. Immunity 2019;50(4):975-991 View Article PubMed/NCBI
  36. Wenzel SE. Asthma: defining of the persistent adult phenotypes. Lancet 2006;368(9537):804-813 View Article PubMed/NCBI
  37. Masoli M, Fabian D, Holt S, Beasley R, Global Initiative for Asthma (GINA) Program. The global burden of asthma: executive summary of the GINA Dissemination Committee report. Allergy 2004;59(5):469-478 View Article PubMed/NCBI
  38. Uddin M, Nong G, Ward J, Seumois G, Prince LR, Wilson SJ, et al. Prosurvival activity for airway neutrophils in severe asthma. Thorax 2010;65(8):684-689 View Article PubMed/NCBI
  39. Holgate S, Bousquet J, Wenzel S, Fox H, Liu J, Castellsague J. Efficacy of omalizumab, an anti-immunoglobulin E antibody, in patients with allergic asthma at high risk of serious asthma-related morbidity and mortality. Curr Med Res Opin 2001;17(4):233-40 PubMed/NCBI
  40. Zhu G, Ye L, Jin M. Research progress of targeted therapy for bronchial asthma. International Journal of Respiration (in Chinese) 2021;41(7):529-535 View Article
  41. Bleecker ER, FitzGerald JM, Chanez P, Papi A, Weinstein SF, Barker P, et al. Efficacy and safety of benralizumab for patients with severe asthma uncontrolled with high-dosage inhaled corticosteroids and long-acting β2-agonists (SIROCCO): a randomised, multicentre, placebo-controlled phase 3 trial. Lancet 2016;388(10056):2115-2127 View Article PubMed/NCBI
  42. Wang Y, Qiu Y. Mechanism, present situation and expectation of Biological targeted therapy for bronchial asthma (in Chinese). Chinese Journal of Lung Diseases (Electronic Edition) 2019;12:790-793 View Article
  43. Zhu L, Ciaccio CE, Casale TB. Potential new targets for drug development in severe asthma. World Allergy Organ J 2018;11(1):30 View Article PubMed/NCBI
  44. Balzar S, Fajt ML, Comhair SA, Erzurum SC, Bleecker E, Busse WW, et al. Mast cell phenotype, location, and activation in severe asthma. Data from the Severe Asthma Research Program. Am J Respir Crit Care Med 2011;183(3):299-309 View Article PubMed/NCBI
  45. Chen N, Zhang S, Gao C. Effects of CRTH2 receptor antagonist on the function of dendritic cells in patients with bronchial asthma (in Chinese). Immunological Journal 2017;33(1):63-67 View Article
  46. Corren J. New targeted therapies for uncontrolled asthma. J Allergy Clin Immunol Pract 2019;7(5):1394-1403 View Article PubMed/NCBI
  47. Zheng W, Wang Z, Jiang X, Zhao Q, Shen J. Targeted drugs for treatment of pulmonary arterial hypertension: past, present, and future perspectives. J Med Chem 2020;63(24):15153-15186 View Article PubMed/NCBI
  48. Yang XS. Progress in drug treatment of pulmonary arterial hypertension (in Chinese). China Modern Medicine 2021;28(5):37-41 View Article
  49. Chen Y, Li J. Current status and prospects of targeted drug therapy for pulmonary arterial hypertension (in Chinese). Chinese Journal of New Clinical Medicine 2020;13(9):852-858 View Article
  50. Montani D, Günther S, Dorfmüller P, Perros F, Girerd B, Garcia G, et al. Pulmonary arterial hypertension. Orphanet J Rare Dis 2013;8:97 View Article PubMed/NCBI
  51. Jiang X, Xing X, Wang X, Yin L, He W. Drugs and drug delivery strategies for treatment of pulmonary arterial hypertension (in Chinese). Yao Xue Xue Bao 2021;56(5):1332-1342 View Article
  52. Barozzi C, Galletti M, Tomasi L, De Fanti S, Palazzini M, Manes A, et al. A Combined targeted and whole exome sequencing approach identified novel candidate genes involved in heritable pulmonary arterial hypertension. Sci Rep 2019;9(1):753 View Article PubMed/NCBI
