Different types of HAP nanoparticles have been used for the delivery of several drug molecules, composites, coatings, and paramagnetic particles. Abbasi Aval et al. developed superparamagnetic HAP-coated Fe
2O
3 nanoparticles, aiming to prevent the agglomeration and oxidation of superparamagnetic particles with the coating
[67][34]. The authors synthesized mesoporous HAP with 12 nm sized pores and a surface area of 148 m
2g
−1 to adsorb a large amount of doxorubicin, a small hydrophobic drug, on the surface of Fe
2O
3 nanoparticles. The nature of the pores was determined by nitrogen sorption isotherms, where, due to a relatively sharp slope of the adsorption–desorption diagram, the presence of cylindrical pores with open ends was confirmed. Under neutral conditions, the positive nature of the HAP surface is caused by the specific adsorption of excess calcium ions and their solubility
[92][28]. The amount of doxorubicin adsorbed on the surface was almost 93%; however, the authors do not mention in which solution or conditions, and the release profiles were studied at pHs 5.5 and 7.4. Within 24 h, in pH 7.4, only 10% of the loaded doxorubicin was released, whereas in the pH 5.5 environment, about 70% of the drug was released, this means that HAP and doxorubicin had a higher affinity when HAP carried positive charges rather than negative
[98][35]. This conjugation with doxorubicin was also seen in another study by Yang et al., with a different morphological approach
[8][36]. The authors synthesized hollow mesoporous HAP nanoparticles with a surface area of 163.2 m
2g
−1 and a pore size of 3.3 nm. The samples were placed in phosphate buffer at pH 7.4, and the vehicles showed a fast release for the first 30 min and slow release from 0.5 to 50 h, which corresponds to a pseudo-first-order release profile. They also mentioned that due to this behavior, it could be assumed there was no interaction between the HAP matrix and the doxorubicin molecules, and the release was significantly higher on mesoporous hollow nanoparticles than normal nanoparticles and higher at pH 4.5 than pH 7.4. However, in a study by Storm et al., doxorubicin was encapsulated in higher amounts on negatively charged liposomes than on neutral ones
[99][37]. The main mechanism of adsorption of doxorubicin, in this case, may not be caused by electrostatic interactions but rather hydrogen bond interactions between the OH
− group of doxorubicin and the OH
− group of HAP. This is reasonable because, in a study by Yulia et al., by combining quantum chemistry calculations and spectroscopic techniques, an ibuprofen/nanoHAP complex was studied
[54][38]. The authors reported that the main interactions of the system were the hydrogen bonds between both OH
− groups of HAP and ibuprofen and a strong interaction between ibuprofen’s carbonyl group and the Ca
2+ center of HAP
[54][38]. Moreover, even though it has been proved that electrostatic interactions play a major role in adsorption onto HAP surfaces, it does not fully account for the adsorption of biomolecules. For example, the adsorption of human serum albumin occurs under conditions where the adsorbent and the adsorbate are negatively charged. This process was dominated by entropy, structural rearrangements, changes of hydration, and co-adsorption of electrolytes. Moreover, studies suggest that the secondary structure of the biomolecules and desorption of water also play critical roles
[100,101][39][40].
In a study by Barroug and Glimcher, the anti-tumor drug cisplatin was adsorbed by HAP crystals of 93 × 29 nm
[102][41]. The authors mentioned the effect of the solution’s composition and ionic strength, in which an increase in the ionic strength of the solution significantly reduced the affinity between the HAP surface and the cisplatin molecules. This dependence of adsorption on the solution composition is driven by electrostatic interactions, as the surface is covered by adsorbate, and charge neutralization and adsorbate–absorbate repulsion occur as well. In these experiments, the HAP samples synthesized at a pH close to 10 had isoelectric points at around 7.0, and the highest uptakes were observed after equilibrium with phosphate buffers rather than Tris buffers due to the presence of phosphate ions, which can also be explained by the hydrolyses of cisplatin in aqueous solutions
[102][41]. The authors also reported that under the conditions of the experiments (pH 7.4, phosphate 10 mM), the HAP crystals and the cisplatin were oppositely charged, which resulted in an electrostatic attraction between both surfaces. With this being said, the medium in which the adsorption between HAP and the drug occurs plays a major role in its performance and release, as the hydrated derivatives and the presence of different ions can cause displacements in the native forms of the drugs.
