Promising application of polyoxometalates in the treatment of cancer, infectious diseases and Alzheimer's disease.

As shown in studies conducted in recent decades, polyoxometalates (POMs), as inorganic metal oxides, have promising biological activities, including antitumor, anti-infectious and anti-Alzheimer's activities, due to their special structures and properties. However, some side effects impede their clinical applications to a certain extent. Compared with unmodified POMs, POM-based inorganic-organic hybrids and POM-based nanocomposite structures show significantly enhanced bioactivity and reduced side effects. In this review, we introduce the biological activities of POMs and their derivatives and highlight the side effects of POMs on normal cells and organisms and their possible mechanisms of action. We then propose a development direction for overcoming their side effects. POMs are expected to constitute a new generation of inorganic metal drugs for the treatment of cancer, infectious diseases, and Alzheimer's disease.Graphical abstract.

Introduction

POMs are polyanionic oxides described as clusters of addenda atoms in their highest oxidation number, such as tungsten (W), molybdenum (Mo), niobium (Nb), antimony (Sb), and vanadium (V), with the eventual presence of heteroatoms [(X)], such as phosphorus (P), boron (B), and (or) silicon (Si), and linked by oxygen anions [1-5]. The three-dimensional structure of POMs is mainly composed of either corner-sharing (one bridging μ2-oxo group) or edge-sharing (two bridging μ2-oxo groups) of MO6 octahedra [6]. POMs exhibit an overwhelming variety of shapes and sizes, including the Keggin- ([XM12O40]n–), Wells–Dawson- ([X2M18O62]n–) and Anderson-type ([XM6O24]n–) structures (Fig. 1) [7] POMs are relatively stable with strong electron acceptance and transfer abilities, which allow the formation of derivatives with different structures via coupling with metal or organic groups [8]. The main advantage provided by POMs, which are programmable, is that the structure of metal oxide cluster anions can be designed and modified such that many elements can be easily introduced into the POM framework. Due to their unique properties, POMs show an overwhelming diversity in size, structure, and physicochemical capabilities, such as shape, redox potential, surface charge distribution, polarity, and acidity [4]. Their biologically relevant activity is closely related to their composition, shape, and size. In the 1980s, Jasmin et al. first found that ammonium 21-tungsto-9-antimoniate [HPA-23, (NH4)17Na (NaSb9W21O86)] could protect against DNA and RNA viruses [8, 9]. Many polyoxometalate derivatives have been synthesized and exhibit biological activities for tumor [5], viral [particularly human immunodeficiency virus (HIV) and hepatitis B virus (HBV)] [10], bacterial [11], and Alzheimer’s disease (AD) therapy [12]. For example, [NH3Pri]6[Mo7O24]∙3H2O (PM-8) significantly inhibits the growth of a variety of tumors, including the MX-1 murine mammary cancer, Meth A sarcoma and MM46 adenocarcinoma cell lines [13, 14]. The Keggin-type structure of polyoxotungstates demonstrates marked antiherpetic activity. Due to their benefits, the development of novel POMs for use as new drug candidates can be expected.

Fig. 1

Overview of POMs with the most common archetypes. A Keggin, B Wells–Dawson, C Anderson

However, despite the successful application of certain POMs, most pure inorganic POMs exhibit high and long-term toxicity, which hinders their clinical applications. The development of POMs is limited by three main factors: (1) due to the special charge and structure of POMs, they exhibit severe toxic side effects at high dosages [1, 2]. (2) As negatively charged clusters, their surfaces are evenly distributed with tightly packed oxygen atoms, which leads to a generally weak and unspecific interaction between the POM and biomolecules [1]. (3) Most POM archetypes are thermodynamically and kinetically unstable, their conformational change depends on surrounding environmental factors, such as the solution concentration and the coexistence of foreign inorganic or organic matter, and at micromolar concentrations, POMs can be degraded into a mixture of smaller fragments at physiological pH [2-5].

Intriguingly, due to the tunability and physiochemical properties of the POM structure [15], different types of organic or inorganic groups can be easily introduced into the POM framework to modify and synthesize multiple functional compounds [4, 16–19]. Strategies such as encapsulation technology [15, 17] and the grafting of bioactive organic ligands onto the nuclei of inorganic POMs [20] have been used to minimize their toxicity and improve their bioactivity. Moreover, their lower cost and easier synthesis have made the medicinal properties of POMs the focus of attention [1, 10].

In this review, we provide a comprehensive overview of the biological activities of POMs and their potential biomedical applications in the treatment of cancer, infectious diseases, and AD and detail their possible toxic side effects on healthy cells (animals). In addition, we expound why POMs remain the potential next generation of clinical drugs despite their shortcomings.

Application of POMs in antitumor therapy

Application of purely inorganic POMs

POMs, a discrete cluster of metal oxide anions, have been studied to determine their potential pharmaceutical applications. POMs exhibit considerable potential as metallodrugs in antitumor therapy. However, their toxicity remains an unresolved issue, which impedes their clinical application.

In 1988, Yamase et al. found that the synthesis of PM-8 could inhibit the growth of tumors in different mouse models. PM-8 is somewhat more active than certain approved drugs, such as 5-fluorouracil (5-FU), in vitro and in vivo [21]. The toxicity of PM-8 is low despite application of a high dose of 250 mg/kg, and the mice maintained their weight for an average for 14 days [21]. In 1993, Yamase et al. proposed that the antitumor mechanism of PM-8 involves its reduction to [Me3NH]6[H2MoV12O28(OH)12(MoVIO3)4]·3H2O (PM-17) and that PM-17 reduces and kills cancer cells [21]. Flavin mononucleotide (FMN) is a coenzyme for some oxidative enzymes and the principal form of riboflavin in cells and tissues and acts as an electron carrier for electron transfer (from NADH to coenzyme Q). During this process, the multielectron reduction of [Mo7O24]6− to PM-17 is biologically initiated through the one-electron reduction of the 1:1 [Mo7O24]6−-FMN complex that forms on the tumor cell mitochondria and results in suppression of tumor growth due to the inhibition of ATP generation [22]. The toxicity of PM-17 is significantly higher than that of PM-8. Treatment with 25 mg/kg PM-17 significantly inhibited the growth of Meth A sarcoma tumors on the 14th day. However, continuous administration of PM-17 could lead to body weight loss. It is possible that PM-17 is a reduced species of PM-8, and the toxic effects on weight appear to be associated with the production of PM-17 resulting from the 12-electron reduction of [Mo7O24]6− [21]. It has been suggested that PM-8 preferentially enters tumor cells and exerts its antitumor effects by forming PM-17 and inhibiting the formation of ATP. Furthermore, the toxicity of PM-17 in mice has been examined through hematological and serological analyses. No hepatic or renal dysfunction is observed with the administration of the therapeutic dose to human pancreatic cancer cells (AsPC-1) [22]. Despite the notable effects of PM-8 and PM-17, purely inorganic POMs may have long-term toxicity, which limits their clinical application in cancer therapy.

