**5. Albumin-Based Nanoparticles**

Albumin is a natural, water-soluble globular protein and attractive macromolecular carrier which has a biodegradable property. Albumin is non-immunogenic, non-toxic, non-antigenic and biocompatible [88,89]. A large number of drugs can be incorporated into the nanoparticle-matrix because albumin molecules have different binding sites [90]. Albumin structure is shown in Figure 6.

**Figure 6.** Structure of albumin [8]. Note that the oxygen atoms of almost all the carboxyl groups of amino acids are not shown in the structure. Copyright ©2019, Elsevier.

Albumin-based nanoparticles allow electrostatic interaction of cationic and anionic charge; drugs show non-covalent and covalent interaction with albumin nanoparticles. Figure 7 demonstrates the successful use of albumin and albumin nanoparticles for cancer treatment [89]. The presence of primary amino acid groups in albumin, such as lysine, indicates a vital role in cross-linking [91]. Albumin is prepared by controlled desolvation, coacervation, and emulsion formation. Commercially available forms of albumin are ovalbumin (egg white), human serum albumin, albumin extracted from soybeans, albumin present in bovine serum capsules, grains, and milk [92], where egg albumin has a molecular weight of up to 47,000 Da.

Furthermore, ovalbumin is non-toxic, sensitive to temperature or pH, and economical; it gives effective results in food matrix design, stabilization of foams and emulsions, and a is a good candidate for sustainable drug release [93]. A bovine serum capsule has a size of up to 69,323 Da, and due to its non-toxic behaviour, and ligand binding property it is extensively used for drug delivery applications [94]. Human serum albumin has a molecular weight of 66,500 Da and peripheral uptake, non-toxicity and biodegradability properties make it beneficial for pharmaceutical applications [95]. Albumin nanoparticles have several useful properties such as easy incorporation of various drugs and the ability to bind with proteins, due to presence of carboxylic and amino group on nanoparticle surface [96].

**Figure 7.** The successful use of albumin and an albumin nanoparticle (Abraxane) for cancer treatment [89]. Copyright ©2020, Elsevier.

Modification of albumin with PEG has not only improved the blood circulation but also provides a gateway in the pharmaceutical industry for cancer treatment drugs [97]. Albumin nanoparticles show a better affinity for cancer treatment drugs such as doxorubicin, curcumin, Abraxane, and tacrolimus [98]. Kim et al. [98] prepared HSA nanoparticles loaded with curcumin; these nanoparticles show higher solubility. Dreis et al. [99] have developed a system for the preparation of doxorubicin-loaded HSA nanoparticles. Using doxorubicin-loaded HSA nanoparticles, the toxic effect of anticancer drugs was reduced, and the multidrug resistance issue was resolved. Joshi et al. [89] discussed nanocarriers for pulmonary cancer. Surface modification of a nanoparticle helps in the effective movement of nanoparticles across the mucus layer. Surface functionalization of nanoparticles was performed using various methods such as adsorption, conjugation, and surface coating. Here, the surface of albumin modified with a neutral molecule polyethylene glycol enabled the movement through the mucus layer of the respiratory tract [89]. Surface modification based upon the required application is possible due to many reactive groups on the surface of albumin. Iwao et al. [100] presented a strategy for a site-specific drug delivery system for the cure of ulcerative colitis (UC). The authors prepared modified human serum albumin (HSA), and myeloperoxidase (MPO) and prepared nanoparticles (HSA NPs) conjugated with 5-aminosalicylic acid (5-ASA). The specific contact between 5-ASAHSANPs and MPO was examined using quartz crystal microbalance analysis.

Furthermore, Siri et al. [101] presented the effect of an albumin nanoparticle structure with its function as a drug release system. In this study, albumin nanoparticles were irradiated with gamma rays (cross-linker) by using the desolvation method. This method causes albumin nanoparticles to generate new hydrophobic pockets which make it a sound drug delivery system. The hydrophobic drug, Emodin, was used as a sample to check the release behavior. The formation of nanoparticle pockets enhanced the encapsulation property of the system. Stein et al. [102] studied the preparation of stable mTHPC-albumin nanoparticles using nanoparticle albumin-bound (nab)-technology to develop a system for drugs that are not very water-soluble. In this study, the advantages of nanotechnology and albumin with the ability of high tumor enrichment and the selective light initiation of the photosensitizer Temoporfin (mTHPC) were associated with a new delivery system for reliable tumor treatment. The nanoparticles were characterized according to size distribution and particle size, and the effect of this method on the nanoparticles as well as mTHPC stability was studied. Table 2 shows polymer/polymer modified chitosan-, alginate-, and albumin-based nano polymers for drug delivery systems.