  53. García-Lunar I, Pereda D, Ibanez B, García-Álvarez A. Neurohormonal modulation as a therapeutic target in pulmonary hypertension. Cells 2020;9(11):E2521 View Article PubMed/NCBI
  54. Rothman AM, Arnold ND, Pickworth JA, Iremonger J, Ciuclan L, Allen RM, et al. MicroRNA-140-5p and SMURF1 regulate pulmonary arterial hypertension. J Clin Invest 2016;126(7):2495-2508 View Article PubMed/NCBI
  55. He YY, Yan Y, Jiang X, Zhao JH, Wang Z, Wu T, et al. Spermine promotes pulmonary vascular remodelling and its synthase is a therapeutic target for pulmonary arterial hypertension. Eur Respir J 2020;56(5):2000522 View Article PubMed/NCBI
  56. Liu M, Galli G, Wang Y, Fan Q, Wang Z, Wang X, et al. Novel therapeutic targets for hypoxia-related cardiovascular diseases: the role of HIF-1. Front Physiol 2020;11:774 View Article PubMed/NCBI
  57. Nie X, Shen C, Tan J, Wu Z, Wang W, Chen Y, et al. Periostin: A potential therapeutic target for pulmonary hypertension?. Circ Res 2020;127(9):1138-1152 View Article PubMed/NCBI
  58. Merkus D, van Beusekom HMM, Boomars KA. Protease-activated receptor 1 as potential therapeutic target in pulmonary arterial hypertension. Cardiovasc Res 2019;115(8):1260-1261 View Article PubMed/NCBI
  59. Cheng XW, Narisawa M, Jin X, Murohara T, Kuzuya M. Sirtuin 1 as a potential therapeutic target in pulmonary artery hypertension. J Hypertens 2018;36(5):1032-1035 View Article PubMed/NCBI
  60. 2018 ESC/EACTS Guidelines on myocardial revascularization. Rev Esp Cardiol (Engl Ed) 2019;72(1):73 View Article PubMed/NCBI
  61. Guo X, Chen J, Chen X. Research progress of treatment of coronary heart disease in elderly patients (in Chinese). Medical Recapitulate 2021;27(11):2189-2193 View Article
  62. Hu W. Progress and analysis of the relationship between inflammatory factors and coronary heart disease. Cardiovascular Disease Electronic Journal of Integrated Traditional Chinese and Western Medicine 2020;8(22):21-22 View Article
  63. Dinarello CA, Simon A, van der Meer JW. Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases. Nat Rev Drug Discov 2012;11(8):633-652 View Article PubMed/NCBI
  64. Thompson PL, Nidorf SM. Anti-inflammatory therapy with canakinumab for atherosclerotic disease: lessons from the CANTOS trial. J Thorac Dis 2018;10(2):695-698 View Article PubMed/NCBI
  65. Naugler WE, Karin M. The wolf in sheep’s clothing: the role of interleukin-6 in immunity, inflammation and cancer. Trends Mol Med 2008;14(3):109-119 View Article PubMed/NCBI
  66. Bacchiega BC, Bacchiega AB, Usnayo MJ, Bedirian R, Singh G, Pinheiro GD. Interleukin 6 inhibition and coronary artery disease in a high-risk population: a prospective community-based clinical study. J Am Heart Assoc 2017;6(3):e005038 View Article PubMed/NCBI
  67. Suzuki A, Tamamura T, Okai T. Five-year administration of tocilizumab to a patient with rheumatoid arthritis complicated by severe chronic heart failure. Nihon Rinsho Meneki Gakkai Kaishi 2014;37(6):488-492 View Article PubMed/NCBI
  68. Cui L, Zhao T, Hu H, Zhang W, Hua X. Association study of gut flora in coronary heart disease through high-throughput sequencing. Biomed Res Int 2017;2017:3796359 View Article PubMed/NCBI
  69. Koeth RA, Wang Z, Levison BS, Buffa JA, Org E, Sheehy BT, et al. Intestinal microbiota metabolism of L-carnitine, a nutrient in red meat, promotes atherosclerosis. Nat Med 2013;19(5):576-585 View Article PubMed/NCBI
  70. Liu Y, Dai M. Trimethylamine N-Oxide generated by the gut microbiota is associated with vascular inflammation: new insights into atherosclerosis. Mediators Inflamm 2020;2020:4634172 View Article PubMed/NCBI