POM-1 to POM-6 ([(CH3)4N]2Na6.5(NH4)2[SnII1.5(WO2(OH))0.5(WO2)2(SbW9O33)2]·32H2O, POM-1; Na11(NH4)[(MnII(H2O))3(SbW9O33)2]·45H2O, POM-2; Na5K7[(VIVO)3(AsW9O33)2]·29H2O, POM-3; [(CH3)4N]2Na7[(MnIII(H2O))3(SbW9O33)2]·24.5H2O, POM-4; Na10[MnII2(H2O)6(WO2)2(SbW9O33)2]·40H2O, POM-5; Na6[Cu2II(H2O2)2(H2W12O42)]26·H2O, POM-6), particularly POM-1 and POM-2, exert stronger biological effects against malignant cell lines, particularly platinum-resistant cell lines, and thus have a more promising future in cancer treatment compared with standard anticancer drugs such as cisplatin and carboplatin [23]. POM-1 is more cytotoxic than cisplatin in a neuroblastoma cell line (KCN) and an Ewing’s sarcoma cell line (CADO-ES-1) but not in hepatocellular carcinoma or renal cancer cell lines. POM-2 has a very similar median lethal dose (LD50) for neuroblastoma cell lines (SHEP-SF, KCN) and CADO-ES-1 in the range of 6.85 to 9.84 μM [24]. POM-1 can suppress tumor growth by inhibiting the activity of NTPDase, and no significant liver or renal toxicity is observed at the suppressive dose (Table S1) [25]. However, all six abovementioned POMs are stable in the body and not easily metabolized, which results in toxic effects. In 2021, Liu et al. reported hierarchically structured giant polyoxometalate superclusters, (NH2Me2)22K12Na12 [(Sn (CH3)2)2O]4{[CeW5O18] [TeW4O16]- [Ce Sn (CH3)2]4[TeW8O31]4}2·ca.186 H2O. This compound shows obvious cytotoxicity against human cervical carcinoma cell line (HeLa), breast cancer cell line (MCF-7), human liver tumor cell line (HepG2), human non-small-cell lung cancer cell line (A549), human liver cancer cell line (SMMC-7721), and murine melanoma cell line (B16F17). Notably, this compound is also highly toxic to kidney epithelial cells according to the MTT assay [26]. Consequently, the application of this compound in cancer treatment is limited by its toxicity. The most effective way to solve this problem is to improve its cancer-specific targeting.

With good antitumor properties, purely inorganic POMs also exhibit inherent toxicity to the body or normal cells. Due to the charge, polarity and redox properties of most POM surfaces, POMs show poor biocompatibility and relatively low stability under physiological conditions. Additionally, the surface features of POMs limit their infiltration into cells [27]. As a result, POMs are not easily excreted or expurgated from the body, leading to long-term toxicity [28]. POMs may also bind to proteins through high-affinity electrostatic interactions, which possibly blocks the cell cycle and binding to proteins in cells and may thereby result in potential cytotoxicity [27, 29]. For example, various POMs identify and inhibit different kinases, including hexokinase, phosphofructokinases, and protein kinase CK2, in a noncompetitive manner [30]. Protein kinases are generally upregulated in many cancer cells, and their inhibition has been suggested a potential mechanism contributing to the antiapoptotic and anticancer effects of POMs. In addition, some POMs could be identified as histone deacetylase (HDAC) inhibitors that inhibit the growth of cancer cells [31]. To reduce the cytotoxicity of POMs on normal cells, it is worth exploring the structure–activity relationships of POMs and methods for enhancing their biological targeting. Consequently, the modification of purely inorganic POMs, such as through organic–inorganic hybrid-based functionalization or encapsulation and POM-based nanocomposites, could significantly reduce the toxicity of POMs and improve their antitumor activity. Moreover, it has been reported that POMs and copper (II) can form the compound K7Na3[Cu4(H2O)2(PW9O34)2]20·H2O (PW9Cu). This compound is cytotoxic to a human osteosarcoma cell line (MG-63) and a rat osteosarcoma cell line (UMR106). The abovementioned experiment revealed a more serious antiproliferative effect of PW9Cu in MG-63 cells than in a normal osteoblast cell line (MC3T3-E1). The main mechanism of the toxicity of PW9Cu to cells is the production of reactive oxygen species (ROS) and a reduction in glutathione (GSH) levels [18].

Application of inorganic–organic hybrid POMs

When modified by organic groups, POMs can exhibit reduced toxic side effects. Changes in the surface structure, charge and polarity of POM-based inorganic–organic hybrids lead to improved cell penetration, increased selectivity, and decreased toxicity.

The first reported organometallic polyoxometalate, [PW11O39(TiCp)]4−(Cp: η5-C5H5), forms a complete class of organometallic compound derivatives [19]. In 2003, J Liu et al. investigated POMs containing organometallic groups, that is, polyoxotungstate [CoW11O39(CpTi)]7−. The anion CoW11(CpTi) can inhibit the growth of many types of tumor cells, including colon cancer cell line (HLC), leukemia cell line (HL-60) and SMMC-7721 cell line. The antitumor activity of CoW11(CpTi) is similar to that of cyclophosphamide and 5-FU, but the cytotoxicity of CoW11(CpTi) is significantly lower than that of 5-FU. The IC50 (50% inhibitory concentration) of CoW11(CpTi) against SMMC-7721 and HeLa cells lines are only 3.2 and 11.5 μM, respectively. However, the IC50 values for peripheral lymphocyte cells and marrow cells are 442 and 730 mM, respectively. In vitro and in vivo experiments have shown that CoW11(CpTi) is less toxic. In mice, the LD50 of CoW11(CpTi) is 2898 mg/kg with a 95% confidence limit (95% Cl) of 2792–3004 mg/kg [19]. In 2020, Joshi A et al. reported a Strandberg-type POM ([HP2Mo5O23]5−) functionalized with a flexible organic ligand, 4,4’-bipyridine (4,4’-H2bpy), to form [{4,4’-H2bpy} {4,4’-Hbpy}2{H2P2Mo5O23}]·5H2O. This hybrid POM has higher stability and exerts a synergistic effect in tumor treatment [26]. The cytotoxic effect of this compound has been studied in vitro on normal murine fibroblast cell line (L929). The ligand alone (IC50 = ∼40 µM) is more toxic to normal cells than the synthesized compound (IC50 > 100 µM). The results showed that [HP2Mo5O23]5− reduces the toxicity of this organic ligand. The IC50 values obtained for HepG2, A549 and MCF-7 cell lines are 33.79 µM, 25.1 7 µM, and 32.11 µM, respectively. In addition, the researchers investigated the mechanism of its antitumor effect and concluded that the compound might regulate apoptosis and necrosis pathways [32]. Interestingly, Xue et al. constructed a novel bioinorganic hybrid system, [Mo154]@VLPs, using virus-like particles (VLPs) of the human papilloma virus capsid protein L1 and molybdenum-containing polyoxometalate of [Mo154]. An MTT assay was employed to investigate the survival rate of [Mo154]@VLPs on normal human embryonic kidney cell line (HEK293). The results showed that 90% and 82% cell viability are maintained with 50 µM and 10 µM [Mo154]@VLPs, respectively. Therefore, [Mo154]@VLPs are slightly cytotoxic to HEK293 cells [33].