**Table 2.** Shows the modified chitosan-, alginate-, and albumin-based nano polymer for drug delivery systems [8].


### **6. Hydroxyapatite-Based Nanoparticles**

Hydroxyapatite (HAp) has great applications in the biomedical field and is considered the best option in the pharmaceutical field due to its excellent bioactivity and biocompatibility. Hydroxyapatite is derived from the mineral compounds of human bones, teeth, and hard tissues. The basic units of HAp are calcium and phosphates (CaP) characterized as M14M26(PO4)6(OH)2, in which M1 and M2 are two crystallographic arrangements. The stability of CaP is directly related to the presence of water molecules during synthesis and the medium where it was applied [103].

Furthermore, HAp shows good mechanical strength, a porous structure, osteointegration, and osteoconductive properties. HAp can be used as an implant material due to its granular particles, porous structures, load-bearing ability and excellent biocompatibility. The combination of HAp with phosphates, such as calcium pyrophosphate and β-tricalcium phosphate (β-TCP), means that this material has a vast number of properties. The use of hydroxyapatite in the implantation, free layer of fibrous tissue composed by carbonated apatite is generated on its surface, which helps in the binding of the implant to the living bone through an osteoconduction mechanism. HAp prevents any toxicity effect during implantation, and its porous structure gives excellent diffusion properties. HAp is used in tissue engineering as a scaffold, in dental enamel repair, in medicine, for cancer cell treatment and as a bone cement [104,105]. A recent study investigated that HAp shows strong bonding due to its porous structure [106]. HAp powder was synthsized using a hydrothermal method with the use of calcium nitrate [Ca(NO3)2.4H2O] for calcium and potassium dihydrogen phosphate [(NH4)2HPO4] and phosphorous, and it was used as a precursor. The use of HAp derivatives is in high demand in the field of orthopedics. This is undoubtedly beneficial for both commercialization and research purposes; it means that the use of composites is studied and experimented with, enhancing the performance of the previous defective bones. Li et al. [107] successfully synthesized a core–shell nanocarrier (PAA–MHAPNs) based on a grafting method. This synthesized system showed excellent results; for example, it had improved loading in terms of the quantity of anticancer drug (doxorubicin hydrochloride), electrostatic properties, and promising for application in pH-sensitive drug release systems. The loading capacity increased up to 79% at low pH. The cytotoxicity analyses designated that the PAA–MHAPNs was biocompatible. Overall, the synthesized systems have great ability as drug nanocarriers for drug delivery, excellent biocompatibility, and pH-responsive features for future intracellular drug delivery. Venkatasubbu et al. [108] presented functionalized hydroxyapatite (HAp) with folic acid (FA) modified polyethylene glycol (PEG) for therapeutic applications. In this study, in vitro analysis of anticancer drug (paclitaxel) loading in modified HAp was performed. The authors studied the initial rapid release of the drug and then the sustained release, and presented a review of three types of hydroxyapatite-based nanoparticles: magnetic HAp, luminescent HAp, and immunomagnetic HAp for bioimaging applications. Various research work on the antimicrobial property of HAp nanoparticles was presented in this study. Additionally, the silver doping particle in HAp increases its antimicrobial property by cross-linking a silver nanoparticle with a thiol group of

bacteria, and HAp shows good compatibility with bone marrow stem cells [109]. Table 3 shows the advantages, disadvantages, biomedical applications and methods of synthesis of hydroxyapatite.

If we observe the bone at the microscopic level, we find the cellular composition of osteocytes and the matrix. A matrix composed of collagen fibers helps to give strength and flexibility to the bone and is associated with HAp microcrystals and mineral salts for hardness. The bone tissue is constantly replaced and remodeled, leading to the name Bone Remodeling. The stimulus from the osteocytes supports to initiate osteoclast and osteoblast for remodeling [110]. Bioactive ceramics act as an HAp layer on the fractured part, help to rise the osteoblast quickly to heal bone. Furthermore, studies proposed a combination of the HA layer with high-density polyethylene (HDPE) as a auxiliary material for bone [111–115]. This has been tested and commercially named HAPEXTM. Previously provided empirical results for osteoblast over a bioactive ceramic layer of HAp particles [112]. Composites from the bioactive ceramics joint with HAp particles and collagen fibres have possibility to act as an artificial substitute for bone [116]. The established graft have excellent mechanical properties [117]. HAp/alumina has been proposed as a bone substitute [118]. One study also concludes that mixing P2O5 glass with HAp achieves close to natural bone properties [119].


**Table 3.** Shows the advantages, disadvantages, biomedical applications, and methods of preparation for hydroxyapatite [120].
