Next Article in Journal
β-Elemene Reverses Gefitinib Resistance in NSCLC Cells by Inhibiting lncRNA H19-Mediated Autophagy
Previous Article in Journal
Evaluation of Serial Procalcitonin Levels for the Optimization of Antibiotic Use in Non-Critically Ill COVID-19 Patients
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Pharmaceuticals
Volume 17
Issue 5
10.3390/ph17050625
pharmaceuticals-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Research Progress of Drug Delivery Systems Targeting the Kidneys

by
Li-Feng Huang
†,
Qiao-Ru Ye
†,
Xiao-Cui Chen
,
Xiao-Rong Huang
,
Qiao-Fei Zhang
,
Chun-Yu Wu
,
Hua-Feng Liu
* and
Chen Yang
*
Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Institute of Nephrology, Affiliated Hospital of Guangdong Medical University, Zhanjiang 524001, China
*
Authors to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Pharmaceuticals 2024, 17(5), 625; https://doi.org/10.3390/ph17050625
Submission received: 18 March 2024 / Revised: 3 May 2024 / Accepted: 10 May 2024 / Published: 13 May 2024
(This article belongs to the Section Pharmaceutical Technology)
Browse Figures
Versions Notes

Abstract

:
Chronic kidney disease (CKD) affects more than 10% of the global population, and its incidence is increasing, partially due to an increase in the prevalence of disease risk factors. Acute kidney injury (AKI) is an independent risk factor for CKD and end-stage renal disease (ESRD). The pathogenic mechanisms of CKD provide several potential targets for its treatment. However, due to off-target effects, conventional drugs for CKD typically require high doses to achieve adequate therapeutic effects, leading to long-term organ toxicity. Therefore, ideal treatments that completely cure the different types of kidney disease are rarely available. Several approaches for the drug targeting of the kidneys have been explored in drug delivery system research. Nanotechnology-based drug delivery systems have multiple merits, including good biocompatibility, suitable degradability, the ability to target lesion sites, and fewer non-specific systemic effects. In this review, the development, potential, and limitations of low-molecular-weight protein–lysozymes, polymer nanomaterials, and lipid-based nanocarriers as drug delivery platforms for treating AKI and CKD are summarized.

Graphical Abstract

1. Introduction

Chronic kidney disease (CKD) affects more than 10% of the global population, and its incidence is increasing, partially due to increases in the prevalence of disease risk factors, such as diabetes, hypertension, obesity, and old age [1]. Acute kidney injury (AKI) is a syndrome with multiple etiologies [2] that affects approximately 1.33 million patients per year, leading to a significant impact on hospitalization and mortality rates, especially in severely ill patients [3]. AKI is a risk factor for CKD and accelerates its progression to ESRD [4].
Immune dysfunction and renal inflammation are the major pathological features of CKD that aggravate renal function loss. Hormones and immunosuppressants are common forms of medication used to treat CKD that suppress renal inflammation. However, the long-term use of high concentrations of these drugs is associated with adverse effects and inefficiency [5,6,7]. The known pathogenic mechanisms of CKD provide several potential therapeutic targets; however, some targets are cell specific. Transforming growth factor-β (TGF-β) plays a key role in triggering renal fibrosis during the development of CKD and is positively correlated with the severity of the disease [8]. Although anti-TGF-β treatment inhibits the pro-fibrotic effects of renal resident cells, such as renal tubular epithelial cells and fibroblasts, the loss of TGF-β may lead to the hyperactivation of immune cells and increase renal inflammation [9]. Similarly, renin–angiotensin system blockade delays the progression of proteinuria and hypertensive nephropathy [1,10]. However, the stimulation of AT1 in macrophages or T cells attenuates renal fibrosis [11,12]. In summary, the off-target effects of existing therapeutics limit their use for the treatment of different kidney diseases. Therefore, cell-specific drug delivery systems may provide suitable therapeutic approaches for AKI and CKD.

Overview of Targeted Drug Delivery Systems

Targeted drug delivery systems (TDDSs) are drugs encapsulated in a carrier that can be selectively concentrated and localized into target organs, tissues, cells, or intracellular structures via topical administration or systemic blood drug circulation. For drugs to be considered as TDDSs, they require five key characteristics: positioning (releasing the drug at the specified location), controlled release [13], non-toxicity, biocompatibility, and biodegradability [14]. The primary purpose of targeted drug administration is to improve drug efficacy and reduce the rate of adverse effects [15]. Improvements in dosing strategies also improve safety, effectiveness, reliability, and patient compliance; therefore, TDDSs are increasingly valued by the global medical community.
Based on the various targeting mechanisms available, targeted drug delivery can be categorized as passive or active or as physical chemistry targeting [13]. Passive targeted drug delivery utilizes the physiological characteristics of specific tissues and organs to naturally create distribution differences in the body, thereby achieving a targeting effect. Active targeted drug delivery refers to drugs or carriers endowed with abilities to combine with special targets. Active TDDSs include three main components: drugs, carriers, and targeted ligands. The encapsulated drugs include small-molecule proteins, small-molecule nucleic acids, or small-molecule precursor drugs (Figure 1A). With the advancement of nanotechnology, an increasing number of beneficial nanomaterials have been developed. Nanomaterials have been utilized as carriers for drug delivery in various studies, including chitosan [16,17], poly lactic-co-glycolic acid (PLGA) [18,19], lipid nanocarriers [20], and polyamidoamine dendrimers (PAMAMs) [21]. Additionally, small molecule peptides, such as low-molecular-weight proteins (LMWPs) [22] and elastin-like polypeptides (ELPs) [23], can also serve as effective carriers. Furthermore, the use of cell-derived extracellular vesicles as drug delivery vehicles is a current area of research interest [24] (Figure 1B). The use of drugs encapsulated by carriers can enhance their effects by improving their absorption and lowering their dosages, resulting in fewer adverse effects than traditional medicine [25]. Similarly, the encapsulation of drugs by these carriers has been shown in other studies to enhance their effects by improving absorption and reducing dosages, thereby minimizing the rate of adverse effects compared to traditional medicine [25,26,27]. Targeted ligands are specific functional groups and biologically active molecules [28] including peptides, antibodies, TRX-20, and DSPE-PEG-GLU (Figure 1C). Chemical bonds connect the carrier that encapsulates the drug, forming a targeting complex to direct its action to the kidney (Figure 1D,E). Physical chemistry targeting involves the application of various physical and chemical methods to facilitate the targeted delivery of therapeutic agents for specific drug effects at a particular site [29].

2. Kidney-TDDS

2.1. LMWPs and Small-Molecule Peptide TDDSs

2.1.1. LMWP–Lysozyme

The glomerular filtration barrier includes charge and molecular barriers that prevent large molecules from passing from the blood into the urine (Figure 2A). LMWPs with molecular weights of <30 kDa can cross the glomerular filtration barrier freely and are absorbed by the proximal tubules via megalin/cubilin-mediated endocytosis (Figure 2B). Lysozymes (LZM) weighing 14.3 kDa are considered non-immunogenic [30] and are ideal carriers for the delivery of drugs to the proximal tubules [31].
Imatinib, an anticancer drug, can also be used to treat renal interstitial fibrosis, as it inhibits platelet-derived growth factor receptors (PDGFRs) and Abelson tyrosine kinases (c-Abl) [32]. Dolman et al. prepared a kidney-targeted LZM–imatinib complex using a platinum-based linker that accumulates in renal proximal tubular cells 30-fold more accurately than imatinib in equal doses without any cardiotoxicity [33]. Baicalin (BAI) is a Chinese herbal medicine that reduces insulin resistance and protects the kidneys. In their recent study, Zheng et al. synthesized a BAI-LZM conjugate that mitigated diabetic nephropathy (DN) better than BAI alone in a rat model through the inhibition of inflammation by targeting NF-kB signaling [34]. In a similar manner, Pan et al. covalently connected methylprednisolone (MP) with LZMs via an ester bond, increasing the targeting efficiency of active MP by approximately 14 times compared to that of free MP. Moreover, the use of tissue imaging in their study showed that the conjugate quickly reaches the kidney and continues acting in the kidney for up to 12 h [35]. Not only do LZMs improve drug utilization, but also they reduce the rate of adverse effects caused by the drug in question due to their excellent targeting ability. Nevertheless, further optimization is necessary before the commercial production and purification of LZMs [36].

2.1.2. Peptides

Peptides are highly selective, effective, and relatively safe [37]. Engel et al. constructed a complex that modified ELP–vascular endothelial growth factor (VEGF) with the inactive peptide KTP (CLPVASC) to target renal tubules. Compared with ELP-VEGF, KTP-ELP-VEGF was found to mitigate renal vascular stenosis and improve filtration functions in a swine chronic renovascular disease (RVD) model by inhibiting macrophage infiltration and reducing fibrosis [38]. Basic fibroblast growth factors (bFGFs) were found to reduce apoptosis and excessive endoplasmic reticulum stress in a renal ischemia–reperfusion (I/R) model [39]. However, they easily diffuse into the body, significantly reducing the drug concentration in the kidneys and leading to adverse effects. In their recent study, Song et al. prepared a targeted injured kidney (KIT, CNWMINKEC)-bFGF compound that utilized KIT to bind to kidney injury molecule-1 (KIM-1), a transmembrane glycoprotein that is highly expressed in damaged tubules during I/R-induced AKI. KIT-bFGF significantly reduced tubular apoptosis and protected against renal I/R through the ERK1/2 and Akt signaling pathways [40]. Compared to biologics and small molecules, peptides have the advantages of permeability, high selectivity, and ease of internalization by cells [41]. However, one disadvantage of peptides is that they are easily cleared from the body due to their low molecular weight (<5000 Da).