POMs combined with drug molecules are also popular for tumor treatment because drugs are more selective and less toxic. 5-FU is a widely used anticancer drug but exhibits obvious defects, such as toxicity to marrow, severe gastrointestinal reactions and low selectivity [34]. Combining 5-FU with POMs significantly improves the selectivity. For example, the combination of 5-FU with the Keggin POM [PW12O40]3− exhibits lower toxicity than the free drug on HEK293 cells [35]. W was selected over Mo due to its remarkable redox stability [36]. The LD50 of the new compound (C4H3FN2O2)3HSi·W12O40·3H2O is 1158.25 mg/kg (95% Cl 1072.87–1596.54 mg/kg). The toxicity of this compound is significantly lower than that of 5-FU and pure POM [37]. Two rare earth-substituted Keggin-type polyoxometalate compounds, K10C4H4FN2O2Y(PW11O39)2·10H2O (FYPW) and K9(C4H4FN2O2)2La (PW11O39)2·18H2O (FLaPW), have similar toxicities but higher antitumor activities than 5-FU against HeLa and HepG2 cells at the same dose [35]. The rare earth elements Nd and 5-FU have been combined with tungstosilicic polyoxometalate to form K26(C4H4FN2O2)8Nd (SiW11O39)4·5H2O (FNSW). FNSW has lower cytotoxicity in HEK293 cell line (median toxic concentration (TC50) = 45.9 µM) than 5-FU (TC50 = 14.7 µM) and C4H4FN2O2H3SiW12O40·12H2O (FSW) (TC50 = 28.8 µM). FNSW also exerts a stronger inhibitory effect on HepG2 cells than 5-FU and FSW [8]. Rare earth elements change the cell membrane fluidity, permeability, ATP activity, intracellular and extracellular ion exchange, cell mitosis and DNA synthesis to affect the function of tumor tissues and cells [38]. Therefore, the rare earth element Nd could be used to improve the biological activity of POMs. In addition, K9(C4H4FN2O2)2Nd (PW11O39)2·25H2O (FNdPW) is a chemically synthesized drug that contains synthesized rare earth elements, which have low cytotoxicity. FNdPW significantly decreases the viability of A549 cell line and induces apoptosis by inducing significant activation of caspase 3-dependent signaling pathways [39]. Separately, the POM-BP complex Mo4Zol2MnIII has been studied in a mouse xenograft model bearing human Ewing sarcoma cell line (SK-ES-1), which revealed good results. The experiments showed that the POM-BP complex does not reduce the weight of the mice, indicating that the complex exhibits low toxicity to the body [20].

A cytotoxicity study using noncancerous breast epithelial cells (MCF-10A) and breast cancer cells (MCF-7 and MDA-MB-231) have shown that POM-biomolecule conjugates derived from the conjugation of a Tris-modified POM cluster (Tris–POM–Tris) (Tris: Tris(hydroxymethyl)aminomethane) with certain organic molecular forms of CA–POM–CA (CA: cholic acid) and DHCA–POM–DHCA (DHCA: dehydrocholic acid) exhibit improved bioactivity and induce reduced side effects. These novel POM–biomolecule hybrid compounds exert potential synergistic effects and lower cytotoxicity (Table S1) [40]. In addition, glycine-functionalized POMs (K2Na [AsIIIMo6O21(O2CCH2NH3)3]6H2O) exhibit lower toxicity to normal cells (human umbilical vein endothelial cell line, HUVECs) and better antiproliferative effects in vitro [41, 42]. In addition, Wang et al. designed and synthesized a new POM complex with a sandwich structure [Na (H2O)4] [{Na3(H2O)5} {Mn3(bpp)3} (SbW9O33)2}] ·8H3O (MnSbW-bpp, bpp = 1,3-bis(4-pyridyl) propane) based on a flexible ligand. In addition, the IC50 values of MnSbW-bpp to normal human kidney inherent cell line (HMC) are 33.5 µM, whereas the IC50 values to other cancer cells are almost always below 10 µM, which indicates that MnSbW-bpp is more toxic to cancer cells than normal cells (Table S1) [43].

Application of novel POM nanocomposites

POMs have a special and complex architecture with dimensions up to the nanoscale. Natural or synthetic biopolymers, as nanocarriers for a variety of drugs, can enhance drug stability and help maintain the biological activity of drugs with decreased side effects through encapsulation [44]. The choice of carrier material has an important influence on the pharmacokinetics of nanodrugs [45]. The pharmacokinetics and pharmacodynamics of a series of POMs can be improved by conjugation with carriers, and the toxicity of POM-based nanocomposites is lower than that of POMs alone.

Chitosan is a linear polysaccharide derived from the deacetylation of chitin, a process that forms natural metabolites in organisms. Chitosan is nontoxic and can be completely absorbed by organisms, which indicates its great advantages as an agent for the sustained release of drugs [46]. POMs have been observed to be toxic only at very high doses, but at concentrations below 0.01 mg/ml, no significant signs of cell death are detected among human oral epidermoid cancer cell line (KB), MCF-7 cell line, human prostate cancer cell line (PC-3), or A549 cell line. However, the chitosan/EuWA (EuWA: [Cs ⊂ Eu6As6W63O218(H2O)14(OH)4]25−) nano-complex is highly toxic to cancer cells even at a dose of 7 μg/mL [47]. This complex is a good example of enhanced toxicity caused by nanoencapsulation. Both carboxymethyl chitosan (CMC) and trimethyl chitosan (TMC) are ideal drug carriers for the encapsulation of intact bioactive POMs. Marked differences in the uptake by HeLa cells are found between POM-CMC (POM: K6H2[CoW11TiO40] ·13H2O ({CoW11TiO40})) and POM-TMC nanoparticles. TMC, as a stabilizer of CoW11TiO40, can transport POMs, improve their selectivity and reduce their toxic effects on normal cells and tissues [48, 49]. In addition, Pérez-Álvarez et al. reported that Wells–Dawson-type [P2Mo18O62]6− phosphomolybdate can be loaded into covalently crosslinked chitosan nanogels that can act as nanocarriers for local delivery [50]. Their work showed that selected chitosan nanocarriers have great potential for the delivery of POMs into tumor cells due to their pH-triggered delivery ability, which inhibits the release of cytotoxic drugs at physiological pH.

