TY  - 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 . .

TY  - JOUR
AU  - Ignjatović, Nenad
AU  - Penov Gaši, Katarina
AU  - Wu, Victoria
AU  - Ajduković, Jovana
AU  - Kojić, Vesna V.
AU  - Vasiljević-Radović, Dana
AU  - Kuzmanović, Maja
AU  - Uskoković, Vuk
AU  - Uskoković, Dragan P.
PY  - 2016
UR  - http://dais.sanu.ac.rs/123456789/15984
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/2644
AB  - In an earlier study we demonstrated that hydroxyapatite nanoparticles coated with chitosan-poly(d,l)-lactide-co-glycolide (HAp/Ch-PLGA) target lungs following their intravenous injection into mice. In this study we utilize an emulsification process and freeze drying to load the composite HAp/Ch-PLGA particles with 17β-hydroxy-17α-picolyl-androst-5-en-3β-yl-acetate (A), a chemotherapeutic derivative of androstane and a novel compound with a selective anticancer activity against lung cancer cells. 1H NMR and 13C NMR techniques confirmed the intact structure of the derivative A following its entrapment within HAp/Ch-PLGA particles. The thermogravimetric and differential thermal analyses coupled with mass spectrometry were used to assess the thermal degradation products and properties of A-loaded HAp/Ch-PLGA. The loading efficiency, as indicated by the comparison of enthalpies of phase transitions in pure A and A-loaded HAp/Ch-PLGA, equaled 7.47 wt.%. The release of A from HAp/Ch-PLGA was sustained, neither exhibiting a burst release nor plateauing after three weeks. Atomic force microscopy and particle size distribution analyses were used to confirm that the particles were spherical with a uniform size distribution of d50 = 168 nm. In vitro cytotoxicity testing of A-loaded HAp/Ch-PLGA using MTT and trypan blue dye exclusion assays demonstrated that the particles were cytotoxic to the A549 human lung carcinoma cell line (46 ± 2%), while simultaneously preserving high viability (83 ± 3%) of regular MRC5 human lung fibroblasts and causing no harm to primary mouse lung fibroblasts. In conclusion, composite A-loaded HAp/Ch-PLGA particles could be seen as promising drug delivery platforms for selective cancer therapies, targeting malignant cells for destruction, while having a significantly lesser cytotoxic effect on the healthy cells.
T2  - Colloids and Surfaces B: Biointerfaces
T1  - Selective anticancer activity of hydroxyapatite/chitosan-poly(D,L)-lactide-co-glycolide particles loaded with an androstane-based cancer inhibitor
VL  - 148
SP  - 629
EP  - 639
DO  - 10.1016/j.colsurfb.2016.09.041
ER  - 

@article{
author = "Ignjatović, Nenad and Penov Gaši, Katarina and Wu, Victoria and Ajduković, Jovana and Kojić, Vesna V. and Vasiljević-Radović, Dana and Kuzmanović, Maja and Uskoković, Vuk and Uskoković, Dragan P.",
year = "2016",
abstract = "In an earlier study we demonstrated that hydroxyapatite nanoparticles coated with chitosan-poly(d,l)-lactide-co-glycolide (HAp/Ch-PLGA) target lungs following their intravenous injection into mice. In this study we utilize an emulsification process and freeze drying to load the composite HAp/Ch-PLGA particles with 17β-hydroxy-17α-picolyl-androst-5-en-3β-yl-acetate (A), a chemotherapeutic derivative of androstane and a novel compound with a selective anticancer activity against lung cancer cells. 1H NMR and 13C NMR techniques confirmed the intact structure of the derivative A following its entrapment within HAp/Ch-PLGA particles. The thermogravimetric and differential thermal analyses coupled with mass spectrometry were used to assess the thermal degradation products and properties of A-loaded HAp/Ch-PLGA. The loading efficiency, as indicated by the comparison of enthalpies of phase transitions in pure A and A-loaded HAp/Ch-PLGA, equaled 7.47 wt.%. The release of A from HAp/Ch-PLGA was sustained, neither exhibiting a burst release nor plateauing after three weeks. Atomic force microscopy and particle size distribution analyses were used to confirm that the particles were spherical with a uniform size distribution of d50 = 168 nm. In vitro cytotoxicity testing of A-loaded HAp/Ch-PLGA using MTT and trypan blue dye exclusion assays demonstrated that the particles were cytotoxic to the A549 human lung carcinoma cell line (46 ± 2%), while simultaneously preserving high viability (83 ± 3%) of regular MRC5 human lung fibroblasts and causing no harm to primary mouse lung fibroblasts. In conclusion, composite A-loaded HAp/Ch-PLGA particles could be seen as promising drug delivery platforms for selective cancer therapies, targeting malignant cells for destruction, while having a significantly lesser cytotoxic effect on the healthy cells.",
journal = "Colloids and Surfaces B: Biointerfaces",
title = "Selective anticancer activity of hydroxyapatite/chitosan-poly(D,L)-lactide-co-glycolide particles loaded with an androstane-based cancer inhibitor",
volume = "148",
pages = "629-639",
doi = "10.1016/j.colsurfb.2016.09.041"
}

