Curcumin nanoparticles
Curcumin is the active compound of Curcuma longa which is renoprotective and has antioxidant, chemotherapeutic and anti-inflammatory impacts [64, 65]. This compound can reduce the nephrotoxic effect of cisplatin by reducing the expression of OCT2 in renal cells [66]. Besides, the phenolic group in the structure of curcumin can inhibit oxidative stress via overexpressing HO-1, GST and NAD(P)Quinine oxidoreductase1 (NQO1), and acting as a ROS scavenger [67,68,69]. Therefore, the combination of cisplatin with curcumin may be considered as a nephroprotective approach. However, curcumin has some significant drawbacks, some of which are low water-solubility, instability at physiological pH, low absorption and poor bioavailability [70, 71]. To solve such problems, curcumin nanoparticles, with dimensions of 10–100 nm, can be useful. The larger surface area of nanoparticles, which increases the dissolution, can enhance the aqueous solubility and bioavailability of curcumin [72].
The effects of curcumin nanoparticles on CDDP-induced nephrotoxicity have been illustrated in Fig. 4. Curcumin nanoparticles could reduce lipid peroxidation, NO and TNF-α productions in the kidneys of orally treated rats following a single intraperitoneal injection of cisplatin. Although the levels of renal GSH and Na+/K+-ATPase activity were decreased by cisplatin, nanocurcumin counteracted these effects, allowing renal cells to maintain the mitochondrial function [73]. While maintaining the polarized state of the plasma membrane could preserve the epithelial function of the renal tubercle, the inhibition of Na+/K+-ATPase in the absence of these nanoparticles caused extracellular fluid to leak into the kidney lumen [73]. Surprisingly, one study has revealed that curcumin nanoparticles enhance the expression of OCT2 in renal cells, which may be due to better solubility and physical–chemical properties of these nanoparticles than free curcumin [66]. Thus, other regulatory mechanisms can be involved here.
Also, the encapsulation of curcumin-cisplatin complex in mPEG-SS-PBAE-PLGA nanoparticles had nephroprotective effects on BalB/c mice. In these nanoparticles, polyethylene glycol (PEG) protected the complex against the reticuloendothelial system (RES), so the drug remained stable in the blood stream. However, the complex was released in the tumor microenvironment upon the pH turned acidic. It should be noted that the DNA binding ability of curcumin-cisplatin complex was similar to that of cisplatin. As a result, this complex could show more antimetastatic effects by inhibiting PI3K/AKT, matrix metallopeptidase 2 and vascular endothelial growth factor receptor 2 (VEGFR2) pathways, while it induced less renal effects by suppressing ROS production [74].
On the other hand, it has been reported that the nephroprotective effects of nanocurcumin is concentration-dependent so that 60 mg/kg body.weight (b.w) of nanoparticles could be more nephroprotective than 30 mg/kg b.w of them [72, 75]. Accordingly, in a clinical study of patients with localized muscle-invasive bladder cancer (MIBC), it was found that although well-tolerated nanocurcumin had no renal complication, patients did not respond well to the treatment. Thus, further studies are needed to determine the effective dose of nanocurcumin in the clinical studies [76].
Liposomes
Liposome is an FDA-approved nanoparticle that are suitable for both targeted (adding ligands) and non-targeted (enhanced EPR effect) drug delivery methods [77].
In order to target cisplatin delivery and reduce its systemic cytotoxicity, anti-epidermal growth factor receptor (EGFR) antibody, which is against EGFR overexpressed on the surface of some cancer cells, can be attached to CDDP liposomal nanoparticles [78]. On the other hand, cisplatin-sodium alginate (SA) encapsulated in EGF-modified liposome, in which CDDP was encapsulated into the hydrophilic core of liposome, could also enhance the bioavailability and efficacy of CDDP delivery to the tumor and reduce kidney complications. Interestingly, while cisplatin has a low aqueous solubility, its binding to anionic SA can greatly increase its solubility [79].