  71. Emoto T, Yamashita T, Kobayashi T, Sasaki N, Hirota Y, Hayashi T, et al. Characterization of gut microbiota profiles in coronary artery disease patients using data mining analysis of terminal restriction fragment length polymorphism: gut microbiota could be a diagnostic marker of coronary artery disease. Heart Vessels 2017;32(1):39-46 View Article PubMed/NCBI
  72. Zang LH. Nanoparticles in the diagnosis and treatment of coronary artery diseases under sports rehabilitation intervention. Ferroelectrics 2021;580(1):283-297 View Article
  73. Uwatoku T, Shimokawa H, Abe K, Matsumoto Y, Hattori T, Oi K, et al. Application of nanoparticle technology for the prevention of restenosis after balloon injury in rats. Circ Res 2003;92(7):e62-e69 View Article PubMed/NCBI
  74. Arora A, Shafiq N, Jain S, Khuller GK, Sharma S, Pandey AK, et al. Development of sustained release “Nanopolypill” of ischemic heart disease drugs - an experimental study. Curr Nanosci 2014;10(6):816-826 View Article
  75. Qi Y, Li J, Nie Q, Gao M, Yang Q, Li Z, et al. Polyphenol-assisted facile assembly of bioactive nanoparticles for targeted therapy of heart diseases. Biomaterials 2021;275:120952 View Article PubMed/NCBI
  76. Sun T, Simmons R, Huo D, Pang B, Zhao X, Kim CW, et al. Targeted delivery of anti-miR-712 by VCAM1-binding Au nanospheres for atherosclerosis therapy. Chemnanomat 2016;2:400-406 View Article
  77. Dou Y, Guo J, Chen Y, Han S, Xu X, Shi Q, et al. Sustained delivery by a cyclodextrin material-based nanocarrier potentiates antiatherosclerotic activity of rapamycin via selectively inhibiting mTORC1 in mice. J Control Release 2016;235:48-62 View Article PubMed/NCBI
  78. Li WL, Song X, Ye L, He Z, Xiao X. Progress on Pathogenesis and Drug Therapy of Alzheimer’s Disease (in Chinese). Chin J Clin Neurosci 2021;29(5):581-589
  79. Wang D, Han RL, Luo H. Research progress of alzheimer’s disease related targets and therapeutic drugs (in Chinese). Journal of Inner Mongolia Medical University 2021;43(4):442-445 View Article
  80. Wen MM, El-Salamouni NS, El-Refaie WM, Hazzah HA, Ali MM, Tosi G, et al. Nanotechnology-based drug delivery systems for Alzheimer’s disease management: Technical, industrial, and clinical challenges. J Control Release 2017;245:95-107 View Article PubMed/NCBI
  81. Poovaiah N, Davoudi Z, Peng H, Schlichtmann B, Mallapragada S, Narasimhan B, et al. Treatment of neurodegenerative disorders through the blood-brain barrier using nanocarriers. Nanoscale 2018;10(36):16962-16983 View Article PubMed/NCBI
  82. Parveen S, Misra R, Sahoo SK. Nanoparticles: a boon to drug delivery, therapeutics, diagnostics and imaging. Nanomedicine 2012;8(2):147-166 View Article PubMed/NCBI
  83. Yadav KS, Chuttani K, Mishra AK, Sawant KK. Long circulating nanoparticles of etoposide using PLGA-MPEG and PLGA-pluronic block copolymers: characterization, drug-release, blood-clearance, and biodistribution studies. Drug Develop Res 2010;71(4):228-239 View Article
  84. Hu JP, Cao DD, Ju BW, Yang JH. Study on nasal absorption of Cistanche deserticola phenylethanol glycosides nanoemulsion in vivo. Zhongguo Zhong Yao Za Zhi 2020;45(20):4896-4901 View Article PubMed/NCBI
  85. Movassaghian S, Moghimi HR, Shirazi FH, Torchilin VP. Dendrosome-dendriplex inside liposomes: as a gene delivery system. J Drug Target 2011;19(10):925-932 View Article PubMed/NCBI
  86. Ye X, Wang C, Liu T, Xiong X, Wu M, Wang B, et al. Preparation of curcumin-loaded modifying borneol cationic liposomes and study on its brain targeting effect (in Chinese). Chinese Journal of Modern Applied Pharmacy 2021;38(12):1469-1473 View Article