2.2. Lipid-Based Nanocarriers

A number of different lipid-based systems have been reported in the literature, including liposomes, micelles, emulsions, and solid lipid nanoparticles (SLNSs) [42]. They are reported to have good biocompatibility, biodegradability, low toxicity, and immunogenicity and are reported to be easy to modify through the use of various ligands and functional molecules.
Liposomes, a commonly used nanocarrier system, are tiny, hollow spherical structures composed of one or two phospholipid molecules with a bilayer membrane structure. Due to their unique structure, liposomes are lipophilic and hydrophobic, making it simple for liposomes to encapsulate water-soluble and lipid-soluble drugs. Mesangial cells are a type of glomerular intrinsic cells that are involved in a variety of biological responses associated with glomerular disease. Liposomes modified with TRX-20 were found to demonstrate specific targeting toward mesangial cells by binding to chondroitin sulfate proteoglycan [43] (Figure 2E). Yuan ZX et al. used TRX-20 to modify the liposomes that encapsulated the drug triptolide (TP) to form a TRX-TP-LP complex [44]. To prolong the circulation of the complex in the blood, PEG was used to further modify the surface of TRX-TP-LP to form PEG-TRX-TP-LP to target mesangial cells in glomeruli. Compared to the equivalent dose of free TP, PEG-TRX-TP-LP attenuated LPS-induced inflammatory responses in vitro. In addition, in vivo, PEG-TRX-TP-LP effectively alleviated the symptoms of membranous nephropathy (MN) in a rat model. Astaxanthin (AST) is a natural, non-toxic xanthophyll carotenoid with antioxidant capacity. Its low stability and solubility severely limit its application. Oxidative stress is one of the main pathological mechanisms caused by diabetic nephropathy. In their recent study, Chen Z et al. used a glucose-PEG600-DSPE ligand to modify liposomes coated with AST to form an AST-GLU-LIP complex, which specifically transports AST by interacting with glucose transporter 1 (GLUT1), which is highly expressed in glomerular mesangial cells in DN [45] (Figure 2E). The findings of their study indicated that AST-GLU-LIP enhanced the bioavailability and antioxidant capacity of AST. Microvascular endothelial cells play a crucial role in the pathogenesis of sepsis-induced inflammation-mediated organ damage, including kidney injury. Although glucocorticoids have anti-inflammatory effects, they do not have the therapeutic potential to alleviate endothelial cell activation during sepsis due to inadequate drug delivery. In their recent study, Li et al. combined the cationic lipid SAINT-C18 (1-methyl-4-(cis-9-dioleyl) methyl-pyridinium chloride), termed SAINT-O-Somes, with dexamethasone. The SAINT-O-Somes were modified with anti-vascular cell adhesion molecule-1 (anti-VCAM-1) antibodies. Dexamethasone-loaded anti-VCAM-1 SAINT-O-Somes specifically targeted VCAM-1-expressed endothelial cells and effectively reduced inflammation in the kidneys during sepsis [46] (Figure 2C). Cationic liposomes may pose a significant disadvantage when administered intravenously, as this form of administration can lead to high levels of toxicity and a lack of specific targeting [28].
Solid lipid nanocarriers are generally prepared from degradable and biocompatible components. They are novel drug carriers with long release time, low toxicity, and better cellular absorption ability than traditional colloidal carriers. Antioxidants such as phenolic compounds have several benefits for the human body [47] and can be used to treat type 2 diabetes mellitus and DN via the inhibition of reactive oxygen species generation [48]. Myristicin is a polyphenolic compound and flavanol glycoside derived from plants that can lower blood sugar and exert anti-apoptotic and anti-inflammatory activities and antioxidant functions [49]. However, it has low bioavailability due to its poor water solubility, thus limiting its application [50]. Ahangarpour et al. formed solid lipid nanoparticles (SLNs) of myricitrin via cold homogenization. Compared with free myristicin, SLNs with myristicin have a better therapeutic effect on DN by inhibiting oxidative stress and increasing antioxidant enzyme production [51]. Celastrol (CLT) is an active ingredient in Tripterygium Wilford that is effective for the treatment of DN but is limited by its toxicity [52]. Endothelial injury and podocyte damage are the major causes of glomerulosclerosis. Wu et al. synthesized CLT–phospholipid nanoparticles (PLNs) and covered the CLT-PLN surface with a VCAM-1-targeting peptide (sequence: VHPKQHRGGSKGC) that specifically released CLT to VCAM-1-positive glomerular endothelial cells and podocytes [53] (Figure 2C,D). CLT-PLN effectively reduced podocyte and endothelial damage and the glomerular inflammatory response, leading to delayed CKD progression with almost no CLT toxicity. These nanoparticles provide an effective delivery strategy to the glomerulus. In addition, lipid-based nanocarriers are excellent carriers for drug delivery due to their biocompatibility, minimal toxicity, degradability, and ease of modification. Most importantly, large-scale production is the greatest advantage of the use of lipid-based nanocarriers relative to other polymer materials [54,55]. However, the synthesis of lipid-based carriers, as well as their size and charge, is important for the kidneys, limiting their ability to achieve targeted drug delivery [56,57]. Maintaining a stable carrier size and selecting an appropriate charge are key factors in targeted drug delivery. Solid lipid nanocarriers still have some shortcomings that need to be addressed, such as the large amount of water present in these nanocarriers, their limited drug-loading capacity, and the possible formation of crystals in solid lipids during storage [58].

2.3. Polymeric Nanoparticle TDDSs

Polymeric materials have attracted increasing attention in medical biology research due to their biodegradability, controlled release, extended cycle time, low toxicity, and ability to carry drugs [18].

2.3.1. Chitosan

Chitosan is the primary derivative of chitin [59]. Chitin is converted into chitosan via enzymatic preparations or chemical processes [60]. Chemical methods are more suitable for large-scale production due to their low cost [60]. Chitosan carriers include polysaccharides and have a mechanism similar to that of ELPs [61]. Szeto-Schiller-31 (SS31) is a mitochondria-targeted peptide that reduces mitochondrial damage by scavenging free oxygen radicals [62]. Liu et al. synthesized SC-TK-SS31 by combining SS31 with l-serine-modified chitosan (SC) using a reactive oxygen species-sensitive thioketal (TK) linker. Through the modification of L-serine, SC-TK-SS31 accumulates in tubular epithelial cells via the specific interaction of L-serine with KIM-1 (Figure 2B), enhancing the therapeutic effect of SS-31 [63]. Wang et al. constructed a stepwise-targeted chitosan oligosaccharide, triphenyl phosphine low-molecular-weight chitosan–curcumin (TPP-LMWC-CUR, TLC), which was used to treat AKI induced by sepsis by clearing excessive reactive oxygen species in tubular epithelial cells. TLC is quickly distributed in the kidneys and specifically internalized by the renal tubules through interactions between the receptor megalin and LMWCs. Due to the high buffering capacity of LMWCs and the positive delocalization charge of TPPs, intracellular TLCs can deliver CURs to the mitochondria [64]. However, chitosan production is expensive. In addition, it is easily affected by several factors, and the efficiency of dissolution is poor, which may account for the low yield. Therefore, the problem of standardized production requires further research efforts for a solution [65].