Targeting tumors with nanoliposomes carrying both cisplatin and RNAs, such as miRNA and siRNA, can also be a nephroprotective approach, which works through changing tumor signaling pathways. RNA-based drug delivery systems have some problems, including rapid RES clearance and enzymatic degradation, short circulating lifetime, and higher cytotoxicity. However, formulating them with liposome can overcome these problems [80]. In this regard, multilayered layer by layer (LbL) nanoparticles (liposomes/poly-l-arginine (PLA)/siRNA of Kristen ras sarcoma viral oncogene homolog (siKRAS) and miR-34a/PLA/HA) containing CDDP were synthesized by encapsulating this drug in the hydrophilic core of phospholipid liposomes. The negatively charged hyaluronic acid was deposited as the last layer to extend blood circulation time and to target the overexpressed CD44 on lung adenocarcinoma cells, which reduce systemic toxicity of CDDP. The siKRAS and miR-34a can regulate KRAS oncogene and restore p53 function, respectively, which block the tumor defense pathways. Therefore, these nanoparticles reduced drug resistance. Moreover, LbL nanoparticles are promising due to their controllable size, high loading capacity, enhanced stability, staged cargo release, and their ability to surface modification [80].
Besides, liposomal cisplatin or lipoplatin are considered as the most effective nano-formulations of cisplatin that have even reached phases 1, 2 and 3 trials [81]. In one study, both monotherapy and combined treatment of lipoplatin with gemcitabine, 5-fluorouracil-leucovorin and paclitaxel were able to keep creatinine at a normal level in patients with one of lung, bladder and gastrointestinal cancers, together with a kidney disease [81]. In another study, cisplatin conjugated to 1-palmitoyl-2-glutaryl-sn-glycero-3-phosphocholine was assembled in the bilayer of liposomal cisplatin composed of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine (DSPE), 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[Methoxyl(polyethyleneglycol)2000] (MPGG2k-DSPE and cholesterol to show a sustainable release of drug. By increasing the size of cisplatin in this way, these nanoparticles reduce the renal clearance of cisplatin, resulting in less nephrotoxic effects [82].
To develop a formulation with an enhanced liposomal loading capacity for curcumin, an automated microfluidic technology was applied. These liposome-curcumin nanoparticles containing cisplatin could reduce the dose-limiting effects of cisplatin on renal cells after a single dose injection to Balb/c mice [83]. Honokiol liposomes, which are composed of liposome and Honokiol, a lipophilic polyphenolic compound derived from Magnolia officinalis, can preserve the redox state of the cell and inhibit the apoptosis caused by caspase-3 in kidney cells. Therefore, the intravenous tail vein injection of these nanoparticles into mice was able to reverse AKI by inhibiting inflammation and fibrosis [84].
To reduce the systemic effects of cisplatin through controlling drug release, a microneedle technique was used to deliver cisplatin-loaded nanoliposomes via skin to head and neck tumors of xenograft mice. These nanoparticles (LCC-NPs) were synthesized by 1,2-dioleoyl-3-trimethy-lammoniumpropane (DOTAP), 1,2-dioleoyl-sn-glycerol-3-phospate (DOPA), cholesterol and DSPE-PEG-ammonium salt. DOPA-encapsulated CDDP not only could prevent aggregation and control liposome size, but also could be dispersed in water to prepare a coating bilayer through adding other mentioned lipids. Moreover, DOTAP allowed liposome to escape from the endosomes and accumulate less in the lysosomes; thus, the degradation of liposome in cytoplasm could induce CDDP release, resulting in the cell cycle arrest at G1 phase and apoptosis. Cholesterol, however, improved selectivity of liposome to tumor. In addition, DSPE-PEG-AA helped these nanoparticles target tumors by attaching its anisamide moiety to the overexpressed sigma receptors on human tumors. These nanoparticles were also pH sensitive and could release cisplatin only into the acidic environment of the tumor, thus reducing systemic toxicity of cisplatin [85].
Chitosan (CS)
These biocompatible and biodegradable nanoparticles have some specific features like, high drug loading capacity, cell membrane permeability, pH-dependent therapeutic unloading and long circulation time [86]. The reactive amino group of glucosamine in the C2 position of chitosan is used to binding with drugs and targeting moieties of cells [87]. Hence, chitosan derivatives can reduce nephrotoxicity of cisplatin. Among the chitosan-based nanocarriers, such as N-naphthyl-N,O-succinyl chitosan (NSCT), N-benzyl-N,O-succinyl chitosan (BSCT) and N-octyl-N-O-succinyl chitosan (OSCT), BSCT nanoparticles displayed the highest loading efficiency (LE) of cisplatin, which can be attributed to the higher degree of succinic group on the polymer chain of BSCT compared to the NSCT and OSCT polymer chains [88].
