Keywords

1 Introduction

The biomaterials such as polymers, metals, ceramics and composites are used in the biomedical applications for the treatment of various diseases. There are different types of polymers are established in the biomedical field because of its improved biocompatibility and biodegradability. In the biomedical applications, these biomaterials are used in the field of drug delivery, drug targeting, imaging, theranostics. There are several polymer based drug delivery systems which are available commercially and also few are clinically approved for the medicinal use [1,2,3,4,5].

The inorganic biomaterials which are used for the biomedical applications such as minerals, metals, metal oxides, glasses, ceramics and other inorganic components. These type of materials have number of advantages than the organic materials which includes mechanical, thermal, magnetic, optical properties and the porous structures [6]. There are also other class of biomaterials which is called as hybrid biomaterials or functionalised biomaterials which contains a mixture of organic and inorganic materials used for the biomedical applications [7, 8]. The inorganic nanoparticles such as gold, iron oxide nanoparticles, carbon dots, quantum dots etc. is easily dispersible in the water with the organic polymers for the surface modification. This type of hybrid biomaterials are used for the diagnostic and therapeutic purposes. Moreover, this type of hybrid materials leads to prepare a novel therapeutic molecules which can be used for imaging because of the excellent properties of inorganic nanoparticles and the surface modification. For fabricating bone graft materials the hybrid biomaterials were used which contains the inorganic ceramic nanoparticles along with the polymer nanocomposites [9, 10].

These hybrid materials containing the organic polymer and the inorganic materials are used particularly in the manufacturing of pharmaceuticals such as drug delivery carriers, scaffolds for tissue engineering etc., and medical devices such as dental implants, vascular stents etc. The organic/inorganic hybrid biomaterials are classified as nanoparticles and nanocomposites and these materials were prepared by many synthesis methods [11]. The reported methods are complex and difficult to process in an industrial level whereas the current scenario demands simpler, cost effective and also requires reproducibility. In addition, there are also some studies they are in continuous efforts to develop a novel class of hybrid materials by overcoming the drawbacks and limitations of the already existing methods. As it is used for the biomedical applications, it should be used safely by all for the clinical purposes. So, it is very important to use the biocompatible materials and also the in-vivo studies are very important to know the pharmacodynamics and pharmacokinetic behaviour of the molecules. Moreover, the interaction studies should be performed with the biological cells, tissues and proteins to understand the complexity and nature of the biomaterials [12, 13].

The hybrid biomaterials containing organic and inorganic nanomaterials were used for the drug delivery applications with different imaging concepts. This approach can also be useful for the theranostic applications for the treatment of various diseases. Therefore, this approach represents a novel strategy for the cancer immunotherapy with the application of hybrid biomaterials. And also, the very novel artificial intelligence is an emerging technology which can contribute in developing personalised biomaterials with the mixture of polymer and inorganic materials. Thus, multidisciplinary approach by involving experts in various fields from biotechnology, medicine, physics, chemistry, pharmacy professionals are necessary for the clinical development of hybrid nanomaterials [14].

2 Organic/Inorganic Hybrid Nanomaterials

The organic/inorganic hybrid nanomaterials can be divided into two groups based on their interaction between the organic and inorganic moieties. The hybrid materials interacts very strongly by formation of covalent bonds or ionic bonds between the organic and inorganic components. This type of materials comes under type 2 hybrid materials in which they can be used to synthesise new materials from alkoxide, minimises the separation of phases and easier to identify the interface between the organic and inorganic components. The type 1 materials are classified as the hybrid materials which interacts with the organic and inorganic components very weakly by the van der Waals, hydrogen and electrostatic bonds. These type of hybrid materials were divided into hybrid nanoparticles and hybrid nanocomposites. The hybrid nanoparticles consists of organic and inorganic nanoparticles or nanomaterials where the hybrid nanocomposites consists of organic and inorganic components which are larger than or in the micro scale. Based on the bonding strength and the process through which they are formulated, these kind of materials were further divided into two different classes [15, 16].