The compound chitosan-[NaP5W30O110]14− (CTS-P5W30) also shows higher cytotoxicity than the standard anticancer drug vincristine along with minimal toxicity to normal cells [Vero cells, a cell line derived from the kidney of the African green (vervet) monkey]. The percent inhibition obtained with 10 μM CTS-P5W30 against HeLa cells and Vero cells is 7–12% and 78–98%, respectively. The cytotoxic behavior of chitosan-encapsulated POMs differs from that of nonencapsulated POMs [16]. The low-molecular-weight carbohydrate polymer nanocomposites CSYC100 and CoW11CpTi show lower toxicity to the C2C12 (normal murine/mouse myoblast cell line) and A549 cell lines. The finding that 95% of the total C2C12 cells remained viable after the experiment indicate that the nanocomposites at a concentration of 1.25 mM exert no toxic effects on C2C12 cells. In contrast, 5 mM bare CoW11CpTi is toxic to A549 cancer cells. Encapsulation increase the viability of the cells from 10 to 55%. CoW11CpTi in complex with CSYC100 can significantly reduce the toxic effects on C2C12 mouse myoblast cells [51]. The encapsulation of POMs makes them more target-oriented with minimal side effects. In 2018, Zamolo et al. synthesized (nBu4N)3H[γ-SiW10O36{(C5H7N2OS) (CH2)4 CONH(CH2)3Si}2O] (TBA-POM-biot2), and cell imaging verified that it targets HeLa cells [52]. In 2019, Pérez-Álvarez et al. prepared chitosan nanogels as delivery nanocarriers for the loading of Wells–Dawson-type [P2Mo18O62]6− phosphomolybdate. The nanogels have excellent properties, including low toxicity and ease of absorption and metabolization [50].

Microspheres such as starch microspheres and liposomes are ideal drug carriers with excellent biocompatibility, biodegradability and physical stability, which can reduce the side effects and incompatibility of drugs [53]. In 2003, Liu et al. reported the antitumoral activity and toxicity of starch-loaded K6H2[CoW11TiO40]·12H2O (CoW11Ti)13 nanoparticles. A cellular toxicity test has shown that CoW11Ti encapsulated by starch is less toxic in vitro than its parent CoW11Ti [17]. Starch-loaded α-K8H6[Si2W18Ti6O77] (Si2W18Ti6) also exhibits significant advantages after encapsulation by starch. A comparison of LD50 results indicates that the acute toxicity of Si2W18Ti6/starch is lower than that of pure POM, and the underlying mechanism is that the starch microspheres may prolong the residence time of the POMs by improving their stability and inhibiting their decomposition into toxic molecules. These three effects observed with starch decrease the toxicity of Si2W18Ti6. Moreover, in vivo experiments have shown that Si2W18Ti6/starch exerts no significant effect on the growth of rat fetuses, and the toxicity to rat fetuses is weak. This complex shows higher antitumor activity and lower toxicity in in vitro and in vivo experiments and no teratogenicity to pregnant rats [54].

In recent years, studies have extensively researched the development of liposomes as drug delivery carriers. The analysis of liposome-encapsulated polyoxometalate (LEP) nanoparticles containing K6[SiW11TiO40]·16H2O (SiW11Ti) has shown that liposomes exert no killing effect on HUVECs, whereas LEPs have reduced side effects compared with SiW11Ti. The toxicity of POMs to normal cells is reduced due to the protective effects of the lipids. The LD50 of SiW11Ti LEP in mice is 2003 mg/kg (95% Cl 1856–2374 mg/kg). An LD50-based comparison between LEPs and POMs (LD50 of SiW11-Ti = 394 mg/kg) indicates that liposome encapsulation reduces the acute toxicity of POMs [55]. Additionally, Razavi et al. synthesized nanolipid-loaded Preyssler (NLP, Preyssler: H14 [NaP5W30O110]) and studied its antitumor activity against HepG2 cells [56]. The IC50 value of the loaded nanoliposomes for normal cells [primary human foreskin fibroblasts (HFFs)] was found to equal 2000 μg/mL at 72 h, which is markedly better than that of sorafenib (16 μg/mL). The entrapment efficiency of nanoliposomes reaches 53.8%, which clearly reduces the toxicity of Preyssler.

A novel platinum (IV)-substituted Keggin-type POM prodrug [PW11O40(SiC3H6NH2)2Pt(NH3)2Cl2]3− (PtIV-PW11) has been designed. Compared with classic cisplatin, PW11 and Pt IV-PW11 exert better inhibitory effects on the growth of HT29 cells (human colorectal cancer cell lines). Researchers then encapsulated PtIV-PW11 with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy (polyethylene glycol)-2000] (DSPE-PEG2000) to form PtIV-PW11-DSPE-PEG2000 nanoparticles (PtIV-PW11-DSPE-PEG2000 NPs). DSPE-PEG2000 NPs exhibit improved cellular targeting in acidic microenvironments, which decreases drug release under high pH conditions and the accumulation in the kidney. PtIV-PW11-DSPE-PEG2000 exhibit lower cytotoxicity against HUVECs cell line and fewer side effects on mice than cisplatin [15]. The Kabanos-type POM [Na{(Mo2VO4)3(μ2-O)3-(μ2-SO3)3(μ6-SO3)}2]15–21 has been modified with gold nanoparticles (AuNPs) to form AuNPs@POM. The results show that AuNPs@POM exerts greater antiproliferative effects on mouse melanoma cell line (B16) than on Vero cells. In other words, AuNPs@POM exhibits lower toxicity to normal cells [57]. In addition, Tang et al. used hollow mesoporous organosilica nanoparticles (HMONs) to encapsulate Mn2(CO)10 (Mo(VI)-based POM clusters), which resulted in the formation of more stable Mn2(CO)10@HMOPMs (HMOPs-CO). To assess the toxicity of HMOPMs-CO and HMOPMs, these researchers performed blood index tests, a major organ histological analysis and evaluation of weight changes in BALB/c mice (10 mg Mo/kg). All the results suggest that both HMOPMs-CO and HMOPMs exhibit low toxicity in vivo [58].