Chitosan polymers can interact with cisplatin through co-ordinate bonds, which attach the carboxylic group of the polymer to the Pt of cisplatin at pH 8.5, so these bonds may be broken at the acidic pH of tumor. In this way, cisplatin will gradually be released into tumor. Therefore, with the targeted release of cisplatin near the tumor tissue, the effects of systemic toxicity such as acute and chronic nephrotoxicity can be eliminated [23, 88]. The treatment of normal renal cells, i.e., RPTEC/TERT1, with cisplatin-loaded nanocarriers showed a lower percentage of necrotic or late apoptotic cells compared with the cells treated with free cisplatin in one study, which might be due to the gradual release of cisplatin from the nanocarriers. In cancer cell lines, while nanocarriers showed a larger percentage of early apoptosis, free cisplatin presented a higher percentage of late apoptosis and necrosis. Early apoptosis is a process that takes place without inflammation when the membranes are intact. Once apoptotic cells lost their membrane integrity, late apoptosis and necrosis can be triggered, resulting in inflammatory responses. Therefore, nanocarriers could induce less inflammatory response in cancer cells compared to free cisplatin [88].
Another formulation of cisplatin complexed with γ-polyglutamic acid (γ-PGA) and CS has also showed fewer toxic effects on renal cells of mice. The γ-PGA/CDDP-CS complex exhibited a pH-dependent release of cisplatin in an in-vitro study after 12 days. At pH 7.4, less cisplatin was released from the γ-PGA/CDDP-CS complex [89]. This could be due to the electrical interaction of CS with the complex, while at pH 5.5 the release of cisplatin was higher [89, 90]. More importantly, despite a high concentration of CDDP in the complex, histological evidence did not show any kidney damage. Indeed, after intraperitoneal administration of the γ-PGA/CDDP-CS particles, most of them were trapped by RES and remained there before being released into the bloodstream. Subsequently, γ-PGA/CDDP-CS particles gradually released from RES, accumulated in the tumor tissue, and released cisplatin in a pH-dependent manner. Therefore, γ-PGA/CDDP-CS formulation is suitable for effective antitumor therapy and reduction of cisplatin-induced nephrotoxicity [89].
Moreover, irradiated chitosan-coated cisplatin and MgO nanoparticles (CHIT/Cis/MgO NPs), named cisplatin nanocomposite (Cis NC), apply minimal stimulatory effects on renal apoptotic and inflammatory cascades, so they are formulated to improve therapeutic efficacy while reducing nephrotoxicity. Anees et al. have shown that the oxidative stress, inflammation and apoptosis were reduced in renal cells of male Wistar rats treated with cisplatin nanocomposite through the regulation of AMPK/PI3K/Akt-mTOR and signal transducer and activator of transcription 1 (STAT1)/p53 signaling pathways [87]. Although cisplatin can activate STAT1 via the induction of ROS and NADPH oxidase activity, and then trigger inflammatory effectors (e.g., iNOS, TNF-α and IL-1β) and apoptotic factors (e.g., p53 and caspases), Cis NC did not significantly induce such changes in the kidneys of treated mice [87]. Also, self-assembly hybrid nanocomposites of CDDP-chitosan have been introduced as promising nano-drug with less nephrotoxicity, as shown in Table 3 [91].
Besides, a study used chitosan/siRNA nanoparticles to passively target kidneys. These nanoparticles altered CDDP-induced apoptotic proteins, e.g., p53, protein kinase C-δ (PKCδ) and GGT, by gene therapy to protect kidneys against CDDP-induced proximal tubule damages [92].
Poly (lactic-co-glycolic acid) (PLGA)
These nanoparticles have numerous advantages like biocompatibility, biodegradability, high drug loading capacity, sustained release, and high permeability [93]. PLGA-based drug delivery systems can decrease systemic toxicity of cisplatin using a more selective and controllable approach [94]. Cisplatin is insoluble in organic solvents and partly soluble in water; hence, the external aqueous phase of these nanoparticles is saturated with cisplatin in order to elevate their drug loading profile [95]. The release pattern of cisplatin from the nanoparticles occurs in two phases. An initial burst release of drug can be attributed to the cisplatin present near the surface, and subsequently, a sustained release pattern will be occurred in response to the degradation of the polymer and releasing cisplatin from the nanoparticle matrix [96]. After treating mice with cisplatin loaded PLGA nanoparticles, their histological examination did not show any kidney damage [96].