2.3.2. Polyamidoamine Dendrimers

In the late 1990s, polyamidoamine dendrimers (PAMAMs) were extensively studied as drug carriers due to their ease of preparation and commercial availability [66]. PAMAMs decorated with neutral or negatively charged groups have been reported to reduce the toxicity caused by strong electrostatic interactions between PAMAMs and cell membranes [67]. PAMAMs increase drug solubility, stability, and bioavailability, facilitate synthesis methods, and are promising dendrimers in the field of drug delivery [68]. Serine-modified PAMAMs are a promising delivery vehicle that target renal tubules (Figure 2B).
Captopril (CAP) is an angiotensin-converting enzyme (ACE) inhibitor associated with rare cases of acute liver injury. Matsuura et al. combined captopril with a disulfide bond in l-serine-modified PAMAMs. In addition, compared to the non-targeted group, up to 82% of the dose of serine-PAMAM-CAP accumulated in the kidneys, and the duration of ACE inhibition was longer than that after the injection of CAP alone [69].
Nitric oxide (NO) contributes to the pathogenesis of renal I/R injury (Schneider et al., 2003, https://www.kidney-international.org/article/S0085-2538(15)49309-3/fulltext). NO donors are physiologically active drugs that release NO into the body. However, the efficient prevention of renal I/R injury requires large amounts of NO donors, and most existing NO donors are rarely distributed in the kidney [70,71]. Katsumi et al. developed S-nitrosyl-L-serine-modified PAMAMs (SNO-Ser-PAMAMs), in which multiple S-nitrosothiols (NO donors) are covalently bound to L-serine-modified dendrimers as kidney-targeted NO donors [72]. In a murine model of renal ischemia–reperfusion (I/R) injury, the intravenous administration of SNO-Ser-PAMAMs effectively attenuated histological damage in the kidneys and reduced blood creatinine levels [72]. Matsuura et al. and Katsumi et al. reported that wrapping CAP and NO donors with dendritic macromolecules with a specific binding modification of serine to KIM-1 localized the drug to the kidneys and increased the retention of the drug in the kidneys without any toxicity. The flexibility and biocompatibility as well as the biodegradability of PAMAMs make them an attractive option for drug delivery [73]. However, there are specific concerns that require further attention. Firstly, unmodified PAMAM materials with positively charged surfaces are generally considered toxic [74]. Secondly, smaller PAMAMs can be easily eliminated by the kidneys; in contrast, larger ones tend to be recognized by the reticuloendothelial system (RES) [75]. To mitigate these effects, surface modifications have been employed to improve both the toxicity profile of the vector and its clearance rate [68]. The toxicity of dendrimers can be reduced by acetylating and PEGylating peripheral positively charged groups to modify them. This approach helps to mitigate the toxic effects of dendrimers, making them a more viable option for various applications [76].

2.3.3. PEG-PLGA/PEI-PCL

PLGA has been approved for use as a drug delivery system in humans by the US Food and Drug Administration and the European Medicine Agency [77]. PLGA-based nanoparticles are easily captured and removed by the reticuloendothelial system following intravenous injection [78]. Polyethylene glycol (PEG) is non-toxic and soluble in water and organic solvents. It has no immunogenicity and is ultimately excreted through the kidneys, making it a suitable drug carrier. Materials such as PLGA-containing PEG chain segments have been designed to regulate their degradation and the release behavior of drugs by controlling their hydrophilic/hydrophobic properties [79]. The use of PEG to modify PLGA increases the overall cycle time and bioavailability.
Asiatic acid (AA) is a triterpenoid compound primarily found in the medicinal plant Centella asiatica. It exhibits a range of biological activities, including anti-inflammatory, anticancer, hepatoprotective, renoprotective, and anti-fibrotic effects [22,80,81]. However, the limited water solubility of AA restricts its application. He et al. used the peptide KTP (sequence: CLPVASC)-modified PLGA-PEG as a drug carrier and wrapped insoluble AA in a vehicle, which targeted renal tubular epithelial cells via megalin-mediated endocytosis (Figure 2B), resulting in protection against renal fibrosis [82]. Toll-like receptors (TLRs) are a type of pattern recognition receptors that play a crucial role in regulating both innate and adaptive immunity [83,84]. The results of a previous study showed that mice with selective knockout of TLR9 in the renal proximal tubules were protected against I/R-induced AKI [85]. Therefore, a selective TLR9 antagonist (ODN2088) could be considered a promising drug for the treatment of AKI. However, TLR9 is expressed in several cells and organs [86] and may be accompanied by diverse effects. A recent study reported that mesoscale nanoparticles based on polymers exhibit a seven-fold greater localization in the proximal tubules of the kidney compared to other organs. This finding suggests a potential targeting advantage for these in renal drug delivery applications [87]. Han et al. packaged the selective TLR9 antagonist ODN2088 into medium-sized PLGA-PEG nanoparticles. Through the endocytosis of tubules, they release the TLR9 antagonist ODN2088 and suppress TLR9 to relieve tubular necrosis and the renal production of pro-inflammatory cytokines caused by I/R reperfusion [88].
Polycaprolactone–polyethyleneimine (PCL-PEI) is a carrier material that can be used for the co-administration of nucleic acid and small-molecule chemical drugs. This polymer can form cationic micelles via self-assembly and load negatively charged drugs, such as nucleic acids, based on the action of the charge. Rhein is a monomeric compound isolated from rhubarb and is a traditional Chinese medicine. It has been found to possess antioxidant, anti-apoptotic, and anti-inflammatory properties that can effectively protect the kidneys; however, its low solubility and poor bioavailability in vivo limit its clinical application [89]. Wang et al. first wrapped Rhein in PCL-PEI to form PRR nanoparticles. The surface of PRR nanoparticles is covered with a layer of liposomes modified by KTP through the action of electrostatic attraction in the PRR to form kidney-targeted lipid nanoparticles (KLPPRs). With the modification of KTP, KLPPR accumulates in the kidneys to a greater level than in other major organs (Figure 2B). In addition, KLPPR is not as easily cleared in the urine as LPPR. Therefore, the use of KLPPR is an effective method for enhancing the distribution and retention of Rhein in the kidneys, as well as increasing its solubility and bioavailability [90].
Although the surface modification of PLGA and PCL can improve the bioavailability of drugs and reduce the rate of side effects caused by said drugs, there are still some challenges that must be addressed. One is developing a novel method to achieve the large-scale production of high-quality drugs [91]. Additionally, limited drug-loading capacity may impose restrictions on their application [92].

2.4. Exosome TDDS

Exosomes are extracellular vesicles secreted by all cell types that are capable of carrying small molecules such as nucleic acids and small protein molecules [93]. Exosome-based treatment utilizes the genetic material carried by the exosome to repair the lesion site. Alternatively, exosomes can serve as natural drug delivery vehicles, transporting specific drugs to the lesion site through modifications [94].
Mesenchymal stromal cells (MSCs) possess the ability to self-renew and facilitate repair [95]. It has been reported that exosomes derived from MSCs (referred to as MSC-exos) have demonstrated an ability to mitigate cisplatin-induced acute kidney injury (AKI) by inhibiting oxidative stress and cell apoptosis [96]. Cao et al. reported that MSC-exos are home to damaged renal tubules expressing VCAM-1 and intercellular adhesion molecule 1 (ICAM-1) during renal I/R injury via integrins [97] (Figure 2B). MiR-125b-5p/p53 has been reported to be the main molecule present in stem cell-derived exosomes that reduces AKI and promotes kidney repair. MSC-exos have a favorable safety profile. In addition, MSC-exos can be removed by the immune system once they have exerted their function; considering this, the potentially tumorigenic effects of MSCs can be considered negligible. However, the possibility of variance between different individuals leads to unstable efficacy; as such, personalized treatment is required.
Apart from MSC-exos, engineered exosomes are a class of modified exosomes that have enhanced drug-loading efficiency, targeting, and resistance to the clearance of natural exosomes after bioengineering technology. Tang et al. incubated dexamethasone with RAW264.7 macrophages to induce the secretion of dexamethasone-containing exosomes and used integrin on the extracellular vesicle surface to specifically bind to ICAM-1 and VCAM-1 to achieve anti-inflammatory effects and reduce the rate of side effects caused by dexamethasone [98] (Figure 2B). In addition to dexamethasone, interleukin (IL)-10 was loaded onto macrophage-derived exosomes by specifically binding to ICAM-1. The extracellular vesicles delivering IL-10 enhance IL-10 stability and target the damaged kidney, resulting in significant renal protection (Figure 2B). These results emphasize the significant feasibility of targeting ICAM and drug vectors [94,99]. Erythrocyte-derived exosomes modified with peptides (sequence: LTHVVWL) that specifically bind to KIM-1 combined with p65 and Snail-1 siRNA loaded into exosomes can be used to treat AKI [100] (Figure 2B).
Compared to other targeted drug delivery systems, exosomes exhibit exceptional biocompatibility and minimal immunogenicity owing to their endogenous nature [101,102]. However, their utilization still encounters certain challenges. Despite the availability of various sources for deriving exosomes, there is a lack of standardized methods for their separation and extraction to ensure optimal purity [101,103,104,105]. Moreover, enhancing the loading efficiency of exosomes remains a formidable task. Meeting clinical translational needs necessitates addressing the arduous problem of producing high-quality and large-scale vectors for disease treatment [103].

3. Challenge and Perspective

Good biocompatibility, biodegradability, and low toxicity are essential features of a highly effective targeted drug delivery vector. In addition, drugs with poor solubility and adverse effects can be administered through carrier encapsulation. However, targeted drug delivery has limitations. Long-term drug use may lead to adverse events related to the stability and purity of the carrier. There is also difficulty in maintaining stable targeting efficiency during repeated dosing.
The specificity, stability, and efficacy of drug delivery require further research regarding targeted delivery strategies. Phage display technology and single-cell sequencing may be useful tools in efforts to discover target molecules or cell-specific ligands. Intelligent response targeting strategies can be designed according to changes in the microenvironment of kidney disease. Changes in targeting strategies and improvements in the durability, stability, and specificity of the vector also require further research.