Interestingly, Zhou J et al. synthesized monodisperse renal-clearable W-based POM nanoclusters (W-POM NCs; average diameter of approximately 2.0 nm) [59]. The as-prepared W-POM NCs show biocompatibility toward normal cells/tissues both in vitro and in vivo because no obvious toxicity was observed over a 30-day period after the treatment of female BALB/c mice with concentrated W-POM NCs. More importantly, W-POM NCs exhibit not only better near-infrared (NIR) light absorption (a coloration effect originating from the existence of electron-trapped W5+) for efficient tumor photothermal therapy but also impressive anti-inflammatory ability (eliminating inflammation-related ROS by the oxidation of W5+ into the W6+ state) to obtain better therapeutic outcomes. Thus, these W-POM NCs are safe and efficient. In 2021, Isakovic AM et al. reported a molecular noble metal-oxo nanoclusters, Na8[Pd13As8O34(OH)6]·42H2O (Pd13) [60]. Pd13 had excellent antitumor potential against human neuroblastoma cell line (SH-SY5Y). The obtained IC50 values for 24 h and 48 h treatment with Pd13 were 7.2 ± 2.2 µM and 4.4 ± 1.2 µM, respectively. The molecular mechanisms of Pd13-induced antitumor action include apoptotic cell death and autophagy induction. Because of a good metabolic stability, Pd13 cannot act cytogenotoxic to the healthy human peripheral blood cell line (HPBCs) at 25 μM (25 μM ≈ 3 × IC50 (24 h) for SH-SY5Y). Additionally, Zheng et al. constructed a novel supramolecular nanocage ((NH2Me2)12[(V5O9Cl)6(tatb)8], VMOP-31). VMOP-31 has been applied to hepatic tumors both in vitro and in vivo. The researchers used human normal bronchial epithelial cell line (BEAS-2B) to study the cytotoxicity of VMOP-31. The obtained IC50 values are markedly lower than those in SMMC-7721, MCF-7, and A549 cell lines, which indicates that VMOP-31 is selectively toxic toward solid tumor cells over normal cells [61]. In addition, peptides can also serve as excellent ligands. As a result, this novel biohybrid could decrease the on-POM folding of the chains and has no tendency to self-assemble into spherical vesicles. The compound ([MnMo6O18{(OCH2)3-CNHCO(CH2)2CO(Ttds-EEEEβA-fQWAVGHL-NHEt)}2]3) displays IC50 values in the range of 10–100 mM [62].

Overall, the encapsulation of bioactive POMs into a biopolymer is a new method for the medical application of these promising drug prototypes and for the development of new composites with functionalized hybrid POMs or specially designed polymers.

Application of POMs for anti-infection therapy

POMs have been shown to be active against a variety of DNA and RNA viruses, including influenza viruses A and B, HBV, hepatitis C virus (HCV), herpes simplex virus, dengue virus and HIV [8, 38–41]. In addition, POMs play an important role in antibacterial activity.

Application of POMs for anti-HIV therapy

According to the 2019 United Nations Joint Program of HIV/acquired immunodeficiency syndrome (AIDS) report, 37.9 million people worldwide are living with HIV, and approximately 1.7 million people are newly infected [63]. HIV remains the main threat to public health worldwide. Currently, combination antiretroviral therapy comprises three or four types of anti-HIV-1 drugs that work against agents during multiple stages of the HIV-1 life cycle, including viral reverse transcriptase, integrase, protease, and viral invasion and fusion. Despite great success, drug resistance and side effects cannot be ignored [3, 64].

HPA-23 was the first POM to be used in clinical trials of AIDS but failed due to its unacceptable adverse effects [3, 64]. Since then, several groups have focused on the synthesis of new derivatives of POMs, which not only make POMs less toxic but also increase their antiviral activity in most cases.

In recent years, the anti-HIV activity of POMs has attracted attention. However, the application of POMs for HIV therapy remains in its infancy, and the toxicity and side effects of POMs have rarely been evaluated. Craig L. et al. studied the anti-HIV activity and toxicity of six structural categories of POMs in human peripheral blood mononuclear cells (PBMC), including HPA-23, X" + W12O40(8−n)− (Keggin), P2W18O626− (Wells–Dawson), W6O192− (Lindqvist), [NaP6W30O110]14− (Preyssler), and W10O324− (decatungstate) [65]. Studies have shown that compounds containing fewer than eight metal ions, such as (n-Bu4N)2W6O19, (n-Bu4N)2Mo6O19, a-(n-Bu4N)2Mo8O26, and K4W4O10(O2)6 (all median effective concentration (EC50) values > 50 μM), have low antiviral activity. However, the anti-HIV activity of the remaining compounds, including the compounds H4SiW12O40, Na6H2Wl2O40, and K8SiW11O39, is equal to or higher than that of HPA-23. The EC50 value of HPA-23 is 0.39 μM. Most polyoxometalates have low toxicity to PBMC, and their IC50 values are lower than that of HPA-23 [65].

As mentioned previously, POMs are unstable under physiological pH conditions (the blood serum pH value is generally 7.4) [17, 22, 55, 66], which limits the development of antiviral POMs. Heteropolytungstates of the Wells–Dawson class containing hydrolytically stable Nb were synthesized by Deborah A Judd et al. The new compounds (α1-K7[P2W17(NbO2) O61] (α11), α2-K6.7H0.3[P2W17(NbO2) O61] (α21), α1-K6.9Li0.1[P2W17NbO62], (α12), and α2-K7[P2W17NbO62] (α22)) are active against HIV-1 and selectively inhibit HIV protease, as evaluated in HIV-1-infected PBMC. These researchers solved the instability problem of POMs (they were stable at pH 7), and the research showed that they all exhibit high inhibitory activity against HIV-1 protease (EC50: 0.17–0.83 μM) and minimal toxicity (IC50: 50 to > 100 μM) [66]. Keggin polyoxotungstate K7(PTi2W10O40)·6H2O (PM-19) [3, 67] not only functions as an anti-HIV agent but also acts against herpes simplex virus (HSV) [67-69]. PM-19 can inhibit the interaction between the HSV envelope protein (gD, glycosylated ectodomain) and cell surface membrane proteins to perform its anti-HSV functions [70]. Additionally, PM-19 is less toxic and more efficient than HPA-23. Recently, Wang et al. introduced an organic amine into the PM-19 structure [K7(PTi2W10O40)] and synthesized a series of novel pyridinium polyoxometalates (A7PTi2W10O40). Their studies showed that the introduction of the organic amine improves the stability of the compounds and reduces the cytotoxicity compared with that of the original compounds. The TD50 value of PM-19 is 9.34 ± 0.32 μM, whereas the TD50 values of the remaining compounds are greater than 25 μM. [3]. Another Keggin polyoxometalate with low cytotoxicity and genotoxicity, PT-1 (K6HPTi2W10O40), also efficiently interferes with HIV reverse transcriptase and integrase by blocking the gp120-binding site of the CD4 receptor and interacting with the gp41 NHR (N36 peptide) to prohibit the entry of the virus [64]. To better understand the toxicity of POMs with different structures, we summarized their toxicity in anti-HIV therapy in Table S2.