2.1 Hybrid Nanoparticles

Generally the nanoparticles are in the size range of 1–100 nm which can be of organic or inorganic materials. This category of nanoparticles affords a wide range of opportunities to examine the material properties with respect to the particle size. For the biomedical applications, mostly the metal groups consists of Au, Ag and Cu nanoparticles were used because of their unique optical, catalytic and electrical properties based on their size [17, 18]. This kind of nanoparticles differ completely from the category of nanocomposites or bulk materials which completely depends on their shape, size, distance and the nature. If these nanoparticles has to be used in the bioapplications it is very important that these particles should be completely dispersed in the aqueous phase. They should have very good chemical stability and it also should be devoid of oxidation or sintering (avoidance of degradation process). To make it stable the polymer stabilizers were used in the synthesis of inorganic nanoparticles in which it improves the dispersion in the aqueous phase and thereby improving the chemical stability. Moreover, these hybrid nanoparticles also improves the processability and biocompatibility of the materials by surface modification process. These kind of nanoparticles have the unique characteristics such as it can behave as both inorganic and organic nanomaterials. Therefore, this type of hybrid nanoparticles could be useful in different kinds of biological applications which also includes imaging, photodynamic therapy. Image assisted delivery, drug delivery applications [19,20,21].

2.2 Hybrid Nanocomposites

Generally the nanocomposites are combination of organic and inorganic nanomaterials. This type of nanocomposites consists of homogenous and heterogenous structures of organic and inorganic materials. Each organic and inorganic material domains are in the range of nanometer scale. Because of the synergy between the organic and inorganic nanomaterials they are considered to be the stronger hybrid nanocomposites. The physicochemical properties of the hybrid nanomaterials depend upon their nature and contents of the individual components of the organic and inorganic materials. When compared to the individual organic and inorganic components, the hybrid nanocomposites have very good mechanical and thermal stability. Moreover, the physicochemical properties (magnetic, electrical, redox) of the hybrid nanocomposites were controlled by the inorganic components because of their porous network. These porous nanostructures of the hybrid materials were used as a suitable candidate for the drug delivery applications. In addition, the hybrid nanocomposites as scaffolds can also be used in tissue regeneration and cell therapy. The porous structures of the hybrid nanomaterials are useful for encapsulation of osteoinductive components which stimulate the cells differentiation for the regeneration of tissues. For example, the hydrogels containing organic and inorganic materials that can be used in an extensive range of biomedical applications [22]. The organic and inorganic hybrid nanocomposites are categorised as matrix materials and hydrogels which are explained in detail below.

2.3 Hybrid Nanomaterials

The studies prove that the researches have utilised the both organic and inorganic nanoparticles for the biomedical applications. To achieve the desirable properties, the position, design and arrangement of individual nanoparticles should be controlled to use in the different fields. There are various synthetic methods were used and they are self-assembly, surface modification, physical blending, metal–organic frameworks (MOFs) and in-situ deposition. These methods are utilised to obtain the desired physicochemical properties by modifying the surface properties and thereby controlling its arrangement. The surface incompatibility between the polymer materials and nanoparticles can be overcome by introduction of polymer or small molecules on the surface of the nanoparticles and this process is called as surface modification. This process improves the nanoparticles dispersion in the polymer matrix and also facilitates the modifications in the matrix which is useful for the wide range of applications [23, 24]. There are several methods to control the aligning of nanoparticles with respect to their physicochemical properties. Hence, there are different kinds of hybrid nanoparticles have been formulated to control the arrangements of nanoparticles using metal organic frameworks (MOFs) and self-assembly methods. Likewise there are methods to develop nanocomposites with the polymer matrix for the improvement of mechanical and other physicochemical properties. The nanoparticles should be well dispersed in the polymer matrix with a high stability to get the desired nanocomposites with the well-defined properties [25, 26]. The homogenous hybrid nanocomposites were categorised into two major classes such as physical and chemical. The synthetic methods of preparing hybrid nanocomposites by means of physical means involves solution and melt blending process and chemical process involves the in-situ deposition methods.

2.3.1 Hybrid Nanoparticles

The surface properties of the inorganic nanoparticles such as the colloidal stability and biocompatibility were not suitable for the biomedical applications. Because of their high surface area to volume ratio, the inorganic components are susceptible to the formation of agglomerates and aggregates. Thereby these inorganic nanoparticles undergoes a very rapid clearance by the reticuloendothelial system (RES). So to improve the biocompatibility, circulation time and stability of the inorganic nanoparticles, it is very important to modify the physicochemical properties by coating with organic polymers. And also, this section deals with the methods like surface modification, metal organic frameworks (MOFs) and self-assembly for polymers hybridization and stabilise the inorganic nanoparticles [27, 28].