As the structure of HAP contains negatively charged OH
− groups, these can interact with positive groups such as amine groups, sodium, and hydrogen ions. These interactions were employed in a drug delivery system using HAP and sodium ampicillin. In a study by Queiroz et al., they made a comparison between HAP and HAP composites that contained other crystalline phases such as TCP. The authors explained that pure HAP adsorbed more ampicillin than the composites with 16 and 57 wt% TCP because of a greater amount of OH
− groups in HAP, which are bridging agents to ampicillin. The higher solubility of TCP also played a major role in decreasing the ampicillin adsorbed, causing ampicillin resorption during the loading process, making it harder for ampicillin to adsorb on the composite surfaces compared to the HAP sample, which was relatively insoluble
[103][42].
4. Genetic Material
HAP can be used as a vector for gene delivery due to their strong affinity and the ionic interactions between calcium ions and the gene backbone
[104][43]. This allows the use of HAP delivery systems for the attachment of regulatory sequences and movement across the cell membrane. One of the main disadvantages of using HAP as a delivery system is that the sintering process can cause the agglomeration of particles, which in the case of gene delivery decreases its transfection efficacy. In a study by Han et al., well-dispersed HAP nanoparticles were obtained by a simple ultrasound-assisted precipitation method with the assistance of glycosaminoglycans
[77][44]. The nanocrystalline nature of the particles was confirmed by the broadening and merge of the three major peaks (211), (112), and (300) at around 2θ = 30, which are characteristic of HAP. They were also able to confirm the presence of carbonate ions due to the peaks at 603 and 567 cm
−1, which are phosphate bands appearing in different sites
[77][44]. The size for the rod-like particles was about 20 × 50 nm and had a zeta potential of −60.9 mV, which improved stability, as mentioned in previous sections. The authors also mentioned that the acoustic cavitation caused by the ultrasound processing dispersed the HAP nanoparticles. The addition of glycosaminoglycans improved the electrostatic interaction between their negatively charged groups and the calcium ions of HAP, resulting in the overall negative charge of HAP nanoparticles. A novel strategy for gene therapy involves the use of biominerals through the nucleation of HAP on a DNA template. The rationale behind this stems from the relation between DNA and HAP in other biological systems and a strong interaction between both materials. As a specific binding activity of HAP exists for DNA, these kinds of complexes are less susceptible to degradation by serum and nucleases
[105][45]. In a study by Bertran et al., DNA was encapsulated into HAP nanoparticles through the fabrication of nanocapsules and crystalline nanorods with DNA inside. The experiments suggested that HAP grew around the DNA matrix
[105][45].