In one study, the combinational therapy of PLGA nanoparticles with Boldine (Bol), which is an antioxidant compound with the ability to reduce cisplatin-induced nephrotoxicity, was investigated on swiss albino mice [97]. PLGA-encapsulated nano-Boldin (NBol) could reduce the cisplatin-induced nephrotoxicity by increasing SOD activity and decreasing LPO level. Furthermore, it was shown that NBol nanopolymers could enter into the cells faster than Bol and prevent DNA damage induced by cisplatin in normal cells [97]. Moreover, N, N’-diphenyl-1, 4-phenylenediamine loaded PLGA nanoparticles (Nano-DPPD) showed an anti-fibrotic activity against CDDP through decreasing CDDP-induced collagen contents in kidneys. These nanoparticles could also reduce CDDP-induced macrophages infiltration, tubular injury score and hydroxyproline contents, as a marker of DNA damage of renal cells [98]. The previous studies had shown that the encapsulation of thymoquinone (THY), as a potent antioxidant and anti-inflammatory compound, into PLGA and polyvinyl alcohol (PVA) polymers, and then using pluronic 127, as a non-anionic surfactant, could improve the poor solubility of THY and increase its bioavailability [99]. In this regard, the co-treatment of PLGA nanoparticle encapsulating THY (NP THY) with cisplatin can reduce cisplatin-induced nephrotoxicity in Ehrlich solid carcinoma (ESC) mice model without losing antitumor properties of cisplatin [100]. Kidney damage markers (i.e., uric acid, urea, creatinine, and cystatin c) were decreased in the treated mice in comparison with the cisplatin group. Also, NP THY protected against the oxidative stress caused by cisplatin via reducing the MDA of kidney tissue, increasing the rates of antioxidant markers (i.e., GSH, SOD, and CAT), and decreasing inflammatory marker levels (i.e., TNF-α, IL-1β, and NF-κB) (93).
Micelles
CDDP-loaded polymeric micelles (CDDP-PMs) are more effective than cisplatin. In comparison with free cisplatin, CDDP-PMs can accumulate better in tumor, decrease renal exposure, and prolong blood circulation [101, 102]. The CDDP-PMs with mean size of 110 nm, loading capacity of 30% W/W, and ζ potential of -12 mV have lower drug-release rate in systemic circulation, but higher drug-release rate in tumor microenvironment [103]. In one study, while free cisplatin could significantly enhance BUN after 13 days, this marker remained at normal range in the mice treated with cisplatin/cl-micelles, even up to 28 days. Moreover, no histopathological alterations were detected in both bone marrow and kidney of the cisplatin/cl-micelle-treated group [101]. Polymeric micelles can have a hydrophilic shell made of PEG which helps these nanoparticles evade RES. By increasing the drug/copolymer ratios from 1:1 to 1:6, both nephrotoxicity and tumor inhibition rate of cisplatin decreases. However, CDDP-PMs with the ratio of 1:3 have the least toxicity and highest therapeutic effect. Also, cisplatin polymeric micelles can be designed to be pH-dependent and release cisplatin over than 10 days [102].
On the other hand, quercetin is an antioxidant flavonoid which can prevent nephrotoxicity and renal damage induced by cisplatin, methotrexate, ciprofloxacin, NaF, HgCl2 and cadmium [103]. However, quercetin is sensitive to temperature, hydroxylation, pH, metal ions and enzymatic activity [104, 105]. Therefore, in order to increase quercetin biological efficacy and bioavailability, some new formulations based on liposomes, nanoemulsions, nanoparticles and micelles have been synthesized [104]. Pluronic F127-encapsulated quercetin (P-quercetin) is a micellar formulation which has shown nephroprotective features at its lower concentrations [88, 106]. Also, quercetin and P-quercetin treatments identically decreased the tubular necrosis caused by cisplatin in cortical areas [105]. Besides, the chitosan polymeric micelles, including N-Octyl-Sulfate chitosan, N-Phthaloyl chitosan-g-mPEG, N-lauryl-carboxymethyl chitosan, and OSCS can also mitigate cisplatin-induced nephrotoxicity. It was identified that these chitosan derivatives have more water solubility and anticancer effects than chitosan, and can decrease the cisplatin-induced cytotoxicity in renal proximal tubular cells. Moreover, cisplatin-OSCS did not change the RPTEC/TERT cells viability [107]. In addition, Soodvilai et al. showed that the pre-treated with the Silymarin (SM)-loaded PMs could increase anticancer effects of cisplatin, while it decreased the necrosis and apoptosis in renal cells [108]. Also, the pre-treatment of cells with benzyl-functionalized succinyl chitosan (BSC) showed a renoprotective effect against cisplatin and other nephrotoxic drugs [109]. Furthermore, SM-loaded BSC PMs could improve the therapeutic effect and bioavailability of SM, and protect kidney against cisplatin [110]. However, both polymer types and the concentration of the SM incorporated in the PMs can change the cytotoxic effects of SM-PMs on RPTEC/TERT1 cells [108].
