Chitosan oligosaccharide lactate coated hydroxyapatite nanoparticles as a vehicle for the delivery of steroid drugs and the targeting of breast cancer cells
Authors
Ignjatović, Nenad
Sakač, Marija

Kuzminac, Ivana

Kojić, Vesna V.

Marković, Smilja B.

Vasiljević-Radović, Dana

Wu, Victoria

Uskoković, Vuk
Uskoković, Dragan

Article (Accepted Version)
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Low targeting efficiency and fast metabolism of antineoplastic drugs are hindrances to effective chemotherapies and there is an ongoing search for better drugs, but also better carriers. Steroid derivatives, 3β-hydroxy-16-hydroxymino-androst-5-en-17-one (A) and 3β,17β-dihydroxy-16-hydroxymino-androst-5-ene (B) as cancer growth inhibitors were chemically synthesized and captured in a carrier composed of hydroxyapatite (HAp) nanoparticles coated with chitosan oligosaccharide lactate (ChOLS). The only difference between the two derivatives is that A has a carbonyl group at the C17 position of the five-membered ring and B has a hydroxyl. This small difference in the structure resulted not only in different physicochemical properties of the A- and B-loaded HAp/ChOSL, but also in different biological activities. The morphology of drug-loaded HAp/ChOSL particles was spherical, but the size depended on the drug identity: d50 = 138 nm for A-loaded HAp/ChOSL and d50 = 223 nm for B-loaded HAp/ChO...SL. Cell-selective toxicity was tested against human breast carcinoma (MCF7 and MDA-MB-231), human lung carcinoma (A549) and human lung fibroblasts (MRC-5). The small selectivity of pure derivatives A and B toward breast cancer cells became drastically increased when they were delivered using HAp/ChOSL particles. Whereas the ratio of the cytotoxicity imposed onto breast cancer cells and the cytotoxicity imposed onto healthy MRC-5 fibroblasts ranged from 1.5 to 1.7 for pure A and from 1.5 to 2.3 for pure derivative B depending on the concentration, it increased to 5.4 for A-loaded HAp/ChOSL and 5.1 for B-loaded HAp/ChOSL. FACS analysis demonstrated poor uptake of HAp/ChOSL particles by MCF7 cells, suggesting that the drug release occurs extracellularly. The augmented activity of the drugs was most likely due to sustained release, although the favorable positive charge of the carrier, allowing it to adhere to the negatively charged plasma membrane and release the drugs steadily and directly to the hydrophobic cell membrane milieu, was delineated as a possible complementary mechanism.
Keywords:
chitosan oligosaccharide lactate / hydroxyapatite / nanoparticles / drug delivery / cancer cell targetingSource:
Journal of Materials Chemistry B, 2018, 6, 6957-6968Publisher:
- Royal Society of Chemistry
Funding / projects:
- Molecular designing of nanoparticles with controlled morphological and physicochemical characteristics and functional materials based on them (RS-45004)
- United States National Institutes of Health (NIH) / National Institute of Dental and Craniofacial Research (NIDCR), Grant K99-DE021416
Note:
- This is the peer-reviewed version of the article: Ignjatović, Nenad L., Marija Sakač, Ivana Kuzminac, Vesna Kojić, Smilja Marković, Dana Vasiljević-Radović, Victoria M. Wu, Vuk Uskoković, and Dragan P. Uskoković. 2018. “Chitosan Oligosaccharide Lactate Coated Hydroxyapatite Nanoparticles as a Vehicle for the Delivery of Steroid Drugs and the Targeting of Breast Cancer Cells.” Journal of Materials Chemistry B, https://doi.org/10.1039/C8TB01995A
- http://cer.ihtm.bg.ac.rs/handle/123456789/2482
DOI: 10.1039/C8TB01995A
ISSN: 2050-750X; 2050-7518
PubMed: 30931125
WoS: 000449701500007
Scopus: 2-s2.0-85056324409
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IHTMTY - JOUR AU - Ignjatović, Nenad AU - Sakač, Marija AU - Kuzminac, Ivana AU - Kojić, Vesna V. AU - Marković, Smilja B. AU - Vasiljević-Radović, Dana AU - Wu, Victoria AU - Uskoković, Vuk AU - Uskoković, Dragan PY - 2018 UR - http://dais.sanu.ac.rs/123456789/4066 UR - https://cer.ihtm.bg.ac.rs/handle/123456789/3146 AB - Low targeting efficiency and fast metabolism of antineoplastic drugs are hindrances to effective chemotherapies and there is an ongoing search for better drugs, but also better carriers. Steroid derivatives, 3β-hydroxy-16-hydroxymino-androst-5-en-17-one (A) and 3β,17β-dihydroxy-16-hydroxymino-androst-5-ene (B) as cancer growth inhibitors were chemically synthesized and captured in a carrier composed of hydroxyapatite (HAp) nanoparticles coated with chitosan oligosaccharide lactate (ChOLS). The only difference between the two derivatives is that A has a carbonyl group at the C17 position of the five-membered ring and B has a hydroxyl. This small difference in the structure resulted not only in different physicochemical properties of the A- and B-loaded HAp/ChOSL, but also in different biological activities. The morphology of drug-loaded HAp/ChOSL particles was spherical, but the size depended on the drug identity: d50 = 138 nm for A-loaded HAp/ChOSL and d50 = 223 nm for B-loaded HAp/ChOSL. Cell-selective toxicity was tested against human breast carcinoma (MCF7 and MDA-MB-231), human lung carcinoma (A549) and human lung fibroblasts (MRC-5). The small selectivity of pure derivatives A and B toward breast cancer cells became drastically increased when they were delivered using HAp/ChOSL particles. Whereas the ratio of the cytotoxicity imposed onto breast cancer cells and the cytotoxicity imposed onto healthy MRC-5 fibroblasts ranged from 1.5 to 1.7 for pure A and from 1.5 to 2.3 for pure derivative B depending on the concentration, it increased to 5.4 for A-loaded HAp/ChOSL and 5.1 for B-loaded HAp/ChOSL. FACS analysis demonstrated poor uptake of HAp/ChOSL particles by MCF7 cells, suggesting that the drug release occurs extracellularly. The augmented activity of the drugs was most likely due to sustained release, although the favorable positive charge of the carrier, allowing it to adhere to the negatively charged plasma membrane and release the drugs steadily and directly to the hydrophobic cell membrane milieu, was delineated as a possible complementary mechanism. PB - Royal Society of Chemistry T2 - Journal of Materials Chemistry B T1 - Chitosan oligosaccharide lactate coated hydroxyapatite nanoparticles as a vehicle for the delivery of steroid drugs and the targeting of breast cancer cells VL - 6 SP - 6957 EP - 6968 DO - 10.1039/C8TB01995A ER -
@article{ author = "Ignjatović, Nenad and Sakač, Marija and Kuzminac, Ivana and Kojić, Vesna V. and Marković, Smilja B. and Vasiljević-Radović, Dana and Wu, Victoria and Uskoković, Vuk and Uskoković, Dragan", year = "2018", abstract = "Low targeting efficiency and fast metabolism of antineoplastic drugs are hindrances to effective chemotherapies and there is an ongoing search for better drugs, but also better carriers. Steroid derivatives, 3β-hydroxy-16-hydroxymino-androst-5-en-17-one (A) and 3β,17β-dihydroxy-16-hydroxymino-androst-5-ene (B) as cancer growth inhibitors were chemically synthesized and captured in a carrier composed of hydroxyapatite (HAp) nanoparticles coated with chitosan oligosaccharide lactate (ChOLS). The only difference between the two derivatives is that A has a carbonyl group at the C17 position of the five-membered ring and B has a hydroxyl. This small difference in the structure resulted not only in different physicochemical properties of the A- and B-loaded HAp/ChOSL, but also in different biological activities. The morphology of drug-loaded HAp/ChOSL particles was spherical, but the size depended on the drug identity: d50 = 138 nm for A-loaded HAp/ChOSL and d50 = 223 nm for B-loaded HAp/ChOSL. Cell-selective toxicity was tested against human breast carcinoma (MCF7 and MDA-MB-231), human lung carcinoma (A549) and human lung fibroblasts (MRC-5). The small selectivity of pure derivatives A and B toward breast cancer cells became drastically increased when they were delivered using HAp/ChOSL particles. Whereas the ratio of the cytotoxicity imposed onto breast cancer cells and the cytotoxicity imposed onto healthy MRC-5 fibroblasts ranged from 1.5 to 1.7 for pure A and from 1.5 to 2.3 for pure derivative B depending on the concentration, it increased to 5.4 for A-loaded HAp/ChOSL and 5.1 for B-loaded HAp/ChOSL. FACS analysis demonstrated poor uptake of HAp/ChOSL particles by MCF7 cells, suggesting that the drug release occurs extracellularly. The augmented activity of the drugs was most likely due to sustained release, although the favorable positive charge of the carrier, allowing it to adhere to the negatively charged plasma membrane and release the drugs steadily and directly to the hydrophobic cell membrane milieu, was delineated as a possible complementary mechanism.", publisher = "Royal Society of Chemistry", journal = "Journal of Materials Chemistry B", title = "Chitosan oligosaccharide lactate coated hydroxyapatite nanoparticles as a vehicle for the delivery of steroid drugs and the targeting of breast cancer cells", volume = "6", pages = "6957-6968", doi = "10.1039/C8TB01995A" }
Ignjatović, N., Sakač, M., Kuzminac, I., Kojić, V. V., Marković, S. B., Vasiljević-Radović, D., Wu, V., Uskoković, V.,& Uskoković, D.. (2018). Chitosan oligosaccharide lactate coated hydroxyapatite nanoparticles as a vehicle for the delivery of steroid drugs and the targeting of breast cancer cells. in Journal of Materials Chemistry B Royal Society of Chemistry., 6, 6957-6968. https://doi.org/10.1039/C8TB01995A
Ignjatović N, Sakač M, Kuzminac I, Kojić VV, Marković SB, Vasiljević-Radović D, Wu V, Uskoković V, Uskoković D. Chitosan oligosaccharide lactate coated hydroxyapatite nanoparticles as a vehicle for the delivery of steroid drugs and the targeting of breast cancer cells. in Journal of Materials Chemistry B. 2018;6:6957-6968. doi:10.1039/C8TB01995A .
Ignjatović, Nenad, Sakač, Marija, Kuzminac, Ivana, Kojić, Vesna V., Marković, Smilja B., Vasiljević-Radović, Dana, Wu, Victoria, Uskoković, Vuk, Uskoković, Dragan, "Chitosan oligosaccharide lactate coated hydroxyapatite nanoparticles as a vehicle for the delivery of steroid drugs and the targeting of breast cancer cells" in Journal of Materials Chemistry B, 6 (2018):6957-6968, https://doi.org/10.1039/C8TB01995A . .