Abalone shell-derived Mg-doped mesoporous hydroxyapatite microsphere drug delivery system loaded with icariin for inducing apoptosis of osteosarcoma cells
Hydroxyapatite (HAP) porous microspheres with very high specific surface area and drug loading capacity, as well as excellent biocompatibility, have been widely used in tumour therapy. Mg2+ is considered to be a key factor in bone regeneration, acting as an active agent to stimulate bone and cartilage formation, and is effective in accelerating cell migration and promoting angiogenesis, which is essential for bone tissue repair, anti-cancer, and anti-infection. In this study, abalone shells from a variety of sources were used as raw materials, and Mg2+-doped abalone shell-derived mesoporous HAP microspheres (Mg-HAP) were prepared by hydrothermal synthesis as Mg2+/icariin smart dual delivery system (ICA-Mg-HAP, IMHA). With increasing of Mg2+ doping, the surface morphology of HAP microspheres varied from collapsed macroporous to mesoporous to smooth and non-porous, which may be due to Mg2+ substitution or coordination in the HAP lattice. At 30% Mg2+ doping, the Mg-HAP microspheres showed a more homogeneous mesoporous morphology with a high specific surface area (186.06 m2/g). The IMHA microspheres showed high drug loading (7.69%) and encapsulation rate (83.29%), sustained Mg2+ release for more than 27 days, sustained and stable release of icariin for 60 hours, and good responsiveness to pH (pH 6.4 > pH 5.6). In addition, the IMHA delivery system stimulated the rapid proliferation of bone marrow mesenchymal stem cells and induced apoptosis in MG63 cells by blocking the G2 phase cycle of osteosarcoma cells and stimulating the high expression of apoptotic genes (Bcl-2, caspase-3, -8, -9). This suggests that the abalone shell-based IMHA may have potential applications in drug delivery and tumour therapy.
Below is the content of the Citations in the paper which has been de-formatted, however, the content stays consistent with the original.
1. Mushtaq, A.; Zhang, H.; Cui, M.; Lin, X.; Huang, S.; Tang, Z.; Hou, Y.; Zubair Iqbal, M.; Kong, X. ROS-responsive chlorin e6 and silk fibroin loaded ultrathin magnetic hydroxyapatite nanorods for T1-magnetic resonance imaging guided photodynamic therapy in vitro. Colloids Surf Physicochem Eng Aspects. 2023, 656, 130513.
2. Ribeiro, J. P.; Domingues, R. M. A.; Babo, P. S.; Nogueira, L. P.; Reseland, J. E.; Reis, R. L.; Gomez-Florit, M.; Gomes, M. E. Highly elastic and bioactive bone biomimetic scaffolds based on platelet lysate and biomineralized cellulose nanocrystals. Carbohydr Polym. 2022, 292, 119638.
3. Wang, G.; Lv, Z.; Wang, T.; Hu, T.; Bian, Y.; Yang, Y.; Liang, R.; Tan, C.; Weng, X. Surface functionalization of hydroxyapatite scaffolds with MgAlEu-LDH nanosheets for high-performance bone regeneration. Adv Sci (Weinh). 2022, 10, e2204234.
4. Cheng, M.; Liu, M.; Chang, L.; Liu, Q.; Wang, C.; Hu, L.; Zhang, Z.; Ding, W.; Chen, L.; Guo, S.; Qi, Z.; Pan, P.; Chen, J. Overview of structure, function and integrated utilization of marine shell. Sci Total Environ. 2023, 870, 161950.
5. Huang, H.; Du, M.; Chen, J.; Zhong, S.; Wang, J. Preparation and characterization of abalone shells derived biological mesoporous hydroxyapatite microspheres for drug delivery. Mater Sci Eng C Mater Biol Appl. 2020, 113, 110969.
6. Pan, P.; Geng, Y.; Hu, L.; Liu, Q.; Liu, M.; Cheng, M.; Chen, L.; Chen, J. Biologically enhanced 3D printed micro-nano hybrid scaffolds doped with abalone shell for bone regeneration. Adv Compos Hybrid Mater. 2022, 6, 10.