2.3.1.1 Surface Modification Method

The inorganic nanoparticle surfaces could be improved by two different kinds of methods consists of adsorption (physical) and grafting (chemical) methods (Table 1). The surface modifications by physical methods were attained by the surface adsorption and reaction with the small molecules. And the surface modifications by chemical methods were achieved by the grafting of polymer molecules in which the functional groups acts as a site for chemical bonding (Fig. 1). The most common agent used for the inorganic nanoparticles are the silane coupling agents which has bifunctional groups forms a bridge/bond between the two phases [29]. The silane coupling agent contains R–Si-(OR)3 in which the R = CH3O–, CH3CH2O– acts as an anchor and it reacts with the –OH groups present on the surface of the metal oxides (M) forming a Si–O–M bond. The R forms an alkyl bridge between the functional group and the silicon atom through a condensation reaction. The surface modification by the silane molecules undergoes by the four different types and they are (i) the alkoxyl groups should be hydrolysed in the water for the liberation of alcohols and producing a reactive silane molecule, (ii) self-condensation of silanol groups takes place during hydrolysis, (iii) the reactive silane groups were adsorbed by means hydrogen bond formation in the hydroxy groups of the metal oxide surfaces, (iv) and these molecules liberates water during heating then the remaining silane groups condensed with metal oxide groups through the conversion of hydrogen bonds into covalent bonds. Chen et al. prepared a nanoscintillator which is silica coated for the photodynamic therapy. For the synthesis of nanoscintillator, nanoparticles SrAl2O4:Eu2+ (SAO) were coated with silane precursors such ad tetra ethyl orthosilicate (TEOS) and aminopropyltriethoxysilane (APTES). These nanoscintillator which are coated with silica have a large number of functional amine group results in positively charged surface [30].

Table 1 Synthesis of hybrid nanomaterials by surface modification method
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Fig. 1
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Surface modification of nanoparticles for biomedical applications (reprinted with permission from MDPI nanomaterials [42])

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Chemical method is another approach for the surface modification of nanoparticles. It includes the grafting of polymers to the surface that improves the functional characteristics and modifies the surface morphology of the inorganic nanoparticles [31]. There are two methods for chemical grafting and the first one is that it links the polymers with the surface of the inorganic nanoparticle. This process tends to low grafting density because of the reactivity of the functionalised polymer chains. The second approach is that to increase the grafting density the surface initiated polymerisation process is involved. This process includes radical, cationic, anionic polymerisation methods which involves the distribution of the functionalised grafted polymers from the nanoparticle surface. The monomers which are polymerised from the inorganic nanoparticle surface in the grafting method. They will easily penetrate the aggregated nanoparticles which reacts on the activated surface on the polymer because of its low molecular weight. The density and the thickness of the polymer could be controlled by the rate of polymerisation and the nature of monomer. In a study they have grafted poly (2-(methylsulfonyl) ethyl acrylate) using 12-(2-bromoisobutyramido) dodecanoic acid on the surface of superparamagnetic iron oxide nanoparticles through the polymerisation reaction [32, 33].

2.3.1.2 Self-Assembly

This method involves the controlling of accumulation of inorganic nanoparticles by improving their properties in a controlled way (Table 2). The nanoparticles or other distinct constituents in which they unite together via directly or indirectly through the specific interactions [43, 44]. The block copolymers play an important role in self-assembly of nanoparticles because ABA triblock chemical structures along with the nanoparticles provides well-defined interactions. Through the specific interactions these block copolymers self-assemble into the ordered nanostructures. Those specific interactions occurs by the block copolymers and they are dipole–dipole, covalent, non-covalent, steric hindrance, columbic attraction or repulsion. Balancing the hydrophilic and lipophilic balance (HLB) of the block copolymer has a great influence on the self-assembly of nanoparticles. Moreover, by controlling the HLB of the block copolymer, the morphology of the self-assembled nanoparticles can be maintained. In addition to the block copolymers, the inorganic nanoparticles are also used for the functionalization or as the templates to provide stable self-assembled nanostructures. Mostly, the magnetic nanoparticles were combined with the block copolymers to produce a well-defined nanostructures. In a report, they have used pH sensitive magnetic nanoparticles (PMNs) as a functionalising agent on the block copolymers to obtain a self-assembled iron oxide nanoparticles. PMNs exhibited improved imaging for targeting the cancer cells through the self-assembly of iron oxide nanoparticles. This is because of the selective targeting ability of the PMNs which also showed photodynamic activity which kills and prevent the growth of cancer cells (Fig. 2) [45,46,47].

