Passive and active targeting strategies in hybrid layered double hydroxides nanoparticles for tumor bioimaging and therapy

Applied Clay Science 181 (2019) 105214

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Review article

Passive and active targeting strategies in hybrid layered double hydroxides nanoparticles for tumor bioimaging and therapy Karina Nava Andradea, Ana María Puebla Pérezb, Gregorio Guadalupe Carbajal Arízagaa, a b

T

⁎

Departamento de Química, Universidad de Guadalajara, Marcelino García Barragán 1421, C.P. 44430 Guadalajara, Jalisco, Mexico Departamento de Farmacobiología, Universidad de Guadalajara, Marcelino García Barragán 1421, C.P. 44430, Guadalajara, Jalisco, Mexico

A R T I C LE I N FO

A B S T R A C T

Keywords: Layered double hydroxide Active targeting Passive targeting Theranostic Cancer Hybrid

Layered double hydroxides (LDH) are recognized as a base to prepare a wide range of materials owing the versatility to modify the composition and structure of the particles, some of them with nanometric sizes. Within the biomedical science, there is a rising interest in preparing multifunctional materials to treat or identify cancer cells. This review presents three levels of molecular engineering techniques used to hybridize LDH nanoparticles aiming to produce multifunctional materials with a specific action in malignant tumors. The first level has been more developed and is related to modify the composition of the layered structure and interlayer spaces, whereas the other levels belong to more advanced strategies involving the assembly of different components. All the levels lead to produce hybrid materials, and the goal of this review is to correlate the molecular engineering techniques with the active and passive targeting mechanisms that promote the accumulation of the hybrid LDH nanoparticles in the desired cells and promote a more effective treatment or diagnosis. Finally, a discussion on the lack of information will be presented in order to identify the following the research questions that must be addressed to improve the state of the art before these particles were translated to clinical assays.

1. Introduction Cancer is one of the main leading cause of death worldwide, and the incidence and mortality rates have increased in recent years (Fitzmaurice et al., 2017). In the search for a precise diagnosis and effective treatments, researchers have focused on nanoparticles. Among the extensive list of nanoparticle compositions (polymeric, metal, ceramic, and so on), layered double hydroxides (LDH) is a family of ceramic materials that could allow the development of more effective anticancer treatments. These nanomaterials have been extensively studied as drug carriers due to their excellent biocompatibility, low cytotoxicity, pH-sensitivity response, and high chemical stability, which have been well understood since 2007 (Del Hoyo, 2007; Kuthati et al., 2015). In addition to the drugs transport, numerous investigations and reviews have demonstrated the promising application of LDH as systems for controlled release of other bioactive molecules, such as genetic material which offer promising alternative for gene therapy (Choi et al., 2018a). Since the first report of intercalation of nucleoside phosphates and DNA fragments in LDH (Choy et al., 1999), several articles has demonstrated efficiency of LDH as vehicles for gene therapy for the treatment of human diseases (Saha et al., 2017; Choi et al., 2018a) and more recently, the commercial application for protection of plants and

⁎

crops has been demonstrated (Mitter et al., 2017b; Worrall et al., 2019). Several anticancer agents of different chemical nature, such as 5fluorouracil, methotrexate, cyclophosphamide, doxorubicin, cisplatin, carboranes, genetic material have been successfully incorporated into LDH (Kuthati et al., 2015). The interlayer compounds could be stabilized mainly by electrostatic interactions, hydrogen bonding, and van der Waals forces and, in some cases, coordinative bonding (Tsukanov and Psakhie, 2016; Arizaga et al., 2008). The therapeutic agent incorporated in LDH preserve the tumor inhibition ability and shows greater chemical stability, controlled release, better cellular internalization and, consequently, greater bioavailability compared to the free agent (Oh et al., 2006; Choi et al., 2018b). Then, the therapeutic efficacy of drugs increases using lower doses and adverse side effects are also reduced (Rives et al., 2014; Kura et al., 2014). This efficiency is increased also with recent advances in conjugating existing drugs to modulate the stimuli-response functionality when assembled to LDH nanohybrids (Kankala et al., 2017; Liu et al., 2019). Besides, a new generation of therapeutic agents involves molecules activated by external physical stimuli like indocyanine green, porphyrins and indole-3-acetic acid, which are activated by laser (Kankala et al., 2015a; Chen et al., 2015; Wei et al., 2015) or magnetic nanoparticle for magnetothermal therapy (Komarala et al., 2016).

Corresponding author. E-mail address: [email protected] (G.G.C. Arízaga).

https://doi.org/10.1016/j.clay.2019.105214 Received 11 April 2019; Received in revised form 3 July 2019; Accepted 10 July 2019 0169-1317/ © 2019 Elsevier B.V. All rights reserved.

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Fig. 1. The relationship between the functionalities of LDH and the generation of molecular engineering modifications applied to LDH nanoparticles.

stating that “a hybrid material consists of at least two components – usually an inorganic and an organic component – that are molecularly dispersed in the material.” (Kickelbick, 2014). Some general methods to prepare hybrid LDH particles with molecularly dispersed organic/inorganic components for biomedical applications are coprecipitation, anion exchange, reconstruction, and exfoliation-reassembly (Choi et al., 2018b).

Recently, assemblies of LDH have given rise to theranostics systems, which are particles with the ability to transport drugs for the therapy along with a moiety with magnetic or optical response useful in diagnosis (Chen et al., 2013b; Jiezhong et al., 2014; Arratia-Quijada et al., 2016). This combination enables the simultaneous detection, diagnosis, and monitoring of cancer therapy. To increase the efficiency in treatment and diagnosis, the LDH particles or LDH-based assemblies should target a specific tissue, if this occurs, also the harmful effects on normal cells would be reduced. Once the procedures to load LDH nanoparticles with drugs are already reviewed (Del Hoyo, 2007; Saha et al., 2017; Choi et al., 2018b) as well as the modifications to provide diagnosis (Kuo et al., 2015), this article is focused on the strategies to add passive and active targeting on LDH nanoparticles. Firstly, this article briefly describes the traditional methods to synthesize hybrid LDH and then it will detail the functionalization levels of first, second and third generation designed to add multi-functionalities to the LDH nanoparticles with the aim to use them as tumor-targeted diagnosis or therapies.

a) Coprecipitation is a simple technique for the direct synthesis of LDH nanohybrids. This method consists of the slow addition of a solution containing the divalent and trivalent cations to a solution containing the target anion, increasing the pH by addition of a base or urea hydrolysis that leads to precipitation of the LDH. This technique allows intercalation of a wide variety of inorganic anions, organic molecules and even large biomolecules that could be difficult to incorporate by other methods (Mishra et al., 2018). b) The anion exchanges. In this strategy, anions initially present in the preformed LDH, preferably nitrate or chloride, are replaced by specific anions (Miyata, 1983). LDH nanohybrids are prepared by stirring the LDH precursor in a solution containing an excess of the anion to be intercalated. The anion-exchange capacity of LDH depends mainly on affinity for incoming anion, exchange medium, pH value and chemical composition of the layers (Evans and Slade, 2006).

