Biomaterial-assisted tumor therapy: A brief review of hydroxyapatite nanoparticles and its composites used in bone tumors therapy

Abstract

Malignant bone tumors can inflict significant damage to affected bones, leaving patients to contend with issues like residual tumor cells, bone defects, and bacterial infections post-surgery. However, hydroxyapatite nanoparticles (nHAp), the principal inorganic constituent of natural bone, possess numerous advantages such as high biocompatibility, bone conduction ability, and a large surface area. Moreover, nHAp's nanoscale particle size enables it to impede the growth of various tumor cells via diverse pathways. This article presents a comprehensive review of relevant literature spanning the past 2 decades concerning nHAp and bone tumors. The primary goal is to explore the mechanisms responsible for nHAp's ability to hinder tumor initiation and progression, as well as to investigate the potential of integrating other drugs and components for bone tumor diagnosis and treatment. Lastly, the article discusses future prospects for the development of hydroxyapatite materials as a promising modality for tumor therapy.

Keywords: MFH; PTT; bone tumor therapy; drug delivery; hydroxyapatite nanoparticles; tumor cell apoptosis.

Graphical abstract

FIGURE 1

Cytotoxicity of nHAp on tumor cells. (A) Treatment with nHAp caused changes in the morphology of human glioma SHG44 cells and U251 cells. (B) Tumor cells engulf nHAp through various endocytic mechanisms. (C) nHAp is degraded in the acidic microenvironment of lysosomes, and H⁺ diffuses into the cytoplasm through proton pumps. To maintain charge neutrality, Cl⁻ and H₂O enter the lysosome, causing lysosome swelling and rupture, releasing large amounts of Ca²⁺, PO₄ ^3-, and OH⁻, reaching toxic concentrations, inducing cell apoptosis. (D) Illustration of the possible molecular mechanism of the inhibitory effect of nHAp on 4T1 cells. (A) Reproduced with permission (Chu et al., 2012). Copyright 2012, Int J Nanomedicine. (B), (C) Reproduced with permission (Khalifehzadeh and Arami, 2020). Copyright 2020, Advances in Colloid and Interface Science. (D) Reproduced with permission (Zhao et al., 2018). Copyright 2017, ACS Nano.

FIGURE 2

(A) Schematic diagram of the preparation process of HA-BSA-PTX nanoparticles and the experimental design of the in vivo osteosarcoma model. (B) In vitro drug release evaluation of HA-BSA-PTX nanoparticles in PBS solution at pH 7.4 and 6.5 with Tween 80 (0.1%, v/w). (C) MTT assay was used to evaluate the in vitro toxicity of HA-BSA nanoparticles, free PTX, and HA-BSA-PTX nanoparticles on hFob1.19 cells and 143B cells. With increasing dosage, HA-BSA-PTX nanoparticles showed the best toxicity to 143B cells and lower toxicity to hFob1.19 cells than PTX alone. (D) Weight of osteosarcoma tissue treated with control (PBS), HA-BSA nanoparticles, PTX alone, and HA-BSA-PTX nanoparticles, and survival time of nude mice. (E) mRNA expression levels of ALP and OCN after osteogenic induction for 14 days with co-culture of BMSCs cells and each group at a concentration of 10 μg/mL. Reproduced with permission (Liu et al., 2021). Copyright 2020, Advanced Healthcare Materials.

FIGURE 3

(A) Apoptosis and gene expression after co-culturing GCTBs with CS/nHAp/Zol. (Ai) Analysis of apoptosis and necrosis in GCTBs cells co-cultured with CS/nHAp for 2 days using flow cytometry. Percentage of necrotic and apoptotic cells in GCTBs. CS/nHAp/Zol upregulated the apoptotic rate of the cells. (Aii) Relative expression of apoptotic and osteoclast-related genes in GCTBs after co-culturing with CS/nHAp/Zol for 2 days. (B) Biocompatibility and osteogenic differentiation-promoting ability of CS/nHAp/Zol. (Bi) Cell proliferation activity of hBMSCs co-cultured with the scaffold for 1, 4, and 7 days as detected by CCK-8, and the effect of co-culturing with the scaffold for 4 and 7 days on hBMSCs ALP activity. (Bii) Hemolysis test of the scaffold materials, and both groups of scaffolds did not cause hemolysis. (C) Antibacterial ability of CS/nHAp/Zol. From top to bottom are the bacterial counts and antibacterial rates of two types of scaffolds co-cultured with standard Staphylococcus aureus, clinical Staphylococcus aureus, and clinical Escherichia coli for 24 h. Reproduced with permission (Lu et al., 2018b). Copyright 2018, Materials Science and Engineering: (C).

FIGURE 4

(A) Schematic diagram of the preparation and biological application of nHAp/GO particles and nHAp/GO/CS scaffolds. (B) Photothermal performance of nHAp/GO/CS scaffold on osteosarcoma after irradiation with near-infrared (NIR) at 808 nm (0.6 W/cm²) for 150 s. In vivo infrared thermal image (Bi) and temperature rise curve (Bii) of HOS tumor tissue. (C) Magnetic heating performance of PLGA/MF-nHAP under a frequency of 500 kHz and a magnetic field intensity of 3 mT. The material temperature increased with increasing reaction time. (D) Cell survival rate of MG-63 cells co-cultured with nanoparticles and exposed to a magnetic field for 30 min, measured by CCK-8 assay. The experimental group had PLGA/MF-nHAP and an external magnetic field applied, the Black group had no nanoparticles, and the Control group had PLGA/MF-nHAP but no external magnetic field applied. About 78% of MG-63 cells in the experimental group were non-viable after magnetic heating treatment. (E) Mechanism of MHAp scaffold material in promoting the proliferation of MC3T3-E1 cells. (A), (Bi) and (Bii) Reproduced with permission (Ma et al., 2020). Copyright 2020, Materials Today. (C), (D) Reproduced with permission (Li et al., 2019). Copyright 2019, Regenerative Biomaterials. (E) Reproduced with permission (Zhu et al., 2017a). Copyright 2017, ACS Nano.

FIGURE 5

Incorporating selenium element into nHAp material to achieve anti-tumor effects. (A) Synthesis method and schematic diagram of anti-osteosarcoma effect of B-SeHANs. (B) The uptake results of B-SeHANs, R-SeHANs, and N-SeHANs by MNNG/HOS cells. After co-cultured for 12 h, the LCSM images of the three SeHANs internalized by MNNG/HOS cells (Bi), and the SeHAN uptake by MNNG/HOS cells was quantified by FCM and plotted as a curve (Bii). Compared with non-biomimetic SeHANs, B-SeHANs accumulated more in cells. (C) Compared with R-SeHANs and N-SeHANs, the release kinetics of selenium ions from B-SeHANs showed better acidic reaction characteristics. Reproduced with permission (Li et al., 2020). Copyright 2018, J Biomed Nanotechnol.

FIGURE 6

(A) Schematic diagram of stimulus-responsive HAp-GS material fabrication and its biological applications. (B) Schematic diagram of the experimental protocol for PLGA/HAp/HACC antimicrobial materials. (A) Reproduced with permission (Jin et al., 2019). Copyright 2019, Advanced Functional Materials. (B) Reproduced with permission. Copyright 2018, Acta Biomater.