Table 2 Synthesis of hybrid nanoparticles by self-assembly
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Fig. 2
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Self-assembly nanomaterials for biomedical applications (reprinted with permission from RSC advances [51])

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2.3.1.3 Metal–Organic Frameworks (MOFs)

The MOFs has the ability to protect the active moieties from degradation and also it improves the drug loading efficiency. Because of their even porosity, it has a good pore volume and shell surface to increase the drug loading capacity. And also, the metals are connected by the strong coordination bonds with the multidentate organic ligands which results in the high mechanical and thermal stability [52]. There are various functional materials such as graphene based materials, carbon nanotubes, quantum dots, metal nanoparticles and biomolecules were combined to form the hybrid nanomaterials (Table 3). So, it will be easy for the drug molecules in which it can be loaded in the MOFs which acts as a drug carriers to target the disease region and also it improves the stability. This leads to the commercialisation of few nanodrugs such as Abraxane, Ambisome and Doxil [53, 54]. In addition, MOFs can be attained by the single-component nanostructures with good physicochemical properties, intriguing morphological structures, improved BET (Brunauer–Emmett–Teller) surfaces and high porosity. Moreover, the fabrication methods for the MOFs include solution, diffusion and hydrothermal techniques [55]. The solution method is the most widely used method in which it contains organic ligands, metal elements and other materials in a solvent were stirred at a specified time and temperature. The purification process involves the filtration method in which the solvent is evaporated and whereas the diffusion method involves the long reaction process under mild condition which can be of liquid, gas or gel diffusion. Firstly, the gel diffusion method is a process in which the organic ligands are dispersed in the gel containing metal ion solution which forms a crystals of MOFs. Secondly, in the liquid diffusion process the organic ligands are dissolved in the solvent containing metal ions to form MOF crystals. Thirdly, the gas diffusion involves the process of mixing metal ion with the volatile organic ligand solution to form MOFs. An another method of preparing MOFs is the hydrothermal method in which it can be obtained by involving the organic ligands, metal ions, solvents and the other required materials in the polytetrafluoroethylene liner. These materials are kept in the high temperature reactor for the initiation of reaction process to form MOFs [56,57,58,59]. In a study, they have used an autophagy inhibitor 3-methyladenine (MA) in the MOFs (zeolitic imidazole framework) which has high drug loading capacity and they found that it has a strong anticancer activity. The MOFs have high encapsulating efficiency, particles with uniform size and shape, exceptional biocompatibility and high stability. Furthermore, the MA-ZIF exhibits strong anticancer effect by inhibiting the autophagy in the tumour bearing mice and also delivers the drug in a controlled manner with improved permeability. In addition, because of the improved permeability and retention, the active molecule accumulates in the tumour tissue more than normal because of the angiogenesis in the tumour tissue (Fig. 3) [60,61,62].

Table 3 Synthesis of hybrid nanomaterials by MOFs method
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Fig. 3
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Biomedical applications of MOFs (reprinted with permission from Wiley Interdisciplinary Reviews: Nanomedicine and Nanobiotechnology [69])

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2.4 Hybrid Nanocomposites

The hybrid nanocomposites are intended to increase the optical, magnetic, electrical, rheological and mechanical properties. In this type of nanocomposites, the inorganic nanoparticles such as metal and metal oxides were incorporated in the polymer matrices. The only disadvantage in this type of hybrid nanocomposites is that it undergoes agglomeration if there is any inadequate distribution of nanoparticles in the polymer matrices. And also, this may leads to affect the physico chemical properties of the nanocomposites. Therefore, to increase the dispersion behaviour, the surface modification process is followed to create a strong repulsion between the nanoparticles on the polymer matrices. There are different methods were developed to get a well-defined characteristics to obtain an improved physico chemical properties [29].

2.4.1 Physical Blending

The conventional method for the preparation of hybrid nanocomposites is physical blending and this consists of solution and melt blending. Solution blending involves the direct mixing of polymer and inorganic nanoparticles in the solvent [29]. Then the hybrid nanocomposites is obtained by precipitation, filtration and removal of solvents. The main disadvantage of the solution blending method is that identifying a suitable solvent, its removal and the toxicity of the solvents. In a study, they have prepared polystyrene-zinc oxide nanocomposites by solution blending method and then they were casted as film. Firstly, the ZnO nanoparticles dissolved in the dimethylacetamide and polystyrene with vigorous stirring. After mixing, the obtained polystyrene-zinc oxide mixture were casted into films at 90 °C to get the nanocomposite film. This technique evenly distribute the ZnO nanoparticles in the polymer matrix and it also has improved stability [70].