2. Methods to synthesize hybrid LDH nanoparticles The advanced materials produced with LDH particles for theranostics proposals mostly contain organic components, and these materials can be classified as hybrids, according to a modern definition 2

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hydrothermal post-treatments determined these features, for example, the reaction time and concentration of reagents regulate the size and shape during co-precipitation, while the time and temperature are the most important influence in hydrothermal treatments (J. Oh et al., 2002). The control of the size is crucial for passive targeting and it is important to take into account that the release rate of drugs also depends on the particle size (Yazdani et al., 2019). In the following section, it will be noted that these chemical procedures are in most of the cases devoted to regulate the passive targeting as these methods influence the composition and microstructure of the LDH particles. b) Second generation modifications involve non-covalent coating and self-assembly (Park et al., 2015). For example, coating of LDH with biomolecules or polymers, such polyethylene glycol (PEG) derivatives, improve the stability and dispersity due to steric and electrostatic factors (Li et al., 2011), and prolong its circulation time and accumulation in tumor through protecting the nanocarriers against the attack of plasmatic proteins and opsonization (Yan et al., 2014). We have identified that reports promoting a second generation coating satisfies the addition of one functionality, regarding the targeting, the coating could regulate the electric charge of the particles to promote accumulation is specific cells, however, the coating could limit or avoid the release of intercalated drugs within the LDH particles. A smart covering of second generation should simultaneously control the targeting properties and diagnosis or therapy efficiency, as the chitosan covering of LDH, which is capable to regulate the surface charge (Wei et al., 2012) phototherapy efficiency (Wei et al., 2015) and the release within a therapeutic window (Kankala et al., 2015b). The second generation also considers the self-assembling of functional components onto external surface of LDH nanohybrids (Wang et al., 2013) to add multifunctionality (Park et al., 2015) as in the case of assemblies with iron-based magnetic nanoparticles to guide the assembly through a magnetic field, as well as the addition of gold nanoparticles to improve the quality of computerized tomography imaging (see second generation in Fig. 1). These functionalization's by physisorption are based on electrostatic interactions, van der Waals forces and hydrogen bonds (Treccani et al., 2013). The assembly by physisorption is a simple process of low energy and it has demonstrated effectiveness even in the stabilization of gene material for real agricultural applications (Mitter et al., 2017a; Worrall et al., 2019). In a typical procedure, the LDH particles are first synthesized and then added to a solution with the component that must be assembled, for example, magnetic nanoparticles, gene material or polymer covering agents. We have identified that the assembly by adsorption mainly occurs with metallic particles and molecules lacking ionic sites like PEG or molecules where ionic and cationic sites co-exist as in the case of amino acids or chitosan.

c) Reconstruction or rehydration method is based on the structural memory effect of LDH (Chibwe and Jones, 1989). In this technique, the pristine LDH is calcined, and the resulting mixed metal oxides are immersed in a solution of the new anion to give rise to the LDH nanohybrid. Reconstruction is the peculiar property of LDH to recover the lamellar structure after calcination and rehydration. This strategy is usually employed for intercalation of large-sized anions or to avoid competitive intercalation with the original anions. However, amorphous phases are often produced as side products (Evans and Slade, 2006). d) The exfoliation-reassembling technique was recently developed. It is used to intercalate or encapsulate large anionic molecules or polymers. This method consists treating the pristine LDH with formamide or reflux in alcohol to separate the layers. The subsequent reassembling reaction produces LDH nanohybrid when the exfoliated LDH nanosheets are added to a solution containing the desired anion (Wang and Hare, 2012). Neutral species or with low charge density are demanding guests to intercalate. In these cases, pre-intercalation by smaller or larger guests is an effective way to expand the interlayer space to favor the incorporation of this type molecules (Carbajal Arízaga et al., 2016; Evans and Slade, 2006). Also, hydrothermal and microwave treatments are often applied to control particle size, crystallinity, specific surface area and other physicochemical properties (Benito et al., 2006; Herrero et al., 2009). 3. Molecular engineering of multifunctional LDH nanohybrids Although the general methods of synthesis cited above provide the basis to prepare hybrid LDH, the control of synthesis conditions, additional treatments or assemblies with other components are needed to finely regulate the microstructure and composition that allow obtaining a material with therapy, diagnosis and targeting functionalities. The modification of the interlayer and external surfaces of LDH with diverse agents have been reported by Park et al. (2015). The evolution of chemical modification strategies at the nanoscale to improve the bioavailability of LDH are classified as first, second and third generation molecular engineering processes represented in Fig. 1 and described as follows: a) The first generation is the manipulation of structural properties, such as the control of composition, size, and morphology. These structural modifications are focused in the cationic and anionic sites to regulate the targeting function, reduce toxicity and add other functionalities to the particles (See section 4.1 and 4.2). Fig. 1 depicts examples of the isomorphic substitution of Al3+ cations for Gd3+ within the layers (Guan et al., 2017b) to prepare contrast agents for magnetic resonance imaging (MRI). Fig. 1 also depicts the intercalation of photo-functional anions, such as indocyanine green (ICG) (Li et al., 2016) that provides particles with imaging functions or 5-fluorouracil (5FU) to treat cancer cells. The ion exchange reactions are preferred to intercalate active agents since the energy consumption is low and this method is preferred to introduce small ions such as 5-FU or folate, although in some cases, this method is also capable to intercalate large molecules such as DNA, ATP, nucleoside monophosphates and oligonucleotides (Choy et al., 1999, 2000). Regarding large ions, the intercalation is likely more effective when the co-precipitation method is used (Wang et al., 2018) since the activation energy required in the exchange is avoided, another advantage is that a lower amount of the new molecule can be used, unlike the ion-exchange reaction where a high concentration of the ion to intercalate in needed to compete with the ion to replace. The size and morphology also provide a way to increase the bioavailability of LDH nanoparticles. The synthesis conditions and

c) The third generation is the covalent conjugation of LDH nanohybrids with specific molecules for active targeting or detection functionalities (D. H. Park et al., 2015). Covalent bonds are generated between hydroxyl groups of the laminar surfaces and targeting ligands or fluorescent probes (Park et al., 2005). Silanization is a widely used technique for introducing functional groups on inorganic surfaces (Oh et al., 2009a). It consists of the hydrolysis of silane molecules followed by condensation between the Si-OH groups of silanol and the OH groups of a lamellar surface (Treccani et al., 2013). The organic chain of silanol could contain diverse functional groups which remain active for the subsequent retention of drugs (Kankala et al., 2017) or an antibody to improve the ragetind as represente in the third generation scheme in Fig. 1 4. Passive and active targeting To optimize the therapeutic or diagnosis response functionalities of 3