  87. Ye Z. Cognitive impairment in Parkinson’s disease (in Chinese). Science & Technology Review 2017;35(19):49-55 View Article
  88. Harris MK, Shneyder N, Borazanci A, Korniychuk E, Kelley RE, Minagar A. Movement disorders. Medical Clinics of North America 2009;93(2):371-388 View Article PubMed/NCBI
  89. Gong J, Li QQ, Wang P, Zhang Y. Molecular mechanisms and drug targets of Parkinson’s disease associated with mitochondrial damage. Chinese Journal of Modern Applied Pharmacy 2021;38(13):1647-1658 View Article
  90. Du L, Jin Y. Brain-targeted nasal drug delivery systems for the treatment of neurodegenerative diseases (in Chinese). Journal of International Pharmaceutical Research 2016;43(1):104-109 View Article
  91. Stenslik MJ, Potts LF, Sonne JW, Cass WA, Turchan-Cholewo J, Pomerleau F, et al. Methodology and effects of repeated intranasal delivery of DNSP-11 in a rat model of Parkinson’s disease. J Neurosci Methods 2015;251:120-129 View Article PubMed/NCBI
  92. Zhao L, Ye M, Yu Y, Wang J. Intranasal administration of dopamine liposome in Parkinson’s disease (in Chinese). Biotech World 2016;2(99):214-215
  93. Lu CT, Zhao YZ, Yang W, Yu XC, Li X, Jin RR, et al. Experimental study of icariin nanoliposomes mediated by cavitation effect in the treatment of Parkinson’s disease via nasal olfactory region (in Chinese). 2015. Available from: https://kns.cnki.net/KCMS/detail/detail.aspx?dbname=SNAD&filename=SNAD000001686594. Accessed November 11, 2021
  94. Cheng Z, Huang J, Zhu W, Zhao Y. Effect of Intranasal administration of ilcarin propylene glycol-liposome on enhancing neuro-recovery in hemiparkinsonian rats (in Chinese). Journal of Liaoning University of Traditional Chinese Medicine 2017;19(10):29-32 View Article
  95. Cai W, Li J, Zhang M, Wang J, Hao J, Gu N. Research progress in the application of nanotechnology for the treatment of Parkinson’s disease (in Chinese). Progress in Pharmaceutical Sciences 2020;44(2):133-144
  96. Katsuyama T, Tsokos GC, Moulton VR. Aberrant T Cell Signaling and Subsets in Systemic Lupus Erythematosus. Front Immunol 2018;9:1088 View Article PubMed/NCBI
  97. Thong B, Olsen NJ. Systemic lupus erythematosus diagnosis and management. Rheumatology (Oxford) 2017;56(suppl_1):i3-i13 View Article PubMed/NCBI
  98. Li H, Yin J, Li C. Advances in B-cell targeting therapy for systemic lupus erythematosus (in Chinese). Journal of Shenyang Medical College 2021;23(5):482-485 View Article
  99. Feng RF, Xia YM. The targeted drug-based therapeutic strategies for patients with systemic lupus erythematosus (in Chinese). Dermatology Bulletin 2020;37(5):513-520+528. Available from: https://kns.cnki.net/kcms/detail/detail.aspx?FileName=ZYXW202005014&DbName=DKFX2020. Accessed November 11, 2021
  100. Mitka M. Treatment for lupus, first in 50 years, offers modest benefits, hope to patients. JAMA 2011;305(17):1754-1755 View Article PubMed/NCBI
  101. Zhang L, Li T, Xu L, Li L, Zheng Q. Model based efficacy evaluation of belimumab in patients with systemic lupus erythematosus (in Chinese). Chinese Journal of Clinical Pharmacology and Therapeutics 2021;26(2):174-181 View Article
  102. Xu H, Kuang N, Zhang Y, Min W. Research progress in treatment of rheumatoid arthritis (in Chinese). Journal of Nanchang University (Medical Sciences) 2020;60(5):97-102 View Article
  103. Abbasi M, Mousavi MJ, Jamalzehi S, Alimohammadi R, Bezvan MH, Mohammadi H, et al. Strategies toward rheumatoid arthritis therapy; the old and the new. J Cell Physiol 2019;234(7):10018-10031 View Article PubMed/NCBI
