Application prospect of calcium peroxide nanoparticles in biomedical field

Xincai Wu; Xu Han; Yang Guo; Qian Liu; Ran Sun; Zhaohui Wen; Changsong Dai

doi:10.1515/rams-2022-0308

Open Access Published by De Gruyter Open Access March 10, 2023

Application prospect of calcium peroxide nanoparticles in biomedical field

Xincai Wu , Xu Han , Yang Guo , Qian Liu , Ran Sun , Zhaohui Wen and Changsong Dai

From the journal REVIEWS ON ADVANCED MATERIALS SCIENCE

https://doi.org/10.1515/rams-2022-0308

Abstract

In recent years, calcium peroxide (CaO₂) has attracted widespread attention in the medical community due to its excellent antitumor and antibacterial properties, and has gradually become a hot research topic in the biomedical field. CaO₂ reacts with water (H₂O) to produce calcium ion (Ca²⁺), oxygen (O₂), and hydrogen peroxide (H₂O₂), where Ca²⁺ is suitable for calcium death caused by calcium overload, O₂ is suitable for O₂-dependent anticancer therapy, and H₂O₂ is suitable for H₂O₂-dependent anticancer therapy. In addition, H₂O₂ can also be used in the antibacterial field to treat bacterial infections. All these make the CaO₂ to become a kind of excellent antitumor and antibacterial drug. This study mainly reviews the preparation and surface modification of CaO₂, probes into the latest progress about CaO₂ nanoparticles in the field of tumor treatment and antimicrobial therapy. Finally, the challenges that CaO₂ still faces in the future research field are clarified, and its prospects are forecasted.

Keywords: CaO2 ; cancer treatment; antimicrobial therapy

Abbreviations

CaO₂: calcium peroxide
CaO: calcium oxide
Ca(OH)₂: calcium hydroxide
Ca²⁺: calcium ion
CAT: catalase
CaCl₂: calcium chloride
CDT: chemodynamic therapy
CPO: chloroperoxidase
CT: computed tomography
C. tetani: Clostridium tetani
DMOS: dendritic mesoporous organosilica
DOX: doxorubicin
ECM: extracellular matrix
EDT: enzyme dynamic therapy
EDTA·2Na: ethylenediamine tetra acetic acid disodium salt
EPR: enhanced permeability and retention
E. coli: Escherichia coli
F. nucleatum: Fusobacterium nucleatum
GOx: glucose oxidase
GNPs: gold nanoparticles
GSH: glutathione
GSSH: oxidized glutathione
HA: hyaluronic acid
HCl: hydrochloric acid
HIF-1a: hypoxia inducible factor-1 alpha
HRP: horseradish peroxidase
H₂S: hydrogen sulfide
H₂O₂: hydrogen peroxide
H₂O: water
ICG: indocyanine green
IFP: interstitial fluid pressure
LA: lauric acid
l-arg: l-arginine
MnO₂: manganese dioxide
MSN: manganese silicate nanoparticle
MOFs: metal–organic frameworks
MRP2: multidrug resistance protein 2
MRI: magnetic resonance imaging
MS: monostearin
NIR: near-infrared
NO: nitric oxide
NP: nanoparticle
O₂: oxygen
¹O₂: singlet oxygen
O₂ ^·–: superoxide anion
OA: oleyl-amine
OD: optical density
·OH: hydroxyl radical
OH⁻: hydroxyl ions
PAA: polyacrylic acid
PDA: polydopamine
PDT: photodynamic therapy
PEG: polyethylene glycol
P-gp: P-glycoprotein
PS: photosensitizer
PTT: photothermal therapy
PVP: polyethylene pyrrolidone
ROS: reactive oxygen species
SEM: scanning electron microscope
SC: sodium citrate
SDT: sonodynamic therapy
SH: sodium hyaluronate
ST: starvation therapy
S. aureus: Staphylococcus aureus
TA: tannic acid
TACE: transcatheter arterial chemoembolization
TEM: transmission electron microscopy
TME: tumor microenvironment

1 Introduction

So far, cancer is still a major risk factor threatening human health. The traditional methods of cancer treatment mainly include surgery, radiotherapy, and chemotherapy. Although it has a certain therapeutic effect, the unavoidable side effects and poor specificity of cancer cells, so far, cannot meet the needs of cancer treatment. With the progress and development of modern science and technology, new tumor treatment methods such as chemodynamic therapy (CDT) [1,2], photodynamic therapy (PDT) [3,4,5], photothermal therapy (PTT) [6,7], sonodynamic therapy (SDT) [8], and calcium overload [9] emerge as the times requirement, which broadens the mode of diagnosis and treatment related to cancer. It brings more hope for cancer patients. However, affected by the tumor microenvironment (TME), the emerging tumor treatment methods are also difficult to play effectively.

For bacterial infection, antibiotics are the most commonly used method to treat bacterial infection [10]. Although it reduces the morbidity and mortality of human beings, its long-term and overuse makes multi-drug-resistant bacterial infection one of the world’s public health threats [11,12]. At present, oxidative stress induced by reactive oxygen species (ROS) can effectively treat bacterial infection, which is favored by researchers because of its destructive effect on bacteria.

Under acidic conditions, CaO₂ with structural peroxy bond reacts with H₂O to form a large amount of H₂O₂(0.47 g H₂O₂/g CaO₂) and a small amount of O₂(0.2222 O₂/g CaO₂) [13,14], accompanied by the release of Ca²⁺. Therefore, the introduction of CaO₂, on the one hand, reshape the TME to ensure the effective play of anticancer therapy such as O₂-dependent (chemotherapy, PDT), H₂O₂-dependent (CDT), and calcium overload, while, on the other hand, effectively inhibit bacterial infection.

This article mainly summarized the preparation and surface modification of CaO₂, probes into the latest progress about CaO₂ nanoparticles in the field of tumor treatment and antimicrobial therapy. The schematic diagram of the review is shown in Figure 1.

Figure 1

Schematic diagram of the review: Preparation, surface modification, and application of CaO₂ NPs in tumor and bacteria. Ion interference therapy: reproduced with permission from previous study [15]. © 2019 Elsevier Inc. O₂ dependence therapy: reproduced with permission from previous study [16]. Copyright © 2021, American Chemical Society. H₂O₂ dependence therapy (the field of tumor therapy): reproduced with permission from previous study [17]. © 2021 Elsevier B.V. All rights reserved. H₂O₂ dependence therapy (the field of bacterial therapy): reproduced with permission from previous study [18]. © 2021 Wiley‐VCH GmbH; Surface modification: reproduced with permission from previous study [19]. © 2021 Elsevier B.V. All rights reserved. Preparation method: reproduced with permission from previous study [18]. © 2021 Wiley‐VCH GmbH. Notes: polyethylene glycol (PEG), polyethylene pyrrolidone (PVP), hyaluronic acid (HA), sodium hyaluronate (SH), tannic acid (TA), calcium chloride (CaCl₂), calcium oxide (CaO), calcium hydroxide (Ca(OH)₂).

2 Preparation and surface modifiers of CaO₂

2.1 Preparation of CaO₂

At present, there are three main methods to prepare CaO₂ at home and abroad: CaCl₂ method, CaO method, and Ca(OH)₂ method. Ca(OH)₂ method is divided into traditional method, spray drying method, and air cathode method. Among them, CaCl₂ method and traditional Ca(OH)₂ method belong to hydrolytic precipitation method and are the most commonly used methods for preparing CaO₂ [20].

2.1.1 CaCl₂ method

General preparation process: first of all, ammonia water is injected into an alkaline solution of metal chloride (such as CaCl₂), and in the agitation state, H₂O₂ containing a stabilizer is injected to activate the reaction [21]. The reaction equation is as follows:

(1) CaC l 2 + H 2 O 2 + 2 N H 3 · H 2 O + 6 H 2 O = Ca O 2 · 8 H 2 O + 2 N H 4 Cl ,

(2) Ca O 2 · 8 H 2 O → Ca O 2 + H 2 O .

Without the addition of stabilizer, low temperature reaction is needed, and the preparation process is complicated and the cost is high. At present, the method of preparing CaO₂ at room temperature by introducing stabilizer is widely used to improve the utilization rate of H₂O₂ and the yield of CaO₂, and to overcome the problems of complex preparation process and high cost under low temperature production conditions.