4

MgAl/Cl−

MgAl/Cl−

MgAl/CO32−

Fe2+Fe3+/Cl−

MTX Intercalation by coprecipitation

5-FU Intercalation by coprecipitation Survivin siRNA Self-assembly

–

MgAl/CO32

MgAl/NO3−

MgAl/Cl−

MgAl/Cl−

pEGFP-N1 DNA (plasmid) a) Self-assembly b) Intercalation by anion exchange MTX Intercalation by coprecipitation MTX Intercalation by coprecipitation Cisplastin (CP) Self-assembly

MTX Intercalation by coprecipitation 5-FU Intercalation by coprecipitation –

–

–

Therapeutic agent

Molecular engineering

a) MgAl/CO32– b) MgAl/NO3−

MgAl/NO3−

Fe2+Fe3+/Cl−

MgAl/NO3−

MgAl/CO32−

MgAl/Cl

−

LDH/Anion

–

–

CdHgTe quantum dots Self-assembly –

Cu2+ Self-assembly

64

Cyanine-5.5 Silane coupling reaction

–

–

or FITC a) Self-assembly b) Intercalation by anion exchange

ICG Intercalation by anion exchange

FITC Silane coupling reaction –

FITC Intercalation by anion exchange FITC Silane coupling reaction

Photoactive agent

Hyaluronic acid (HA), PEG Self-assembly

Particle size ≈ 110 nm Size control BSA coating Self-assembly Fe2+Fe3+ Composition control Magnet-triggered a) Particle size ≈ 100 nm Size control b) Folic acid Silane coupling reaction Particle size ≈ 100 nm Size control

Particle size ≈ 130 nm Size control PEGylated phospholipid coating Self-assembly Modulation surface charge with NH2, COOH and PEG5000 Silane coupling reaction

Particle size: a) 20 nm b) 180 nm Size control

Fe2+Fe3+ Composition control Magnet-triggered Modulation charge with Chitosan (CS) Silane coupling reaction

Folic acid Silane coupling reaction

Particle size < 200 nm Size control

Hexagonal or rod Morphology control

Targeting agent

Table 1 Systems based on LDH nanoparticles designed for passive targeting.

Reduction in tumor volume orthotopic cancer model: LDH-MTX, 81.5%; MTX, 45%. Accumulation of MTX: LDH-MTX, 3.5-fold higher tumor-to-liver ratio and 5-fold higher tumor-to-blood ratio, compared to free MTX Cytotoxicity, HepG2 cancer cells,

Reduction in tumor volume in in vivo xenograft model: a) LDH-Survivin, 12% b) FA-LDH-Survivin, 66.4%

Cellular internalization degree of the CdHgTe@DMF increased with the enhancing of the magnetic field gradient

Accumulation of: Positive LDH-NH2: lungs Negative LDH-COOH: liver Neutral LDH-PEG5000: enhanced blood circulation time, low accumulation ROI analysis, persistent tumor uptake at 3 h: 64 Cu-LDH-BSA, 7.2 ± 0.5%ID/g 64 Cu-BSA, 3.4 ± 0.1%ID/g

Reduction in tumor volume in S(180) tumor-bearing mice: LDH-MTX, 66%; MTX, 33%

Reduction in tumor volume in in vivo orthotopic model: LDH-MTX, 81.4%; MTX, 27.5%

Inhibition of cell proliferation: 10% KB cells (FR-overexpressed) 1% A549 cells (FR-deficient) In vivo pharmacokinetic assays: Increase in half-life of 5-FU and bioavailability up to 400% compared with free drug Specific accumulation LDH-ICG: liver and spleen Monolayer CS-LDH-ICG: lungs Double layer CS-LDH-ICG: lungs and liver Location into NSC34 cells: a) cytoplasm and nucleus b) only into the cytoplasm

Intracellular distribution mainly: Particle hexagonal: cytoplasm Particle rod-like: nuclei Accumulation in MNNG/HOS cells is related to particle size: 50 nm > 200 nm > 100 nm > 350 nm

Targeting evidence

Tumor-targeted drug delivery by CD44 receptor

Tumor-targeted drug delivery by EPR

Targeted siRNA delivery a) EPR-based clathrinmediated b) FR-mediated endocytosis

Tumor-targeted delivery, magnet-triggered

In vivo PET imaging. Tumor-targeted delivery based on EPR effect

In vivo NIR imaging. Organ-targeted delivery system by modulation surface charge

Longer blood circulation time and EPR targeting

Tumor-targeted drug delivery by EPR

In vivo NIR imaging. Organ-targeted delivery system by modulation surface charge Intracellular imaging. Targeted genes delivery to intracellular compartments

Intracellular imaging. Targeted delivery to intracellular compartments Intracellular imaging. Targeted uptake by clathrinmediated endocytosis with EPR Intracellular imaging. Targeted delivery mediated by FR Tumor-targeted drug delivery, magnet-triggered

Potential application

(continued on next page)

(Dong et al., 2016)

(Choi et al., 2016)

(Park et al., 2016)

(Jin et al., 2016)

(Shi et al. 2015)

(Kuo et al., 2015)

(Yan et al., 2014)

(Choi et al., 2014)

(Li, Zhang, Yu, Guo, Chaudhary, and Wang, 2013b)

(Wei, Cheng, Liao, Kao, Weng, and Lee, 2012)

(Guo-Jing et al., 2011)

(Oh et al., 2009)

(Oh et al., 2009a)

(Xu et al., 2008)

Reference

K.N. Andrade, et al.

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Potential application

Reference

LDH nanohybrids, they predominantly should be delivered and accumulated at the specific site through passive or active targeting (Saha et al., 2017). While the passive targeting is a consequence of the enhanced permeability and retention (EPR) effect, which favors the accumulation of therapeutic agents in the interstitial space of tumor due to deterioration of the vascular and lymphatic system effect (Maeda, 2012; Greis, 2010), the active targeting promotes selective recognition of target cells through the response to stimuli of tumor microenvironment or ligands that bind to specific receptors overexpressed in cancer cells, thus favoring the cellular internalization and the release of the agents more efficiently (Morachis et al., 2012). The next sections present cases giving evidences of the achieved targeting with a tailored design of LDH nanohybrids. 4.1. Passive targeting Several types of research showed that the microstructural features of LDH nanoparticles such as size, shape and surface charge, influence circulation time, penetration rate and cellular internalization (Vasti et al., 2016; Kura et al., 2014). Table 1 provides the list of cases demonstrating the passive targeting dependent on these features, while this section will exemplify the passive targeting achievements classified according to the microstructural or physicochemical features regulated by molecular engineering. The recognition of tumor tissues through the acidic micro-environment will be included in this section as the pHsensitive degradation of the LDH hybrids influences the passive internalization through increasing permeability.