7. Karunakaran, G.; Cho, E. B.; Kumar, G. S.; Kolesnikov, E.; Sudha, K. G.; Mariyappan, K.; Han, A.; Choi, S. S. Citric acid-mediated microwave-hydrothermal synthesis of mesoporous f-doped HAp nanorods from bio-waste for biocidal implant applications. Nanomaterials (Basel). 2022, 12, 315.
8. Qi, Y.; Qian, Z.; Yuan, W.; Li, Z. Injectable and self-healing nanocomposite hydrogel loading needle-like nano-hydroxyapatite and graphene oxide for synergistic tumour proliferation inhibition and photothermal therapy. J Mater Chem B. 2021, 9, 9734-9743.
9. Wen, Z.; Wang, Z.; Chen, J.; Zhong, S.; Hu, Y.; Wang, J.; Zhang, Q. Manipulation of partially oriented hydroxyapatite building blocks to form flowerlike bundles without acid-base regulation. Colloids Surf B Biointerfaces. 2016, 142, 74-80.
10. Ma, Q.; Liao, J.; Tian, T.; Zhang, Q.; Cai, X. A potential flower-like coating consisting of calcium-phosphate nanosheets on titanium surface. Chin Chem Lett. 2017, 28, 1893-1896.
11. Munir, M. U.; Salman, S.; Javed, I.; Bukhari, S. N. A.; Ahmad, N.; Shad, N. A.; Aziz, F. Nano-hydroxyapatite as a delivery system: overview and advancements. Artif Cells Nanomed Biotechnol. 2021, 49, 717-727.
12. Pan, P.; Yue, Q.; Li, J.; Gao, M.; Yang, X.; Ren, Y.; Cheng, X.; Cui, P.; Deng, Y. Smart cargo delivery system based on mesoporous nanoparticles for bone disease diagnosis and treatment. Adv Sci (Weinh). 2021, 8, e2004586.
13. Doan, V. H. M.; Mondal, S.; Vo, T. M. T.; Ly, C. D.; Vu, D. D.; Nguyen, V. T.; Park, S.; Choi, J.; Oh, J. Fluorescence conjugated nanostructured cobalt-doped hydroxyapatite platform for imaging-guided drug delivery application. Colloids Surf B Biointerfaces. 2022, 214, 112458.
14. Nenen, A.; Maureira, M.; Neira, M.; Orellana, S. L.; Covarrubias, C.; Moreno-Villoslada, I. Synthesis of antibacterial silver and zinc doped nano-hydroxyapatite with potential in bone tissue engineering applications. Ceram Int. 2022, 48, 34750-34759.
15. Słota, D.; Florkiewicz, W.; Piętak, K.; Pluta, K.; Sadlik, J.; Miernik, K.; Sobczak-Kupiec, A. Preparation of PVP and betaine biomaterials enriched with hydroxyapatite and its evaluation as a drug carrier for controlled release of clindamycin. Ceram Int. 2022, 48, 35467-35473.
16. Govindan, B.; Swarna Latha, B.; Nagamony, P.; Ahmed, F.; Saifi, M. A.; Harrath, A. H.; Alwasel, S.; Mansour, L.; Alsharaeh, E. H. Designed synthesis of nanostructured magnetic hydroxyapatite based drug nanocarrier for anti-cancer drug delivery toward the treatment of human epidermoid carcinoma. Nanomaterials (Basel). 2017, 7, 138.
17. Karunakaran, G.; Cho, E. B.; Kumar, G. S.; Kolesnikov, E.; Karpenkov, D. Y.; Gopinathan, J.; Pillai, M. M.; Selvakumar, R.; Boobalan, S.; Gorshenkov, M. V. Sodium dodecyl sulfate mediated microwave synthesis of biocompatible superparamagnetic mesoporous hydroxyapatite nanoparticles using black Chlamys varia seashell as a calcium source for biomedical applications. Ceram Int. 2019, 45, 15143-15155.
18. Franco, D.; Calabrese, G.; Petralia, S.; Neri, G.; Corsaro, C.; Forte, L.; Squarzoni, S.; Guglielmino, S.; Traina, F.; Fazio, E.; Conoci, S. Antimicrobial effect and cytotoxic evaluation of Mg-doped hydroxyapatite functionalized with Au-nano rods. Molecules. 2021, 26, 1099.
