Manganese-doped Calcium Phosphate Nanoclusters with Hierarchical Structure: Construction and Performance

doi:10.15541/jim20260004

Abstract

Abstract: Manganese (Mn), with its unique multivalent nature, has been widely used in biomedical applications, including anticancer therapy and bone formation. However, in cancer treatment, it still faces challenges in achieving synergistic improvements in both catalytic and photothermal properties. In this study, a hierarchical structure (Mn:nCaP@Lys) was constructed through lysine (Lys) coupling and pH control utilizing manganese-doped calcium phosphate nanoclusters (Mn:nCaP, (2.50±0.64) nm) as structural units. Influence of hierarchical structuring on the photothermal conversion and catalytic performance of Mn:nCaP was discussed to optimize its biological effects. Experimental results showed that various Mn:nCaP@Lys samples with different particle sizes were successfully constructed by adjusting pH using a method of 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride/N-hydroxysuccinimide (0.09 mol/L)-mediated Lys (0.04 mol/L) coupling reaction. By increasing pH from 7.0 to 11.0, the particle size of Mn:nCaP@Lys was controllably increased from (57.27±7.83) nm to (95.70±14.16) nm. Compared to Mn:nCaP, Mn:nCaP@Lys showed better catalytic activity over 4 h. Moreover, the hierarchical structure material synthesized at pH 9.0 exhibited the strongest catalytic activity and good heating capacity, but its heating capacity was weaker than that of Mn:nCaP at pH 10.0 and 11.0. Biocompatible Mn:nCaP@Lys displayed enhanced tumor cell inhibition and increased chemo-therapeutic sensitization compared to Mn:nCaP. This study presents an effective method for improving the biological effects of Mn, supporting its application in biomedical fields.

Key words: nano-calcium phosphate, manganese ion, hierarchical structure, size effect

CLC Number:

TQ318

CHEN Junrui, TANG Xinli, CAO Wuqing, HAN Yingchao. Manganese-doped Calcium Phosphate Nanoclusters with Hierarchical Structure: Construction and Performance[J]. Journal of Inorganic Materials, DOI: 10.15541/jim20260004.