5-FU Intercalation by anion exchange

Therapeutic agent

LDH/Anion

Table 1 (continued)

Molecular engineering

Photoactive agent

Targeting agent

Targeting evidence

IC50 = 7.14 μg/mL L02 normal cell, IC50 = 22.81 μg/mL

4.1.1. Particle size Oh et al. (2009) reported that the rate of cellular uptake of LDH is highly dependent on particle size. They synthesized four different-sized hexagonal LDH labeled with luminescent fluorescein isothiocyanate (FITC) by a silane coupling reaction. The cellular uptake was evaluated in osteosarcoma cells. The results showed that LDH-FITC particles with a size of 50, 100 and 200 nm were selectively internalized into cells through clathrin-mediated endocytosis with EPR. In contrast, LDH with a size of 350 nm was not mediated by any specific endocytic pathway, resulting in very low cellular uptake. Moreover, retention studies showed the particles smaller than 100 nm might readily decompose in cellular organelles and lead to rapid exocytosis. Therefore, the particle size of LDH hybrids should fall into the range of 100 to 200 nm for high uptake and prolonged retention in the cells (Chem. Asian J., 2009; Oh et al., 2009; Choi and Choy, 2011). Also, assays in vivo revealed that LDH hybrids with sizes in the 100–200 nm range selectively distribute in liver, lung, spleen, and kidney, but not in brain or heart of mice (Choi et al., 2009). The size range between 50 and 300 nm reported in this case can be regulated by a hydrothermal treatment, which is a first generation strategy, in this procedure concentration of reagent is inversely proportional to the particle size (Oh et al., 2002). Recently, Choi et al. (2016) incorporated methotrexate (MTX) in LDH nanoparticles (LDH-MTX). The targeting capacity of this nanohybrid with an average particle size of 100 nm has been evaluated in vivo. The biodistribution studies indicated that the LDH hybrid exhibited targeting drug delivery since mice injected with LDH-MTX showed concentrations 3.5-fold higher tumor-to-liver ratio and five-fold higher tumor-to-blood ratio of MTX than those treated with free MTX. The low toxicity in vitro and in vivo suggest LDH-MTX with a particle size of 100 nm can be promising injectable chemotherapy with high targeting capacity that enhances the therapeutic efficacy. Likewise, Choi et al. (2018a) reported the passive targeting of LDH loaded with mercaptoundecahydro-closo-dodecaborate (BSH) anions, which were used in boron neutron capture therapy (Choi et al., 2018b). The LDH-BSH hybrid with 100 nm particle size promoted the simultaneous targeting in vivo model by the EPR effect and clathrin-mediated endocytosis. 5

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approved by the FDA for clinical use, into LDH nanoparticles coated with different amounts of chitosan through the silane coupling reaction. Chitosan molecules provide partially positive charges on the external surfaces of LDH nanohybrids attributed to protonation of the amino groups. The biodistribution studies revealed that LDH-ICG showed high accumulation in the liver and spleen, while the LDH-ICG with a monolayer of chitosan accumulated in lungs and LDH-ICG with a double layer of chitosan accumulated in lungs and liver. Besides, trimethylammonium modified double chitosan-coated LDH-ICG showed high accumulation in the liver indicating that the charge on the surface drives the targeting. Intercalation and functionalization of LDH with amino acids could be an easy and practical way to regulate the charge since the R groups completing the amino acid head cover a wide range of charges and the particles will retain nanometric size. Silanization is another procedure to regulate the charge whith the advantage that this reaction occurs exclusively in the surface of LDH, thus leaving the interlayer space for intercalation of therapy or diagnosis agents. Similarly, Kuo et al. (2015) demonstrated the passive targeting of LDH nanohybrids by modulating the external surface charge of LDH with various organic groups. They intercalated cyanine-5.5 (Cy5.5), a NIR-fluorescent dye, into LDH nanoparticles and evaluated the biodistribution in vivo. The results showed high accumulation of positively charged amine-LDH in the lungs, while negatively charged carboxylateLDH accumulated in the liver. Furthermore, neutral LDH-PEG5000 enhanced blood circulation time, without high accumulation in specific organs. In another case, although LDH were covered with BSA to avoid aggregation by regulating the charge, a specific biodistribution was detected. Shi et al. (2015) reported, for the first time, the potential use of LDH for positron emission tomography (PET) imaging. They explored chelator-free labeling LDH with radioisotopes for in vivo PET imaging. Upon surface covering with bovine serum albumin (BSA), 64Cu2+ and 44 3+ Sc cations were successfully adsorbed on the LDH-BSA nanoparticles with excellent efficiency and stability. PET imaging showed rapid and persistent tumor uptake of 64Cu-LDH-BSA in 4 T1 breast cancer through passive targeting. Then, LDH can allow the design of a platform for targeted PET imaging. The cases in this section demonstrated that the second generation of molecular engineering modification (by covering the LDH nanoparticles with chitosan, BSA, for example) enables the surface charge control and promote the targeting of LDH-based nanoparticles with therapeutic agents and diagnosis probes.

In another study, Li et al. (2013a, 2013b) prepared LDH-FITC with a size of 20 and 180 nm. They evaluated the uptake of LDH nanohybrid in the mouse motor neuron (NSC 34) cell line. The results demonstrated that 20 nm sized LDH hybrid display similar uptake in cytoplasm and nucleus, while LDH-FITC with a size of 180 nm was located only in cytoplasm (Li et al., 2013a, 2013b). Hence, the design of LDH nanoparticles with different sizes can provide the selective release of drugs or genes in specific intracellular compartments (Chen et al., 2013a, 2013b; Li et al., 2013a, 2013b). The size modulation is determined by the synthesis conditions which belong to the first generation of molecular engineering procedures and the systematic study to controls the size within the 20–350 nm range can be found elsewhere (Oh et al., 2002; Li et al., 2013a, 2013b; Xu et al., 2006). Although the selective accumulation in organs and organelles of LDH nanoparticles depending on the size has been demonstrated, the design of the size must include conclusive studies proving effectiveness of additional functions in hybrid particles once the drug release profiles, drug load, zeta potential and sedimentation rates, for example, are also affected by the size. Another consideration which has not been reported is the effect of the thickness in the targeting; commonly, the LDH present platelet morphology and the thickness contains the edges of layers, which are prone to present crystal defects thus leading to changes in reactivity. 4.1.2. Particle shape Xu et al. (2008) evaluated the role of LDH particle shape in cellular uptake. They prepared LDH-FITC with two morphologies: hexagonal sheets and rods. They demonstrated that both types of LDH nanoparticles are quickly internalized in mammalian cells via clathrinmediated endocytosis. Furthermore, they suggested that LDH nanoparticles escape the endosome due to the ability to buffer the endosomal pH, allowing the nanorods targeting the nucleus, while hexagonal nanosheets remain in the cytoplasm. Therefore, the control of morphology and size of LDH nanoparticles could promote the target to specific intracellular compartments (Xu et al., 2008; Li et al., 2013a). 4.2. Targeting the tumor microenvironment The tumor microenvironment has unique physiological characteristics, such as acidic pH (Webb et al., 2011), hypoxia (Brown and Wilson, 2004) and positive regulation of specific enzymes (Rica et al., 2012). The nanocarriers can be designed to be inert during the circulation until they reach tumor tissues where they are converted to actively targeted forms (Du et al., 2016; Wang et al., 2017). In this way, the release of the drug could be improved at the target site, enhance cellular internalization and allow more distribution of drug into the tumor. By targeting the tumor microenvironment, the size of the tumor is reduced and prevents pro-cancer behaviors such as angiogenesis (Kydd et al., 2017). In LDH nanoparticles the tumor microenvironment is recognized due to the basicity of the hydroxyl groups covering each of the layered units.