From this point of view, the introduction of new elements makes the newly developed POMs not only more stable and less toxic than the original compounds but also plays an important role in anti-HIV treatment.

Application of POMs for anti-HBV/HCV therapy

POMs are also potential candidates for anti-HBV and HCV therapy [4, 19, 71]. For example, Cs2K4Na [SiW9Nb3O40]·H2O (POM93) can inhibit the secretion and replication of HBV antigens in vitro in a dose- and time-dependent manner [72]. POM93 is located on the surface of cells rather than the interior and exhibits less cytotoxicity than the commercially available hepatitis B drug in HepG2 cells [71]. In addition, a study of its acute toxicity showed no abnormal changes after single doses up to 5000 mg/kg body weight in Wistar rats. An assessment of sub chronic toxicity in Wistar rats also showed that POM93 is safe for the respiratory, digestive, reproductive and other systems. Compared with the untreated group, a histopathological analysis of various organs and their surrounding structures in the rats showed no inflammation, lesions or pathological changes after POM93 treatment [4]. The pharmacokinetics of POM93 indicates that the kidney and liver may be possible toxic sites [73]. Qi et al. administered POM93 to human HBV-transgenic mice at a dose of 6 × 10−5 mol/(kg day) for 28 days, which also proved that POM93 is safe and does not cause damage to liver tissue [72]. It can, therefore, be speculated that POM93 is safe for the human body and can serve as a highly effective anti-HBV drug. In addition, POM93 has a wide range of antiviral activities, such as activities against HIV, HSV, HCV and influenza A/influenza B [71].

As previously reported, POM-4, POM-6, and particularly POM-12 (Cs2K4Na [SiW9Nb3O40]·H2O) exhibit anti-HCV abilities. Yue Qi et al. [74] proposed that POM-12 can destroy the integrity of HCV by destroying the lipid layer of the viral envelope. A human lung cancer cell line (Huh7.5.1) viability study showed that the EC50 and TC50 values of POM-12 against HCV infection are 0.8 μM and 119 μM, respectively. A cytotoxicity assay with POM-12 indicated that it exerts no significant effect on Huh7.5.1-cell viability and can be used as a potential drug to protect individuals from hepatitis C virus infection in combination with ribavirin, a common drug used to treat HCV, or as a substitute for ribavirin. In addition to HCV, POM-12 also exerts an inhibitory effect on other flaviviruses, such as Dengue virus (DENV), Japanese encephalitis virus (JEV), and Zika virus (ZIKV). Studies have indicated that POM-12 can directly damage the integrity of these viruses and inhibit the replication of JEV at a post-entry step. The IC50 values of POM-12 against DENV, JEV and ZIKV are 1.16 μM, 1.9 μM and 0.64 μM, respectively. The TC50 value of POM-12 is 149.1 μM, which suggests that POM-12 does not suppress the virus by increasing cytotoxicity [75]. POM-12 exerts an effective inhibitory effect on flaviviruses, but its mechanism of action on different viruses is different and related to the surface topology and charge of virions. POM-12 may be modified to suppress these similar viruses.

In addition, the application of polyoxometalates for anti-HBV/HCV therapy is listed in Table S2.

Application of POMs for anti-influenza virus therapy

In recent years, influenza virus infection has remained a major threat to public health. As broad-spectrum drugs, POMs can protect against several respiratory viruses, including mycovirus, influenza virus, and coronaviruses, both in vitro and in vivo. Assessments of cytopathic effect inhibition and neutral red uptake assays have shown that HS-81 [Cs4[(Cl(CH2)3Si)2O]SiW11O39], HS-86 [(CH3)4N]4[(CH2 = CHSi)2O]SiW11O39], HS-106 [(Me3NH)8Si2W18Nb6O77nH2O], and HS-116 [(LysineH)7KSi2W18Nb6O7218H2O], among others, exhibit significant anti-respiratory syncytial virus (RSV) inhibitory activities and low cytotoxicity to embryonic African green monkey kidney cell line (MA-104) and human larynx epidermoid carcinoma cell line (HEp-2). The IC50 values of these POMs range from 2 to 100 μM, and no difference has been found among the compounds against different types of RSV strains [4, 5, 9].

Keggin-type polyoxometalate PM523 (iPrNH3)6H[PTi2W10O38(O2)2]·H2O affects influenza virus (FluV) A, FluV B, RSV and the measles virus in vitro. PM523 is not markedly cytotoxic in canine kidney cells (MDCK), and the TC50 is lower than that of ribavirin [76]. PM-523 inhibits FluV A virus replication in MDCK cells by inhibiting fusion of the viral envelope and cell membrane [76-79]. The researchers found that PM523, when used in combination with ribavirin, is not only more effective against FluV activity but also less toxic to MDCK cells than either compound alone, as determined by the trypan blue exclusion method. Moreover, the combinations exert synergistic effects in mice infected with Flu-V A (H1N1). The combination of PM523 and ribavirin at a ratio of 1:16 resulted in a higher number of surviving mice than those obtained with either compound alone at the same dose and even twice the dose [77, 78].

Heteropolyoxometalates with Keggin-type structures are also inhibitors of FluV but are unstable at physiological pH, which limits their development. A new series of manganese-substituted mixed-valence rare earth borotung state heteropolyoxometalates, Ln2H3[BW9VIW2VMn (H2O) O39]·12H2O (Ln (2)); Ln = La, Ce, Pr, Nd, Sm, Eu or Gd), as well as their corresponding heteropoly acids (Ln (0)), have been synthesized, and their effects against the influenza virus in MDCK cells have been investigated. Compared with archetype heteropolyacids, these newly synthesized compounds exhibit obvious thermal stability and acid–base stability. Most importantly, Ln (2) exhibits high activity against FluV A/B and less toxicity than Ln (0). The higher thermal stability of Ln (2) leads to slower decomposition and a moderate concentration of dissociated metal ions, such as Ln3+ and WO42−, which results in its lower toxicity compared with that of Ln (0) [80]. Thus, POMs have been identified as promising first-line therapeutics against acute respiratory diseases and are characterized by their low toxicity and high efficiency. The application of polyoxometalates for influenza virus therapy is summarized in Table S2.