Exosomes
Exosomes are 30–200 nm extracellular vesicles which have some specific CD-markers, like CD63 and CD9, and contain miRNAs, mRNAs, lipids and proteins [111]. It has been established that exosomes, especially those derived from human umbilical cord derived mesenchymal stem cells (HUMSC), can play a paramount role in the diagnosis and treatment of diseases. In this regard, we can take advantages of HUMSC exosomes to treat kidney disorders such as cisplatin-induced renal damage. In fact, the protective effects of HUMSC on the cisplatin-induced damages are present through inhibiting Bcl2 and increasing Bim, Bid, Bax, cleaved caspase-9, and cleaved caspase-3. In addition, HUMSC-exosomes have been able to rise the renal cell viability and the proportion of G1 phase cells. Moreover, the exosomes could inhibit cisplatin-caused apoptosis [112]. Moreover, a carbon monoxide(CO)-loaded hemoglobin-vesicle (CO-HbV) as renoprotectant has been able to reduce nephrotoxic effect of CDDP through inhibiting caspase-3-mediated apoptosis. CO delivery to tumor can contribute to tumor growth inhibition in B16-F10 melanoma cell-bearing mice because CO is toxic to tumor, but not normal tissues. This is due to the fact that binding CO to cytochrome c oxidase can trigger different responses in normal and cancer cells [113].
Microspheres
Microspheres are spherical particles with the size ranging from 1 to 1000 μm. Gelatin microspheres (GM) can reduce nephrotoxic effects of cisplatin through offering a targeting drug delivery system. Cisplatin can enter into the hydrogel via a simple method, and then be released into tumor through the degeneration of the hydrogel. On the other hand, it has been established that cancer cells mostly secrete matrix metallopeptidase enzymes, like gelatinase and collagenase, that can be effective in the releasing CDDP near the tumor site by degradation of GMs [114].
pH-sensitive polymeric nano-formulation
Lipid-coated cisplatin/oleanolic acid calcium carbonate nanoparticles (CDDP/OA-LCC NPs) are pH sensitive nanoparticles that show an increased tumor efficacy and blood circulation time [115]. Oleanolic acid (OA) is a pentacyclic triterpenoid which has both anti-oxidative and anti-inflammatory effects. The synergic effect of OA with CDDP is suitable for drug co-delivery. These nanoparticles have been able to decrease cisplatin-induced nephrotoxicity. In this regard, Shi et al. showed that OA could induce the antioxidant enzymes by activating the nuclear factor erythroid 2–related factor 2 (Nrf-2) [115]. In this way, it could eliminate the toxic effects caused by ROS. Moreover, NF-κB and AKT/mTOR pathways were deactivated by activating AMPK to reduce the release of pro-inflammatory cytokines and resistance to cisplatin [115]. Moreover, in another study a nanoparticle was designed using pH-sensitive CaCO3 cores (CDDP/OA-LCC NPs) to co-deliver CDDP and OA. Thus, Pt could release more at acidic condition. This is because the CaCO3 cores are stable at pH 7.4, while they rapidly collapse at pH 5.5 and release encapsulated drugs. This nano-drug not only showed better pharmacokinetic characteristics, e.g., prolonged blood circulation, selective tumor targeting, and higher antitumor efficacy, but also could mitigate CDDP-induced nephrotoxicity [115].