4.2.2. pH-responsive release Tumor tissues have an extracellular pH between 6.5 and 6.8, slightly more acid than in normal tissues due to the Warburg effect. Rapid proliferation and growth of tumor cells cause an insufficient supply of nutrients and oxygen; this promotes cell glycolysis and increases the production of lactic acid (Heiden et al., 2009). The acidic tumor microenvironment is used to activate the release of bioactive molecules and contrast agents and therefore, accumulating this component in the tumor. The main strategies detected to modulate the pH response in LDH are the covering with protonatable functional groups, which respond to a slight pH change, the incorporation of peptides to promote internalization in acidic environments, and the preparation of labile nanocarriers under acidic conditions (Du et al., 2016; Wang et al., 2017). The Bronsted basicity of LDH is a key to trigger acidic conditions of tumors and then release the intercalated therapeutic or imaging agents (Oh et al., 2012; Zhu et al., 2016). For example, Li et al. (2017b) prepared the zinc (II) phthalocyanine octa sulfonate (ZnPcS8) photoactive photosensitizer in a slightly acidic environment. The adsorption ZnPcS8 onto LDH nanoparticles inactivated the fluorescence emission and singlet oxygen generation, which is desired to avoid damage in normal tissues, however, photoactivity was activated by incubation of LDHZnPcS8 in aqueous solution at pH 6.5, i.e., when a tumor

4.2.1. Surface charge Besides particle size and shape, the surface charge of nanocarriers also influences the EPR effect due to changing the systemic circulation times and intratumorally processes. It has been well documented that nanoparticles with a negative surface charge circulate in the blood for a longer time (Morachis et al., 2012). However, nanoparticles with positive charges favor electrostatic interactions with negatively charged cell membranes, improving their internalization and inhibiting the redistribution into the systemic circulation (Pozuelo et al., 2014). Hence, nanocarriers with a net positive charge such as LDH nanoparticles are prone to accumulate in tumor tissues. Wei et al. (2012) described the in vivo biodistribution of an LDH nanohybrid by near-infrared (NIR) imaging. The strategy consisted in the intercalation of indocyanine green (ICG), a NIR fluorescent agent 6

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Table 2 Systems based on LDH nanoparticles designed for active targeting. LDH/Anion

Molecular engineering Therapeutic agent

Photoactive agent

Targeting agent

Low molecular weight heparin (LMWH) Intercalation by coprecipitation

CdTe quantum dots Self-assembly

Anti-XLF antibody Intercalation by anion exchange/ Selfassembly

NiAl/Cl−, NO3−

DOXO Intercalation by anion exchange

or FITC Self-assembly

Folic acid Self-assembly

MgAl/CO32−

Survivin siRNA Self-assembly

–

MgAl/NO3−

DOXO Intercalation by coprecipitation

DOXO, Folic acid Intercalation by coprecipitation

a) Particle size ≈ 100 nm Size control b) Folic acid Silane coupling reaction Folic acid Intercalation by coprecipitation

MgAl/NO3−

–

ICG Intercalation by coprecipitation

Folic acid Intercalation by coprecipitation

MgAlGd/NO3−

DOXO Intercalation by coprecipitation

Gd Substitution FITC Self-assembly

Folic acid Intercalation by coprecipitation

MgAl/NO3−

DOXO Self-assembly

DOXO, Folic acid Self-assembly

Folic acid Self-assembly

MgAl/Cl−

siRNA Self-assembly

–

Mannose-SiO2 Self-assembly

MgAl/Cl−

5-FU Intercalation by anion exchange

–

BSA-Ang2/ BSA-RVG/ BSA coating Self-assembly

MgAl/NO3−

DOXO Self-assembly

–

Bevacizumab antibody Covalent conjugation

MgAl/Cl

−

microenvironment is found. The results of in vivo fluorescence imaging demonstrated that the LDH-ZnPcS8 hybrid was activated in tumor tissues inducing a 95.3% tumor inhibition and exhibited minimal skin phototoxicity. Furthermore, in vitro photothermal activity of LDHZnPcS8 was significantly enhanced compared to free ZnPcS8, decreasing 170-fold the half maximal inhibitory concentration (IC50 value). Therefore, it is possible to develop activatable photodynamic therapy based on LDH hybridized with phthalocyanines with a first-generation

Targeting evidence

Potential application

Reference

Luminal area in rat model of arterial injury: QD-1D2-LMWH-LDH: 0.3 mm2 LMWH: 0.2 mm2 1D2: 0.15 mm2 Cell viability (1 μg /mL): Hela cells, 20% HEK 293 T normal cell, 72% Reduction in tumor volume in in vivo xenograft model: a) LDH-Survivin, 12% b) FA-LDH-Survivin, 66.4% Cytotoxicity, HepG2 cancer cells, IC50 ≈ 60 μg/mL 3 T3 normal cell, IC50 ≈ 170 μg/mL Cell viability (8 μg /mL): KB cancer cells, LDH-ICG: 64.2% LDH-ICG-FA:12.6% Cytotoxicity: KB cancer cells, FITC/DOX/Gd-LDH IC50 = 28.73 μg/mL FITC/FA-DOX/Gd-LDH IC50 = 9.53 μg/mL Cytotoxicity, KB cancer cells, IC50 = 4.90 μg/mL L02 normal cell, IC50 = 13.84 μg/mL Inhibition of cell proliferation: U2OS cancer cells (100 μg CD-siRNA/mL) Man-SiO2@LDH, ≈66% LDH, ≈25% Cytotoxicity (IC50) U87 cancer cells, 5-FU/LHD, 2.86 μg/mL 5-FU/LDH/Ang2: 0.917 μg/mL N2A cancer cell, 5-FU/LHD, 12.35 μg/mL 5-FU/LDH/RVG: 7.25 μg/ mL Cell viability (1 μg DOXO/ mL): SH-SY5Y cancer cells, 43.4% L02 normal cell, ≈60% Reduction in tumor volume in vivo cancer model: SiO2@LDH-Bev-DOX, 66% SiO2@LDH-DOX, 50%