The injecting of ammonia provides the required alkaline environment for the synthesis of CaO₂ material and neutralizes the by-product hydrochloric acid (HCl), which promotes the forward progress of the reaction [22]. Similarly, sodium hydroxide as an alkaline substance, cannot replace ammonia to provide a suitable alkaline environment for the synthesis of CaO₂ NPs. The reason might be that sodium hydroxide is a strong base environment which can easily generate Ca(OH)₂ precipitation and excessive hydroxyl ions to promote H₂O₂ decomposition.

CaCl₂ method has the advantages of simple preparation process, low cost, mature technology, and suitable for small-scale production. However, due to the use of dilute solution production, the decomposition loss of H₂O₂ in mother liquor is large, and energy consumption is large, resulting in low product content of CaO₂, generally 50–60%.

2.1.2 CaO method

The general preparation process: CaO is dissolved in H₂O to generate Ca(OH)₂ solution, and after the temperature of the reaction solution is stable, H₂O₂ is added to obtain CaO₂·8H₂O. After filtering and drying the filter cake, anhydrous calcium peroxide (CaO₂₎ is obtained. The reaction equation is as follows:

(3) CaO + H 2 O → Ca ( OH ) 2 ,

(4) Ca ( OH ) 2 + H 2 O 2 + 6 H 2 O → Ca O 2 · 8 H 2 O ,

(5) Ca O 2 · 8 H 2 O → Ca O 2 + H 2 O .

The preparation of CaO₂ by CaO method has the advantages of cheap raw materials, simple preparation process, simple equipment, no need to add ammonia and other substances, and basically no problem of discharge of the three wastes.

2.1.3 Ca(OH)₂ method

2.1.3.1 Traditional Ca(OH)₂ method

General preparation process: under the action of stabilizer, Ca(OH)₂ is slowly added to H₂O₂ to get CaO₂. After further drying anhydrous, CaO₂ material can be obtained [23]. The reaction equation is as follows:

(6) Ca ( OH ) 2 + H 2 O 2 + 6 H 2 O → Ca O 2 · 8 H 2 O ,

(7) Ca O 2 · 8 H 2 O → Ca O 2 + 8 H 2 O .

The purpose of introducing stabilizer is to make the reaction proceed at room temperature and improve the utilization rate of H₂O₂ and the stability of the product. When no stabilizer is added, low temperature reaction is required where the reaction temperature should be controlled below 5℃, which is of high cost and high energy consumption.

Because CaO₂ is slightly soluble in H₂O, most of the domestic Ca(OH)₂ is dissolved in ammonium solution to generate ammonium complex, and then the free Ca²⁺ in the complex reacts with H₂O₂ to prepare CaO₂ substance. The reaction equation is as follows:

(8) Ca ( OH ) 2 + 2 N H 4 Cl → Ca ( N H 3 ) 2 C l 2 · 2 H 2 O → CaC l 2 + 2 N H 3 · H 2 O ,

(9) CaC l 2 + H 2 O 2 + 2 N H 3 · H 2 O + 6 H 2 O → Ca O 2 · 8 H 2 O + 2 N H 4 Cl .

The preparation of CaO₂ by Ca(OH)₂ method simplifies the production and preparation process, reduces energy consumption and production cost, and the technology is mature. However, because it is also produced by dilute solution, the product yield and the content of CaO₂ are not high, and the content of CaO₂ is generally 50–60%.

2.1.3.2 Spray drying method

Under the condition of cooling and constant stirring, the concentrated suspension of Ca(OH)₂ water reacted with the concentrated H₂O₂, and the resulting mixture was spray dried directly after the reaction [24]. This method can obtain anhydrous CaO₂ with good dispersion and uniform particle size without separation and purification. The reaction equation is as follows:

(10) Ca ( OH ) 2 + H 2 O 2 → Ca O 2 + 2 H 2 O ,

(11) CaO + H 2 O 2 → Ca O 2 + H 2 O .

Compared with the traditional preparation method, spray drying method has the following advantages: (a) H₂O₂ and Ca(OH)₂ are cheap and easy to obtain. (b) It saves time and cost without separation and purification. (c) It improves the utilization rate of H₂O₂ and the yield of CaO₂. (d) Energy saving. (e) Continuous production and intermittent production can be carried out, so that the product has good uniformity.

However, this method is also faced with problems such as heavy equipment investment, easy blockage of pipes, high energy consumption, and explosive risk. In addition, high concentration of H₂O₂ is lacking in China.

2.1.3.3 Air cathode method

In order to further solve the problem of high cost of H₂O₂, this method is a low-cost H₂O₂ production process after the industrialization of producing H₂O₂ by anthraquinone method. Ca(OH)₂ reacts with diluted H₂O₂ to generate CaO₂·8H₂O. The mother liquor is removed after centrifugation, and the obtained NaOH is recycled or discharged in time. CaO₂ product can be obtained by grinding the product after vacuum drying of filter cake. The reaction equation is as follows:

(12) Cathode : O 2 + H 2 O + 2 e − → H O 2 − + O H − ,

(13) Anode : 2 O H − → 2 e − + + H 2 O + 1 2 O 2 .

Compared with traditional preparation methods, CaO₂ prepared by air cathode method can reduce production cost, but it still has the following limitations: (a) The utilization rate of H₂O₂ and the yield of CaO₂ are low. (b) High energy consumption. (c) The separation of CaO₂ is difficult and the production cost is increased due to its fine particles and colloids. (d) Additional crushing device is required. (e) CaO₂ products obtained are heterogeneous.

Table 1 presents a comparison of advantages and disadvantages between different preparation methods.

Table 1

Comparison of advantages and disadvantages between different preparation methods

	Advantages	Disadvantages
CaCl₂ method	Simple process Low cost Mature technology Suitable for small-scale production	Low utilization of H₂O₂ High energy consumption The output is low
CaO method	Raw materials are cheap The preparation process is simple The equipment is simple There is no discharge of three wastes	Not exactly mentioned
Traditional method	Process simplification Energy consumption reduction Reduction of production cost Technical maturity	The output is low
Spray drying method	Raw materials are cheap No need for separation and purification Saves time and cost Increased H₂O₂ utilization Increase in output Saves energy	Large investment in equipment The pipeline is easy to be blocked High energy consumption Explosive
Air cathode method	Reduction in production cost	Low utilization of H₂O₂ The output is low High energy consumption The difficulty of separation increases the cost Need crushing equipment The product is heterogeneous

2.2 Surface modifiers of CaO₂

CaO₂ NPs prepared by traditional methods often has some phenomena such as different particle size, different morphology, and poor stability. Therefore, surface modifiers are often used to regulate the particle size, morphology, and stability of CaO₂ NPs. In addition, some surface modifiers can endow CaO₂ NPs with different functions.

Common surface modifiers include PEG, PVP, CO-520, HA, SH, TA, polyacrylic acid (PAA), ethylenediamine tetra acetic acid disodium salt (EDTA·2Na), sodium citrate (SC), polydopamine (PDA) etc., among which PEG is the most common method [23,25,26,27].

Zheng [28] prepared CaO₂ NPs without adding surface modifier and with adding surface modifier, and the results are as follows: 1) Pure CaO₂ NPs: the particle size is different and the dispersion is poor, showing agglomerate morphology; 2) PDA-CaO₂ NPs: the particle size is different, about ∼ 150 nm, and the agglomeration is serious; 3) PDA-SC-CaO₂ NPs: the particle size is small, about 30 nm, with a filamentous structure; 4) SC-CaO₂ NPs: uniform particle size, monodisperse spherical structure, and good dispersibility; 5) PAA-CaO₂ NPs: the particle size is different, and the phenomenon of agglomeration is serious; 6) EDTA·2Na-CaO₂ NPs: different particle size, showing cross-linked reticular structure.

Park et al. [29] successfully synthesized/CaO₂ NPs by introducing TA in the process of CaO₂ NPs synthesis. Figure 2A shows the particle size distribution and scanning electron microscope (SEM) images of three kinds of TA/CaO₂ NPs. It can be seen from the diagram that the three kinds of TA/CaO₂ NPs have the problems of relatively uniform particle size, relatively regular morphology, and poor dispersion.