  104. Xia J, Zhu Y, Ren H, Li S, Wang J. Researches on nanomedicines in targeted therapy of rheumatoid arthritis (in Chinese). Chinese Journal of Pharmaceuticals 2019;50(7):712-721 View Article
  105. Kim SH, Kim JH, You DG, Saravanakumar G, Yoon HY, Choi KY, et al. Self-assembled dextran sulphate nanoparticles for targeting rheumatoid arthritis. Chem Commun (Camb) 2013;49(88):10349-10351 View Article PubMed/NCBI
  106. Yang Y, Guo L, Wang Z, Liu P, Liu X, Ding J, et al. Targeted silver nanoparticles for rheumatoid arthritis therapy via macrophage apoptosis and Re-polarization. Biomaterials 2021;264:120390 View Article PubMed/NCBI
  107. Kim J, Kim HY, Song SY, Go SH, Sohn HS, Baik S, et al. Synergistic oxygen generation and reactive oxygen species scavenging by manganese ferrite/ceria co-decorated nanoparticles for rheumatoid arthritis treatment. ACS Nano 2019;13(3):3206-3217 View Article PubMed/NCBI
  108. An L, Li Z, Shi L, Wang L, Wang Y, Jin L, et al. Inflammation-targeted celastrol nanodrug attenuates collagen-induced arthritis through NF-κB and Notch1 pathways. Nano Lett 2020;20(10):7728-7736 View Article PubMed/NCBI
  109. Rendon A, Schäkel K. Psoriasis pathogenesis and treatment. Int J Mol Sci 2019;20(6):E1475 View Article PubMed/NCBI
  110. Greb JE, Goldminz AM, Elder JT, Lebwohl MG, Gladman DD, Wu JJ, et al. Psoriasis. Nat Rev Dis Primers 2016;2:16082 View Article PubMed/NCBI
  111. Honma M, Hayashi K. Psoriasis: Recent progress in molecular-targeted therapies. J Dermatol 2021;48(6):761-777 View Article PubMed/NCBI
  112. Shen SX, Wang G. New progress in pathogenesis and immunotargeted therapy of psoriasis (in Chinese). Journal of Practical Dermatology 2018;11(5):281
  113. Yang K, Oak ASW, Elewski BE. Use of IL-23 Inhibitors for the treatment of plaque psoriasis and psoriatic arthritis: a comprehensive review. Am J Clin Dermatol 2021;22(2):173-192 View Article PubMed/NCBI
  114. Ru Y, Wang Q, Liu X, Zhang M, Zhong D, Ye M, et al. The chimeric ubiquitin ligase SH2-U-box inhibits the growth of imatinib-sensitive and resistant CML by targeting the native and T315I-mutant BCR-ABL. Sci Rep 2016;6:28352 View Article PubMed/NCBI
  115. Jabbour E, Kantarjian H. Chronic myeloid leukemia: 2018 update on diagnosis, therapy and monitoring. Am J Hematol 2018;93(3):442-459 View Article PubMed/NCBI
  116. Li Y, Hao G, Wang X, Cheng Y. Clinicalresearch of children with chronic myeloid leukemia treated with targeted therapy (in Chinese). Journal of China Pediatric Blood and Cancer 2019;24(1):27-31 View Article
  117. Xia Y. Progress in experimental research of targeted drugs for chronic myelogenous leukemia (in Chinese). Journal of Clinical Medical 2016;3(12):2446-2447 View Article
  118. Serrano-Del Valle A, Reina-Ortiz C, Benedi A, Anel A, Naval J, Marzo I. Future prospects for mitosis-targeted antitumor therapies. Biochem Pharmacol 2021;190:114655 View Article PubMed/NCBI
  119. Zhang A, Kong L. Epidemic situation and countermeasures of chronic diseases (in Chinese). Chinese Journal of Prevention and Control of Chronic Diseases 2005;13(1):1-3
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  • Journal of Exploratory Research in Pharmacology
  • pISSN 2993-5121
  • eISSN 2572-5505

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Delivery System for Targeted Drug Therapy in Chronic Diseases

Yuan-Qi Jiang, Jin-Peng Chen, Yu-Jie Dong, Fu-Jun Zhou, Cheng-Wang Tian, Chang-Qing Chen
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