Another pH-sensitive nanoparticle is polyphosphazene-cisplatin (polycisplatin) that has been able to reduce the cisplatin nephrotoxicity by increasing drug accumulation in tumors. Although polycisplatin at the dose of 1.95 mg Pt/kg had less tumor suppressive effect than CDDP, it showed a better efficacy than CDDP at higher doses (> 3.9 mg Pt/kg). On the other hand, novel Pt-bisphosphonate polymer-metal complex nanoparticles (Pt-bp-NPs) are another pH sensitive nanoparticles that have led to a fast drug release in acidic extracellular environment of tumor, resulting in less systemic toxicity of cisplatin [116]. Cisplatin-loaded poly (l-glutamic acid)-g-methoxy poly ethylene glycol 5 k nanoparticles (PLG-g-mPEG 5 k) are also a pH and temperature sensitive nanoparticle which demonstrate longer blood circulation and reduced Pt accumulation in kidney, so they can decrease cisplatin-caused renal damages [117].
Other nanoparticles
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-LHRH-peptide conjugated dextran nanoparticles: gonadotropin-releasing hormone (GnRH) or luteinizing hormone-releasing hormone (LHRH) is a hormone that regulates the pituitary–gonadal axis. To create a targeting delivering system, this hormone is a suitable ligand because its receptor is overexpressed in most tumors. Dextran-SA-CDDP-LHRH has been able to increase the blood circulation of cisplatin and reduce the systemic toxicity and renal accumulation of this drug. Interestingly, while CDDP mostly was removed from kidneys, these nanoparticles were taken up by RES in mice [118].
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-Gallic acid-loaded eudragit-Rs 100 nanoparticles: 3,4,5-trihydroxy benzoic acid (Gallic acid) has some polyphenolic compounds; hence, gallic acid and its nanoparticles have antioxidant, anti-inflammatory, antimutagenic, anti-carcinogenic, and mucoadhesive features. According to a previous study, both 10 mg/kg nano gallic acid and 50–100 mg/kg gallic acid can ameliorate the mitochondrial levels of MDA, ROS, TNF-α and IL-6 in renal, and increase the levels of mitochondrial antioxidant enzymes (e.g., SOD and CAT) [119].
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-Polymer nanosystems-Gambogic Acid-Urolithin A (P2Ns-GA-UA): urolithin A (UA) is a metabolic compound with antioxidant and anti-inflammatory features that results from the transformation of ellagitannins by the gut bacteria. Compelling evidence indicated that oral administration of UA decreased the cisplatin-caused histopathological and morphological abnormalities, AKI and mortality in the rat models. This is because the UA nanoparticles can downregulate both p53-inducible genes and NRF2. Moreover, they maintain the levels of PARPΙ, AKI-related miRNA (miR-192-5p and miR-140-5p), intracellular NAD+, mitochondrial oxidative phosphorylation at their normal ranges. Furthermore, renal expression of NFR2-inducible genes [thioredoxin reductase I (Txnrd I), metallothionein (Mt I), sulfiredoxin I homolog (srxn I)], NFR2 protein, p53 protein and its inducible genes [i.e., activating transcription factor 3(Atf3), cyclin-dependent kinase inhibitor 1A (cdknla)(p21), transformation-related protein 53-inducible nuclear protein 1 (Trp53inp1)(sIp)] were significantly less in the mice treated with P2Ns-GA-UA compared to the cisplatin group. On the other hand, P2Ns-GA UA did not affect the hypoxic state of the renal. In general, P2Ns-GA UA treated group had less oxidative phosphorylation deficiencies and kidney apoptosis [120].
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-Cisplatin-polyacrylic acid (PAA) nano capsule (CDDP-PAA-NC): conjugating CDDP to PAA helps to enhance drug loading and reduce drug leakage through replacing anionic chlorides in the drug with carboxylic residues in PAA. We can also inhibit the drug leakage via encapsulating this complex in PVA/superparamagnetic iron oxide (SPIO) shell. A prolonged blood circulation enhances the opportunity for nano-drugs to accumulate in tumor by leaky sites in vessels. Thus, these nanoparticles could successfully decrease the cisplatin-induced nephrotoxicity, while they increased CDDP tumor accumulation, and prolonged drug release [121].