Florescence imaging Drug delivery targeted by antibodies

(Gu et al., 2012)

Intracellular imaging. Tumor-targeted drug delivery mediated by FR

(Li, Li, Wang, Wang, Zameel Cader, Jun, Evans, Duan, and O'Hare, 2013a) (D. H. Park et al., 2016)

Targeted siRNA delivery a) EPR-based clathrinmediated b) FR-mediated endocytosis

Intracellular imaging. Targeted delivery mediated by FR

(Guan et al., 2016)

Photothermal therapy (PTT). Targeted delivery mediated by FR

(C. Li et al., 2016)

Fluorescence imaging and MRI Targeted drug delivery mediated by FR

(Guan, Liang, Li, and Wei, 2017a)

Targeted delivery mediated by FR

(Mei et al., 2017)

Targeted delivery by lectin receptor-mediated endocytosis

(Li et al., 2017a)

Excellent colloidal stability and targeting capability mediated by LPL-receptor/ nAchR

(Zuo et al., 2017)

Drug delivery targeted by antibodies

(Zhu et al., 2017)

molecular engineering procedure. On the other hand, the pH-responsivity can be achieved by modifiying the therapy agent as the case of doxorubicin conjugated to hydrazone to form a complex which can be intercalated in a LDH matrix by an easy ion-exchange process (Liu et al., 2019). Wu et al. (2017) reported preparation of a magnetic core of Fe3O4 coated with LDH nanoparticles intercalated with methotrexate (MTX). This hybrid compound exhibited high cytotoxic activity in cancer cells, 7

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targeting is much lower, and all the detected cases are listed in Table 2. This section will describe the strategies to modify the surface of LDH for active targeting. Recognition of targets at a molecular level is the primary active targeting strategy, based on the identification and binding of ligands to specific receptors overexpressed in the surface of cancer cells. The most studied ligands bonded to LDH for active targeting are small molecules, peptides, antibodies and aptamers (Pozuelo et al., 2014), which are recognized by receptors of folate, transferrin, lectins, epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), vascular cell adhesion molecule (VCAM-1) and integrins, among others, (Kim, 2003; Yao et al., 2016; Choi et al., 2011). Functionalization of nanoparticles with specific ligands leads to better cellular uptake through receptor-mediated endocytosis (RME). Once internalized, the nanohybrid dissociate and release therapeutic agents in the intracellular space (Pozuelo et al., 2014). Also, the speed of the targeted administration of non-permeable drugs or the multidrug resistance is reduced (Choi et al., 2011; Yao et al., 2016; Choi et al., 2018b). As the ligand must be exposed in the surface of the nanohybrid, there are generally added by third generation procedures. The choice of ligand depends on the target and type of nanocarrier as follows:

but low toxicity in normal cells. Through in vitro assays, they demonstrated that the controlled release of MTX occurs by anion exchange and degradation of the nanosystem under acidic conditions. This assembly is designed through first generation molecular engineering methods to control the composition which responds to the acidic environment, while the assembly with Fe3O4 through a second-generation strategy provides the magnetic targeting ability. In addition to the targeting, the pH responsiveness may be also regulated to release therapy agents just after the entrance in the cells as demonstrated with gene material (DNA, nucleosides and oligonucleotides) intercalated in LDH composed by magnesium and aluminum cations, this composition maintains the integrity of the nanohybrid at acidic environments and release the active material below pH 3 (Choy et al., 1999). These result demonstrated how the composition can be tuned and that it is quite possible to design LDH nanoparticles with the ability to disintegrate at lysosome pH, improving the concentration of active compounds after trespassing the cell wall (Choy et al., 2000). 4.2.3. Magnetic targeting Magnetic targeting uses magnetic nanoparticles assisted with an external magnetic field to promote accumulation in tumor tissues. To date, LDH nanohybrids reported with magnetic activation consist mainly of magnetic-core/LDH-shell hierarchical prepared by co-precipitation, assembly layer by layer or in situ growth, which are secondgeneration methods (Nejati et al., 2014; Lv et al., 2015; Li et al., 2013a). Guo-Jing et al. (2011) reported a supramolecular system named DMF, prepared by assembling of dextran, magnetic Fe-LDH nanoparticles and 5-fluorouracil (5-FU). In vivo studies demonstrated the release of the drug in target organs, with reasonable specificity and circulation time. Pharmacokinetic assays showed an increase in the half-life of 5-FU and bioavailability up to 400% compared to the free drug, as well as a decrease in plasma clearance. Therefore, DMF has a potential application as a targeted delivery system for drugs and genes due to its excellent biocompatibility, low cytotoxicity, controlled release and targeting ability (Sun, Gou, and Dong 2013; Guo-Jing et al., 2011). The assembly was also capable of forming liposomes, after reverse evaporation and the particles exhibit greater magnetic sensitivity and better drug controlled release (Huang, Xue, and Gou, 2013). Afterward, Jin et al. (2016) reported an assembly based on magnetic Fe(II)-Fe(III) LDH intercalated with 5-FU and coated with dextran. This assembly was used as a support of CdHgTe quantum dots (QD), and the resulting nanohybrid showed superparamagnetic properties from the LDH particles which synergized the photoluminescence intensity in the 575–780 nm range as demonstrated by cellular images. Further, this nanosystem showed an excellent capacity for intracellular transport and cellular image effect; therefore, it is a multifunctional tool to facilitate diagnosis and therapeutic tracing of cancer. The targeting guided by physical methods seems to be a promising strategy since the stability of magnetic particles is higher than that of complex ligands and also the targeting and therapy function could be present in the same magnetic component, as the case of super paramagnetic iron oxide nanoparticles (SPION) capable to produce hyperthermia when subjected to an external magnetic field.