2.4.2 Melt Blending

This technique is a very simple, cost-effective method which effectively removes the toxic solvents. In this method, the inorganic nanoparticles are dispersed in the polymer which is melted by the extrusion technology [71]. Because of the high viscosity of the polymers, it’s difficult to regulate the dispersion of inorganic nanoparticles in the polymer matrix. In a study they have used polypropylene incorporated with nano silica by melt blending method with the addition of maleic anhydride which forms an amino functionalised polypropylene silica nanoparticles (Table 4). The grafting was done by condensation method by the incorporating maleic anhydride functionalised polypropylene and amino functionalised silicon dioxide. Then these blended mixture is dispersed in the polypropylene matrix using Haake Polylab at 140 °C which is refluxed with xylene and completed the blending at 200 °C. The rheological results proved that it increased the melt strength of polypropylene [72].

Table 4 Synthesis of hybrid nanomaterials by physical blending method
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2.4.3 In-Situ Deposition

The in-situ deposition technique is one of the simple and effective method for dispersing the inorganic nanoparticles in the polymer matrix (Table 5). In this method the nanoparticles are uniformly distributed inside the polymer matrices and this method does not involves the usage of solvents [71]. Firstly, the inorganic nanoparticles are mixed with the monomer and this mixture is incorporated into the polymers through the liquid or the gas phase. The in-situ deposition method are prepared by the methods such as stirring, ultrasonication and UV curing (photo initiation) which contains the blend of inorganic nanoparticles with the monomers. In addition, the hybrid nanocomposites or the polymer which cannot be processed under the melt mixing or the solution method can be fabricated by the in-situ deposition method [29]. In a study by Cheng et al., the preparation method involves the mixing of crosslinked dimethacrylate and silver nanoparticles through the photo initiated free radical polymerisation. The silver 2 ethyl hexanoate is mixed with the resin mixture BisGMA-TEGDMA (bisphenol A glycerolate methacrylate-triethylene glycol dimethacrylate) and this mixture undergoes photo polymerisation reaction using visible light. The X-ray photoelectron spectroscopy (XPS) and the morphological analysis proved that the silver nanoparticles are dispersed on the surface of the polymer matrix [77].

Table 5 Synthesis of hybrid nanomaterials by in-situ deposition method
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3 Biomedical Applications

3.1 Detection and Treatment of Cancer

Hybrid nanoparticles contain two or more different materials in the nanometer dimension, which will have the advantages of both individual nanoparticles (Table 6). In the medical field it is believed that this material will have superior properties of individual nanoparticles and is very useful in cancer detection and treatment [82, 83]. Many nanoparticles are manufactured which have the ability to circulate in the blood stream and detect cancer causing tumors [83]. Nanoparticles are used as a drug delivery agent as it can carry comparatively higher drug loads and deliver at targeted tumor sites [84]. Liposomes based on lipid bi layer have high load carrying capability combined with minimum toxicity [85]. Similarly the inorganic mesoporous silica nanoparticles were used and were proven to have targeted drug delivery properties [86]. Nanoparticles can also be engineered to produce thermal energy from optical or radio frequency sources and can be used in photothermal therapy to destroy malignant tumors (Fig. 4) [87]. The nanoparticles produce outstanding results in the treatment of cancer, but the single functionality limits their use; as a result a synergistic multi component system is required to detect, monitor and treat malignancies that arises [88, 89]. This is where the hybrid systems come into play where multiple nanostructures and components are integrated into a single component to form a therapeutic and diagnostic system commonly referred to as theranostic device [90,91,92,93].