19. Jiang, Z.; Gong, Z.; Song, W.; Wu, P.; Deng, C.; Chen, Q.; Yan, T. A promising hydroxyapatite whisker with long-term and high-efficiency antibacterial performance and its potential application in implant. Inorg Chem Commun. 2022, 146, 109860.
20. Martínez-Gracida, N. O.; Esparza-González, S. C.; Castillo-Martínez, N. A.; Serrano-Medina, A.; Olivas-Armendariz, I.; Campos-Múzquiz, L. G.; Múzquiz-Ramos, E. M. Synergism in novel silver-copper/hydroxyapatite composites for increased antibacterial activity and biocompatibility. Ceram Int. 2020, 46, 20215-20225.
21. Wei, J. Q.; Liu, Y.; Zhang, X. H.; Liang, W. W.; Zhou, T. F.; Zhang, H.; Deng, X. L. Enhanced critical-sized bone defect repair efficiency by combining deproteinized antler cancellous bone and autologous BMSCs. Chin Chem Lett. 2017, 28, 845-850.
22. Hou, H. H.; Lee, B. S.; Liu, Y. C.; Wang, Y. P.; Kuo, W. T.; Chen, I. H.; He, A. C.; Lai, C. H.; Tung, K. L.; Chen, Y. W. Vapor-induced pore-forming atmospheric-plasma-sprayed zinc-, strontium-, and magnesium-doped hydroxyapatite coatings on titanium implants enhance new bone formation-an in vivo and in vitro investigation. Int J Mol Sci. 2023, 24, 4933.
23. Yu, S.; Sun, T.; Liu, W.; Yang, L.; Gong, H.; Chen, X.; Li, J.; Weng, J. PLGA cage-like structures loaded with Sr/Mg-doped hydroxyapatite for repairing osteoporotic bone defects. Macromol Biosci. 2022, 22, e2200092.
24. Paramasivan, M.; Sampath Kumar, T. S.; Kanniyappan, H.; Muthuvijayan, V.; Chandra, T. S. Biomimetic ion substituted and Co-substituted hydroxyapatite nanoparticle synthesis using Serratia Marcescens. Sci Rep. 2023, 13, 4513.
25. Tithito, T.; Sillapaprayoon, S.; Pimtong, W.; Thongbunchoo, J.; Charoenphandhu, N.; Krishnamra, N.; Lert-Itthiporn, A.; Maneeprakorn, W.; Pon-On, W. Development of biomaterials based on biomimetic trace elements co-doped hydroxyapatite: physical, in vitro osteoblast-like cell growth and in vivo cytotoxicity in zebrafish studies. Nanomaterials (Basel). 2023, 13, 255.
26. Pan, P.; Yue, Q.; Yang, X.; Ren, Y.; Alharthi, F. A.; Alghamdi, A.; Su, J.; Deng, Y. Structure engineering of yolk-shell magnetic mesoporous silica microspheres with broccoli-like morphology for efficient catalysis and enhanced cellular uptake. Small. 2021, 17, e2006925.
27. Yu, L.; Pan, P.; Yu, B.; Yang, X.; Yue, Q.; Alghamdi, A. A.; Ren, Y.; Deng, Y. Interface assembly to magnetic mesoporous organosilica microspheres with tunable surface roughness as advanced catalyst carriers and adsorbents. ACS Appl Mater Interfaces. 2021, 13, 36138-36146.
28. Weng, R.; Zhang, L.; Cao, Y.; Wang, Z.; Zhao, C.; Wang, J.; Zhao, C. Two-dimensional borocarbonitrides nanosheets engineered sulfonated polyether sulfone microspheres as highly efficient and photothermally recyclable adsorbents for hemoperfusion. Chem Eng J. 2023, 463, 142365.
29. Zhong, R.; Zhong, Q.; Huo, M.; Yang, B.; Li, H. Preparation of biocompatible nano-ZnO/chitosan microspheres with multi-functions of antibacterial, UV-shielding and dye photodegradation. Int J Biol Macromol. 2020, 146, 939-945.
30. Yang, Y.; Qiao, X.; Huang, R.; Chen, H.; Shi, X.; Wang, J.; Tan, W.; Tan, Z. E-jet 3D printed drug delivery implants to inhibit growth and metastasis of orthotopic breast cancer. Biomaterials. 2020, 230, 119618.