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-Hyaluronan–cisplatin conjugate nanoparticles (HCNPs) entrapped in Eudragit S100-coated pectinate/alginate microbeads (PAMs) (HCNP-PAMs): enzyme- or pH-dependent systems can be used to deliver drugs to colon. Pectin is a natural polysaccharide which can inhibit metastasis through attaching to the galectin-3 receptor. The use of pectin alone as a microencapsulation matrix needs high concentrations of pectin in electrospray method, owing to its low carboxyl groups; therefore, alginate is mixed with pectin to solve this problem. However, this matrix quickly releases drugs under gastric condition, which can be solved by coating Eudragit on the surface of these microbeads. Moreover, hyaluronan not only can form stable complexes with CDDP, but also can actively target CD44 receptors on cells, and ameliorate the cisplatin-induced nephrotoxicity [122].
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-Cysteine Pt(IV) prodrug NPs: as mentioned earlier, intracellular thiol-containing molecules can induce cisplatin resistance in tumors. However, these nanoparticles are made of poly(disulfide amide) polymers that can reverse the drug resistance by a GSH-scavenging process, which rapidly induced the release of Pt ions in a thiol-rich medium. Thus, they are suitable for increasing CDDP efficiency, as they can deliver the active Pt to cisplatin-resistant cells and deplete GSH concentration in the cells. In addition, these nanoparticles activate apoptotic pathways by increasing p53 and caspase-3, and decreasing Bcl2. Interestingly, they had less systemic toxicity, including nephrotoxicity [123].
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-Hyaluronic acid-cisplatin/polystyrene-polymetformin (HA-CDDP/PMET): it is used for co-delivery of metformin (MET) and CDDP to lung cancer. In a study, this nanoparticle could enhance the survival rate of animals without inducing nephrotoxicity. This was due to the fact that this nanoparticle could accumulate in the kidneys less than cisplatin. On the other hand, apoptosis was upregulated in tumor cell by the synergistic effect of CDDP and MET in HA-CDDP/PMET NPs, resulting in the regulation of cleaved PARP protein [124].
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-Aptamers (Apt): Apts have some significant features, including great tissue penetration, low toxicity, lack of immunogenicity, thermal stability, high surface modification and being non-reactive to negatively charged proteins of blood circulation. Indeed, Apts interact only with their receptors on surface of tumor cells, resulting in less cisplatin accumulation in kidney and less nephrotoxicity in comparison with free CDDP at the same doses [125].
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-Glycyrrhetinic acid (GA) Aliginate acid (ALG) Pt nanoparticles: alginate is a biodegradable and non-toxic polysaccharide which operating as the shell and skeleton of nanoparticles. The presence of several carboxy groups in the structure of this polymer give it a negative surface charge. Therefore, GA-ALG@Pt NPs cannot interact with blood elements and show low systemic toxicity and long blood circulation [126].
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-Silk fibroin peptide/baicalein nanofibers (SFP/BA NFs): this nano-formulation could enhance the CDDP uptake and localization to mitochondria in renal cells, which led to an inhibition of the cisplatin-induced ROS formation and mitochondrial membrane potential disruption. As a result, they successfully protected against cisplatin-induced AKI via improving antioxidant responses, e.g., SOD and GSH, and suppressing DNA damage and the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway activation in kidney [127].
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-Folate grafted albumin nanoparticles: folic acid receptors are over-expressed on the surface of various cancer cells, so this vitamin can be used for targeted therapy. Based on one study, the administration of cisplatin loaded folic acid decorated bovine serum albumin nanoparticles (Cp-FA-BSA-Nps) limits the cisplatin adverse effects on kidneys [128].
The histopathological effects of cisplatin and nanoparticles on kidneys
As shown in Table 3, both metallic and polymer nanoparticles have been able to reduce or completely remove the negative effects of cisplatin on kidney tissue in in-vivo studies. In this regard, the treatment of animals with cisplatin has been able to induce tubular, glomerular and interstitial damages. Among CDDP-induced tubular injuries, we can mention necrosis, atrophy, increase in eosinophilic material, dilation, vacuolation, cystic dilatation, cast formation, brush border damage, fibrosis, edema, hemorrhage, swelling, infiltration of inflammatory cells. Moreover, CDDP-induced glomerular damage includes congestion, Bowman's capsule collapse, atrophy, necrosis, thickening basement membrane, widening Bowman's space, and capsule deformation. As summarized in Table 3, we can see that the reviewed nanoparticles have been able to neutralize the histopathological effects of CDDP on renal tissues [54, 57, 58, 72, 87, 99, 120].