Table 4. Drug delivery applications for HAP and its respective cargos.
|
Cargo |
Heat Treatment |
Size |
Potential |
SSA |
Porosity |
Pore Volume |
Morphology |
Amount Adsorbed |
Application |
Reference |
|
|
(°C) |
(nm) |
(mV ) |
(m | 2 | g | −1 | ) |
(%) |
(cm | 3 | g | −1 | ) |
(-) |
(mg) |
|
|
|
Fibrinogen |
|
|
|
- |
2.53 |
2.39 |
- |
Spheres |
2.93 mg/m | 2 |
|
|
|
Insulin |
80 overnight |
60 |
|
|
|
|
|
2.24 mg/m | 2 |
Diabetes |
[74] | [4] |
|
Col-I |
|
|
|
|
|
|
|
|
1.12 mg/m | 2 |
|
|
|
BSA |
1250 |
4 h |
1000 |
−37 |
0.9 |
micropores |
- |
Granules |
65.7 µg/mL |
- |
[7] | [9] |
|
BSA |
1000 |
15 h |
100 |
0 |
25.4 |
micropores |
- |
Granules |
78.3 µg/mL |
|
|
BSA |
600 |
3 h |
39 |
−0.55 |
40 |
- |
- |
- |
4.0 mg/m | 2 |
|
|
Proteins |
MG |
600 |
3 h |
39 |
−0.55 |
40 |
- |
- |
- |
1.0 µg/m | 2 |
Blood compatibility |
[85] | [20] |
BSA |
700 |
3 h |
43 |
−0.9 |
20 |
- |
- |
- |
9.8 mg/m | 2 |
|
MG |
700 |
3 h |
43 |
−0.9 |
20 |
- |
- |
- |
1.5 µg/m | 2 |
|
|
|
BSA |
600 |
4 h |
32 |
- |
73 |
- |
- |
|
89 µg/mg |
Delivery |
[19] |
|
BSA |
700 |
4 h |
36 |
- |
66 |
- |
- |
|
85 µg/mg |
|
|
|
Cyt c |
60 |
3 h |
60 × 30 |
−24 |
96 |
|
0.79 |
Rod |
60 µg/mg |
|
|
|
MGB |
|
|
|
|
|
|
|
|
43 µg/mg |
Delivery |
[32] | [17] |
|
BSA |
|
|
|
|
|
|
|
|
78 µg/mg |
|
|
Peptides |
APWHLSSQYSRT |
1350 |
1 h |
- |
- |
0.05 |
- |
- |
Granules |
1 nmol |
|
|
|
STLPIPHEFSRE |
|
|
- |
- |
|
|
|
|
2.4 nmol |
Delivery |
[28] | [15] |
|
VTKHLNQISQSY |
|
|
- |
- |
|
|
|
|
2.5 nmol |
|
|
Drugs |
Doxorubicin |
100 |
24 h |
400 × 600 |
- |
163.2 |
mesopores |
0.53 |
Oval |
3 × 10 | 5 | mol/g |
Breast cancer |
[8] | [36] |
|
Ibuprofen |
1000 |
2 h |
79 |
- |
- |
- |
- |
Plates |
- |
Arthritis |
[54] | [38] |
|
Cisplatin |
80 |
93 × 29 |
- |
96.8 |
- |
- |
Plates |
2.4 mg/g |
Cancer |
[102] | [41] |
|
Ampicilin |
1200 |
1 h |
8–9 ×10 | 3 |
- |
- |
Mesopores |
|
Spheres |
6.5 mg/g |
Bacterial infection |
[103] | [42] |
DNA |
Fish sperm DNA |
80 |
1.5 h |
20 |
- |
- |
- |
- |
Spheres |
11 µg/mg |
Gene therapy |
[105] | [45] |
|
EGFP-N1 pDNA |
170 |
2 h |
40–60 |
- |
- |
- |
- |
Rod |
0.02 µg/ug |
Gene therapy |
[106] | [46] |
|
CDglyTK |
35 |
72 h |
23–34 |
+16.8 |
- |
- |
- |
Feather |
- |
Antitumor |
[107] | [47] |
Sintering Temperature |
- |
- |
60 °C |
600 °C |
950 °C |
1250 °C |
1350 °C |
Sample |
Natural HAP (cm | −1 | ) |
Si-HAP (cm | −1 | ) |
HAP-p (cm | −1 | ) |
HAP (cm | −1 | ) |
HAP (cm | −1 | ) |
HAP (cm | −1 | ) |
HAP (cm | −1 | ) |
|
1540 |
- |
1540 |
1462.48 |
1456 |
- |
1540 |
C-O |
1548 |
- |
- |
- |
- |
- |
- |
|
1418 |
- |
- |
1418.2 |
876 |
- |
- |
C=O |
1653 |
- |
1650 |
1621.94 |
- |
- |
- |
C-N |
1560 |
- |
1560 |
- |
- |
- |
- |
N-H |
1560 |
- |
1560 |
- |
- |
- |
- |
Peptide |
- |
- |
1400 |
- |
- |
- |
- |
P-O |
1087 |
1089 |
1020 |
1100 |
1091 |
1100 |
1087 |
O-H |
3569 |
3570 |
- |
3571 |
3572 |
3575 |
- |
SiO | 44− |
- |
881 |
- |
- |
- |
- |
- |
- |
498 |
- |
- |
- |
- |
- |
Reference |
[30] | [5] |
[31] | [16] |
[32] | [17] |
[6] | [18] |
[30] | [5] |
[7] | [9] |
[28] | [15] |