4. Conclusions

The kidney, as a major organ responsible for the excretion of metabolites, receives about 25% of the total cardiac blood transfusion. The selection of targeted delivery vectors with reduced nephrotoxicity to minimize potential harm is essential for the successful translation of biotechnology into clinical applications. Targeted therapy of the kidney has demonstrated its potential for the treatment of different kidney diseases (Table 1). It remains necessary to find suitable drug delivery vectors and continuously optimize renal targeting strategies in the future.

Author Contributions

L.-F.H., Q.-R.Y. and X.-C.C.: conceptualization, resources, and writing—original draft. X.-R.H., Q.-F.Z. and C.-Y.W.: resources and writing—original draft. H.-F.L. and C.Y.: supervision, funding acquisition, and writing—review and editing. All authors have read and agreed to the published version of the manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (grant numbers: 82370705, 81700627, 81670654, and 81974095), the Natural Science Foundation of Guangdong Province (grant numbers: 2023A1515030024, 2021A1515011581, and 2019A1515010678), Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases (grant number: 2022B1212030003), the Discipline Construction Project of Guangdong Medical University (grant number: 4SG21229G), the National Clinical Key Specialty Construction Project (Institute of Nephrology, Affiliated Hospital of Guangdong Medical University), and the Affiliated Hospital of Guangdong Medical University Clinical Research Program (grant number: LCYJ2018C008).

Acknowledgments

We thanks Zhen-nan Ye, Ji-xin Tang, and Ning An for resources and suggestions.

Conflicts of Interest

The authors declare that they have no competing interests.

Abbreviations

AA: asiatic acid; ACE: angiotensin-converting enzyme; AKI: acute kidney injury (AKI); AST: astaxanthin; BAI: baicalin; bFGFs: basic fibroblast growth factors; c-Abl: Abelson tyrosine kinase; CAP: captopril; CKD: chronic kidney disease; CLT: celastrol; CUR: curcumin; DN: diabetic nephropathy; DSPE-PEG-GLU: phospholipid–polyethylene glycol–glucose; ELP: elastin-like polypeptides; ESRD: end-stage renal disease; GLUT1: glucose transporter 1; I/R: ischemia–reperfusion: ICAM-1: intercellular adhesion molecule-1; KIM-1: kidney injury molecule-1; KLPPRs: kidney-targeted lipid nanoparticles; LMWC: low-molecular-weight chitosan; LMWPs: low-molecular-weight proteins; LZM: lysozymes; MN: membranous nephropathy; MSCs: mesenchymal stromal cells; MP: methylprednisolone; NO: nitric oxide; PAMAM: polyamidoamine dendrimers; PCL-PEI: polycaprolactone–polyethyleneimine; PDGFR: platelet-derived growth factor receptors; PEG: polyethylene glycol; PLGA: poly lactic-co-glycolic acid; RES: reticuloendothelial system; RVD: chronic renovascular disease; SLNs: solid lipid nanoparticles; SS31: Szeto-Schiller-31; TDDs: targeted drug delivery systems; TGFβ: transforming growth factor-β; TLC: triphenyl phosphine low-molecular-weight chitosan–curcumin; TLRs: Toll-like receptors; TP: triptolide; TRX-20: 3,5-dipentadecyloxybenzamidine hydrochloride; VCAM-1: vascular cell adhesion molecule-1; and VEGF: vascular endothelial growth factor.