Table 6 Hybrid nanostructure based systems for theranostic applications
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Fig. 4
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Polymer-Lipid hybrid nanocarrier system showing the monolithic polymer matrix and the core shell type (redrawn from [143])

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The functional nanostructures which are used as a contrast agent, fluorescence imaging etc. are incorporated onto the surface to the another inner compartment of another structural nanocomponents[94]. These structural nanocomponents could be a polymer, liposome, micelle etc. that serve as a drug carrier or components like gold nanoparticles that can be used in photothermal therapy [95, 96]. These hybrid nanostructures when administered intravenously should circulate in the blood stream for more than two hours and have the ability to be readily filtered out by the liver and kidneys [97]. The theranostic agents provide both diagnosis and treatment with the same material. A hybrid nanoparticle composite of doxorubicin and calcium carbonate hybrid nanoparticles were used for chemotherapy and cancer related imaging applications [98]. The enhanced permeability and retention effect causes the nanomaterial to selectively attach to the tumor tissues [99]. In the in-vivo studies the hybrid nanomaterial composites showed excellent anticancer properties. Antigens were encapsulated inside nanoparticles and delivered to improve the B and T cell responses. These materials can directly act on antigen presenting cells thereby triggering the activation of antigen specific T cells [100].

A uniform core shell spherical nanoparticles made of bovine serum albumin and polymethylmethacrylate core was made. This protein hydrophobic polymer conjugate functions as a drug delivery agent and possess additional features owing to their amphiphilic molecular structures and island growth. In the in-vivo studies camptothecin encapsulated BSA/PMMA nanohybrid material showed enhanced anti tumor activity [101]. Kang et al. prepared gold nanoparticle based vaccines where conjugated with a recombinant ovalbumin for the analysis of CD8+ T cell response and delivery into lymph nodes [102]. The in-vivo mice study showed remarkable tumor inhibition properties and a higher interferon gamma production. The study also showed the importance of nanoparticle size in the therapeutical applications. In another study, Zhang et al. constructed a novel mannose targeting LPNP vaccine system based on a biodegradable polymer PCL-PEG-PCL and cationic lipid DOTAP for the delivery of an antigen and a toll like receptor (TLR 7/8). The vaccine had a hydrophobic inner core of PCL-PEG-PCL with imiquimod, a lipid layer, a cationic DOTAP lipid and a mannose targeting moiety. The vaccine delivery with Monophosphoryl lipid A (MPLA) and imiquimod (IMQ) with a hybrid nanoparticle system showed promising antigen delivery [103].

Yong Min Huh et al. developed adenovirus based hybridised magnetic nanoparticle system based on manganese doped iron oxide that had the capabilities of targeted infection and magnetic resonance imaging. The adenovirus was selected as it showed specificity to the cells with overexpression of coxsackievirus receptor and outstanding gene delivery capability [104]. Polydopamine coated nano star shaped gold nanoparticles showed improved photothermal efficiency. When doxorubicin were administered along with polydopamine coated gold nanoparticle the material showed remarkable antitumor immune response. The in-vivo studies also showed a long term anti tumor immunity response [105]. In another study by Wu et al. gold nanoflowers with Chlorin e6 and a polydopamine coating was used in the photothermal therapy applications. The material showed lower cytotoxicity and phototoxicity and had a combined effect for killing cancer cells [106]. A poly (ethylene glycol)/ poly (ethylene imine) co grafted iron nanoparticles were prepared and shown to have improved tumor resistance. This magnetic hyperthermia based material produced tumor associated antigens and elicited anti tumor immune response [107].

Photosensitizers used in the non-invasive photodynamic therapy has low selectivity for tumors and also aggregates under physiological conditions [108]. Lanthanide ion doped upconversion nanoparticles acts as a transducer by up converting absorbed near infra-red light to the high energy visible light. A highly efficient NIR-triggered PDT system based on LiYF4: Yb/Er upconversion nanoparticles were coupled with a photosensitizer of a β-carboxyphthalocyanine zinc (ZnPc-COOH) molecule by a direct electrostatic interaction, which produced singlet oxygen (1O2). This helps in the deep tissue penetration of visible light to treat deep tumors. The infra-red photons absorbed by lanthanide ions in a host lattice produces high energy photon [109]. Nano scintillated ionizing radiation was used which overcame the issue of low skin penetration depth in the photodynamic therapy [110]. The ionizing X-rays showed tissue penetration which was multiple times deeper than infrared radiations. The interaction of high energy X ray photons with nano scintillator occurs through a cascading of photo electric effect and Compton scattering that generates many electron hole pairs [111]. This trapping of electron and hole creates luminescence and leads to the production of 1O2 which is cytotoxic in nature [112]. The microenvironment of the tumor plays a big role in the efficacy of the photodynamic therapy as a low oxygen microenvironment increase tumor metasis and promote resistance to chemotherapy [113, 114].