Figure 2

(A) Particle size distributions of (a) TA (10 mg)/CaO₂, (b) TA (25 mg)/CaO₂, and (c) TA (50 mg)/CaO₂. SEM images of (d) TA (10 mg)/CaO₂, (e) TA (25 mg)/CaO₂, and (f) TA (50 mg)/CaO₂ [29]. (B–D) The TEM of PEG/CaO₂ NPs [21,30,31]. (E) The TEM of SH-CaO₂ NPs [15]. (F) TEM images of PVP/CaO₂ spherical aggregates synthesized in the presence of CaCl₂ at different concentrations: (a) 2.1, (b) 4.2, (c) 8.4, (d) 25.2, (e) 42, and (f) 168 × 10⁻³ M, respectively [32]. The inset in (a) shows an image at a higher magnification [32]. (G) TEM images of PVP/CaO₂ spherical aggregates synthesized in the presence of PVP at different concentrations: (a) 43.2, (b) 30.9, (c) 21.6, (d) 6.17, (e) 1.23, and (f) 0 mg·mL⁻¹, respectively [32]. The inset in (a) shows an image at a higher magnification [32]. (A) Reproduced with permission from a previous study [29]. © 2020 by the authors. Licensee MDPI, Basel, Switzerland. (B) Reproduced with permission from a previous study [21]. Copyright © 2011 Elsevier B.V. All rights reserved. (C) Reproduced with permission from a previous study [30]. © 2021 Elsevier B.V. All rights reserved. (D) Reproduced with permission from a previous study [31]. © 2017 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. (E) Reproduced with permission from a previous study [15]. © 2019 Elsevier Inc. (F and G) Reproduced with permission from a previous study [32]. © 2019 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim.

Khodaveisi et al. [21], Yin et al. [30], and Liu et al. [31] successfully prepared PEG-modified CaO₂ NPs (Figure 2B–D). Transmission electron microscopy (TEM) images showed that although PEG as a surface modifier could alleviate the agglomeration problem of CaO₂ NPs in aqueous solution [21], NPs often showed irregular size and morphology. In addition, the method requires a time-consuming washing process to stabilize pH [29].

He et al. [26] successfully prepared CaO₂ NPs modified by CO-520 by reverse microemulsion method. The introduction of CO-520 gives CaO₂ NPs a good dispersion, but it still faces the problems of different size and irregular morphology.

Shen et al. [32] successfully synthesized CaO₂ nanocrystals and spherical aggregates with controllable size and uniform morphology by adjusting the concentration of CaCl₂ and PVP on the basis of solving the CaO₂ NPs agglomeration problem (Figure 2F and G). Most of all, CaO₂ NPs modified by PVP should be dispersed in ethanol for preservation after synthesis, as drying might promote CaO₂ NPs irreversible aggregation [32].

Zhang et al. [15] successfully prepared SH-CaO₂ NPs by using SH as surface modifiers (Figure 2E). In addition, Han et al. [25] successfully prepared HA-CaO₂ NPs by using HA as surface modifiers. The introduction of SH and HA not only gives CaO₂ NPs the advantages of good dispersion, uniform size, and uniform morphology but also gives it the function of active targeting to improve its enrichment rate in tumor tissue.

Table 2 describes the effects of the presence or absence of surface modifiers on the morphology, particle size, and stability of CaO₂ NPs, and the potential application of partially modified NPs to cancer cells.

Table 2

Comparison of the differences between CaO₂ NPs after different modification

NPs	Surface modification	Appearance	Particle size	Stability	Other
CaO₂	None	Inhomogeneity	Inhomogeneity	Poor	None
CaO₂	PDA	Inhomogeneity	About ∼150 nm	Poor	PTT
CaO₂	PDA, SC	Filamentous structure	About ∼30 nm	Relatively poor	PTT
CaO₂	SC	Spherical type	Homogeneity	Good	None
CaO₂	PAA	Inhomogeneity	Inhomogeneity	Poor	Responsive drug release
CaO₂	EDTA·2Na	Cross-linked reticular structure	Inhomogeneity	Relatively poor	None
CaO₂	TA	Comparative homogeneity	Comparative homogeneity	Poor	Improves the catalytic efficiency of Fenton reaction
CaO₂	PEG	Irregular	Inhomogeneity	Good	Prolonging the half-life of blood circulation of NPs
CaO₂	CO-520	Irregular	Inhomogeneity	Good	None
CaO₂	PVP	Regular	Homogeneity	Good	None
CaO₂	SH	Regular	Homogeneity	Good	Active targeting
CaO₂	HA	Regular	Homogeneity	Good	Active targeting

3 Application of CaO₂ in tumor therapy

CaO₂ as a promising anticancer material, introduced into the nanodrugs delivery system might regulate the TME. The construction of a multi-functional nano-therapy platform based on CaO₂ NPs can achieve a single treatment for tumors, and even achieve a combined antitumor effect. This chapter mainly focuses on several anticancer therapies based on CaO₂ NPs.

3.1 O₂-dependent anticancer therapy

3.1.1 Enhanced chemotherapy

Chemotherapy refers to the use of highly cytotoxic chemotherapeutic drugs to interfere with the proliferation of cancer cells and then kill cancer cells to achieve the purpose of tumor treatment, independent of external energy, and also suitable for the treatment of deep tumors that are difficult to reach by laser.

The permeability of nanodrugs in the tumor site is an important factor affecting the effectiveness of chemotherapy. The poor permeability of nanodrugs in tumor site is mainly affected by TME, including heterogeneous blood supply, interstitial fluid pressure (IFP), and extracellular matrix (ECM) [33]. First of all, because the heterogeneous blood supply of tumor tissue is mainly distributed around the tissue, coupled with the high oxygen consumption of tumor cells, hypoxia has become a prominent feature of advanced solid tumors. Compared with normal physiological blood vessels, hypoxia up-regulates hypoxia inducible factor-1alpha (HIF-1a) and multidrug resistance protein 2 (MRP2), inducing immunosuppression and immune escape of tumor cells, resulting in multidrug resistance and rendering tumor-related chemotherapy drugs ineffective [34,35,36]. Therefore, hypoxia poses a great challenge to O₂-dependent chemotherapy. Second, in tumor tissue, IFP increases gradually from outside to inside, which hinders the further spread of nanodrugs to deep tumors. In addition, ECM further hinders the penetration of nanodrugs in the tumor site, due to the fact that collagen is the main component of tumor tissue and is expressed in a HIF-1a-dependent manner. In the hypoxic environment of tumor tissue, collagen deposition increases the density of ECM, which affects the penetration of nanodrugs in the tumor site. This section mainly discusses how to improve the antitumor effect of chemotherapy drugs from the point of view of hypoxia and ECM.

CaO₂ has more advantages than other O₂ producing materials, and its biocompatibility and biodegradability are better.

CaO₂ can not only produce O₂ in situ but also provide reaction substrate for other O₂-producing materials (for example, provide raw material for manganese dioxide (MnO₂) to produce O₂ under acidic TME), as shown in equation (14) [37].

(14) Mn O 2 + H 2 O 2 + 2 H + → Mn 2 + + 2 H 2 O + O 2 .

In situ O₂ production of CaO₂ can regulate TME, downregulate HIF-1a and MRP2, reverse multidrug resistance of tumor cells, overcome hypoxia-induced chemotherapy limitation etc., and improve the therapeutic effect of chemotherapy drugs. Zhang et al. [38] constructed an intelligent O₂ nanocarrier coated with solid lipid monostearin (MS) for CaO₂/MnO₂ to comprehensively optimize doxorubicin (DOX) transport and enhance chemotherapy effect. Due to the high expression of lipase in tumor cells, NPs are passively accumulated in tumor tissues through enhanced permeability and retention (EPR) effect and ingested by tumor cells [39]. The MS shell of NPs is degraded by lipase, exposing core NPs (CaO₂/MnO₂) and releasing O₂ and DOX. After cancer cells death, the incomplete reaction core NPs are released and further reacted in the ECM to continue to release O₂ and DOX. O₂ reduces the collagen deposition in ECM through the down regulation of HIF-1a, improves the permeability of DOX, makes O₂ and DOX molecules easy to spread to the deep part of tumor, and induces further death of cancer cells.