5.1. Small molecules The use of small particles as active ligands improves pharmacokinetic properties, reduced likelihood of immunogenicity allowing a repeated administration, and reduces the cost. This type of ligands can allow preparation for targeted administration systems for tumors with relatively simple conjugation chemistry and minimal influence on selfassembly. Among most studied molecules are folic acid, anisamide and sugars (Pozuelo et al., 2014). Folic acid (FA) is essential for the synthesis of nucleotide bases and cell survival. This vitamin specifically targets folate receptors which have various isomorphic structures, each with specific tissue distribution (Low and Kularatne, 2009). The α-folate receptor is overexpressed in > 40% of human cancers, and the β-folate receptor is expressed in malignant cells of hematopoietic origin and activated macrophages. Conjugation of folic acid to the surface of nanovehicles must occur through the γ-carboxyl site to retain the binding capacity to the receptor and promote the RME process (Sudimack and Lee, 2000). As FA is the targeting agent, this molecule is attached to LDH simultaneously loaded with therapy or diagnosis agents. In the next two examples, FA was added by a simple co-intercalation route which is a first-generation modification: first, the incorporation of FA in an LDH intercalated with doxorubicin (DOX). The LDH/DOX-FA nanohybrid presented high cytotoxicity in cancer cells, which overexpress the folate receptor, and low toxicity in normal cells (Guan et al., 2016; Mei et al., 2017). Second, Li et al. (2016) developed a specific agent for photothermal therapy (PTT). They co-intercalated indocyanine green (ICG) and folic acid (FA) in LDH. The LDH/ICG-FA nanohybrid showed a functional capacity for targeting, biocompatibility and low cytotoxicity. In vitro assays showed that very low dosage of LDH/ICG-FA markedly increased photothermal conversion efficiency and effectiveness of PTT, due partly to increased cellular uptake promoted by targeting FA. The LDH/ICGFA nanohybrid with integrated fluorescence imaging and photothermal therapy can be useful in cell labeling and PTT. In these examples, FA was intercalated in the LDH, however, for targeting purposes, this compound is desired to be present in the outer surface of the particles to reduce the content of in the entire nanohybrid. In this regard, another proposal involves the addition of FA by a third generation method, where the LHD surfaces are modified with a silane covering that retains FA (Yan et al., 2013; Park et al., 2016). The targeting of FA is demonstrated when KB cell was treated with an LDH intercalated with methotrexate MTX. The LDH-MTX hybrid reduced cell viability by 10–20%, whereas the addition of FA by silanization reduced > 70%

5. Active targeting Active targeting improves the specific recognition of cancer cells by favoring the cellular internalization, thus increasing the therapy and diagnosis efficiency of the nanoparticles (Morachis et al., 2012). The main strategies to confer active targeting to LDH nanoparticles consist in designing a surface with a chemical composition reactive to the tumor microenvironment or in hybridizing the surface with magnetic particles to guide the path to the tumor, or with organic ligands that bind to specific receptors overexpressed in cancer cells (Pozuelo et al., 2014). The amount of reports describing LDH nanohybrids for active 8

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conjugate peptide ligands to the LDH surface with excellent colloidal stability and targeting ability. The research group used angiopep-2 (Ang2) peptide and rabies virus glycoprotein (RVG), which can bind to low-density lipoprotein receptors (LRP) and nicotinic acetylcholine receptors (nAchR) that are express widely in neuroblastoma and glioblastoma, respectively. Each peptide was covalently conjugated to bovine serum albumin (BSA), previously modified. Then, LDH intercalated with 5-FU was coated with peptide-BSA and free BSA, by electrostatic interaction. Once immobilized, peptide-BSA and BSA were cross-linked using glutaraldehyde. The targeting ability of the system was confirmed by the delivery of 5-FU to inhibit the growth of brain tumor cells. In comparison with LDH/5-FU, the peptide-BSA-LDH nanohybrid improved cellular uptake, attributed to targeting of ligand and the internalization through endocytosis mediated by ligand receptor.

compared to the free MTX. Also, Park et al. (2016) confirmed the advantages offered by active targeting strategy compared with passive. They described in vivo and in vitro delivery system for Survivin siRNA(siSurvivin) assembled in passive LDH with a particle size of 100 nm and active LDH conjugated with folic acid (FA). In vitro studies demonstrated that LDH-FA/ siSurvivin promoted greater gene silencing at mRNA and protein levels, compared to 100 nm LDH/siSurvivin, as well as a three-fold suppression of tumor volume in vivo. This antitumor effect was attributed to 1.2-fold higher selective accumulation of siSurvivin in tumor tissue compared to other organs. Therefore, the hybridization with FA can increase the efficiency of therapeutic agents to combat cancers overexpressing the folate receptor (Yan et al., 2013; Park et al., 2016). Regarding the targeting with diagnosis agents, Guan et al. (2017a) reported incorporation of folic acid (FA) and doxorubicin (DOX) in LDH doped with gadolinium (Gd3+) followed by surface adsorption of fluorescein isothiocyanate (FITC). The presence of gadolinium in LDHGd/FA-DOX/FITC promoted good contrast effect in Magnetic Resonance Imaging (MRI), whereas FITC imparted its property of fluorescence imaging. Also, FA allowed efficient and selective delivery of DOX chemotherapeutic agent in cancer cells. These results suggest the potential use of LDH-Gd / FA-DOX / FITC in the bimodal targeted diagnosis and cancer therapy. Another investigation with small ligands corresponds to the use of hyaluronic acid (HA). Dong et al. (2016) availed of high recognition and binding capacity of HA to the CD44 receptor, a transmembrane glycoprotein involved in cell-cell interactions and migration, overexpressed in various types of cancer. They reported the intercalation of 5-FU in LDH and coating with HA-PEG. In contrast with LDH/5-FU, the LDH/5-FU/HA-PEG hybrid showed greater toxicity in cancer cells with overexpression of CD44 receptor and lower cytotoxicity in normal cells. The functionalization of LDH with HA-PEG is a promising strategy for the design of biocompatible administration systems with tumor targeting property. It has also been reported that numerous cancer cells express lectins on its surface that can be activated with sugar molecules since carbohydrate-lectin interaction is precise (Yau et al., 2015). The use of a sugar moiety as a ligand provides a low binding affinity that can be compensated by increasing ligand density or conjugation with multiple ligands to promote multivalent interactions (Lepenies et al., 2013). After a slight chemical modification, sugar fractions such as mannose, lactose, and galactose can be bound to the surface of nanocarrier (Ghazarian et al., 2011). These sugar ligands are scarcely assembled to LDH. The only one report identified is that of Li et al. (2017a, 2017b), they developed a nanohybrid based on LDH for targeted delivery of siRNA to cancer (U2O2) cells, using mannose as a targeting moiety. First, they coated LDH with SiO2 and, subsequently, they conjugated it covalently with mannose. Uptake data in osteosarcoma cells demonstrated mannose-SiO2@LDH can specifically direct delivery of siRNA through endocytosis mediated by lectin receptor and suppress tumor growth 2.5 times more than the particles without mannose. The use of small molecules like sugars and hyaluronic acid could have the advantage over folate or FA to suppress the risk which some researchers have found between the progression of malignant cell associated to the supplementation of FA (Kim, 2004).