Perfluorocarbon based oxygen nanoparticles were delivered to improve the hypoxic tumor microenvironment even though the efficiency is quite less as the oxygen quantity is less [115]. Human serum albumin, chlorin e6, and manganese di oxide nanoparticles (HSA-MnO2-Ce6) were prepared to overcome tumor related hypoxia and treat bladder cancer by a photodynamic therapy. Manganese dioxide nanoparticles reacted with hydrogen peroxide improved the PDT efficiency by the production of O2. These were performed in an in-vivo mouse experiment and showed good PDT efficiency [116]. Hyperthermia is another factor that causes destruction of cancer cells [117]. The thermal gradient that develops will be maximum at the body surface and reduces as it penetrates the tissues. Indocyanine green (ICG) dye in combination with a nanocarrier is used to improve its photothermal efficiency. These was shown in an in-vivo study when the ICG nanohybrid particles targeted large tumor particles. An Indocyanine green, 1,2 distearoyl-sn-glycero-3-phosphethanolamine-N-[methoxy (polyethylene glycol) coated iron oxide nanoparticles were constructed for dual modal imaging as a theranostic agent. The hybrid material showed excellent photostability and temperature increment upon treatment with NIR laser [118].

A gene editing nanohybrid system prepared by Mout et al. had a CRISPR/Cas9-ribonucleoprotein with cationic arginine gold nanoparticle based system. The system showed an improved cytoplasmic delivery for the gene editing system [119]. A nanohybrid containing PEGylated triangular gold nanoparticles conjugated with a peptide P75 was prepared (TGN-PEG-P75). The system had an affinity towards epidermal growth factor receptor and is overexpressed in non-small cell lung cancer (NSCLC) cells due to the interaction between anti-epidermal growth factor receptor (EGFR) and the peptide. The material behaved as an efficient theranostic device showing visual guidance and inhibition of the NSCLC cells by the photothermal therapy effect [120]. A 3D bioprinting method was adopted to produce nanohybrids of PEGDA, laponite and hydroxyapatite. The material was intended for usage as a bone scaffold [121]. A nanocomposite scaffold made of 3D printed porous calcium phosphate polylactic acid conjugated with human bone morphogenetic protein-2 (rhBMP-2) showed delivery of both rhBMP-2 and calcium ions and promoted differentiation of stem cells [122].

In another study functionalized graphene oxide (GO) nanosheets that has angiogenic genes incorporated into GelMA hydrogel showed good revascularization in the diseased heart [123]. Also, graphene oxide and reduced graphene oxide embedded PEG/PA hydrogel showed good chondrogenesis and adipogenesis [124]. Liu et al. prepared crosslinked functionalized graphene oxide acrylate (Goa) with CNT and poly (ethylene glycol) acrylate with oligo (polyethylene glycol) fumarate hydrogel. The material showed excellent biocompatibility as enhanced proliferation and spreading of PC12 cells were observed on the conducting hydrogels [125]. Gold nanoparticles embedded in GelMA to form hybrid nanostructures and showed improved cell matrix adhesion. The amount of gold nanoparticles decides the proliferation and osteogenic differentiation of the stem cells [126].

A hybrid nanostructure based scaffold made of PLGA/Mg(OH)2 showed good anti-inflammatory properties. In the in-vivo study using a mouse model the hybrid material showed regeneration of renal glomerular tissue and had a very low inflammatory response [127]. Starch modified hyperbranched polyurethane with carbon dot silver nanomaterials based hybrid structures shows improved thermal, mechanical properties along with high biocompatibility and infection resistance [128]. Owing to these features the material can be used as a material for self-expandable stents. A vascular stent made of cobalt-chromium, Sirolimus loaded PLGA with a surface modified coating of Mg(OH)2 nanoparticles showed less inflammatory response by in stent restenosis as part of intimal hyperplasia [129]. Improving the endothelialisation is one of the most sought after way to improve the efficiency of the vascular stent implantation [130]. A collagen/gold nanocomposite material showed excellent biomechanical and thermal properties [131]. The in-vivo studies in a rat model showed excellent vascular regeneration, higher antifibrotic ability and anti-inflammatory responses. A polyhedral oligomeric silsesquioxane poly (carbonate-urea) urethane nanocomposite was attached with anti CD34 antibodies to improve endothelialisation by capturing the endothelial progenitor cells. Thus this material can be used as an ideal coating for catheter stents due to its superior biocompatibility and biophysical properties [132].