Considering the complexity, heterogeneity, and diversity of tumor tissue, the effect of single therapy is effective after all, so He et al. [40] prepared a kind of nanocarrier (DOX-CaO₂-Fe/MS) with self-supply of O₂ and H₂O₂ to realize the combined antitumor therapy of chemotherapy and CDT. Due to the overexpression of lipase in cancer cells, MS is degraded and iron oleate and DOX-CaO₂ are released when nanocarriers accumulate in tumor tissue through EPR effect and are absorbed by cancer cells. Iron oleate releases Fe³⁺ by hydrolysis. CaO₂ reacts with water in acidic environment to form H₂O₂ and release loaded DOX. Subsequently, Fe³⁺ reacts with H₂O₂ to produce O₂ and Fe²⁺, the former downregulated the expression of HIF-1a and P-glycoprotein (P-gp) and enhanced the chemotherapy effect of DOX, while the latter continued to react with H₂O₂ to produce hydroxyl radical (·OH) and enhance the effect of CDT. It has been proved that nanomaterials have excellent anticancer effect and good biosafety through in vivo and in vitro experiments.

Wang et al. [41] used CaO₂ NPs as a synergist in cooperation with transcatheter arterial chemoembolization (TACE) to improve its antitumor effect. After intratumoral injection, CaO₂ NPs react with H₂O to form O₂, H₂O₂, hydroxyl ions (OH⁻), and Ca²⁺, to reshape TME and induce calcium overload. In addition, due to the regulation of TME, the therapeutic effect of chemotherapy drugs in TACE has been effectively improved. The results in vitro and in vivo showed that the synergistic antitumor effect of CaO₂ NPs + TACE group was significant.

Zhang et al. [42] constructed a nanohybrid material (CaO₂@FePt-DOX@PDA@CM) camouflaged by the membrane of 4T1 cancer cells, which enhances the therapeutic effect of cancer by cooperating with chemotherapy, CDT, Ca²⁺ overload, and PTT. 4T1 cancer cell membrane has the ability of immune escape and homologous targeting to tumor cells. After the nanohybrid material was internalized by cancer cells, the O₂-producing characteristics of CaO₂ were used to alleviate the hypoxia of tumor cells, downregulate the expression of HIF-1a and P-gp, and enhance the chemotherapeutic effect of DOX, the H₂O₂-producing characteristics of CaO₂ were used to enhance the CDT effect of FePt, and the Ca²⁺-releasing characteristics of CaO₂ were used to induce mitochondrial damage, upregulate Cytochrome C and Caspace-3, and achieve calcium overload. In addition, the existence of PDA gives nanohybrid materials excellent photothermal conversion properties, which can enhance the efficiency of Fenton reaction while giving full play to PTT. In vitro and in vivo studies have shown that nanohybrid materials can cooperate with a variety of anticancer therapies and effectively improve the therapeutic effect by optimizing individual advantages.

3.1.2 Enhanced PDT

PDT is one of the effective antitumor therapies approved by the US Food and Drug Administration (FDA), which is a promising antitumor strategy. PDT consists of three basic components: light, photosensitizer (PS), and oxygen source [43]. The antitumor mechanism of PDT is that PS reacts with molecular oxygen under laser irradiation at a specific wavelength to produce efficient singlet oxygen (¹O₂), which causes irreversible damage to tumor cells and blood vessels and leads to photoinduced tumor cell death.

Figure 3 illustrates the basic principles of PDT, PS change from ground state to instantaneous singlet state (¹PS^*) under the irradiation of light source. There are two alternative paths for instantaneous singlet states: (1) Transition from instantaneous singlet state to ground state. (2) The transition from instantaneous singlet state to long-lived excited triplet state (³PS^*). The excitation triplet also includes type I and type II reaction processes: (1) Type I: The cation or anion radical is formed by electron or proton transfer between ³PS* and substrate. Subsequently, these free radicals react with molecules such as H₂O or O₂ to form cytotoxic ROS (superoxide anion (O₂ ^·–), ·OH, and H₂O₂) [44]. (2) Type II: Excited triplet transfers energy directly to oxygen molecules, producing highly active ¹O₂ [45]. Type I and Type II photochemical reactions can occur simultaneously, and the ratio between the two is determined by the type of PS and the concentration of O₂ [23,46]. According to the latest research progress, compared with O₂-dependent type II PDT, type I PDT is not O₂-dependent, ROS is more toxic, and has a broader prospect in the treatment of hypoxic tumors [44,47]. However, for most PDT photosensitizers, type II photochemical processes dominate [48]. Therefore, this chapter mainly discusses the application of CaO₂ NPs in enhancing O₂-dependent type II PDT.

Figure 3

PDT and CaO₂ enhanced PDT basic schematic diagram.

However, whether PDT effect can play effectively is mainly limited by O₂. The consumption of O₂ in tumor cells by PDT will further aggravate the hypoxia of tumor cells which will lead to further weakening of PDT treatment effect or even treatment failure and tumor cells metastasis which form a vicious cycle. The effective way to improve the PDT effect of O₂ consumption is to establish an O₂ supply system to reduce O₂ consumption and improve the utilization rate of O₂. CaO₂ NPs as an O₂ supply system is a promising material for regulating acid TME and enhancing PDT. After introducing CaO₂ NPs into tumor cells, O₂ generated through disproportionation reaction with H₂O compensated for the O₂ consumed during PDT treatment and promoted the effective play of PDT effect (Figure 3).

Sun et al. [49] loaded CaO₂ NPs (PCN-224-CaO₂-HA) modified by HA on the basis of porphyrin metal–organic frameworks (MOFs) to target and enhance PDT (Figure 4). Among them, HA can target tumor cells with overexpression of CD44+ receptor, while protecting CaO₂ NPs. PCN-224-CaO₂-HA releases PS and O₂ after targeting and uptake by tumor cells. Subsequently, PS was irradiated by 650 nm laser to achieve enhanced PDT. In vitro and in vivo experiments showed that PCN-224-CaO₂-HA could target tumor cells and enhance PDT.

Figure 4

Schematic representation of PCN-224 combined with HA-modified CaO₂ NPs for enhanced PDT [49]. Reproduced with permission from a previous study [49]. © The Royal Society of Chemistry.

In order to accelerate the decomposition of H₂O₂ into O₂, Ren et al. [50] designed and synthesized a cascade of catalytically enhanced UIO@Ca-Pt NPs. Among them, the multi-nanometer MOFs material modified by porphyrin PS can effectively avoid the accumulation of PS. Under acidic TME, CaO₂ reacts with H₂O to produce H₂O₂, which can be decomposed into H₂O and O₂ due to its instability, but its decomposition rate is slow. While the introduced PT-NPs can be used as an effective catalyst to accelerate the decomposition of H₂O₂ into O₂. As a result, the NPs greatly improved the antitumor efficacy of PDT.

Although the above cases partly overcome the problem of insufficient oxygen source of PDT, the consumption of ROS by the highly expressed glutathione (GSH) in tumor cells still limits the antitumor effect of PDT. Therefore, the effect of single treatment is limited after all, and combined antitumor therapy is necessary.

Gulzar et al. [51] constructed a multi-mode image-guided nanocomposite CaO₂-MnO₂-UCNPs-Ce6/DOX (Ca-Mn-NUC). When the nanocomposite is endocytosed by tumor cells, CaO₂ generates O₂ in situ under acidic TME, providing sufficient oxygen source for PDT. After MnO₂ converts GSH to oxidized glutathione (GSSH), it can reduce the consumption of ROS, further enhance the oxidative stress of tumor cells, and finally enhance PDT. In addition, the O₂ generated can also improve chemotherapy, and ultimately achieve chemotherapy/PDT combined treatment, which is highly anticancer. The nanocomposite can also provide computed tomography (CT) and magnetic resonance imaging (MRI) dual-mode imaging for real-time monitoring of anticancer effects.

Chen et al. [52] developed a TME-responsive CaO₂-based nanosystem (CF@CO@HC) using a bottom-up approach, which has the ability of GSH consumption and ROS self-amplification, and can cooperate with PDT and CDT for cancer treatment. The nanosystem consists of CaO₂ (CaO₂-FM) doped with PS as core, hybrid silicone skeleton (Cu-ONS), and local hydrophobic cage (HC) as shell. After the nanosystem was internalized by cancer cells, the hybrid organosilicon skeleton was cleaved under the reduction of high concentration of GSH to release Cu⁺. CaO₂ reacts with H₂O in acidic environment to form H₂O₂ and O₂, and releases the doped PS derivative 4-FM. Subsequently, the generation of H₂O₂ enhances Cu⁺-mediated CDT. The generation of O₂ enhances 4-FM-mediated PDT. In addition, GSH consumption further increases the production of ROS. Therefore, the nanosystem provides a strategy to increase revenue and reduce expenditure for cancer treatment, and effectively enhances cancer treatment.

