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Article

Fe/Mg-Modified Carbonate Apatite with Uniform Particle Size and Unique Transport Protein-Related Protein Corona Efficiently Delivers Doxorubicin into Breast Cancer Cells

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Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya 47500, Selangor, Malaysia
2
Chemical Engineering, Monash University, Clayton 3800, VIC, Australia
3
Health and Wellbeing cluster, Global Asia in the 21st Century (GA21) Platform, Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Subang Jaya 47500, Selangor, Malaysia
*
Author to whom correspondence should be addressed.
Nanomaterials 2020, 10(5), 834; https://doi.org/10.3390/nano10050834
Received: 13 March 2020 / Revised: 31 March 2020 / Accepted: 1 April 2020 / Published: 27 April 2020
(This article belongs to the Special Issue Application of Nanomaterials for Drug Delivery)
Breast cancer is the abnormal, uncontrollable proliferation of cells in the breast. Conventional treatment modalities like chemotherapy induce deteriorating side effects on healthy cells. Non-viral inorganic nanoparticles (NPs) confer exclusive characteristics, such as, stability, controllable shape and size, facile surface modification, and unique magnetic and optical properties which make them attractive drug carriers. Among them, carbonate apatite (CA) particles are pH-responsive in nature, enabling rapid intracellular drug release, but are typically heterogeneous with the tendency to self-aggregate. Here, we modified the nano-carrier by partially substituting Ca2+ with Mg2+ and Fe3+ into a basic lattice structure of CA, forming Fe/Mg-carbonate apatite (Fe/Mg-CA) NPs with the ability to mitigate self-aggregation, form unique protein corona in the presence of serum and efficiently deliver doxorubicin (DOX), an anti-cancer drug into breast cancer cells. Two formulations of Fe/Mg-CA NPs were generated by adding different concentrations of Fe3+ and Mg2+ along with a fixed amount of Ca2+ in bicarbonate buffered DMEM (Dulbecco’s Modified Eagle’s Medium), followed by 30 min incubation at 37 °C. Particles were characterized by turbidity analysis, z-average diameter and zeta potential measurement, optical microscopy, field emission scanning electron microscopy (FESEM), Fourier transform infrared spectroscopy (FTIR), energy dispersive X-ray (EDX), flame atomic absorption spectroscopy (FAAS), pH dissolution, drug binding, cellular uptake, thiazolyl blue tetrazolium bromide (MTT) assay, stability analysis, and protein corona study by LCMS (Liquid chromatography-mass spectrometry). Both formulations of Fe/Mg-CA displayed mostly uniform nano-sized particles with less tendency to aggregate. The EDX and FAAS elemental analysis confirmed the weight (%) of Ca, Fe and Mg, along with their Ca/P ratio in the particles. A constant drug binding efficiency was noticed with 5 μM to 10 μM of initial DOX concentration. A pH dissolution study of Fe/Mg-CA NPs revealed the quick release of DOX in acidic pH. Enhancement of cytotoxicity for the chemotherapy drug was greater for Fe/Mg-CA NPs as compared to CA NPs, which could be explained by an increase in cellular internalization as a result of the small z-average diameter of the former. The protein corona study by LCMS demonstrated that Fe/Mg-CA NPs exhibited the highest affinity towards transport proteins without binding with opsonins. Biodistribution study was performed to study the effect of DOX-loaded Fe/Mg-CA NPs on the tissue distribution of DOX in Balb/c 4T1 tumor-bearing mice. Both formulations of Fe/Mg-CA NPs have significantly increased the accumulation of DOX in tumors. Interestingly, high Fe/Mg-CA NPs exhibited less off-target distribution compared to low Fe/Mg-CA NPs. Furthermore, the blood plasma analysis revealed prolonged blood circulation half-life of DOX-loaded low and high Fe/Mg-CA NPs compared to free DOX solution. Modifying CA NPs with Fe3+ and Mg2+, thereby, led to the generation of nano-sized particles with less tendency to aggregate, enhancing the drug binding efficiency, cellular uptake, and cytotoxicity without hampering drug release in acidic pH, while improving the circulation half-life and tumor accumulation of DOX. Therefore, Fe/Mg-CA which predominantly forms a transport protein-related protein corona could be a proficient carrier for therapeutic delivery in breast cancer. View Full-Text
Keywords: nanoparticles (NPs); inorganic NPs; doxorubicin (DOX); breast cancer; carbonate apatite (CA); Fe/Mg-carbonate apatite (Fe/Mg-CA); pH responsive drug delivery; cytotoxicity; cellular uptake; protein corona; divalent and trivalent cations; biodistribution; blood plasma nanoparticles (NPs); inorganic NPs; doxorubicin (DOX); breast cancer; carbonate apatite (CA); Fe/Mg-carbonate apatite (Fe/Mg-CA); pH responsive drug delivery; cytotoxicity; cellular uptake; protein corona; divalent and trivalent cations; biodistribution; blood plasma
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MDPI and ACS Style

Haque, S.T.; Karim, M.E.; Abidin, S.A.Z.; Othman, I.; Holl, M.M.B.; Chowdhury, E.H. Fe/Mg-Modified Carbonate Apatite with Uniform Particle Size and Unique Transport Protein-Related Protein Corona Efficiently Delivers Doxorubicin into Breast Cancer Cells. Nanomaterials 2020, 10, 834. https://doi.org/10.3390/nano10050834

AMA Style

Haque ST, Karim ME, Abidin SAZ, Othman I, Holl MMB, Chowdhury EH. Fe/Mg-Modified Carbonate Apatite with Uniform Particle Size and Unique Transport Protein-Related Protein Corona Efficiently Delivers Doxorubicin into Breast Cancer Cells. Nanomaterials. 2020; 10(5):834. https://doi.org/10.3390/nano10050834

Chicago/Turabian Style

Haque, Sheikh T., Md. E. Karim, Syafiq A.Z. Abidin, Iekhsan Othman, Mark M.B. Holl, and Ezharul H. Chowdhury 2020. "Fe/Mg-Modified Carbonate Apatite with Uniform Particle Size and Unique Transport Protein-Related Protein Corona Efficiently Delivers Doxorubicin into Breast Cancer Cells" Nanomaterials 10, no. 5: 834. https://doi.org/10.3390/nano10050834

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