References

  1. Ruiz-Ortega, M.; Rayego-Mateos, S.; Lamas, S.; Ortiz, A.; Rodrigues-Diez, R.R. Targeting the progression of chronic kidney disease. Nat. Rev. Nephrol. 2020, 16, 269–288. [Google Scholar] [CrossRef]
  2. Kellum, J.A.; Romagnani, P.; Ashuntantang, G.; Ronco, C.; Zarbock, A.; Anders, H.J. Acute kidney injury. Nat. Rev. Dis. Primers 2021, 7, 52. [Google Scholar] [CrossRef]
  3. Geo, H.N.; Murugan, D.D.; Chik, Z.; Norazit, A.; Foo, Y.Y.; Leo, B.F.; Teo, Y.Y.; Kadir, S.; Chan, Y.; Chai, H.J.; et al. Renal Nano-drug delivery for acute kidney Injury: Current status and future perspectives. J. Control Release 2022, 343, 237–254. [Google Scholar] [CrossRef]
  4. Mehta, R.L.; Cerda, J.; Burdmann, E.A.; Tonelli, M.; Garcia-Garcia, G.; Jha, V.; Susantitaphong, P.; Rocco, M.; Vanholder, R.; Sever, M.S.; et al. International Society of Nephrology’s 0by25 initiative for acute kidney injury (zero preventable deaths by 2025): A human rights case for nephrology. Lancet 2015, 385, 2616–2643. [Google Scholar] [CrossRef]
  5. Wojciechowski, D.; Wiseman, A. Long-Term Immunosuppression Management: Opportunities and Uncertainties. Clin. J. Am. Soc. Nephrol. 2021, 16, 1264–1271. [Google Scholar] [CrossRef]
  6. Quan, X.Y.; Chen, H.T.; Liang, S.Q.; Yang, C.; Yao, C.W.; Xu, Y.Z.; Liu, H.F.; An, N. Revisited Cyclophosphamide in the Treatment of Lupus Nephritis. Biomed. Res. Int. 2022, 2022, 8345737. [Google Scholar] [CrossRef]
  7. Li, Z.H.; An, N.; Huang, X.J.; Yang, C.; Wu, H.L.; Chen, X.C.; Pan, Q.J.; Liu, H.F. Cyclosporine A blocks autophagic flux in tubular epithelial cells by impairing TFEB-mediated lysosomal function. J. Cell Mol. Med. 2021, 25, 5729–5743. [Google Scholar] [CrossRef]
  8. Sravani, S.; Saifi, M.A.; Godugu, C. Riociguat ameliorates kidney injury and fibrosis in an animal model. Biochem. Biophys. Res. Commun. 2020, 530, 706–712. [Google Scholar] [CrossRef]
  9. Gu, Y.Y.; Liu, X.S.; Huang, X.R.; Yu, X.Q.; Lan, H.Y. TGF-beta in renal fibrosis: Triumphs and challenges. Future Med. Chem. 2020, 12, 853–866. [Google Scholar] [CrossRef]
  10. Loutradis, C.; Price, A.; Ferro, C.J.; Sarafidis, P. Renin-angiotensin system blockade in patients with chronic kidney disease: Benefits, problems in everyday clinical use, and open questions for advanced renal dysfunction. J. Hum. Hypertens. 2021, 35, 499–509. [Google Scholar] [CrossRef]
  11. Wen, Y.; Rudemiller, N.P.; Zhang, J.; Jeffs, A.D.; Griffiths, R.; Lu, X.; Ren, J.; Privratsky, J.; Crowley, S.D. Stimulating Type 1 Angiotensin Receptors on T Lymphocytes Attenuates Renal Fibrosis. Am. J. Pathol. 2019, 189, 981–988. [Google Scholar] [CrossRef] [PubMed]
  12. Zhang, J.D.; Patel, M.B.; Griffiths, R.; Dolber, P.C.; Ruiz, P.; Sparks, M.A.; Stegbauer, J.; Jin, H.; Gomez, J.A.; Buckley, A.F.; et al. Type 1 angiotensin receptors on macrophages ameliorate IL-1 receptor-mediated kidney fibrosis. J. Clin. Invest. 2014, 124, 2198–2203. [Google Scholar] [CrossRef]
  13. Adepu, S.; Ramakrishna, S. Controlled Drug Delivery Systems: Current Status and Future Directions. Molecules 2021, 26, 5905. [Google Scholar] [CrossRef]
  14. Goldberg, M.; Langer, R.; Jia, X. Nanostructured materials for applications in drug delivery and tissue engineering. J. Biomater. Sci. Polym. Ed. 2007, 18, 241–268. [Google Scholar] [CrossRef]
  15. Pandey, J.; Dubey, R.; Kate, A.; Prasad, B.; Sinha, A.; Mishra, M.S. Nanomedicines: A Focus on Nanomaterials as Drug Delivery System with Current Trends and Future Advancement. Drug Res. 2022, 72, 355–366. [Google Scholar] [CrossRef] [PubMed]
  16. Gong, X.; Gao, Y.; Shu, J.; Zhang, C.; Zhao, K. Chitosan-Based Nanomaterial as Immune Adjuvant and Delivery Carrier for Vaccines. Vaccines 2022, 10, 1906. [Google Scholar] [CrossRef]
  17. Gao, Y.; Wu, Y. Recent advances of chitosan-based nanoparticles for biomedical and biotechnological applications. Int. J. Biol. Macromol. 2022, 203, 379–388. [Google Scholar] [CrossRef]
  18. Su, Y.; Zhang, B.; Sun, R.; Liu, W.; Zhu, Q.; Zhang, X.; Wang, R.; Chen, C. PLGA-based biodegradable microspheres in drug delivery: Recent advances in research and application. Drug Deliv. 2021, 28, 1397–1418. [Google Scholar] [CrossRef] [PubMed]
  19. El-Hammadi, M.M.; Arias, J.L. Recent Advances in the Surface Functionalization of PLGA-Based Nanomedicines. Nanomaterials 2022, 12, 354. [Google Scholar] [CrossRef]
  20. Nsairat, H.; Khater, D.; Sayed, U.; Odeh, F.; Al Bawab, A.; Alshaer, W. Liposomes: Structure, composition, types, and clinical applications. Heliyon 2022, 8, e09394. [Google Scholar] [CrossRef]
  21. Wang, J.; Li, B.; Qiu, L.; Qiao, X.; Yang, H. Dendrimer-based drug delivery systems: History, challenges, and latest developments. J. Biol. Eng. 2022, 16, 18. [Google Scholar] [CrossRef]
  22. Xu, P.; Zhang, H.; Dang, R.; Jiang, P. Peptide and Low Molecular Weight Proteins Based Kidney Targeted Drug Delivery Systems. Protein Pept. Lett. 2018, 25, 522–527. [Google Scholar] [CrossRef] [PubMed]
  23. Milligan, J.J.; Saha, S.; Jenkins, I.C.; Chilkoti, A. Genetically encoded elastin-like polypeptide nanoparticles for drug delivery. Curr. Opin. Biotechnol. 2022, 74, 146–153. [Google Scholar] [CrossRef] [PubMed]
  24. Ferreira, D.; Moreira, J.N.; Rodrigues, L.R. New advances in exosome-based targeted drug delivery systems. Crit. Rev. Oncol. Hematol. 2022, 172, 103628. [Google Scholar] [CrossRef] [PubMed]
  25. Mitchell, M.J.; Billingsley, M.M.; Haley, R.M.; Wechsler, M.E.; Peppas, N.A.; Langer, R. Engineering precision nanoparticles for drug delivery. Nat. Rev. Drug Discov. 2021, 20, 101–124. [Google Scholar] [CrossRef] [PubMed]
  26. Blanco, E.; Shen, H.; Ferrari, M. Principles of nanoparticle design for overcoming biological barriers to drug delivery. Nat. Biotechnol. 2015, 33, 941–951. [Google Scholar] [CrossRef]
  27. Kou, L.; Bhutia, Y.D.; Yao, Q.; He, Z.; Sun, J.; Ganapathy, V. Transporter-Guided Delivery of Nanoparticles to Improve Drug Permeation across Cellular Barriers and Drug Exposure to Selective Cell Types. Front. Pharmacol. 2018, 9, 27. [Google Scholar] [CrossRef] [PubMed]
  28. Shang, S.; Li, X.; Wang, H.; Zhou, Y.; Pang, K.; Li, P.; Liu, X.; Zhang, M.; Li, W.; Li, Q.; et al. Targeted therapy of kidney disease with nanoparticle drug delivery materials. Bioact. Mater. 2024, 37, 206–221. [Google Scholar] [CrossRef] [PubMed]
  29. Zhao, X.Y.; Li, S.S.; He, Y.X.; Yan, L.J.; Lv, F.; Liang, Q.M.; Gan, Y.H.; Han, L.P.; Xu, H.D.; Li, Y.C.; et al. SGLT2 inhibitors alleviated podocyte damage in lupus nephritis by decreasing inflammation and enhancing autophagy. Ann. Rheum. Dis. 2023, 82, 1328–1340. [Google Scholar] [CrossRef]
  30. Taghavi, F.; Moeinpour, F.; Khojastehnezhad, A.; Abnous, K.; Taghdisi, S.M. Recent applications of quantum dots in optical and electrochemical aptasensing detection of Lysozyme. Anal. Biochem. 2021, 630, 114334. [Google Scholar] [CrossRef]
  31. Liu, C.P.; Hu, Y.; Lin, J.C.; Fu, H.L.; Lim, L.Y.; Yuan, Z.X. Targeting strategies for drug delivery to the kidney: From renal glomeruli to tubules. Med. Res. Rev. 2019, 39, 561–578. [Google Scholar] [CrossRef]
  32. Floege, J.; Eitner, F.; Alpers, C.E. A new look at platelet-derived growth factor in renal disease. J. Am. Soc. Nephrol. 2008, 19, 12–23. [Google Scholar] [CrossRef]
  33. Dolman, M.E.; van Dorenmalen, K.M.; Pieters, E.H.; Lacombe, M.; Pato, J.; Storm, G.; Hennink, W.E.; Kok, R.J. Imatinib-ULS-lysozyme: A proximal tubular cell-targeted conjugate of imatinib for the treatment of renal diseases. J. Control Release 2012, 157, 461–468. [Google Scholar] [CrossRef]
  34. Zheng, X.P.; Nie, Q.; Feng, J.; Fan, X.Y.; Jin, Y.L.; Chen, G.; Du, J.W. Kidney-targeted baicalin-lysozyme conjugate ameliorates renal fibrosis in rats with diabetic nephropathy induced by streptozotocin. BMC Nephrol. 2020, 21, 174. [Google Scholar] [CrossRef]