Application of POMs for antibacterial therapy

Polyoxometalates also play a crucial role as antibacterial agents because they exhibit both synergistic and direct antibacterial activity. A study found that K6[P2W18O62]·14H2O (P2W18), K4[SiMo12O40]·3H2O (SiMo12), K7[PTi2W10O40]·6H2O (PTi2W10), and K9H5[α-Ge2Ti6W18O77]·16H2O (Ge2Ti6W18) enhance the antibacterial activity of β-lactams against methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant Staphylococcus. aureus (S. aureus, VRSA) [81, 82]. The mechanism underlying the inhibition by P2W18, SiMo12, and PTi2W10 is associated with the inhibition of the transcription processes of the mecA and pbp genes into mRNA, but that of Ge2Ti6W18 may be associated with the inhibition of a posttranscriptional process. The IC50 values of P2W18, SiMo12, and PTi2W10 against Vero cells are 120 μM, 500 μM and 1000 μM, respectively [81]. Additionally, Keggin-type structural (hetero)polyoxotungstates with a lacunary hole, such as undecatungstosilicate ([SiW11O39]82, SiW11), also improve the antibacterial activity of β-lactams against MRSA [83]. The polyoxotungstates K27[KAs4W40O140] and K18[KSb9W21O86], which are highly negatively charged, and Keggin-structural polyoxotungstates exhibit potent anti-Helicobacter pylori (H. pylori) activity. These polyoxotungstates can be taken up by H. pylori cells, the periplasmic space or the inner membrane to change the bacterial morphology into U-shaped or coccoid forms and subsequently induce bactericidal effects [84]. A study showed that polyoxotungstates, particularly those that are highly negatively charged against H. pylori, are stronger than polyoxomolybdates [84]. The newly generated organoantimony (III)-containing heteropolytungstates, such as [(PhSbIII)4(A-α-GeIVW9O34)2]12−, [(PhSbIII)4(A-α-PVW9O34)2]10−, and [{2-(Me2NCH2C6H4)SbIII}3(B-α-AsIIIW9O33)]3−, Na{2-(Me2HN+CH2)C6H4SbIII}AsIII2W19O67(H2O)]10−, [{2-(Me2HN+CH2)C6H4SbIII}2AsIII2W19O67(H2O)]8−, and [{2-(Me2HN+CH2)-C6H4SbIII}{WO2(H2O)}{WO(H2O)}2(B-β-AsIIIW8O30)(B-α-AsIIIW9O33)2]14− inhibit the growth of different Gram-positive and Gram-negative bacteria, and their bioactivity can be tuned by controlling the number and type of introduced organoantimony(III) groups [85, 86]. The novel decavanadate cluster complex [H2V10O28] [4-picH]4·2H2O exerts antimicrobial effects against Gram-positive and Gram-negative bacteria as well as fungi in vitro. Comet and plasmid nicking assays have demonstrated that the complex causes negligible damage to DNA and an inappreciable amount of cytotoxic damage compared with the similar sodium decavanadate salt Na6[H2V10O28]·18H2O [87]. Thus, this new complex may become a new antimicrobial agent. Chitosan has good biocompatibility, and composite films with antibacterial activity can be prepared by encapsulating POM with chitosan. For example, G. F et al. encapsulated POMs ((NH4)6V10O28 (V10), H5PMo10V2O40 (Mo10V2), and Na4W10O32 (W10)) in chitosan and synthesized a series of novel nanocomposites that exhibit improved cell penetration and better antibacterial ability [88].

In addition, POMs are excellent carriers and stabilizers for antibacterial agents. Based on the activity of polyoxometalates (Ag3PW12O40 = AgPW) against Gram-positive bacteria, a new type of composite material, AgPW@PDA@Nisin, which has a shell-core structure, was successfully synthesized using conjugated nisin on the surface of polydopamine as the shell and AgPW as the core [89]. This newly synthesized material can destroy the cytoplasmic membrane of S. aureus, change its permeability and induce its death. The minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) were found to equal 4 and 32 μg/mL, respectively. An MTT assay was performed to determine the effects of AgPW@PDA@Nisin on human dermal fibroblasts (HDF-α), and the results indicated that nanoflowers exhibit low cytotoxicity. Ag+ is an effective antibacterial agent that can interact with proteins and cell structures to destroy the physiological functions of bacteria. A silver-encapsulated Preyssler-type POM, [AgP5W30O110]14− (AgP5W30), reportedly exhibits antibacterial activity by continuously releasing Ag+ in exchange with Na+ [90]. The new materials synthesized by combining POMs with other antibacterial agents can greatly improve the antibacterial activity and reduce the cytotoxicity of POMs, and this method provides a new idea for the development of antibacterial materials.

Hemant K. Daima et al. functionalized tyrosine-reduced AuNPs (AuNPsTyr) [91] and tyrosine-reduced AgNPs (AgNPsY) using two different POMs, 12-phosphoric acid (PTA) and 12-phosphomolybdic acid (PMA). The introduction of POMs increases the activity of the nanomaterials against the Gram-negative bacterium Escherichia coli. The introduction of AuNPsTyr also increases the activity against A549 cells [92]. Most importantly, none of the nanoparticles, including AgNPsY, AgNPsY@PMA, and AgNPsY@PTA, show nontoxicity in human PC-3 cells. These studies indicate that the surface corona of POMs exerts a strong effect on the toxicity and biological applicability of nanomaterials. In addition, the introduction of POMs has increased the use of nanomaterials in the field of antimicrobials. Because POMs are only located on the periphery of bacterial cells, future studies should attempt to identify potential targets of extracellular or membrane-related proteins to elucidate the interaction mechanism between POMs and bacterial cells and improve the targeting properties of POM-based nanocomposites [93].

POMs as inhibitors of amyloid β peptide aggregation for the treatment of Alzheimer’s disease

AD is a degenerative disease of the central nervous system characterized by extracellular amyloid plaques and intracellular neurofibrillary tangles [12, 94]. According to the latest research results, aggregation of the amyloid β peptide (Aβ) into amyloid fibrils and the generation of excessive ROS are two essential mechanisms of AD pathogenesis. Recent advances have demonstrated that polyoxometalates are inhibitors of Aβ aggregation in the treatment of AD [12, 94–98]. POM-K8[P2CoW17O61], which has a Wells–Dawson structure, can inhibit Aβ fibril formation. Furthermore, the recognition of Aβ and amyloid inhibition may be correlated with the size of the POM, whereas selective inhibition may be related to the specific electrostatic interaction between the POM and Aβ. Studies have shown that while the smaller Anderson compound has no activity, the larger Keggin compound has moderate activity, and the largest Dawson compound exhibits the highest inhibitory activity. POMs might bind to the His13 to Lys16 (HHQK) cationic cluster of Aβ to interfere with fibril formation. In addition, studies have shown that transition metal (such as Ni(II)-, Co(II)- or Pt(II)-)-functionalized POM derivatives with specific histidine chelating sites have better anti-Aβ activity and peroxide inhibitory activity than the parental POM. These compounds can pass although the blood–brain barrier (BBB) and be metabolized after 48 h [94, 99].