5.3. Antibodies Antibodies are glycoproteins with high binding affinity to specific receptors. These biomolecules have an average molecular weight of 150 kDa and hydrodynamic radius of 15 to 20 nm. Fully humanized chimeric antibodies with minimal immunogenicity such as bevacizumab, trastuzumab, cetuximab, and rituximab, or only its active fragments, can allow the design of tumor-targeted nanohybrid materials (Richards et al., 2016; Pozuelo et al., 2014). Gu et al. (2012) described the immobilization of an antibody in LDH nanoparticles to treat atherosclerosis. The methodology to prepare the hybrid consisted of adding free sulfhydryl groups to the anti-XLF antibody (H93.7C.1D2/48, 1D2), which then was crosslinked to low molecular weight heparin (LMWH), an antirestenotic agent. Subsequently, they conjugate LMWH-1D2 to the LDH through an intercalation/adsorption process. The successful preparation of LDH/LMWH-1D2 was confirmed by SDS-PAGE electrophoresis. In vivo evaluation, in a model of arterial injury in rats, demonstrated targeted and controlled drug release at the injured site, minimizing luminal loss and thrombotic occlusion. Recently, Zhu et al. (2017) reported the assembly of SiO2 nanospheres covered by a polycrystalline shell of LDH and then, a third generation modification with an amino silane and EDC allowed to covalently immobilize Bevacizumab, an antibody that recognizes the vascular endothelial growth factor (VEGF) secreted in excess by tumor tissues. The whole hybrid material was then loaded with DOXO. In vitro studies demonstrated the potential use of SiO2@ LDH- Bevacizumab as a targeted delivery system for chemotherapeutic drugs due to the ability to detect VEGF, enhance the antitumor efficacy of DOXO and reduce cardiac and hepatic toxicity of the drug. As observed in this examples, the assembling of antibodies to LDH requires third generation procedures to establish the proper linkage. Although these methodologies successfully retained the active antibody, there is a risk to denature the protein with the reaction conditions and reagents used, then, softer methods to produce an effective LDHAntibody hybrid is needed. Besides, when the LDH were loaded with a chemical therapy/diagnosis agent, the lack of reactivity with the protein must be verified in order to retain the integrity of the antibody. 6. Perspectives

5.2. Peptide The literature has demonstrated sufficient knowledge related to the structure and composition of LDH and the easiness to manipulate them to tune the physicochemical properties and functions. The large number of possible combinations which result from selecting the M(II) and M (III) metal cations, the M(II)/M(III) molar ratio and the variety of inorganic/organic anions in the interlayer space gives the opportunity to contain multiple functions within a single nanoparticle. For example, by controlling the M(II)/M(III) ratio in the layer, the anion capacity is regulated, i.e., the higher the M(III) content, higher the anions

Peptides are amino acid sequences, and molecular size and stability depend on the chain length. A variety of peptides have been described for use as targeting ligands (Garcia-Gallastegui et al., 2012; Roveri et al., 2017). For example, αvβ3 integrin receptors are highly expressed on the surface of osteoclasts, angiogenic endothelial cells, and some solid tumors. Peptide RGD (arginine-glycine-aspartic acid) has been the most studied for tumor targeting nanosystems due to its high specificity (Fu et al., 2018); Zuo et al. (2017) provided an easy strategy to 9

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targeting nanovehicles demands the assembly of more components over the LDH nanoparticles, such as the covering with polymers which limit or modify the drug release profile. In this point, LDH seems to be promising since their surface can be functionalized to add active ligands without the need of a shell-type coverage with a polymer. For example, the surface of a LDH nanoparticle might be partially covered with smaller metal nanoparticles, carbon dots or silanol sites to bind the active ligand, while the remaining surface of the LDH particle would be exposed and ready to release the active ingredient. Another challenge is to find therapeutic agents within the hybrid material, which do not affect the targeting ligand. Chemical therapy agents can degrade, compete or inhibit the active ligands, this could be attenuated if photo- or magneto-thermally activated components are used as they could be activated by external stimuli exclusively when they accumulated over the desired site, in this manner the active ligand would not be affected. In this regard, photo- and magneto-active therapy agents seems are promising to retain the integrity of active ligands, specially antibodies.

concentration, as well as the affinity to the negatively charged cell walls. Also, the magnetism or luminescent properties can be added by selecting Fe (II), Fe (III) and lanthanide cations, which are useful for the magnetic targeting function and magnetothermal therapy. The metal composition also determines the stability against pH, and the hydroxylated surface provides reactivity against the acidic environment of injured tissues, whereas the inclusion of drugs within the interlayer region, provides the therapeutic effect. Additionally, the synthesis conditions (maturing time and temperature, as an example) regulate the size, which is essential for passive recognition. All these functions are tuned by the 1st generation strategy of molecular engineering in single LDH nanoparticle. All these functions do not require traditional multi-assemblies where one component per function is needed. For example, a luminescent-magnetic particle for targeted drug delivery will require a luminescent nanoparticle mixed with a magnetic component, then assembled to a porous polymer coating to load the drug, and then attached to the targeting ligand; this methodology will produce a complex and big-sized system which probably will limit the dosage and transport for in vivo experiments. Although the recognition of targeted tissues is weakly efficient by the solely first-generation modification, the assembly of low-volume ligands like folate ions gives the opportunity to increase recognition without altering the nanometric sized. However, to improve the recognition through active targeting, the assembly of antibodies or ligands is needed, and the size of the particles will increase, but with minimal increment, once the LDH component can provide other several functions. In this regard, the bibliographic analysis indicates that small molecules for active targeting of LDH, except folic acid, are scarcely studied, and the successful cases of hyaluronic acid and mannose motivate and open the opportunity to explore other small ligands. The design of LDH with a targeted ligand for active targeting is not trivial. The natural inorganic LDH surfaces limit the incorporation of active targeting agents, such as genetic material, peptides, and antibodies. However, it can be achieved by post-synthetic chemical modifications with silanes, physisorption or even nanoparticles serving as linkers to the LDH surface, like carbon dots. These strategies of immobilization of ligands in LDH can influence the yield, density and optimal functionality of the ligand, and the study of these factors is still needed. Likewise, there are several receptors available to selective treatment tumor, but a heterogeneous expression of membrane receptors in the diverse populations of cancer cells should be considered. Although these particles give an opportunity to combine treatment strategies, imaging modalities and targeting, the knowledge voids and challenges to face to achieve a useful platform for personalized diagnosis and treatment are: to define colloidal stability of the LDH hybrids once the reduced size could promote aggregation, explore the load capacity of ligands, the efficiency in retaining the activity of ligands and verifying the lifetime of ligands, as well as the drug release profiles of the full hybrid through in vivo assays. The identification of instabilities will guide the way of researchers to find solutions to produce safe theranostic LDH nanohybrids. Another weak point that must be taken into account is to standardize the protocol assays to measure the biochemical markers to determine the targeting efficiency. Especially the colorimetric methods once the LDH are capable of adsorbing organic chromophores and interfering the reads, additionally, several assays also require to separate supernatants and filtration through Millipore membranes limited since the size of the LDH nanohybrids is small enough to pass through the pores. Despite these voids, the multifunctional systems based on LDH promise the development of more efficient anticancer and diagnostic methodologies to resolve problems such as the low solubility of some drugs, non-specific cytotoxicity, deficient pharmacokinetics, and pharmacodynamics, as well as low bioavailability that could lead to acquiring resistance. Furthermore, the increasing number of articles using LDH to design

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