  35. Pan, X.; Xie, F.; Xiao, D.; Zhou, X.; Xiao, J. Design, Synthesis, and Renal Targeting of Methylprednisolone-Lysozyme. Int. J. Mol. Sci. 2020, 21, 1922. [Google Scholar] [CrossRef]
  36. Ercan, D.; Demirci, A. Recent advances for the production and recovery methods of lysozyme. Crit. Rev. Biotechnol. 2016, 36, 1078–1088. [Google Scholar] [CrossRef]
  37. Angell, Y.; Holford, M.; Moos, W.H. Building on Success: A Bright Future for Peptide Therapeutics. Protein Pept. Lett. 2018, 25, 1044–1050. [Google Scholar] [CrossRef]
  38. Engel, J.E.; Williams, M.L.; Williams, E.; Azar, C.; Taylor, E.B.; Bidwell, G.L.; Chade, A.R. Recovery of Renal Function following Kidney-Specific VEGF Therapy in Experimental Renovascular Disease. Am. J. Nephrol. 2020, 51, 891–902. [Google Scholar] [CrossRef]
  39. Tan, X.; Tao, Q.; Li, G.; Xiang, L.; Zheng, X.; Zhang, T.; Wu, C.; Li, D. Fibroblast Growth Factor 2 Attenuates Renal Ischemia-Reperfusion Injury via Inhibition of Endoplasmic Reticulum Stress. Front. Cell Dev. Biol. 2020, 8, 147. [Google Scholar] [CrossRef]
  40. Song, S.; Hou, X.; Zhang, W.; Liu, X.; Wang, W.; Wang, X.; Cao, W.; Xia, Y.; Chen, W.; Shi, C. Specific bFGF targeting of KIM-1 in ischemic kidneys protects against renal ischemia-reperfusion injury in rats. Regen. Biomater. 2022, 9, rbac029. [Google Scholar] [CrossRef]
  41. Vadevoo, S.M.P.; Gurung, S.; Lee, H.S.; Gunassekaran, G.R.; Lee, S.M.; Yoon, J.W.; Lee, Y.K.; Lee, B. Peptides as multifunctional players in cancer therapy. Exp. Mol. Med. 2023, 55, 1099–1109. [Google Scholar] [CrossRef] [PubMed]
  42. Xin, Y.; Huang, M.; Guo, W.W.; Huang, Q.; Zhang, L.Z.; Jiang, G. Nano-based delivery of RNAi in cancer therapy. Mol. Cancer 2017, 16, 134. [Google Scholar] [CrossRef]
  43. Morimoto, K.; Kondo, M.; Kawahara, K.; Ushijima, H.; Tomino, Y.; Miyajima, M.; Kimura, J. Advances in targeting drug delivery to glomerular mesangial cells by long circulating cationic liposomes for the treatment of glomerulonephritis. Pharm. Res. 2007, 24, 946–954. [Google Scholar] [CrossRef]
  44. Yuan, Z.X.; Jia, L.; Lim, L.Y.; Lin, J.C.; Shu, G.; Zhao, L.; Ye, G.; Liang, X.X.; Ji, H.; Fu, H.L. Renal-targeted delivery of triptolide by entrapment in pegylated TRX-20-modified liposomes. Int. J. Nanomed. 2017, 12, 5673–5686. [Google Scholar] [CrossRef]
  45. Chen, Z.; Li, W.; Shi, L.; Jiang, L.; Li, M.; Zhang, C.; Peng, H. Kidney-targeted astaxanthin natural antioxidant nanosystem for diabetic nephropathy therapy. Eur. J. Pharm. Biopharm. 2020, 156, 143–154. [Google Scholar] [CrossRef]
  46. Li, R.; Kowalski, P.S.; Morselt, H.W.M.; Schepel, I.; Jongman, R.M.; Aslan, A.; Ruiters, M.H.J.; Zijlstra, J.G.; Molema, G.; van Meurs, M.; et al. Endothelium-targeted delivery of dexamethasone by anti-VCAM-1 SAINT-O-Somes in mouse endotoxemia. PLoS ONE 2018, 13, e0196976. [Google Scholar] [CrossRef]
  47. Rahman, M.M.; Rahaman, M.S.; Islam, M.R.; Rahman, F.; Mithi, F.M.; Alqahtani, T.; Almikhlafi, M.A.; Alghamdi, S.Q.; Alruwaili, A.S.; Hossain, M.S.; et al. Role of Phenolic Compounds in Human Disease: Current Knowledge and Future Prospects. Molecules 2021, 27, 233. [Google Scholar] [CrossRef]
  48. Kaur, N.; Kishore, L.; Singh, R. Dillenia indica L. attenuates diabetic nephropathy via inhibition of advanced glycation end products accumulation in STZ-nicotinamide induced diabetic rats. J. Tradit. Complement. Med. 2018, 8, 226–238. [Google Scholar] [CrossRef] [PubMed]
  49. Lei, Y. Myricitrin decreases traumatic injury of the spinal cord and exhibits antioxidant and anti-inflammatory activities in a rat model via inhibition of COX-2, TGF-beta1, p53 and elevation of Bcl-2/Bax signaling pathway. Mol. Med. Rep. 2017, 16, 7699–7705. [Google Scholar] [CrossRef]
  50. Tatipamula, V.B.; Kukavica, B. Phenolic compounds as antidiabetic, anti-inflammatory, and anticancer agents and improvement of their bioavailability by liposomes. Cell Biochem. Funct. 2021, 39, 926–944. [Google Scholar] [CrossRef]
  51. Ahangarpour, A.; Oroojan, A.A.; Khorsandi, L.; Kouchak, M.; Badavi, M. Antioxidant, anti-apoptotic, and protective effects of myricitrin and its solid lipid nanoparticle on streptozotocin-nicotinamide-induced diabetic nephropathy in type 2 diabetic male mice. Iran. J. Basic. Med. Sci. 2019, 22, 1424–1431. [Google Scholar] [CrossRef]
  52. Huang, W.J.; Liu, W.J.; Xiao, Y.H.; Zheng, H.J.; Xiao, Y.; Jia, Q.; Jiang, H.X.; Zhu, Z.B.; Xia, C.H.; Han, X.T.; et al. Tripterygium and its extracts for diabetic nephropathy: Efficacy and pharmacological mechanisms. Biomed. Pharmacother. 2020, 121, 109599. [Google Scholar] [CrossRef] [PubMed]
  53. Wu, Q.; Wang, J.; Wang, Y.; Xiang, L.; Tan, Y.; Feng, J.; Zhang, Z.; Zhang, L. Targeted delivery of celastrol to glomerular endothelium and podocytes for chronic kidney disease treatment. Nano Res. 2022, 15, 3556–3568. [Google Scholar] [CrossRef] [PubMed]
  54. Ghasemiyeh, P.; Mohammadi-Samani, S. Solid lipid nanoparticles and nanostructured lipid carriers as novel drug delivery systems: Applications, advantages and disadvantages. Res. Pharm. Sci. 2018, 13, 288–303. [Google Scholar] [CrossRef] [PubMed]
  55. Muller, R.H.; Mader, K.; Gohla, S. Solid lipid nanoparticles (SLN) for controlled drug delivery—A review of the state of the art. Eur. J. Pharm. Biopharm. 2000, 50, 161–177. [Google Scholar] [CrossRef]
  56. Hoshyar, N.; Gray, S.; Han, H.; Bao, G. The effect of nanoparticle size on in vivo pharmacokinetics and cellular interaction. Nanomedicine 2016, 11, 673–692. [Google Scholar] [CrossRef]
  57. Ma, Y.; Cai, F.; Li, Y.; Chen, J.; Han, F.; Lin, W. A review of the application of nanoparticles in the diagnosis and treatment of chronic kidney disease. Bioact. Mater. 2020, 5, 732–743. [Google Scholar] [CrossRef]
  58. Chai, G.H.; Xu, Y.; Chen, S.Q.; Cheng, B.; Hu, F.Q.; You, J.; Du, Y.Z.; Yuan, H. Transport Mechanisms of Solid Lipid Nanoparticles across Caco-2 Cell Monolayers and their Related Cytotoxicology. ACS Appl. Mater. Interfaces 2016, 8, 5929–5940. [Google Scholar] [CrossRef]
  59. Wang, W.; Meng, Q.; Li, Q.; Liu, J.; Zhou, M.; Jin, Z.; Zhao, K. Chitosan Derivatives and Their Application in Biomedicine. Int. J. Mol. Sci. 2020, 21, 487. [Google Scholar] [CrossRef]
  60. Younes, I.; Rinaudo, M. Chitin and chitosan preparation from marine sources. Structure, properties and applications. Mar. Drugs 2015, 13, 1133–1174. [Google Scholar] [CrossRef]
  61. Rizeq, B.R.; Younes, N.N.; Rasool, K.; Nasrallah, G.K. Synthesis, Bioapplications, and Toxicity Evaluation of Chitosan-Based Nanoparticles. Int. J. Mol. Sci. 2019, 20, 5776. [Google Scholar] [CrossRef]
  62. Podjarny, E.; Richter, S.; Magen, H.; Bachar, L.; Bernheim, J. High incidence of hypertension in older patients after unilateral nephrectomy. A retrospective study. Isr. J. Med. Sci. 1986, 22, 861–864. [Google Scholar]
  63. Liu, D.; Shu, G.; Jin, F.; Qi, J.; Xu, X.; Du, Y.; Yu, H.; Wang, J.; Sun, M.; You, Y.; et al. ROS-responsive chitosan-SS31 prodrug for AKI therapy via rapid distribution in the kidney and long-term retention in the renal tubule. Sci. Adv. 2020, 6, eabb7422. [Google Scholar] [CrossRef]
  64. Wang, D.W.; Li, S.J.; Tan, X.Y.; Wang, J.H.; Hu, Y.; Tan, Z.; Liang, J.; Hu, J.B.; Li, Y.G.; Zhao, Y.F. Engineering of stepwise-targeting chitosan oligosaccharide conjugate for the treatment of acute kidney injury. Carbohydr. Polym. 2021, 256, 117556. [Google Scholar] [CrossRef]
  65. Thambiliyagodage, C.; Jayanetti, M.; Mendis, A.; Ekanayake, G.; Liyanaarachchi, H.; Vigneswaran, S. Recent Advances in Chitosan-Based Applications-A Review. Materials 2023, 16, 2073. [Google Scholar] [CrossRef]
  66. Luo, K.; He, B.; Wu, Y.; Shen, Y.; Gu, Z. Functional and biodegradable dendritic macromolecules with controlled architectures as nontoxic and efficient nanoscale gene vectors. Biotechnol. Adv. 2014, 32, 818–830. [Google Scholar] [CrossRef]