In addition, Yan et al. [53] designed and synthesized a multistimulus TME response nanoplatform composed of MCMnH NPs and CaO₂ NPs to improve the antitumor effect of the guidance of MRI and photothermal imaging. HA can target tumor cells with overexpression of CD44+ receptor and induce tumor cells to uptake MCMn NPs. Subsequently, MNP realizes PTT under the irradiation of 808 nm laser, and PDT is realized through energy transfer between PTT and Ce6. MnO₂ produces Mn²⁺ and O₂ through a series of reactions in tumor cells. The former reacts with H₂O₂ to form ·OH through Fenton-like reaction to achieve CDT. CaO₂ NPs produces H₂O₂ and O₂ through a series of reactions in tumor cells, and the former enhances CDT. O₂ generated by MnO₂ and CaO₂ NPs downregulates HIF-1a and enhances PDT. In vivo and in vitro experiments show that the nanoplatform has significant antitumor effect through synergistic promotion.

3.2 H₂O₂-dependent anticancer therapy

3.2.1 Enhanced CDT

CDT is a novel and efficient antitumor technology based on ROS and its basic principle is delivering Fenton reaction or type of Fenton-like reaction catalyst using nanotechnology to tumor tissue, under the acidic TME, making H₂O₂ to decompose in the tumor tissue, producing ROS with strong oxidation capacity (·OH), inducing tumor cell apoptosis and killing cancer cells [54,55]. With the gradual deepening of CDT research, various Fenton or Fenton-like reaction catalysts emerged, including Fe²⁺, Fe³⁺, Cu²⁺, Mn²⁺, Mo⁴⁺, Cr⁴⁺, V²⁺, Ti³⁺, Graphene oxide, etc. [56,57,58]. Among them, Fe²⁺ and Fe³⁺ are typical Fenton and Fenton-like catalysts. The reaction equation is as follows:

(15) Ca O 2 + H 2 O → Ca ( OH ) 2 + 1 / 2 O 2 ,

(16) Ca O 2 + 2 H 2 O → Ca ( OH ) 2 + H 2 O 2 ,

(17) Fe 2 + + H 2 O 2 → Fe 3 + + OH − + ·OH ,

(18) Fe 3 + + H 2 O 2 → Fe 2 + + H + + HO 2 · .

CDT works independent of O₂ and external energy compared to other cancer treatments [59,60]. Therefore, CDT is more suitable for deep tumors with hypoxia or difficult to reach by laser.

At present, antitumor research on CDT is still in the initial stage. However, there are many factors affecting the efficiency of CDT. In order to improve the therapeutic effect of CDT, researchers mainly proposed the following methods: Change TME (increase H₂O₂ concentration, decrease GSH level, decrease pH value) and select suitable catalyst and combine with other anticancer therapy effectively. In addition, in order to improve the efficacy of CDT, current studies mostly focus on the catalytic activity of nanomaterials, but ignore their biocompatibility and biodegradation.

CaO₂ NPs have good biocompatibility and biodegradability. CaO₂ NPs and H₂O generate H₂O₂ and O₂ through disproportionation reaction (equations (15) and (16)), in which the former provides sufficient substrates for subsequent CDT, thus ensuring the effective play of CDT effect and enhancing the antitumor effect of CDT. The latter regulates TME and reverses hypoxia in tumor cells [61,62,63]. Therefore, considering the advantages of CaO₂ NPs, it is particularly important to construct a nano-therapy platform based on CaO₂ NPs.

Due to the limited H₂O₂ concentration (∼100 µM) in tumor cells, ROS production is difficult to maintain. Based on this, Han et al. [25] prepared a H₂O₂ self-supporting nanotubule platform CaO₂-Fe₃O₄@HA-Cy7 NPs for guiding targeted and imaging CDT. The HA can target the tumor cell receptor over-expressed by CD44+ and reach the cell through endocytosis, which is hydrolyzed by hyaluronidase in the cytoplasm and releases near-infrared (NIR) fluorescent group markers, CaO₂, and Fe₃O₄. Through further reaction, the H₂O₂ consumed by CDT can be compensated and the therapeutic effect of CDT can be enhanced. NIR fluorescence and magnetic resonance bimodal imaging provide timely CDT therapeutic effect of NPs in vivo. In vivo antitumor studies have shown that CaO₂-Fe₃O₄@HA-Cy7 NPs have excellent tumor specificity, enhanced CDT efficacy, and good biocompatibility.

Mamat et al. [64] constructed CaO₂/Fe₃O₄ nanocomposites coated with oleyl-amine (OA). The NPs inhibited the premature reaction of CaO₂, overcame the deficiency of H₂O₂ in tumor tissues, and realized the non-oxidative generation of ROS and efficient CDT. The results show that the nanocomposites material has significant tumor growth inhibition ability and good biocompatibility, and has great clinical transformation value in tumor therapy.

GSH is another important factor that limits the efficacy of CDT therapy. Therefore, reducing GSH expression level in cancer cells to reduce ROS consumption is an effective way to improve the efficiency of CDT treatment. In addition, the commonly used Fenton and Fenton-like reaction catalysts (Fe²⁺ and Fe³⁺) have high catalytic efficiency only under strong acidic conditions (pH 2–4), maximizing the therapeutic effect of CDT, on the contrary, the catalytic efficiency is relatively low under neutral and weak acidic conditions. Therefore, Kong et al. [65] explored a new combination of antitumor therapy by designing and synthesizing a Cu-ferrocene modified CaO₂ NPs (CaO₂/Cu-ferrocene). In terms of CDT enhancement, this scheme not only solves the problem of insufficient H₂O₂ in tumor cells, but also overcomes the problems of high expression of GSH and low efficiency of Fenton and Fenton-like reaction catalysts in tumor cells. The NPs remain stable under neutral conditions and rapidly release H₂0₂ under acidic TME. Among them, H₂O₂ and ferrocene generate ·OH through Fenton reaction, which achieves CDT, while Cu²⁺ reacts with GSH to generate GSSH and Cu⁺, which reduces the consumption of ROS by GSH and improves the catalytic efficiency of Fenton and Fenton-like reaction catalysts, thus greatly improving the therapeutic effect of CDT. In vitro and in vivo experimental results showed that the consumption of GSH and the production of ·OH significantly enhanced the therapeutic effect of CDT.

In addition, in order to improve the killing effect of NPs on tumor cells, the combined antitumor application based on CDT has also been reported one after another [66,67,68]. Compared with single anticancer therapy, two or more CDT-based treatment modes can achieve better anticancer effects.

The combination of chemotherapeutic drugs and ROS for tumor therapy is also an effective treatment strategy to improve the efficiency of CDT [69,70,71,72]. Gao et al. [73] designed and synthesized a self-supplied O₂/H₂O₂ nanocatalysis drug CaO₂@DOX@ZIF-67, and constructed a pH responsive CDT/chemotherapy combined antitumor treatment platform (Figure 5a). The NPs are taken up by acid lysosomes after entering the tumor cells. Subsequently, the MOFs decomposes and releases Co²⁺, CaO₂ and DOX. The Co²⁺ reacts with H₂O₂ to achieve CDT, and DOX to achieve chemotherapy. In addition, CaO₂ further reacts to generate H₂O₂ and O₂ to improve the TME, reverse hypoxia of tumor cells, avoid multidrug resistance of cancer cells, enhance CDT and chemotherapy, and enhance the combination therapy of the two. The experimental results show that CaO₂@DOX@ZIF-67 had good antitumor activity. Therefore, the nanocomposite is expected to be a candidate for pH-responsive chemotherapy/CDT combined antitumor therapy, and has great clinical transformation value.

Figure 5

CDT-based anticancer therapies: (a) Combined treatment of CDT and chemotherapy [73]. (b) Combined treatment of CDT and ST [76]. (c) Combined treatment of CDT and PDT [77]. (a) Reproduced with permission from a previous study [73]. © 2019 The Authors. Published by WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim. (b) Reproduced with permission from a previous study [76]. © 2021 Elsevier Ltd. All rights reserved. (c) Reproduced with permission from a previous study [77].

Starvation therapy (ST) is to starve the tumor cells by cutting off the blood supply to the tumor tissue [74] or cutting off the nutrition source of the tumor cells [75]. Glucose is the energy source for the growth and proliferation of tumor cells. Reducing the concentration of glucose in tumor cells can effectively cut off the energy supply of cancer cells and inhibit or kill cancer cells. Glucose oxidase (GOx) is an endogenous redox enzyme that specifically oxidizes glucose to gluconic acid and H₂O₂. In recent years, GOx has been widely used in the treatment of tumor starvation, but its anticancer effect is limited by the hypoxic condition of tumor. Based on this, Zhang et al. [76] coated CaO₂@Fe(OH)₃ nanometer composites and GOx in bio-compatible liposomes to prepare nanometer composite drugs, and their synthesis steps and antitumor mechanism are shown in Figure 5b. When the NPs entered the tumor cells, the degradation of CaO₂@Fe(OH)₃ nanocomposites were triggered in acidic TME to generate H₂O₂ and Fe³⁺. Second, H₂O₂ and Fe³⁺ react to generate O₂ and Fe²⁺. The former can reverse the problem of tumor hypoxia, make up for the O₂ consumed by GOx in the process of oxidizing glucose, cut off the energy material (glucose) of tumor tissue, realize the purpose of starving tumor cells, and strengthen ST, the latter triggers Fenton reaction to produce ·OH with strong oxidation capacity, which realizes CDT. In addition, the products gluconic acid and H₂O₂ obtained by GOx in the process of glucose oxidation reduce the pH value of tumor tissue, provide the best reaction conditions for CDT, and further supplement its required substrate (H₂O₂) and improve the effect of CDT. The experimental results confirmed that the anticancer effect of CDT/ST combination was significant.

PDT is an anticancer therapy based on ROS. Compared with CDT, both of them have the common goal of achieving tumor therapy by means of ROS. Liu et al. [77] designed a thermosensitive nano-system of H₂O₂/O₂ MSNs@CaO₂-ICG@LA for CDT/PDT combination therapy of tumor cells (Figure 5c). The NPs were prepared by loading CaO₂ NPs and indocyanine green (ICG) with manganese silicate nanoparticles (MSNs) and further modifying lauric acid (LA) on their surface. When the NPs reached the tumor cells through the endocytic pathway, ICG generated heat and ¹O₂ under the irradiation of 808 nm laser, the former caused the phase transformation of LA (from solid phase to liquid phase), and the latter realized PDT. In addition, exposed CaO₂ NPs further react with H₂O to generate H₂O₂ and O₂. The production of H₂O₂ provides sufficient substrates for subsequent CDT and enhances CDT. The production of O₂ alleviates tumor hypoxia and enhances PDT. MSNs are gradually exposed with further consumption of CaO₂ NPs, and react with GSH in cancer cells to release a large amount of Fenton-like reaction catalyst Mn²⁺, which is used to self-supply CDT of H₂O₂. The consumption of GSH by MSNs further promotes the continuous production of ROS in cancer cells. In conclusion, the team utilized PDT/CDT combined anticancer therapy to increase ROS sources in tumor cells while maintaining ROS production in tumor cells through GSH consumption. Experimental results in vivo and in vitro show that the strategy has remarkable anticancer effect and can effectively inhibit the growth of cancer cells.

3.3 Calcium overload

Calcium overload belongs to ion interference therapy, which is a new and efficient antitumor technology and has attracted more and more attention in recent years [17,78]. Calcium overload refers to the dysfunction of calcium balance system and disorder of calcium distribution under the action of some factors, resulting in abnormal increase in intracellular calcium concentration. Calcium overload has been linked to tumor death, but the root cause of cancer cell death remains unclear. Therefore, cancer cell death caused by calcium overload may be related to the following factors or the result of a combination of factors:

Induction of tumor cell death by activating mitochondrial apoptosis pathway [15,79,80,81,82,83].
It is related to macroscopic calcification induced by microscopic calcium overload, leading to the death of cancer cells [15] (it is worth noting that tumor cell calcification can assist CT imaging and monitor the treatment process [84]).
It is related to interfering the process of mitochondrial oxidative phosphorylation, damaging mitochondria and inactivating phospholipase in cytoplasm, thus causing irreversible damage to tumor cells [85].

Ca²⁺ are mainly stored in organelles such as cytoplasm, mitochondria, and endoplasmic reticulum, and are endogenous substances necessary for the maintenance of organisms in vivo. As one of the second messengers, Ca²⁺ play an important regulatory role in the proliferation and migration of tumor cells [86,87]. As tumor cells are characterized by abnormal differentiation and proliferation, reduced apoptosis, and high metastasis, low concentration of Ca²⁺ in the cytoplasm is a necessary condition to avoid apoptosis of tumor cells when cancer occurs [88,89]. As a result, improving the Ca²⁺ concentration in the cytoplasm of tumor is an effective treatment strategy for antitumor. Unfortunately, due to the long neglect of Ca²⁺-induced cell damage, there have been few reports on the antitumor application of calcium overload when designing anticancer drugs based on calcium nanomaterials. This section introduces the strategy of calcium overload in the treatment of tumors [30].

Zhang et al. [15] designed and synthesized a kind of ultra-small SH-CaO₂ NPs by taking advantage of the special cellular biological effect of Ca²⁺ and its enhancement effect on H₂O₂ oxidative stress, and systematically studied the anticancer effect induced by Ca²⁺. Due to the pH responsiveness of CaO₂ NPs, under acidic TME, CaO₂ slowly decomposes into free Ca²⁺ and H₂O₂, leading to calcium overload and oxidative stress, respectively. In addition, the low expression of catalase (CAT) in tumor cells [90] and continuous oxidative stress can lead to the functional disorder of protein, trigger desensitization of calcium-related channels, and lead to uncontrolled accumulation of Ca²⁺ in tumor cells [91]. The anticancer mechanism of the nanocomposite is shown in Figure 6a. The experimental results showed that the survival rate of tumor cells decreased with the increase in SH-CaO₂ NPs concentration, (Figure 6b). The significant killing effect of SH-CaO₂ NPs was not limited by tumor type, and it could effectively kill multiple types of cancer cells (Figure 6c). In addition, Alizarin Bordeaux staining and von Kossa staining could clearly identify the calcification area caused by calcium overload in Figure 6d. According to the above results, SH-CaO₂ NPs have significant anticancer effect.

Figure 6

(a) Schematic representation of the functional pattern of SH-CaO₂ NPs. (b) Cell viability assay in 4T1 cells incubated with CaCl₂ or SH-CaO₂ NPs. (c) Cell viability assay in human tumor cells (HeLa, A549, and MB231) or normal cells (LO2) incubated with SH-CaO₂ NPs. Normal cells were more tolerant to SH-CaO₂ NPs. (d) Identification of the products of exocytosis in vitro with Alizarin Bordeaux staining and von Kossa staining, which show the calcified areas in red and black, respectively [15]. Reproduced with permission from a previous study [15]. © 2019 Elsevier Inc.

However, compared with most solid tumors, the antitumor effects of monotherapy are limited. Therefore, researchers have successively developed combined therapies based on calcium overload to improve the therapeutic effect of tumors.

Liu et al. [84] used dendritic mesoporous organosilica (DMOS) bound by tetra-sulfide bonds as nanometer carriers, loaded with chloroperoxidase (CPO) and sodium-hyaluronate-modified CaO₂ NPs (CaO₂-HA NPs), and improved the stability of CPO and the limited H₂O₂ level in tumor cells. A novel combined treatment strategy of hydrogen sulfide (H₂S) gas, enzyme dynamic therapy (EDT), and Ca²⁺ interference was developed, as shown in Figure 7A. The NPs are enriched in tumor cells through enhanced EPR effect and specific targeting effect of HA on tumor cells. Subsequently, HA is degraded by hyaluronidase and CaO₂ further reacts with H₂O to generate H₂O₂ and Ca²⁺. In addition, DMOS have GSH responsiveness, releasing CPO, consuming GSH, and generating H₂S gas under high GSH environment in tumor cells, and finally realizing multi-modal antitumor therapy under CT imaging. In vitro experiment results confirmed that when DCC-HA NPs were co-cultured with mouse fibroblasts (L929 cells) for a certain period of time, the survival rate of L929 cells remained high even at a high concentration of NPs, indicating that DCC-HA NPs had good biocompatibility (Figure 7B). Subsequently, DCC-HA NPs were co-cultured with mouse 4T1 cells for a period of time. It was found that the survival rate of 4T1 cells not only decreased with the increase in NPs concentration, but also decreased much more than the survival rate of tumor cells under other conditions (Figure 7C). In vivo results confirmed that 4T1 tumor cells were transplanted into mice and significantly inhibited after 14 days of NPs treatment (Figure 7D). All the above results indicate that the TME responsive nanocomposite has significant anticancer effect.

Figure 7

(A) ((a) Schematic illustration of the synthesis and (b) antitumor performance of the DCC-HA NPs). (B) The cell viability of L929 cells after incubation with different concentrations of DCC-HA NPs for 24 h (n = 3). (C) Cell cytotoxicity of 4T1 cells under different conditions (n = 3). ***p < 0.001. (D) Digital photographs of tumor-bearing mice after different treatments for 14 days [84]. Reproduced with permission from a previous study [84]. © 2021 Wiley‐VCH GmbH.

Jiang et al. [92] constructed a nanoplatform containing UCNPs-Ce6@RuR@mSiO₂@PL-HA NPs (UCRSPH) and SA-CaO₂ NPs. After entering tumor cells, the composite nanometer platform was irradiated by NIR (980 nm) to alter TME, reverse tumor hypoxia, and achieve Ca²⁺ interference therapy and PDT self-enhancement. In addition, the nanoplatform provides fluorescence imaging and CT imaging to further guide in vivo antitumor therapy. In conclusion, the nanometer platform shows a potent combined anticancer potential with minimal toxic side effects on normal cells.

Chen et al. [93] designed and synthesized a new CaO₂@TA-FE^III nanodrug delivery system for enhancing CDT. Its anticancer mechanism is: TA and Fe^III form TA–Fe nanocoating on the surface of spherical CaO₂ nanoaggregate. When the nanocomposite enters tumor cells, H₂O₂ is generated through degradation, which solves the problem of insufficient H₂O₂ in CDT. In addition, TA of nanomaterials reduced Fe^III to Fe^II, improved the catalytic efficiency of Fenton reaction, generated ·OH, induced irreversible oxidative damage to tumor cells, promoted calcium overload, and accelerated the death of tumor cells. The experimental results in vitro and in vivo indicate that the nanocomposite is a promising novel and highly effective antitumor nanoplatform with good tumor treatment effect.

In addition to the anticancer therapies mentioned above, other anticancer therapies based on CaO₂ NPs are shown in Table 3.

Table 3

Application of hybrid nanomaterials based on CaO₂ NPs in tumor field

Synthesized NPs	Applications	Year	Ref.
PLLA/CaO₂@ZIF-67	CDT	2023	[94]
CaO₂-MNPs	Chemotherapy	2021	[95]
CaO₂@Mn-PDA NPs	PTT/CDT	2021	[96]
CFM	Radiotherapy/CDT	2020	[97]
CaO₂@ZIF-8@MPN	CDT/Ca²⁺ overload	2021	[17]
CaO₂/DOX@Cu/ZIF-8@HA	CDT/chemotherapy	2021	[98]
DOX-CaO₂-Fe/MS NPs	CDT/chemotherapy	2021	[40]
CaO₂@ZIF-8@THPP	PDT/ion-interference	2023	[99]
CaO₂@Co-ferrocene	Calcium-overload/CDT	2021	[100]
CaO₂@ZIF-Fe/Ce6@PEG	CDT/PDT/Ca²⁺ overload	2021	[101]
CaO₂@Au nano-shells	CDT/PTT/chemotherapy	2022	[102]
Fe-GA/CaO₂@PCM	Calcium-overload/CDT/PTT	2020	[103]
RB/CaO₂ (RBC NPs)	Immune-mediated therapeutic/SDT	2021	[104]
CaO₂/Cu-ferrocene	Ca²⁺/ROS synergistic tumor therapy	2021	[9]
CaO₂@CuS-MnO₂@HA	PTT/PDT/Ca²⁺ overload/immunotherapy	2022	[105]
CaO₂/TF/CUR	Calcium-overload/apoptosis of iron/chemotherapy	2021	[30]
CaO₂@HMSNs-PAA	Inducing apoptosis of cancer cells by oxidative stress	2020	[106]

4 Antimicrobial therapy

Bacterial infection has become one of the main problems threatening human health [107,108,109]. CaO₂ NPs have attracted much attention due to their small size, increased surface contact area with bacteria and damage to bacteria [110]. The antibacterial mechanism of CaO₂ NPs is related to the production of ROS (¹O₂, O₂ ^·–, H₂O₂ and ·OH). Relevant literature has shown that ROS induced oxidative stress is one of the important antibacterial mechanisms for the construction of ROS, which can effectively treat bacterial infection [111].

ROS treats bacterial infections by destroying cell membranes [112], and lipid peroxidation caused by free radicals is one of the ways to change cell membranes [113]. However, due to the thicker cell wall structure of Gram-positive bacteria, the lipids seen in Staphylococcus aureus (S. aureus) are not affected. In addition, negatively charged ROS cannot easily penetrate negatively charged cell membranes, but H₂O₂, as a type of ROS, can easily penetrate cell membranes for bacteriostatic purposes [114].

ROS on cell walls are produced by negatively charged cell membranes interacting with positively charged NPs [115]. ROS can damage the cell membrane by interacting with the cell wall of bacteria, inhibit further growth of cells, leak the internal cell components, and finally lead to the death of bacteria. Therefore, it is necessary to develop a new kind of biological material with high antibacterial ability. Shen et al. [32] synthesized CaO₂ nanocrystals and spherical aggregates with controllable size and uniform morphology using CaCl₂ as precursor by wet chemical process. By changing the concentration of CaCl₂ and PVP, the particle size of CaO₂ nanocrystals and their spherical aggregates can be adjusted in the range of 15–100 nm. The results of bacteriostatic experiment showed that the spherical aggregates showed obvious size dependent bacteriostatic effect. In addition, CaO₂ NPs synthesized with Ca(NO₃)₂ as the precursor showed similar antibacterial activity (Table 4). It can be seen that the small-sized CaO₂ nanocrystals and their spherical aggregates have great potential in antibacterial applications.

Table 4

Minimum inhibitory concentrations (MIC) of CaO₂ NPs prepared using Ca(NO₃)₂ as precursor [32]

Bacteria	MIC at pH 7.4 (µg·mL⁻¹)		MIC at pH 5.8 (µg·mL⁻¹)
Bacteria	CaCl₂ as precursor	Ca(NO₃)₂ as precursor	CaCl₂ as precursor	Ca(NO₃)₂ as precursor
C. tetani	60	60	60	60
F. nucleatum	60	60	60	60
E. coli	120	120	120	100

Note: C. tetani: Clostridium tetani, F. nucleatum: Fusobacterium nucleatum, E. coli: Escherichia coli.

Moreover, Thi et al. [116] developed a new hydrogel preparation method for antimicrobial therapy by promoting in situ cross-linking hydrogel formation mediated by horseradish peroxidase (HRP) using CaO₂. General preparation process: Gelatin-hydroxyphenyl propionic acid (GH) polymer, HRP, and CaO₂ were used as raw materials, and the GH/C hydrogel was prepared by mixing the polymer solution with different concentrations of HRP and CaO₂ solution (volume ratios of GH:HRP:CaO₂ = 8:1:1). The introduction of CaO₂ can give hydrogel system the following two advantages:

On the premise of not affecting biocompatibility, H₂O₂ is gradually generated to form hydrogel system.
Dynamic hydrogel matrix was constructed to stimulate surrounding tissues by continuously releasing Ca²⁺, H₂O₂, and O₂.

Then, the antibacterial activity of GH/C hydrogel was evaluated by measuring the optical density (OD) value of the bacterial suspension at 600 nm. The antibacterial activity of GH/C hydrogel is related to the content of CaO₂, and its antibacterial activity increases with the increase in the dosage of CaO₂, among which GH/C 0.5 shows the highest antibacterial effect (Figure 8). Therefore, although GH/C hydrogel could not kill bacteria, it could also effectively inhibit the growth rate of E. coli and S. aureus. We believe that the formation of in situ crosslinked hydrogels mediated by HRP/CaO₂ has potential application value in the treatment of bacterial infection.

Figure 8

In vitro antibacterial activities of GH/C hydrogels depending on CaO₂ concentration against (a) E. coli and (b) S. aureus [116].

Traditional titanium implants can effectively treat bacterial infection after modification, but the resulting anti-inflammatory response is also ignored. Therefore, He et al. [18] constructed a dual drug loading system (TNT@IL-4/GelMA@CaO₂) to treat bacterial infections while inhibiting the occurrence of pro-inflammatory reactions (Figure 9). In vitro and in vivo experiments show that the drug loading system can effectively treat bacterial infection and regulate pro-inflammatory response. In short, the drug loading system provides a good example for the development of advanced titanium implants with anti-inflammatory and antibacterial properties.

Figure 9

Zhang et al. [117] prepared a hydrogel library (OMCN) with self-activated nitric oxide (NO) release to cooperate with NO and PTT in the fight against bacterial infection. First of all, H₂O₂ formed by the reaction of CaO₂ with H₂O can oxidize l-arginine (l-arg) to form NO, which is used to treat bacterial infection. In addition, thanks to the excellent photothermal effect of OMCN, PTT can increase the production of NO gas and cooperate with sterilization at the same time. In vivo and in vitro studies showed that the material had good synergistic antibacterial activity under the laser irradiation of 808 nm, and there was no obvious toxicity. Therefore, the prepared hydrogel library provides a promising strategy for antibacterial in the future.

In addition, Table 5 describes other antibacterial applications based on CaO₂ NPs.

Table 5

Application of CaO₂ NPs-based hybrid nanomaterials in the field of bacteria

Synthesized NPs	Application	Year	Ref.
Ca@PDA_Fe-CNO	Bacteriostasis	2022	[118]
CaO₂@SiO₂/CS	Bacteriostasis	2022	[119]
CaO₂/GQDs@ZIF-67	Bacteriostasis	2021	[16]
BNP@TI	Bacteriostasis	2022	[120]
CaO₂@PDA	Bacteriostasis	2022	[121]
CaO₂-TiOx@Ti₃C₂	Bacteriostasis	2023	[122]
CPA	Bacteriostasis	2021	[123]

5 Biological effects and biosafety of CaO₂ NPs

Whether CaO₂ NPs can achieve further clinical progress is closely related to its biological effects and biosafety.

The biological effects and biosafety of CaO₂ NPs have been preliminarily explored in the relevant data [124,125]. The relevant data are encouraging, but there is still a certain distance from further clinical conversion. For example, when CaO₂ NPs circulate in the vessel, it will react with H₂O in advance, and its product H₂O₂ is toxic and may affect normal tissues and cells. In the following studies, a more systematic in vitro and in vivo biosafety assessment should be conducted to further reveal the biological distribution and excretion of CaO₂ NPs in vivo, providing more powerful evidence for biological effects and biosafety.

6 Conclusion and future perspective

The preparation technology and surface modification of CaO₂ NPs have been relatively mature. Although CaO₂ NPs have achieved good results in tumor treatment and bacterial infection, there are still some challenges to be overcome in future research. If the following problems are solved, CaO₂ NPs are expected to continue to move forward in the field of biomedicine.

There are many factors affecting the effect of chemotherapy, including hypoxia, low pH value and overexpression of GSH etc. [126,127,128,129]. At present, most research are from the perspective of hypoxia, that is, through exogenous supply of O₂ and endogenous production of O₂ to alleviate the hypoxic environment in tumor cells, reduce MDR and enhance the effect of chemotherapy. However, there are few reports on how to overcome low pH value and overexpression of GSH to enhance the effect of chemotherapy. Therefore, in the future, it is necessary to study how to enhance the effect of chemotherapy from the aspects of low pH value and GSH overexpression.
The effect of PDT is affected by TME, the selection of effective PS and the management of light dose [130,131]. Up to now, great progress and achievements have been made in the study of PS selection and optical quantum management [132,133,134,135]. However, there are still many challenges in cancer treatment that regulates TME to enhance type II PDT.
As we all know, the best pH range to maximize the effect of CDT is 2–4 [136], while the pH value of tumor tissue is about 6.5 [54]. Although GOx and gold nanoparticles (GNPs) are often used to improve pH in tumor tissues, it is necessary to develop pH-independent CDT nanocatalysts. In addition, most of the previously reported CDT nanocatalysts are transition metal-based nanoparticles, which can cause acute inflammation and toxicity in vivo. Therefore, the development of CDT nanocatalyst with high biosafety and good biodegradability is a more feasible scheme for the development of CDT in future.
In a certain range, the smaller the size of NPs, the stronger the penetration of tumor tissue, and the better the therapeutic effect on bacterial infection. In addition, most studies have shown that spherical NPs are slightly less permeable in tumor tissue than other shapes [33]. Therefore, it is necessary to adjust the shape and size of NPs to improve the permeability and antibacterial activity of tumor tissues.
Oxidative stress induced by ROS is one of the effective bacteriostatic mechanisms. CaO₂ NPs can self-amplify ROS and effectively treat bacterial infection. Although the bacteriostatic effect is remarkable, the treatment mode is relatively simple. Therefore, it is necessary to use CaO₂ NPs to design a nanohybrid material based on CaO₂ and to develop a novel bacteriostatic mode with better therapeutic effect by using the products of CaO₂ NPs.

In a word, the reports of antitumor and antibacterial infection related to CaO₂ NPs have increased in recent years, but their application in clinical transformation still has a long way to go. Solving the above problems is helpful to speed up their application in clinical transformation. I believe that the hybrid nanomaterials related to CaO₂ NPs will provide a better way for tumor treatment and bacterial infection in the future through continuous optimization and improvement.

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Funding information: This work was supported by the National Natural Science Foundation of China (no. 51873052).
Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.
Conflict of interest: The authors state no conflict of interest.

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Received: 2022-10-09

Revised: 2023-01-27

Accepted: 2023-02-20

Published Online: 2023-03-10

This work is licensed under the Creative Commons Attribution 4.0 International License.

Application prospect of calcium peroxide nanoparticles in biomedical field

Abstract

Abbreviations

1 Introduction

2 Preparation and surface modifiers of CaO₂

2.1 Preparation of CaO₂

2.1.1 CaCl₂ method

2.1.2 CaO method

2.1.3 Ca(OH)₂ method

2.1.3.1 Traditional Ca(OH)₂ method

2.1.3.2 Spray drying method

2.1.3.3 Air cathode method

2.2 Surface modifiers of CaO₂

3 Application of CaO₂ in tumor therapy

3.1 O₂-dependent anticancer therapy

3.1.1 Enhanced chemotherapy

3.1.2 Enhanced PDT

3.2 H₂O₂-dependent anticancer therapy

3.2.1 Enhanced CDT

3.3 Calcium overload

4 Antimicrobial therapy

5 Biological effects and biosafety of CaO₂ NPs

6 Conclusion and future perspective

References

Journal and Issue

Articles in the same Issue

Application prospect of calcium peroxide nanoparticles in biomedical field

Abstract

Abbreviations

1 Introduction

2 Preparation and surface modifiers of CaO2

2.1 Preparation of CaO2

2.1.1 CaCl2 method

2.1.2 CaO method

2.1.3 Ca(OH)2 method

2.1.3.1 Traditional Ca(OH)2 method

2.1.3.2 Spray drying method

2.1.3.3 Air cathode method

2.2 Surface modifiers of CaO2

3 Application of CaO2 in tumor therapy

3.1 O2-dependent anticancer therapy

3.1.1 Enhanced chemotherapy

3.1.2 Enhanced PDT

3.2 H2O2-dependent anticancer therapy

3.2.1 Enhanced CDT

3.3 Calcium overload

4 Antimicrobial therapy

5 Biological effects and biosafety of CaO2 NPs

6 Conclusion and future perspective

References

Journal and Issue

Articles in the same Issue

2 Preparation and surface modifiers of CaO₂

2.1 Preparation of CaO₂

2.1.1 CaCl₂ method

2.1.3 Ca(OH)₂ method

2.1.3.1 Traditional Ca(OH)₂ method

2.2 Surface modifiers of CaO₂

3 Application of CaO₂ in tumor therapy

3.1 O₂-dependent anticancer therapy

3.2 H₂O₂-dependent anticancer therapy

5 Biological effects and biosafety of CaO₂ NPs