Naturally occurring viral nanoparticles like cowpea mosaic virus and bacteriophage Qβ particles were linked with C60 fullerenes to improve their solubility. The bio conjugation was realised by a click chemistry involving poly (ethylene glycol) modified propargyl-O-PEG C60 units. This material had the potential to be used in photo activated tumor therapy applications [133]. A nanohybrid system comprising of a hydrophobic PLGA core loaded with fluorescent quantum dots and with a positive charged glycol chitosan shell. The loaded DNA was released as the pH of the system changes. An in-vivo study using a mouse model confirmed the transfection of DNA into the Langerhans cells present on the skin surface [134]. A treatment device for Rheumatoid arthritis was developed by making a methotrexate drug loaded PLGA with RGD conjugated gold half shell nanoparticles. The developed nanohybrid was injected into an arthritic mouse and the nanoparticles selectively adhered at the inflammation sites. The drug was delivered by a photothermal method after being exposed by near infrared radiation (NIR). The nanohybrid material showed excellent therapeutic efficiency even when smaller dosage of drug is used [135]. A ferromagnetic iron oxide nanoparticle prepared using saline crystal hydrate were encapsulated in a steric stable PEGylated liposome. The intracellular delivery of the targeted ferri liposome in an in-vivo mice mammary tumor cell was observed with a significant reduction in tumor growth [136]. A dumbbell like gold-iron oxide hybrid nanoparticles were prepared and coupled with Herceptin and platin complex. These material could be used as potential nanocarriers for theranostic applications [137].

In a study by Zhu et al. a bifunctional iron oxide silver 125I heterodimers were prepared to be used as imaging modules. The Fe3O4/Ag/125I heterostructured radionuclide nanoparticles showed high radiolabeling combined with a low cell toxicity, where 125I served as the contrast agent. The SPECT images of mice in-vivo study showed the nanoparticles were taken readily by liver and spleen [138]. An Ag–Fe3O4 heterodimer nanocomposite heterodimer system was prepared where nanocrystal sizes could be varied by the synthesis conditions. This material has the advantage for simultaneous two photon fluorescence imaging and magnetic manipulation [139]. A multimodal contrast agent’s i.e. thiol modified gold nanocages and iron oxide nanoparticles were prepared for simultaneous T1–T2 contrast imaging. The prepared hybrid nanoparticles showed excellent biocompatibility with very less aggregation and has good contrast properties [140].

Li etc. prepared gold coated iron oxide nanoroses which can be used in optical imaging, magnetic resonance imaging, photothermal therapy, chemotherapy and aptamer based targeting. The anticancer drug doxorubicin is integrated with nanoroses and is released due to a rise in temperature when near infrared light is absorbed by the gold shell. The aptamers present on the surface provides efficient and selective drug delivery and imaging with high specificity [141]. A theranostic device made of Polystyrene which was embedded with superparamagnetic iron oxide nanoparticles and the drug paclitaxel was loaded in a poly (lactic-co-glycolic acid). The targeting was by conjugating nanocarriers with anti-prostrate specific membrane antigen. The detection studies and the nanocarrier binding activity was carried out in the LNCaP prostrate cancer cells. This material has the advantage of dual modality within the same nanosystem for cancer diagnosis and chemotherapy [142].

4 Conclusions and Clinical Prospects

The hybrid nanoparticle based systems have made significant development in the field of biomedical applications especially cancer therapy. These hybrid nanoparticles show significant function in in-vitro based studies, but once testing is done inside the body environment the behaviour of these materials change. Inside the dynamic body environment the nanoparticles interact with many cells, tissues, proteins and majority of them are cleared out from the body before reaching the targeted site. It requires careful engineering of the chemical and surface properties to improve the efficiency and residence time of these materials. The hybrid nanomaterials will have a combined size larger than individual nanomaterials and are designed in such a way so that they can accumulate preferentially at the tumor sites due to the enhanced permeation and retention (EPR) effect. The biggest challenge is that all the components of the hybrid system should work in tandem and coherently to achieve the desired biomedical function. All the materials individually and together should not elicit any adverse reactions and cause an immunological response. Thus it is imperative to have reliable and biocompatible material and the design and its in-vivo behaviour should be given considerable weightage.