  67. Hsu, H.J.; Bugno, J.; Lee, S.R.; Hong, S. Dendrimer-based nanocarriers: A versatile platform for drug delivery. Wiley Interdiscip. Rev. Nanomed. Nanobiotechnol. 2017, 9, e1409. [Google Scholar] [CrossRef]
  68. Sherje, A.P.; Jadhav, M.; Dravyakar, B.R.; Kadam, D. Dendrimers: A versatile nanocarrier for drug delivery and targeting. Int. J. Pharm. 2018, 548, 707–720. [Google Scholar] [CrossRef]
  69. Matsuura, S.; Katsumi, H.; Suzuki, H.; Hirai, N.; Hayashi, H.; Koshino, K.; Higuchi, T.; Yagi, Y.; Kimura, H.; Sakane, T.; et al. l-Serine-modified polyamidoamine dendrimer as a highly potent renal targeting drug carrier. Proc. Natl. Acad. Sci. USA 2018, 115, 10511–10516. [Google Scholar] [CrossRef]
  70. Guan, W.; Wang, Z.; Liu, Y.; Han, Y.; Ren, H.; Eric Wang, W.; Yang, J.; Zhou, L.; Zeng, C. Protective effects of tirofiban on ischemia/reperfusion-induced renal injury in vivo and in vitro. Eur. J. Pharmacol. 2015, 761, 144–152. [Google Scholar] [CrossRef]
  71. Nilsson, K.F.; Sandin, J.; Gustafsson, L.E.; Frithiof, R. The novel nitric oxide donor PDNO attenuates ovine ischemia-reperfusion induced renal failure. Intensive Care Med. Exp. 2017, 5, 29. [Google Scholar] [CrossRef]
  72. Katsumi, H.; Takashima, R.; Suzuki, H.; Hirai, N.; Matsuura, S.; Kimura, H.; Morishita, M.; Yamamoto, A. S-nitrosylated l-serine-modified dendrimer as a kidney-targeting nitric oxide donor for prevention of renal ischaemia/reperfusion injury. Free Radic. Res. 2020, 54, 841–847. [Google Scholar] [CrossRef]
  73. Fana, M.; Gallien, J.; Srinageshwar, B.; Dunbar, G.L.; Rossignol, J. PAMAM Dendrimer Nanomolecules Utilized as Drug Delivery Systems for Potential Treatment of Glioblastoma: A Systematic Review. Int. J. Nanomedicine 2020, 15, 2789–2808. [Google Scholar] [CrossRef]
  74. Kharwade, R.; Badole, P.; Mahajan, N.; More, S. Toxicity and Surface Modification of Dendrimers: A Critical Review. Curr. Drug Deliv. 2022, 19, 451–465. [Google Scholar] [CrossRef]
  75. Sunoqrot, S.; Bugno, J.; Lantvit, D.; Burdette, J.E.; Hong, S. Prolonged blood circulation and enhanced tumor accumulation of folate-targeted dendrimer-polymer hybrid nanoparticles. J. Control Release 2014, 191, 115–122. [Google Scholar] [CrossRef]
  76. Jain, K.; Kesharwani, P.; Gupta, U.; Jain, N.K. Dendrimer toxicity: Let’s meet the challenge. Int. J. Pharm. 2010, 394, 122–142. [Google Scholar] [CrossRef]
  77. Danhier, F.; Ansorena, E.; Silva, J.M.; Coco, R.; Le Breton, A.; Preat, V. PLGA-based nanoparticles: An overview of biomedical applications. J. Control Release 2012, 161, 505–522. [Google Scholar] [CrossRef]
  78. Zhang, D.; Liu, L.; Wang, J.; Zhang, H.; Zhang, Z.; Xing, G.; Wang, X.; Liu, M. Drug-loaded PEG-PLGA nanoparticles for cancer treatment. Front. Pharmacol. 2022, 13, 990505. [Google Scholar] [CrossRef]
  79. Dai, J.; Dong, X.; Wang, Q.; Lou, X.; Xia, F.; Wang, S. PEG-Polymer Encapsulated Aggregation-Induced Emission Nanoparticles for Tumor Theranostics. Adv. Healthc. Mater. 2021, 10, e2101036. [Google Scholar] [CrossRef]
  80. Huang, S.S.; Chiu, C.S.; Chen, H.J.; Hou, W.C.; Sheu, M.J.; Lin, Y.C.; Shie, P.H.; Huang, G.J. Antinociceptive activities and the mechanisms of anti-inflammation of asiatic Acid in mice. Evid. Based Complement. Alternat Med. 2011, 2011, 895857. [Google Scholar] [CrossRef]
  81. Chen, X.C.; Huang, L.F.; Tang, J.X.; Wu, D.; An, N.; Ye, Z.N.; Lan, H.Y.; Liu, H.F.; Yang, C. Asiatic acid alleviates cisplatin-induced renal fibrosis in tumor-bearing mice by improving the TFEB-mediated autophagy-lysosome pathway. Biomed. Pharmacother. 2023, 165, 115122. [Google Scholar] [CrossRef]
  82. He, J.; Chen, H.; Zhou, W.; Chen, M.; Yao, Y.; Zhang, Z.; Tan, N. Kidney targeted delivery of asiatic acid using a FITC labeled renal tubular-targeting peptide modified PLGA-PEG system. Int. J. Pharm. 2020, 584, 119455. [Google Scholar] [CrossRef]
  83. Arancibia, S.A.; Beltran, C.J.; Aguirre, I.M.; Silva, P.; Peralta, A.L.; Malinarich, F.; Hermoso, M.A. Toll-like receptors are key participants in innate immune responses. Biol. Res. 2007, 40, 97–112. [Google Scholar] [CrossRef]
  84. Fitzgerald, K.A.; Kagan, J.C. Toll-like Receptors and the Control of Immunity. Cell 2020, 180, 1044–1066. [Google Scholar] [CrossRef]
  85. Han, S.J.; Li, H.; Kim, M.; Shlomchik, M.J.; Lee, H.T. Kidney Proximal Tubular TLR9 Exacerbates Ischemic Acute Kidney Injury. J. Immunol. 2018, 201, 1073–1085. [Google Scholar] [CrossRef]
  86. Kumagai, Y.; Takeuchi, O.; Akira, S. TLR9 as a key receptor for the recognition of DNA. Adv. Drug Deliv. Rev. 2008, 60, 795–804. [Google Scholar] [CrossRef]
  87. Williams, R.M.; Shah, J.; Ng, B.D.; Minton, D.R.; Gudas, L.J.; Park, C.Y.; Heller, D.A. Mesoscale nanoparticles selectively target the renal proximal tubule epithelium. Nano Lett. 2015, 15, 2358–2364. [Google Scholar] [CrossRef]
  88. Han, S.J.; Williams, R.M.; D’Agati, V.; Jaimes, E.A.; Heller, D.A.; Lee, H.T. Selective nanoparticle-mediated targeting of renal tubular Toll-like receptor 9 attenuates ischemic acute kidney injury. Kidney Int. 2020, 98, 76–87. [Google Scholar] [CrossRef]
  89. Zhu, Y.; Yang, S.; Lv, L.; Zhai, X.; Wu, G.; Qi, X.; Dong, D.; Tao, X. Research Progress on the Positive and Negative Regulatory Effects of Rhein on the Kidney: A Review of Its Molecular Targets. Molecules 2022, 27, 6572. [Google Scholar] [CrossRef]
  90. Wang, G.; Li, Q.; Chen, D.; Wu, B.; Wu, Y.; Tong, W.; Huang, P. Kidney-targeted rhein-loaded liponanoparticles for diabetic nephropathy therapy via size control and enhancement of renal cellular uptake. Theranostics 2019, 9, 6191–6208. [Google Scholar] [CrossRef]
  91. Operti, M.C.; Bernhardt, A.; Grimm, S.; Engel, A.; Figdor, C.G.; Tagit, O. PLGA-based nanomedicines manufacturing: Technologies overview and challenges in industrial scale-up. Int. J. Pharm. 2021, 605, 120807. [Google Scholar] [CrossRef]
  92. Dethe, M.R.; Prabakaran, A.; Ahmed, H.; Agrawal, M.; Roy, U.; Alexander, A. PCL-PEG copolymer based injectable thermosensitive hydrogels. J. Control Release 2022, 343, 217–236. [Google Scholar] [CrossRef]
  93. Mathieu, M.; Martin-Jaular, L.; Lavieu, G.; Thery, C. Specificities of secretion and uptake of exosomes and other extracellular vesicles for cell-to-cell communication. Nat. Cell Biol. 2019, 21, 9–17. [Google Scholar] [CrossRef]
  94. Tang, T.T.; Lyu, L.L.; Liu, B.C. Research progress of extracellular vesicles in the treatment of renal disease. Sheng Li Xue Bao 2022, 74, 67–72. [Google Scholar]
  95. Maqsood, M.; Kang, M.; Wu, X.; Chen, J.; Teng, L.; Qiu, L. Adult mesenchymal stem cells and their exosomes: Sources, characteristics, and application in regenerative medicine. Life Sci. 2020, 256, 118002. [Google Scholar] [CrossRef]
  96. Zhou, Y.; Xu, H.; Xu, W.; Wang, B.; Wu, H.; Tao, Y.; Zhang, B.; Wang, M.; Mao, F.; Yan, Y.; et al. Exosomes released by human umbilical cord mesenchymal stem cells protect against cisplatin-induced renal oxidative stress and apoptosis in vivo and in vitro. Stem Cell Res. Ther. 2013, 4, 34. [Google Scholar] [CrossRef]
  97. Cao, J.Y.; Wang, B.; Tang, T.T.; Wen, Y.; Li, Z.L.; Feng, S.T.; Wu, M.; Liu, D.; Yin, D.; Ma, K.L.; et al. Exosomal miR-125b-5p deriving from mesenchymal stem cells promotes tubular repair by suppression of p53 in ischemic acute kidney injury. Theranostics 2021, 11, 5248–5266. [Google Scholar] [CrossRef] [PubMed]
  98. Tang, T.T.; Lv, L.L.; Wang, B.; Cao, J.Y.; Feng, Y.; Li, Z.L.; Wu, M.; Wang, F.M.; Wen, Y.; Zhou, L.T.; et al. Employing Macrophage-Derived Microvesicle for Kidney-Targeted Delivery of Dexamethasone: An Efficient Therapeutic Strategy against Renal Inflammation and Fibrosis. Theranostics 2019, 9, 4740–4755. [Google Scholar] [CrossRef]