References

[1] MOFAKHAMI S, SALAHINEJAD E.Biphasic calcium phosphate microspheres in biomedical applications.Journal of Controlled Release, 2021, 338: 527.
[2] QI C, MUSETTI S, FU L H, et al. Biomolecule-assisted green synthesis of nanostructured calcium phosphates and their biomedical applications. Chemical Society Reviews, 2019, 48(10): 2698.
[3] KHALIFEHZADEH R, ARAMI H. Biodegradable calcium phosphate nanoparticles for cancer therapy. Advances in Colloid and Interface Science, 2020, 279: 102157.
[4] SHEKHAR S, ROY A, HONG D, et al. Nanostructured silicate substituted calcium phosphate (NanoSiCaPs) nanoparticles - efficient calcium phosphate based non-viral gene delivery systems. Materials Science & Engineering: C, 2016, 69: 486.
[5] CHEN X, LI H Z, MA Y H, et al. Calcium phosphate-based nanomaterials: preparation, multifunction, and application for bone tissue engineering. Molecules, 2023, 28(12): 4790.
[6] NIE L, HOU M J, WANG T W, et al. Nanostructured selenium-doped biphasic calcium phosphate with in situ incorporation of silver for antibacterial applications. Scientific Reports, 2020, 10: 13738.
[7] MOSINA M, KOVRLIJA I, STIPNIECE L, et al. Gallium containing calcium phosphates: potential antibacterial agents or fictitious truth. Acta Biomaterialia, 2022, 150: 48.
[8] XIE Y F, HE W M, LI F, et al. Luminescence enhanced Eu³+/Gd³+ Co-doped hydroxyapatite nanocrystals as imaging agents in vitro and in vivo. ACS Applied Materials & Interfaces, 2016, 8(16): 10212.
[9] LI C Y, DING Z Y, HAN Y C. In vitro antibacterial and osteogenic properties of manganese doped nano hydroxyapatite. Journal of Inorganic Materials, 2024, 39(3): 313.
[10] LIN K L, WU C T, CHANG J. Advances in synthesis of calcium phosphate crystals with controlled size and shape. Acta Biomaterialia, 2014, 10(10): 4071.
[11] HÖPPEL A, BAHR O, EBERT R, et al. Cu-doped calcium phosphate supraparticles for bone tissue regeneration. RSC Advances, 2024, 14(45): 32839.
[12] LI J, WANG Y Z. Golgi metal ion homeostasis in human health and diseases. Cells, 2022, 11(2): 289.
[13] DUONG T K N, TRUONG T T, PHAN T N L, et al. Near-infrared responsive Au-Mn-HAp nanocomposite for fluorescence imaging and combined phototherapy for breast cancer. Biomaterials Science, 2025, 13(18): 5145.
[14] WU T T, SHI H S, LIANG Y Y, et al. Improving osteogenesis of calcium phosphate bone cement by incorporating with manganese doped β-tricalcium phosphate. Materials Science & Engineering: C, 2020, 109: 110481.
[15] FU L H, HU Y R, QI C, et al. Biodegradable manganese-doped calcium phosphate nanotheranostics for traceable cascade reaction-enhanced anti-tumor therapy. ACS Nano, 2019, 13(12): 13985.
[16] LI C Y, DING Z Y, HAN Y C. Mn-doped nano-hydroxyapatites as theranostic agents with tumor pH-amplified MRI-signal capabilities for guiding photothermal therapy. International Journal of Nanomedicine, 2023, 18: 6101.
[17] LI C Y, HUANG Y, DING Z Y, et al. Mn-doped calcium phosphate nanoclusters with enhanced ability of valence adjustment for MRI guided sequential therapy of tumors from PTT to CDT. ACS Applied Materials & Interfaces, 2025, 17(35): 49148.
[18] GIANOLIO E, BÄCKSTRÖM S, JR PETORAL R M, et al. Characterization of a manganese-containing nanoparticle as an MRI contrast agent. European Journal of Inorganic Chemistry, 2019, 2019(13): 1759.
[19] HOU X Q, YANG X, XU Y W, et al. Manganese-doped mesoporous polydopamine nanoagent for T1-T2 magnetic resonance imaging and tumor therapy. Nano Research, 2023, 16(2): 2991.
[20] SU Q, LIU C C, ZHU J Y, et al. Albumin-stabilized manganese oxide/semiconducting polymer nanocomposites for photothermal-chemodynamic therapy of hepatic carcinoma. Frontiers in Bioengineering and Biotechnology, 2022, 10: 919235.
[21] SONG M L, LIU T, SHI C R, et al. Bioconjugated manganese dioxide nanoparticles enhance chemotherapy response by priming tumor-associated macrophages toward M1-like phenotype and attenuating tumor hypoxia. ACS Nano, 2016, 10(1): 633.
[22] WANG J Q, LIU G. Imaging nano-bio interactions in the kidney: toward a better understanding of nanoparticle clearance. Angewandte Chemie International Edition, 2018, 57(12): 3008.
[23] CHOI J S, CAO J F, NAEEM M, et al. Size-controlled biodegradable nanoparticles: preparation and size-dependent cellular uptake and tumor cell growth inhibition. Colloids and Surfaces B: Biointerfaces, 2014, 122: 545.
[24] MOHARIL P, WAN Z Y, PARDESHI A, et al. Engineering a folic acid-decorated ultrasmall gemcitabine nanocarrier for breast cancer therapy: dual targeting of tumor cells and tumor-associated macrophages. Acta Pharmaceutica Sinica B, 2022, 12(3): 1148.
[25] RAY R, GHOSH S, PANJA P, et al. Rapid mitochondria targeting by arginine-terminated, sub-10 nm nanoprobe via direct cell membrane penetration. ACS Applied Bio Materials, 2023, 6(6): 2338.
[26] TANG X L, DING Z Y, CHEN J R, et al. In vivo distribution and metabolism of calcium phosphate nanomaterials based on fluorescent labeling with rare earth europium ions. Journal of Inorganic Materials, 2025, 40(7): 754.
[27] TANG L, YANG X J, YIN Q, et al. Investigating the optimal size of anticancer nanomedicine. Proceedings of the National Academy of Sciences of the United States of America, 2014, 111(43): 15344.
[28] SINDHWANI S, SYED A M, NGAI J, et al. The entry of nanoparticles into solid tumours. Nature Materials, 2020, 19(5): 566.
[29] SANTIAGO-RODRÍGUEZ L, LAFONTAINE M M, CASTRO C, et al. Synthesis, stability, cellular uptake, and blood circulation time of carboxymethyl-inulin coated magnetic nanoparticles. Journal of Materials Chemistry B, 2013, 1(22): 2807.
[30] WANG Q, HU L S, WANG X Y, et al. Expanding from materials to biology inspired by biomineralization. Interdisciplinary Materials, 2024, 3(2): 165.
[31] CHOU T C. Drug combination studies and their synergy quantification using the Chou-Talalay method. Cancer Research, 2010, 70(2): 440.
[32] GUO L, FANG Y Q, SHAO Z P, et al. pH-induced structural transition during complexation and precipitation of sodium caseinate and ε-poly-l-lysine. International Journal of Biological Macromolecules, 2020, 154: 644.
[33] MORGAN J J, SCHLAUTMAN M A, BILINSKI H. Rates of abiotic MnII oxidation by O2: influence of various multidentate ligands at high pH. Environmental Science & Technology, 2021, 55(21): 14426.