Based on the interference of Aβ fibril formation, researchers have combined K8[P2CoW17O61] with the well-known Aβ targeting peptide inhibitor Aβ15-20 (Ac-QKLVFF-NH2) for self-assembly [95] and combined the unique high NIR absorption properties of gold nanorods with these two Aβ inhibitors [96]. These final compounds display stronger targeting abilities than the parent POMs, inhibit amyloid aggregation in the cerebrospinal fluid of mice and protect cells from Aβ-related toxic effects. The PC12 has been used to probe cellular metabolism using the MTT assay. The results show that POMs could significantly improve the cell survival rate, inhibit Aβ aggregation and reduce the cytotoxicity induced by Aβ [95, 96]. Similarly, peptide-modified Mo-POM nanoparticles have been synthesized by the self-assembly of Aβ target peptides and Mo-POMs [100]. The Peptide@Mo-POMs suppress Aβ aggregation, disaggregate Aβ fibrils, and suppress Zn2+-induced Aβ aggregation. These results provide new ideas for the design and synthesis of Peptide@POMs as Aβ inhibitors in the treatment of AD.

In addition, Ma M et al. developed a redox-activated NIR responsive POM-based nanoplatform (rPOMs@MSNs@copolymer), which can not only hinder Aβ aggregation but also serve as a reducing agent to clean superfluous ROS [101]. The nanoplatform consists of mesoporous silica nanoparticles (MSNs), reduced POMs (rPOMs), and the thermally responsive copolymer poly(N-isopropylacrylamide-co-acrylamide). The coincubation of PC12 cells with Aβ monomer for 48 h increased the ROS levels (174.35%) compared with those found in the untreated group, whereas the ROS levels are significantly decreased to 52.81% after coincubation with rPOMs@MSNs@copolymer under near-infrared laser irradiation. The MTT test showed that rPOMDs@MSNs@copolymer could significantly improve the cell viability (92.6%) of PC12 cells after coincubation with Aβ monomer for 48 h. This material provides a new method for using rPOMs for the NIR photothermal treatment of AD.

In addition, acetylcholinesterase (AChE), an enzyme responsible for the hydrolysis of the neurotransmitter acetylcholine, helps with the formation of β-amyloid. AChE inhibitors such as donepezil, rivastigmine, and galantamine are important in the treatment of neurodegenerative diseases. Recent data in the literature show that POMs can act as inhibitors of AChE, which makes them potential anti-AD drugs. Mirjana B et al. selected two Keggin-type heteropolytungstates, K7[Ti2PW10O40]·6H2O (K-Ti2PW10) and K6H[SiV3W9O40] ·3H2O (K-SiV3W9), with different inhibitory potencies toward AChE activity (IC50 values of 1.04 μM and 480 μM, respectively) to study their toxicity. The in vivo studies have shown that neither POM type can be considered highly toxic. Because there was no influence on the rat body mass and food intake. However, a histopathological analysis showed that K-SiV3W9 could induce reversible liver tissue damage [102]. The IC50 values of the compounds [H2W12O42]10− and [TeW6O24]6− are 0.29 ± 0.01 and 0.31 ± 0.01 μM, respectively [103]. 12-Tungstosilicic acid (WSiA) and 12-tungstophosphoric acid (WPA) have been shown to inhibit AChE activity at nanomolar concentrations. Studies have shown that these two POMs with Keggin-type structures exhibit no genotoxicity or cytotoxicity but can induce mild inhibition of cell growth in a concentration-dependent manner. Furthermore, WSiA and WPA can interact with the β-allosteric site in AChE, and this binding may prevent the conversion of the AChE586-599 region from the α-helical to the β-strand and thereby inhibits the AChE-associated aggregation of amyloid-β pmmc1, which plays a key role in the pathogenesis of AD [104].

It is believed that the application of POMs may contribute to the development of new multifunctional AD therapeutic materials. The application of polyoxometalates for AD therapy is summarized in Table S3.

Summary and outlook

POMs and POM-based hybrid compounds have great potential as antitumor, antiviral (anti-HIV, anti-HBV and so on), antibacterial and anti-AD agents. However, the application of POMs is limited by some drawbacks, including high toxicity and thermodynamic and kinetic instability under physiological conditions [17, 94]. At present, the clinical development of POMs remains in its infancy, and researchers are still developing derivatives of POMs with low toxicity, high stability, and good biological activity to obtain superior antitumor, anti-infection and anti-AD effects. Novel POM-based molecular and composite materials are the focus of current research. The conjugation of organic molecules or bioactive transition metals onto the POM core or skeleton can reduce the POM toxicity. In addition, POM conjugates/encapsulates in some biopolymeric delivery vehicles can significantly reduce the toxicity caused by metal ions and improve their biocompatibility. For example, POMs can be effectively used in sustained-release drug delivery systems by embedding the POMs into nontoxic chitosan and other drug carriers with high biocompatibility, which can enhance their stability at physiological pH. In addition, the incorporation of POMs into nanocomposites can significantly improve their biocompatibility and reduce their toxicity and instability. Furthermore, anticancer, anti-infection and anti-AD drugs can be doped into POM-based nanocomposites to further improve their biological properties. The biological and pharmacokinetic properties of POM-based nanocomposites appear to be superior to those of organically functionalized POMs. The development of more POM-based nanocomposites for anticancer, anti-infection and anti-AD therapy is the focus of future research.

Some possible toxicity mechanisms of POMs have been proposed, and these include competing with acetylated low-density lipoprotein (LDL) for the scavenger receptor of macrophages [95], binding to proteins through electrostatic interactions, tending to be deposited in organs in the body with abundant blood flow, such as the liver, spleen, lungs and kidneys [4], and not being easily excreted by the body [28]. Although possible mechanisms have been proposed, the specific mechanism underlying the action of POMs on cells and the body has not been determined. Future research will focus on the design and synthesis of novel POM hybrids, which currently exhibit excellent toxicity, pharmacokinetic properties, and biological activity. Furthermore, eliminating the toxicity mechanisms of POMs and reducing their high toxicity will open a new avenue for making POMs the next generation of drugs against tumors, viral infections, bacterial infections, and AD.

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