  99. Tang, T.T.; Wang, B.; Wu, M.; Li, Z.L.; Feng, Y.; Cao, J.Y.; Yin, D.; Liu, H.; Tang, R.N.; Crowley, S.D.; et al. Extracellular vesicle-encapsulated IL-10 as novel nanotherapeutics against ischemic AKI. Sci. Adv. 2020, 6, eaaz0748. [Google Scholar] [CrossRef] [PubMed]
  100. Tang, T.T.; Wang, B.; Li, Z.L.; Wen, Y.; Feng, S.T.; Wu, M.; Liu, D.; Cao, J.Y.; Yin, Q.; Yin, D.; et al. Kim-1 Targeted Extracellular Vesicles: A New Therapeutic Platform for RNAi to Treat AKI. J. Am. Soc. Nephrol. 2021, 32, 2467–2483. [Google Scholar] [CrossRef] [PubMed]
  101. Meng, W.; He, C.; Hao, Y.; Wang, L.; Li, L.; Zhu, G. Prospects and challenges of extracellular vesicle-based drug delivery system: Considering cell source. Drug Deliv. 2020, 27, 585–598. [Google Scholar] [CrossRef]
  102. Liang, Y.; Duan, L.; Lu, J.; Xia, J. Engineering exosomes for targeted drug delivery. Theranostics 2021, 11, 3183–3195. [Google Scholar] [CrossRef]
  103. Doyle, L.M.; Wang, M.Z. Overview of Extracellular Vesicles, Their Origin, Composition, Purpose, and Methods for Exosome Isolation and Analysis. Cells 2019, 8, 727. [Google Scholar] [CrossRef]
  104. Jia, Y.; Yu, L.; Ma, T.; Xu, W.; Qian, H.; Sun, Y.; Shi, H. Small extracellular vesicles isolation and separation: Current techniques, pending questions and clinical applications. Theranostics 2022, 12, 6548–6575. [Google Scholar] [CrossRef]
  105. Kimiz-Gebologlu, I.; Oncel, S.S. Exosomes: Large-scale production, isolation, drug loading efficiency, and biodistribution and uptake. J. Control Release 2022, 347, 533–543. [Google Scholar] [CrossRef]
Pharmaceuticals 17 00625 g001
Figure 1. Targeted drug delivery systems: (A) deliverable medications; (B) different types of carriers; (C) different target ligands; (D) different strategies of drug delivery systems; and (E) targeting kidney. Abbreviations: DSPE-PEG-GLU: phospholipid–polyethylene glycol–glucose; LMWPs: low-molecular-weight proteins; PLGA: poly lactic-co-glycolic acid; PAMAMs: polyamidoamine dendrimers; and TRX-20: 3,5-dipentadecyloxybenzamidine hydrochloride. The figure was drawn by Figdraw (www.figdraw.com), accessed on 25 April 2024.
Figure 1. Targeted drug delivery systems: (A) deliverable medications; (B) different types of carriers; (C) different target ligands; (D) different strategies of drug delivery systems; and (E) targeting kidney. Abbreviations: DSPE-PEG-GLU: phospholipid–polyethylene glycol–glucose; LMWPs: low-molecular-weight proteins; PLGA: poly lactic-co-glycolic acid; PAMAMs: polyamidoamine dendrimers; and TRX-20: 3,5-dipentadecyloxybenzamidine hydrochloride. The figure was drawn by Figdraw (www.figdraw.com), accessed on 25 April 2024.
Pharmaceuticals 17 00625 g001
Pharmaceuticals 17 00625 g002
Figure 2. Drugs absorbed via different receptors: (A) the structure of the glomeruli in the kidneys is shown; (B) nanocomplex absorbed via VCAM-1, ICAM-1, megalin/cubilin, and the KIM-1 receptor in renal tubular epithelial cells; (C) nanocomplex absorbed via VCAM-1 receptors in endothelial cells; (D) nanocomplex absorbed via VCAM-1 receptors in podocytes.; and (E) nanocomplexes absorbed by GLUT1 and chondroitin sulfate proteoglycan receptors in mesangial cells. Abbreviations: ICAM-1: intercellular adhesion molecule-1; VCAM-1: vascular cell adhesion molecule-1. The figure was drawn by Figdraw (www.figdraw.com), accessed on 25 April 2024.
Figure 2. Drugs absorbed via different receptors: (A) the structure of the glomeruli in the kidneys is shown; (B) nanocomplex absorbed via VCAM-1, ICAM-1, megalin/cubilin, and the KIM-1 receptor in renal tubular epithelial cells; (C) nanocomplex absorbed via VCAM-1 receptors in endothelial cells; (D) nanocomplex absorbed via VCAM-1 receptors in podocytes.; and (E) nanocomplexes absorbed by GLUT1 and chondroitin sulfate proteoglycan receptors in mesangial cells. Abbreviations: ICAM-1: intercellular adhesion molecule-1; VCAM-1: vascular cell adhesion molecule-1. The figure was drawn by Figdraw (www.figdraw.com), accessed on 25 April 2024.
Pharmaceuticals 17 00625 g002
Table 1. Summary of drug delivery systems targeting kidney-resident cells in different kidney diseases.
Table 1. Summary of drug delivery systems targeting kidney-resident cells in different kidney diseases.
Target CellCarrierDrugApplicationTarget MechanismReference
Tubular epithelial cellsLMWP–lysozymeImatinibRenal fibrosisMegalin/cubilin-mediated endocytosis[33]
Tubular epithelial cellsLMWP–lysozymeBAIDNMegalin/cubilin-mediated endocytosis[34]
Tubular epithelial cellsLMWP–lysozymeMPImprovement in targeting efficiencyMegalin/cubilin-mediated endocytosis[35]
Tubular epithelial cellsPeptide–ELPVEGFRVDMegalin/cubilin-mediated endocytosis[38]
Tubular epithelial cellsPeptide–KITbFGFsI/R-AKIKIT specifically combined with KIM-1[40]
Tubular epithelial cellsSolid lipid nanoparticlesMyristicinDNEndocytosis of tubules[51]
Tubular epithelial cellsChitosanSS31I/R-AKIL-serine special combined with KIM-1[63]
Tubular epithelial cellsLMWCCurcuminAKI induced by sepsisMegalin-mediated endocytosis[64]
Tubular epithelial cellsPAMAMCAPImproved targeting efficiencyL-serine specifically combined with KIM-1[69]
Tubular epithelial cellsPAMAMNO donorsI/R-AKIL-serine specifically combined with KIM-1[72]
Tubular epithelial cellsPEG-PLGAAARenal fibrosisMegalin-mediated endocytosis[82]
Tubular epithelial cellsPEG-PLGAODN2088I/R-AKIEndocytosis of tubules[88]
Tubular epithelial cellsPEG-PCLRheinDNMegalin-mediated endocytosis[90]
Tubular epithelial cellsMesenchymal stromal-cells exosomesMiR-125b-5p/p5I/R-AKIVCAM-1 and ICAM-1 bind with integrin[97]
Tubular epithelial cellsMacrophage-derived exosomesIL-10I/R-AKIVCAM-1 and ICAM-1 bind with integrin[94,99]
Tubular epithelial cellsRed blood cell-derived exosomesSip65, siSnail-1I/R-AKIPeptides specifically combine with KIM-1[100]
Endothelial cellsPhospholipid nanoparticlesCLTDNPeptides combine with VCAM-1[53]
Endothelial cellsMacrophage-derived exosomesDexamethasoneLPS-induced nephropathy and ADR-induced nephropathyVCAM-1 and ICAM-1 bind with integrin[98]
PodocyteSAINT-O-SomesDexamethasoneSepsis-induced AKIVCAM-1 antibody combines with VCAM-1[46]
PodocytePhospholipid nanoparticlesCLTDNPeptides combine with VCAM-1[53]
Mesangial cellsLiposomesTPMNTRX20 specifically binds to chon-droit in sulfate proteoglycan[44]
Mesangial cellsLiposomesASTDNGlucose ligands bind with GLUT1[45]
Abbreviation: AA: asiatic acid; AKI: acute kidney injury; AST: astaxanthin; BAI: baicalin; bFGFs: basic fibroblast growth factors; CAP: captopril; CLT: celastrol; DN: diabetic nephropathy; GLUT1: glucose transporter 1; ICAM-1: intercellular adhesion molecule-1; I/R: ischemia–reperfusion; KIM-1: kidney injury molecule-1; LMWC: low-molecular-weight chitosan; MN: membranous nephropathy; MP: methylprednisolone; PAMAMs: polyamidoamine dendrimers; PCL: polycaprolactone; PEI: polyethyleneimine; PLGA: polylactic-co-glycolic acid; RVD: renovascular disease; SS31: Szeto-Schiller-31; TP: triptolide; VCAM-1: vascular cell adhesion molecule-1; and VEGF: vascular endothelial growth factor.
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Huang, L.-F.; Ye, Q.-R.; Chen, X.-C.; Huang, X.-R.; Zhang, Q.-F.; Wu, C.-Y.; Liu, H.-F.; Yang, C. Research Progress of Drug Delivery Systems Targeting the Kidneys. Pharmaceuticals 2024, 17, 625. https://doi.org/10.3390/ph17050625

AMA Style

Huang L-F, Ye Q-R, Chen X-C, Huang X-R, Zhang Q-F, Wu C-Y, Liu H-F, Yang C. Research Progress of Drug Delivery Systems Targeting the Kidneys. Pharmaceuticals. 2024; 17(5):625. https://doi.org/10.3390/ph17050625

Chicago/Turabian Style

Huang, Li-Feng, Qiao-Ru Ye, Xiao-Cui Chen, Xiao-Rong Huang, Qiao-Fei Zhang, Chun-Yu Wu, Hua-Feng Liu, and Chen Yang. 2024. "Research Progress of Drug Delivery Systems Targeting the Kidneys" Pharmaceuticals 17, no. 5: 625. https://doi.org/10.3390/ph17050625

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop