Advances of typical mesoporous materials and the application in drug delivery

For the excellent drug delivery systems, advanced functional materials are indispensable. In recent years, mesoporous materials have shown a promising prospect and attracted much attention in the field of drug delivery. The research of mesoporous materials as drug carriers becomes to be a hot-spots. As a drug vehicle, it is favored by scientists due to the advantages in increasing drug dissolution and bioavailability, improving drug stability, sustained and controlled drug release, reducing drug side effects, good biocompatibility, targeting and so on. The anticipated in vivo performance for the mesoporous materials based drug delivery systems can be improved through optimizing the synthesis conditions or modifying the materials. In the paper, mesoporous silica nanoparticles (MSNs), mesoporous carbon nanoparticles (MCNs), organic frameworks (OFs), mesoporous hydroxyapatite (mHAp) are selected as the representative mesoporous materials. The structural characteristics, preparation methods, application in the field of drug delivery of above materials are reviewed, and the future research is prospected.


Introduction
Mesoporous material refers to a kind of porous material with a pore diameter of 2-50 nm with the characteristics of extremely high specific surface area, regular and orderly pore structure, narrow pore size distribution and continuously adjustable pore size [1]. Its preponderant characteristics in photology, electricity, thermology, mechanics and catalysis make it widely used in the fields of fine ceramics [2], microelectronics [3], chemical engineering [4], bioengineering and medicine [5,6]. The research and application of mesoporous materials in pharmaceutical field, especially in nano-drug delivery systems (NDDSs), has attracted extensive attention and developed rapidly.
Nano drug delivery systems possess multiple advantages, such as improving drug solubility and bioavailability, reducing toxic and side effects, modifying drug release, targeted therapy, and so on [7][8][9]. NDDSs have shown promising prospect in multiple therapeutic fields and has become one of the new directions of drug research and development. For the excellent nano-drug delivery systems, advanced functional materials which researchers have committed to research and develop are indispensable. The mesoporous silica nanoparticles (MSNs), mesoporous carbon nanoparticles (MCNs), organic frameworks (OFs) and nano hydroxyapatite (mHAp), which are the most typical and commonly used nanomaterials show unique advantages in NDDSs [10][11][12][13]. The application of mesoporous materials in drug delivery system is mainly in the following aspects: (i) increasing drug dissolution and bioavailability, (ii) controlled release, (iii) targeted delivery, and (iv) synergistic therapeutic effect. And the drugs delivered are not only chemical drugs but also genes [14]. For example, Mehmood et al achieved increased bioavailability of Velpatasvir utilized mesoporous silica as the carrier [15].
He et al developed a smart HOF-based delivery system with synergistic chemotherapy-photodynamic therapyphotothermal therapy effect [16]. Jin et al designed a hydrotalcite-gated hollow mesoporous silica delivery system for controlled release of 5-Fluorouracil [17]. Based on the physiological characteristics of colon cancer, Wang et al carried out intensive study on mitochondria-targeting folic acid-modified nanoplatform based on mesoporous carbon and a bioactive peptide [18]. Su et al reported the polyethylenimine functionalized ultrasmall mesoporous silica nanoparticles for siRNA Delivery [19]. The application of representative mesoporous materials in the field of drug delivery systems can be illustrated in Scheme 1.
Hence, we aim to summarize the present state-of-the art of mesoporous materials based drug delivery systems during the last 10 years. The structure characteristics, preparation methods, characterization and the potential applications in drug delivery of mesoporous materials are introduced in this review, and the current challenge and perspective of mesoporous materials based drug delivery systems are also discussed.
2. Structural characteristics and preparation methods of mesoporous materials 2.1. Structural characteristics and preparation methods of MSNs Nano silicon nanoparticles include mesoporous silica nanoparticles (MSNs) and non-mesoporous silica nanoparticles (n-MSNs). Nano-silicon nanoparticles has the characteristics of high purity, small particle size and uniform distribution. n-MSNs refers to crystalline silicon particles with a diameter of less than 5 nm [20]. While MSNs have a regular pore structure and the pore size generally ranged from 1.5 nm to 10 nm with a narrow distribution. What's more, the pore size can be controlled according to the specific requirements. Based on the small pore size, the specific surface area and pore volume are up to 300-1000 m 2 g −1 and 0.6-1 cm 3 g −1 , respectively. When the drug is loaded, the drug can be adsorbed on the surface or inside the pore, which can protect and solubilize the drug, and further improve the bioavailability [21][22][23]. Additionally, the rich charge and a lot of silicon hydroxyl groups existed in the surface of MSNs make it can be modified to achieve the goal of intelligent targeted drug delivery [24]. For example, Cai et al designed a redox and pH triggered mesoporous silica nanoparticles capped by Ferritin to obtain the superior antitumor efficiency [25]. Therefore, in view of the above advantages, MSNs are more concerned by researchers.
Generally, MSNs can be prepared via sol-gel method, hydrothermal method, or microwave synthesis method [26][27][28]. The sol-gel method is one of the most commonly used methods. In the method, tetraorthosilicate is used as the precursor to form the chain structure in the sol and the network structure in the gel through continuous hydrolytic condensation process. Then the template is removed by calcination or extraction to obtain designed MSNs [29]. The sol-gel method has the advantages of mild reaction conditions, controllable particle size and structure, and less by-products [30]. In hydrothermal method, MSNs are synthesized directly under high temperature hydrothermal conditions (180°C). During process, templates are also used and then removed. The synthesized MSNs using hydrothermal method have good hydrothermal stability and low cost, but with high equipment requirements [31]. Microwave method has high efficiency [32], while the reaction speed is not easy to control, and the high requirement for equipment is one of the main disadvantages [33]. Additionally, mesoporous silica based organic-inorganic hybrid systems has attracted more and more attention, based on the great versatility and thanks to the variety of organic groups [22]. The mesoporous silica based functional materials can be synthesized via grafting or co-condensation method used as platforms for the interesting applications in the fields of drug delivery, catalysis, sensors and photovoltaics [26].

Structural characteristics and preparation methods of MCNs
Mesoporous carbon is a new type of non-silicon-based mesoporous materials. The pore size of MCNs can be adjusted during the range of 2-50 nm, and the specific surface area and pore volume are up to 2500 m 2 g −1 and 2.25 cm 3 g −1 , respectively. What's more, the physiological toxicity is negligible [34]. Compared with mesoporous silicon, the mesoporous shapes are various, and the composition, structure and properties of the pore wall are adjustable [35]. What's more, mesoporous carbon based delivery systems possess thermal sensitivity due to the excellent photothermal conversion capability of MCN-PEG [36]. Generally, MCNs can be synthesized via template method [37], Stober method [38], and hydrothermal carbonization method (HTC method) [39]. Under the optimized synthesis conditions, the target product with preponderant thermal and hydrothermal stability can be prepared. Because of its pure carbonaceous backbone, MCNs can interact with most aromatic drug molecules through π-stacking or hydrophobic-hydrophobic interactions [40]. Therefore, it is hopeful to achieve high drug loading capacity and multi-drug simultaneous controlled release through MCNs based drug delivery systems.

Structural characteristics and preparation methods of OFs
Among organic frameworks materials, metal organic frameworks (MOFs), covalent-organic frameworks (COFs), hydrogen-bonded organic frameworks (HOFs) have been extensively studied and applied. The materials have a regular network structure with large surface area and are easy to be modified on the surface.

Structural characteristics and preparation methods of MOFs
MOFs have a neat and infinite network structure composed of metal ions and organic ligands with the ionic bond and/or coordination bond as connecting keys, for example, the structure of MOF-5 ( figure 1(A)) [41]. The metal ions, such as Zn 2+ , Cu 2+ , Zr 4+ , are essential in the skeleton of MOFs, and the pores are generally hydrophilic. The variable metal ions and organic ligands endow MOFs with diverse functions and structures. It is worth noting that the coordination bond between metal ions and organic ligands ensures the degradability of MOFs, avoiding toxic side effects caused by the accumulation of drug carriers. Meanwhile, due to the presence of metal ions, photosensitivity and/or magnetic targeting can be utilized to achieve the goal of targeted diagnosis and synergistic therapy [42,43]. For example, zeolite imidazole framework (ZIF) materials, formed by imidazole or its derivatives as organic ligands linked with Zn 2+ , can rapidly decompose in acidic solutions. The pH sensitivity enables it to specifically release drugs in a weakly acidic microenvironment for targeted drug delivery [44].
MOFs can be synthesized by hydrothermal/solvothermal method, ultrasonic method, microwave method and mechanochemical method [47]. Hydrothermal method is an environmentally friendly method and suitable for water-soluble drugs through one-step synthesis to prepare drug-loaded particles. Although water is the solvent, a large number of ligands generally participate in the reaction. In contrast, organic solvents are expensive, flammable and potentially harmful to human beings and environment in solvothermal method, which is suitable for poorly water soluble drugs [41]. The ultrasonic method has the advantages of simplicity, short reaction time and high efficiency. Seoane et al synthesized a zeolitic imidazolate framework (ZIF-8) as a novel metal-organic frameworks via ultrasonic method under the conditions of 47 kHz, 4 h, 110 W. The size distribution of ZIF-8 was narrow, but the yield was low (2.9%-5.6%) [48]. Mechanochemistry method usually include neat grinding (NG), liquid-assisted grinding (LAG), ion and liquid-assisted grinding (ILAG) [49]. The ZIF-8 nanoparticles with a diameter of about 80 nm and a specific surface area of 1885 m 2 g −1 were prepared by liquid-assisted grinding, methanol as the assistant liquid. The conversion rate is almost 100% [50]. The mechanochemical method has great potential due to the high yield and suitability for large-scale production of MOFs. Additionally, accelerated aging method, micromixer mixing method, and reverse microemulsion method are also used for the synthesis of MOFs [51].

Structural characteristics and preparation methods of COFs
Covalent organic frameworks (COFs), constructed with the light atoms such as carbon, nitrogen, oxygen, borane etc via covalent bonds of organic units, are a kind of novel structurally ordered and highly crystalline porous materials [52]. The typical structure is shown in figure 1(B). Due to the predominate feature of ultra-high porosity and specific surface area, stable framework structure, and excellent structural designability, COFs has attracted extensive attention. The pores in COFs are mostly lipophilic that is favorable for adsorbing lipophilic substances, especially loading lipophilic drugs [53]. Generally, the solvothermal method is a traditional method to synthesize COFs. Briefly, COFs can be obtained at the conditions of >120°C and >72 h in harmful organic solvents [54]. Nowerday, sonochemical method [54], ion-thermal synthesis method [55], microwave-assisted solvothermal method and mechanical grinding method are developed to prepare COFs [56]. In the preparation process, functional groups can also be introduced to achieve the specific purpose, such as porphyrin group, which plays the role of sonodynamic therapy [52].

Structural characteristics and preparation methods of HOFs
HOFs is a kind of crystalline material formed by hydrogen bonds of organic molecules and the structural schematic diagram of representative HOF-8 is displayed in figure 1(C). Compared with MOFs and COFs, HOFs has the advantages of mild synthesis conditions and fine regeneration to be recycled [57]. However, due to the weakness and non-direction of hydrogen bond, the HOFs with the targeted structure are difficult to synthesize and the stability is poor [58], which restrict its application in drug delivery systems. While, the rigidity and directionality of a hydrogen bond building unit are stronger than those of a single hydrogen bond donor/ acceptor pair. In the synthesis, suitable hydrogen bonding building blocks are the key factors to build HOFs with high porosity. And the typical building blocks include diaminotriazine (DAT), pyrazolre, carboxylic acid (-COOH), imidazole, sulfonic acid (-SO 3 H), pyridine and urea [59]. When an organic framework is combined with a H-bond building unit, an expanded framework with topological structures will formed. The pore size is determined by the length of the organic framework. It is worth noting that these organic groups tend to assemble into polymorphs due to the flexibility of hydrogen bonds.
HOFs are usually prepared by re-crystallization methods, like liquid/vapor diffusion, evaporation/cooling, electrophoretic and deposition [60]. In the above methods, the crystallization of HOFs is easily influenced by the reaction solvent, template, concentration and temperature, resulting in polymorphs. Therefore, it is necessary to control synthesis methods and conditions as much as possible to obtain a single crystal form. The methods of liquid/vapor diffusion and evaporation/cooling are beneficial to the growth of HOFs crystals, and are more suitable for assembling stable HOFs [61,62].

Structural characteristics and preparation methods of mHAp
Hydroxylapatite (HAp) is the main inorganic component of bone and teeth. Although it has good biocompatibility, bioactivity and bone conductivity, the small specific surface area limited the application of HAp in the biomedical field [63]. Fortunately, in order to utilize the advantages of large specific surface area and strong adsorption, nano hydroxyapatite (nHAp), especially mesoporous hydroxylapatite (mHAp) has been developed [64]. As a drug carrier, mHAp can achieve the effect of sustained and controlled release [65]. Especially relying on the selective cytotoxicity of mHAp to tumor cells, the damage to normal cells of drugs loaded in mHAp can be reduced or avoided, thus mHAp based drug delivery systems have more accessible biocompatibility and safety.
Generally, mesoporous hydroxyapatite can be prepared by introducing mesopores into nano hydroxyapatite via extensively used template method and microemulsion method [66]. nHAp is commonly prepared by the precipitation method, hydrothermal method, and sol-gel method [67]. The precipitation method can easily control the particle size and morphology of nHAp by adjusting the reaction conditions. The method is easy to operate and low in cost, but the prepared nHAp has poor dispersibility and low crystallinity [68]. In hydrothermal method, aqueous solution as the reaction medium, the materials containing calcium and phosphorus are dissolved and then recrystallize to form nHAp in high temperature and high pressure. The prepared nHAp particles have a controllable crystallization state, high crystallinity and less agglomeration, while the reaction conditions are harsh and high cost [13]. In the sol-gel method, raw materials are mixed in a low viscosity liquid state to form sol, and then the sol is dried and dehydrated into gel followed by further heat treating. This method improves the uniformity of nHAp, but it takes a long time. Inclusion, each synthesis method has its own advantages and disadvantages. In order to obtain the mHAp with satisfied performance, different methods are usually combined to synthesis the title mHAp. For example, Liang et al successfully synthesized mHAp nanoparticles via a facile template-free sonochemistry-assisted microwave method in a short time, as short as 10 min [64]. Besides the above methods, microemulsion method, solid-state reaction, mechanochemical synthesis, thermal decomposition, high-temperature calcination and biomimetic mineralization are also used to synthesize mHAp [67]. What's more, mHAp can also be modified or composite for the purposes of targeted delivery, intelligent response, and theranostic systems [69,70].

Characterization of mesoporous materials
Usually, the size and size distribution, morphology, specific surface area, the pore parameters (size, specific volume), phase purity and the degree of crystallinity are mainly evaluated to characterize mesoporous materials [68]. These characteristics are very important for mesoporous materials because these factors not only effect drug loading efficiency and stability during the formulation process and storage but also are related to their performance in vitro and in vivo. What's more, after drug loaded the drug loading efficiency and stability are also studied. With the fast development of the detection technique, more and more methods are used to characterize mesoporous materials. Some of the common technologies used for characterizing mesoporous materials are summarized in table 1.
The mesoporous materials with fine morphology and similar size or narrow size distribution are expected. In order to guarantee the stability and superior performance in vivo of the mesoporous materials based delivery systems, the proper size and narrow size distribution are required. Generally, SEM, TEM, AFM and STM are employed to intuitively observe the size and morphology [26]. Additionally, the size and size distribution can also be quantitatively detected by DLS. The specific surface area and pore parameters, which could be adjusted during the preparation are related to drug loading. Hence, the specific surface area and pore parameters (size and volume) generally characterized via BET method and BJH method [23]. And the definition of the drug loading efficiency is shown in table 1. XRD and SAXS patterns can indicate the degree of crystallinity and the mesostructural properties (such as hexagonal, ordered or disordered), which can be further proved in the N 2 adsorption-desorption isotherms [13]. FTIR and ATR-FTIR can be used for identifying the molecular structure of an unknown substance, and the strength of the absorption peak can be used to quantify the composition of the molecule or the content of the chemical group. In the characterization of mesoporous material, comparatively analysing the infrared spectra, especially some characteristic absorption peaks of the reactants and anticipated product, whether the title mesoporous material is successfully synthesized can be confirmed. However, inorganic materials are not easily analyzed by FTIR spectroscopy, while Raman spectra can make up for this deficiency [68]. FTIR is often used to determine whether the functional groups are successfully modified on mesoporous materials [11]. Hence, the above methods are combinedly applied for characterize mesoporous materials in studies.

The application of mesoporous materials in drug delivery systems
4.1. The application of MSNs in drug delivery systems Velpatasvir (VLP) is a novel hepatitis C virus (HCV) NS5A inhibitor. But the poor solubility and bioavailability limited its applications in clinic. It was reported that spherical MSNs with good dispersibility were prepared via sol-gel method for loading VLP to increase the oral bioavailability [15]. The specific surface area and pore diameter of MSNs were 602.5 m 2 g −1 and 5.9 nm, respectively. After successfully loading VLP, the average particle size of VLP-MSN was 186 nm. The drugs dissolution rate in VLP-MSN was significantly increased in both pH 1.2 and pH 6.8 media. In vitro cytotoxicity test showed that the median lethal dose of VLP-MSN was 448 μg ml −1 , which was far lower than the actual dosage used in clinic. And the toxicity evaluation further proved the good physiological compatibility and safety of VLP-MSN. The pharmacokinetic study in vivo showed that the bioavailability of VLP-MSN was about twice that of VLP ( figure 2). This result is attributed to the large specific surface area MSNs. And the above results fully proved that VLP-MSN possessed satisfactory dissolution performance in vitro, biocompatibility, low toxicity and high bioavailability. Cai et al designed a redox/pH dual response mesoporous silica based drug delivery system (MSN-S-S-HFn) and proved that MSN-S-S-HFn displayed obvious redox and pH sensitivity, which was beneficial to drug release in the microenvironment of tumor sites. This mainly depends on the surface modification of MSNs. And the further pharmacodynamic test in vitro and in vivo were all proved the superior tumor targeting and anti-tumor effect of MSN-S-S-HFn [25]. Therefore, we can utilize the surface modification of MSNs to achieve targeted delivery for drugs. MSNs is also used to deliver biomacromolecule such as proteins [71][72][73]. Tu et al applied MSNs to deliver antigen albumin (OVA). Firstly, MSNs were synthesized using the template method and modified with cations. Then OVA was adsorbed into the pores (MSN-OVA) and the surface of MSN-OVA was coated using a lipid bimolecular layer to obtain LB-MSN-OVA with the particle size of 190.7 nm. In vitro release study showed that OVA could be sustainedly released from LB-MSN-OVA. Finally, LB-MSN-OVA was encrusted layer by layer over the microneedle array. The SEM and colocalization images illustrated that the microneedles penetrated into the skin and successfully delivered the LB-MSN-OVA after microneedle injection [74]. The study suggested that MSNs diaplayed unique advantages in the field of microneedles.
In short, MSNs as a drug delivery vehicle have been widely applied for increasing the dissolution and bioavailability of poorly soluble drugs and delivering drugs in a targeted manner. MSNs are potential and promising in the field of drug delivery.

The application of MCNs in drug delivery systems
High drug loading, good drug dissolution and biocompatibility are the desired properties for drug carriers. MCNs have been reported as novel drug delivery vehicles with several advantages: increasing of loading capacity and solubility, good biocompatibility and enhanced cytotoxicity. Fan et al synthesized MCNs with excellent water dispersibility and particle size below 200 nm by hydrothermal carbonization method. MCNs were further oxidized into oxidized MCNs (oMCNs), which successfully encapsulated resveratrol (RES) into the pores with high drug loading efficiency (24.8% w/w). Compared with pure RES, oMCNs-RES largely improved the saturated solubility and in vitro dissolution of resveratrol. What's more, oMCNs exhibited good biocompatibility, excellent cellular uptake efficiency, enhanced cytotoxicity and pro-apoptosis effect against TNBC [75]. This study demonstrated that oMCNs-RES was promising in treating TNBC and oMCNs was a potential delivery vector for hydrophobic drugs.
In order to obtain or improve the intelligent response in vivo, a multifunctional platform based on cyclic arginine-glycine-aspartic acid (cRGD) peptide-conjugated hollow mesoporous carbon nanoparticles (cRGD-HMCN) was designed to realize near-infrared (NIR)/pH-responsive drug release and targeted chemophotothermal therapy. The study showed that cRGD-HMCN with a high doxorubicin (DOX) loading efficiency of 246 μg mg −1 exhibited pH/NIR-responsive drug release behavior. Moreover, cRGD-HMCN@DOX combined with near-infrared laser irradiation significantly improve the therapeutic efficacy against PC3 cells in vitro and prostatic carcinoma (PC3) xenograft mouse model in vivo with fewer side effects compared to nontargeting group and any monotherapy (figure 3) [11]. This is mainly based on two points. On the one hand, mesoporous carbon is easy to be modified with functional groups, such as pH-sensitive groups, ligands of the highly expressed receptors in lesion sites (RGD, FA, and so on). On the other hand, mesoporous carbon has thermal energy effect, which can be used for thermal-therapy by near infrared light. Therefore, the drug delivery system based on MSCs can achieve multifunctional therapeutic effects.
All the studies reported illustrate that MCNs based drug delivery systems with the superiority of enhancing drug loading, solubility and good biocompatibility are alternative and promising. What's more, MCNs are easy to be modified for intelligent response to increase the therapeutic effect.

The application of OFs in drug delivery systems
OFs, especially MOFs and COFs, with the advantages of controllable structure and size, and easy surface modification, have received extensive attention and were widely used in the field of drug delivery [76,77]. As vehicles, MOFs and COFs are mainly used to improve drug bioavailability and targetedly deliver drugs [78].
MOF-5, as one of the most typical representative of MOFs family, is a three-dimensional (3D) framework structure composed of terephthalic acid and metal cluster Zn 4 O [79]. Chen et al synthesized MOF-5 with complete structure and uniform particle size via direct addition method and proved the good biocompatibility. Then MOF-5 was loaded with oridonin (ORI) by adsorption method with a high drug loading of 52.86%. The obtained ORI@MOF-5 exhibited sustained release behavior, significant cytotoxicity and apoptosis effects on HepG2 cells. The study suggested that MOF-5 as the carrier can effectively solve the problems of poor solubility and fast metabolism of oridonin. Dong et al constructed a RGD (Arg-Gly-Asp) modified zeolitic imidazolate framework-8 (RGD@ZIF-8) as a novel MOFs based drug delivery system for delivering camptothecin (RGD@CPT@ZIF-8). The prepared RGD@CPT@ZIF-8 exhibited superior targeting property to the cancer cells. More importantly, the RGD@CPT@ZIF-8 nanoplatform shown enhanced cancer cell inhibition due to the excellent pH-responsive and intra-cellular ROS generation [44]. The study showed that MOF-5 based delivery system was potential for enhancing the therapeutic efficiency of anticancer drugs.
In addition, MOFs with therapeutic functions, such as porphyrin-based MOFs, can not only be directly used as cancer therapeutic agents, but also be used as drug carriers to load anticancer drugs, thus realizing synergistic enhancement for tumors therapy [80][81][82]. However, the research on clinical application of MOFs is still in its infancy, and the MOFs with high biological safety are urgently needed. Future research should focus on reducing the toxic and side effects of MOFs and its applicability in cancer treatment.
COFs also be used as drug carriers and showed significant advantages. For example, An imine linked covalent organic framework (RT-COF-1) was synthesized and then conjugated with ibuprofen (IBU) using simple coordination chemistry. Compared with RT-COF-1, the decreased surface area of IBU@RT-COF-1 indicated that IBU was loaded on the surface of RT-COF-1. And the ultraviolet spectra and Fourier transform infrared spectroscopy further proved the successful loading of IBU [83]. Das et al proved that the 2D-COF (TRIPTA-COF ) loaded cisplatin displayed superior inhibition against triple negative breast cancer (TNBC) cells and TRIPTA-COF could be internalized by the cancer cells in a time-dependent manner [84]. In order to improve the controllability of particle sizes and degradability, a dendritic mesoporous silica nanosphere (DMSN)-mediated growth strategy was employed to fabricate hierarchical DMSN@COF hybrids [85]. After the removal of the DMSN template, COF hierarchical particles (COF HP) with tailored particle sizes and degradability were obtained. It is worth noting that the COF HP could be degraded by 55% after incubation for 24 h at pH 5.5 (COF only 15%). And due to the improved porosity and surface area, the loading rate of doxorubicin (DOX) by COF HP was up to 46.8 wt% (COF only 32.1 wt%). The COF HP exhibited a pHresponsive drug release behavior, the released rate of DOX up to 90% within the first 8 h in COF HP faster than that in COF (∼55%). Moreover, the biocompatibility of COF HP and COF, and the significantly stronger cytotoxicity of DOX loaded COF HP than that of DOX loaded COF were proved (figure 4) [85]. In conclusion, COFs and the derivatives based drug delivery systems exhibited obvious advantages.
He et al developed a three-dimensional hydrogen-bonded organic framework (3D-HOF) TCPP-1,3-DPP through top-down fabrication technology with ultrasonic-assistant in the aqueous solution. In order to obtain a fine-dispersed stable colloidal suspension with ltrahigh surface sensitivity, 3D-HOF was exfoliated into atomically thin 1D porous nanoribbons (nr-HOF), based on the fact that 3D-HOF is composed of one dimensional (1D) porous ribbons via robust hydrogen bonding contacts. And then the study proved the high loading capacity of doxorubicin in nr-HOF (Doxo; 29.4%, nr-HOF@Doxo) and desired synergistic chemotherapy-photodynamic therapy-photothermal therapy (PDT-PTT) effects (figure 5). The high loading capacity was mainly attributed to the more fully exposed surface and stronger surface adsorption ability of nr-HOF than that of 3D-HOF. And the superior PDT-PTT effect is due to the components TCPP in the HOF, which will be into free TCPP and 1,3-DPP under acidic conditions. It is well known that TCPP can generate O 2 and thermal energy upon light irradiation. After cellular uptake, TCPP is decomposed from nr-HOF in the lightly acidic environment of cancer cells. Therefore, nr-HOF can be seen as a promising material for effective photodynamic therapy and photothermal therapy for cancer. What's more, the compatibility of nr-HOF was also superficially proved in vitro via cell viability (figure 5) [16].
To sum up, OFs with appealing properties are becoming to be a promising platform for drug delivery. What's more, all the studies boost further development of OFs for drug delivery.

The application of mHAp in drug delivery systems
Owing to the large specific surface area, strong adsorption, good stability and biocompatibility, mHAp was widely used in the field of drug delivery [86,87]. For example, Wang et al prepared Selenium doped hydroxyapatite microspheres (HASe) via hydrothermal route with CaCO 3 as the template to load curcumin. The synthesized HASe was spherical with an average diameter of about 1.0 μm, and a large number of hydroxyapatite nanorods which are 150 nm in length and 20 nm in width adhered to its wall. The drug loading of curcumin was as high as 88.72 mg g −1 , and less than 1.5 mg curcumin was released in 159 h. Moreover, HASe microspheres displayed lower blood toxicity, less damage to normal cells and stronger growth inhibition on osteosarcoma cells, compared with selenium-free HA microspheres [13]. The results showed that Selenium doped in HA played an important role in the performance of hydroxyapatite as the drug carrier. That is to say, except the advantages of mHAp itself, proper modification is helpful to obtain better efficacy. Shuai et al developed a hybrid porous microspheres (ASM) based on silk sericin and nHAp for targetedly delivering doxorubicin [65]. DOX was released from ASMs at a higher rate under acidic conditions (pH = 6.2) than physiological conditions (pH = 7.4), which meant the potentially reduced side effects. What's more, studies on cellular uptake and intracellular distribution showed more efficient and the accumulation in the cell nuclei of DOX by ASM ( figure 6). Hence, the superior effect of cell proliferation inhibition was obtained. The studies above suggested that mHAp based drug delivery systems possess the advantage of synergy and attenuation.  Additionally, in order to achieve the goal of targeted delivery, a large number of studies on the surface modification of mHAp have emerged [69,70]. Verma et al conjugated folic acid (FA) to mHAp surface, and then prepared nanoparticles for targeted delivery of doxorubicin (DOX-FA-Gel-HANPs). The negatively charged FA-Gel-HANPs had high affinity with doxorubicin, and showed remarkable pH-sensitive drug release characteristics. The cytotoxicity of FA-Gel-HANPs was negligible to all kinds of cell lines, while DOX-FA-Gel-HANPs exhibited obvious cytotoxicity, especially to the cell lines with high expression of folate receptor [88]. Therefore, surface modification of mHAp is a strategy to achieve ideal drug delivery with good safety and specific targeting effect.

Conclusions
At present, a great deal of research has been performed on mesoporous materials. In the paper, we summarized the structural characteristics, synthesis methods and characterization, highlighted some major applications of mesoporous materials in the field of drug delivery. As mentioned above, mesoporous materials have been extensively applied based on the following characteristics: (i) The porous structure makes them have a large specific surface area, which is beneficial to increase the dissolution and bioavailability of poorly soluble drugs. (ii) The surface modifiability enables them to be used for controlled release or targeted drug delivery. (iii) The superior biocompatibility and low toxicity endow them with favorable prospects in the field of drug delivery. Beyond that, the metal species in MOFs enable the photosensitivity and/or magnetic targeting fulfilled, and then the goal of targeted diagnosis and synergistic therapy achieved. The tumor cell selectivity of mHAp makes it have lower side effects and better targetability.
However, in order to realize the clinical application of mesoporous materials as drug delivery carriers, we still face some challenges, and future effort should be mainly focused on three aspects: (i) Aggregation phenomenon. The high specific surface area of mesoporous materials makes them have serious , which is a key problem we need to solve. In this issue, stringently controlling the particle size, optimizing the surface charge for appropriate application are the main strategy. (ii) Drug loading. This includes two aspects, on the one hand, whether the amount of drugs loaded by mesoporous materials can meet the application requirements, and on the other hand, whether the loaded drugs will leak during storage, and/or in non-target parts in vivo, because most drugs are loaded on the carrier by adsorption. (iii) Translation. Currently, the research progress of mesoporous materials in drug delivery is mainly in lab-scale. While, there is a astonishing gap between the labscale study and the scale-up processing. Fortunately, the researches have explored the scale-up processing of these mesoporous materials based drug delivery systems. In summary, although mesoporous materials have displayed promising application prospect as a delivery vehicle, it is necessary to prove the feasibility of mesoporous materials as drug delivery carriers through intensive and sufficient study including mechanism study and clinical research.