31. Xuerong, Z.; Ao, S.; Jianping, W.; Xin, Z.; Duoduo, T.; Mingjuan, W.; Lijun, X.; Enhong, Z.; Cui, Z. G. Effects of long noncoding RNA AK093407 on the biological behavior of colon cancer cells and the underlying mechanism. Comb Chem High Throughput Screen. 2023, 26, 289-300.
32. Zhang, J.; Cui, J.; Wang, Y.; Lin, X.; Teng, X.; Tang, Y. Complex molecular mechanism of ammonia-induced apoptosis in chicken peripheral blood lymphocytes: miR-27b-3p, heat shock proteins, immunosuppression, death receptor pathway, and mitochondrial pathway. Ecotoxicol Environ Saf. 2022, 236, 113471.
33. Zhang, J.; Tang, L.; Qi, H.; Zhao, Q.; Liu, Y.; Zhang, Y. Dual function of magnesium in bone biomineralization. Adv Healthc Mater. 2019, 8, e1901030.
34. Zhao, Z.; Espanol, M.; Guillem-Marti, J.; Kempf, D.; Diez-Escudero, A.; Ginebra, M. P. Ion-doping as a strategy to modulate hydroxyapatite nanoparticle internalization. Nanoscale. 2016, 8, 1595-1607.
35. de Wolff, P. Technisch Physische Dienst. Delft, The Netherlands,1957.
36. Pagan, D. C.; Shade, P. A.; Barton, N. R.; Park, J. S.; Kenesei, P.; Menasche, D. B.; Bernier, J. V. Modeling slip system strength evolution in Ti-7Al informed by in-situ grain stress measurements. Acta Mater. 2017, 128, 406-417.
37. Vlasic, T. M.; Servio, P. D.; Rey, A. D. Effect of guest size on the mechanical properties and molecular structure of gas hydrates from first-principles. Cryst Growth Des. 2017, 17, 6407-6416.
38. Teruel Jde, D.; Alcolea, A.; Hernández, A.; Ruiz, A. J. Comparison of chemical composition of enamel and dentine in human, bovine, porcine and ovine teeth. Arch Oral Biol. 2015, 60, 768-775.
39. Sanosh, K. P.; Chu, M. C.; Balakrishnan, A.; Lee, Y. J.; Kim, T. N.; Cho, S. J. Synthesis of nano hydroxyapatite powder that simulate teeth particle morphology and composition. Curr Appl Phys. 2009, 9, 1459-1462.
40. Sharma, R.; Pandey, R. R.; Gupta, A. A.; Kar, S.; Dhayal, M. In situ amino acid functionalization and microstructure formation of hydroxyapatite nanoparticles synthesized at different pH by precipitation route. Mater Chem Phys. 2012, 133, 718-725.
41. Mi, P.; Kokuryo, D.; Cabral, H.; Wu, H.; Terada, Y.; Saga, T.; Aoki, I.; Nishiyama, N.; Kataoka, K. A pH-activatable nanoparticle with signal-amplification capabilities for non-invasive imaging of tumour malignancy. Nat Nanotechnol. 2016, 11, 724-730.
42. Ren, H.H.; Zhao, H. Y.; Cui, Y.; Ao, X.; Li, A. L.; Zhang, Z. M.; Qiu, D. Poly(1,8-octanediol citrate)/bioactive glass composite with improved mechanical performance and bioactivity for bone regeneration. Chin Chem Lett. 2017, 28, 2116-2120.
43. Bhattacharjee, A.; Bose, S. Multifunctional polydopamine - Zn(2+)-curcumin coated additively manufactured ceramic bone grafts with enhanced biological properties. Biomater Adv. 2023, 153, 213487.
44. Marinho, J. P. N.; Neme, N. P.; Matos, M. J. d. S.; Batista, R. J. C.; Macedo, W. A. d. A.; Gastelois, P. L.; Gomes, D. A.; Rodrigues, M. A.; Cipreste, M. F.; Sousa, E. M. B. d. Nanostructured system based on hydroxyapatite and curcumin: a promising candidate for osteosarcoma therapy. Ceram Int. 2023, 49, 19932-19949.
45. Yuan, P.; Min, Y.; Zhao, Z. Multifunctional nanoparticles for the treatment and diagnosis of osteosarcoma. Biomater Adv. 2023, 151, 213466.