Ignjatović, N., Penov Gaši, K., Wu, V., Ajduković, J., Kojić, V. V., Vasiljević-Radović, D., Kuzmanović, M., Uskoković, V.,& Uskoković, D. P.. (2016). Selective anticancer activity of hydroxyapatite/chitosan-poly(D,L)-lactide-co-glycolide particles loaded with an androstane-based cancer inhibitor. in Colloids and Surfaces B: Biointerfaces, 148, 629-639.
https://doi.org/10.1016/j.colsurfb.2016.09.041

Ignjatović N, Penov Gaši K, Wu V, Ajduković J, Kojić VV, Vasiljević-Radović D, Kuzmanović M, Uskoković V, Uskoković DP. Selective anticancer activity of hydroxyapatite/chitosan-poly(D,L)-lactide-co-glycolide particles loaded with an androstane-based cancer inhibitor. in Colloids and Surfaces B: Biointerfaces. 2016;148:629-639.
doi:10.1016/j.colsurfb.2016.09.041 .

Ignjatović, Nenad, Penov Gaši, Katarina, Wu, Victoria, Ajduković, Jovana, Kojić, Vesna V., Vasiljević-Radović, Dana, Kuzmanović, Maja, Uskoković, Vuk, Uskoković, Dragan P., "Selective anticancer activity of hydroxyapatite/chitosan-poly(D,L)-lactide-co-glycolide particles loaded with an androstane-based cancer inhibitor" in Colloids and Surfaces B: Biointerfaces, 148 (2016):629-639,
https://doi.org/10.1016/j.colsurfb.2016.09.041 . .

TY  - CONF
AU  - Ignjatović, Nenad
AU  - Penov Gaši, Katarina
AU  - Wu, Victoria
AU  - Ajduković, Jovana
AU  - Kojić, Vesna V.
AU  - Vasiljević-Radović, Dana
AU  - Uskoković, Vuk
AU  - Uskoković, Dragan
PY  - 2016
UR  - http://dais.sanu.ac.rs/123456789/896
UR  - https://cer.ihtm.bg.ac.rs/handle/123456789/2864
AB  - The applicative potential of synthetic calcium phosphates, especially hydroxyapatite (HAp), has become intensely broadened in the past 10 years, from bone tissue engineering to multiple other fields of biomedicine. Previously we have shown that hydroxyapatite nanoparticles coated with chitosan-poly(D,L)-lactide-co-glycolide (HAp/Ch-PLGA) target lungs following their intravenous administration into mice. For this purpose radioactive 125-Iodine (125I), a low energy gamma emitter, was used to develop a novel in situ method for radiolabeling of particles and investigation of their biodistribution. In this study we utilize an emulsification process and freeze drying to load the composite particles based on hydroxyapatite nanocarrier, chitosane and poly(lactic-co-glycolic acid) with 17β- hydroxy-17α-picolyl-androst-5-en-3β-acetate (A), a chemotherapeutic derivative of androstane. The picolyl androstane derivatives showed high potency in the cell inhibitors of hormonedependent cancers (adenocarcinoma, prostate cancer, cervix carcinoma, colon cancer, etc.). 1H NMR, 13C NMR and high-resolution time-of-flight mass spectrometry (MS) techniques confirmed the intact structure of the derivative A following its entrapment within HAp/Ch-PLGA particles. The synthesized particles of A-loaded HAp/Ch-PLGA were found to be spherical in shape with a uniform size distribution of d50=168 nm. The release of A from HAp/Ch-PLGA was sustained, with no burst release or plateauing after three weeks. The obtained results of the DET and MTT tests show that the particles of A-loaded HAp/Ch-PLGA exhibit almost three times higher cytotoxicity towards lung adenocarcinoma cells (A549) than towards healthy cells (MRC5), while at the same time allowing twice as fast recovery of healthy cells. We have also analyzed the period of recovery of healthy, as well as cancer cells, following the treatment with A-loaded HAp/Ch-PLGA. After treatment with A-loaded HAp/Ch-PLGA, healthy cells recover twice as fast as the malignant ones. Immunofluorescent staining of primary fibroblasts interacting with HAp/Ch-PLGA and A-HAp/Ch-PLGA particles demonstrates no negative morphological or proliferative effects on cells.
PB  - Belgrade : Materials Research Society of Serbia
C3  - Programme and The Book of Abstracts / Eighteenth Annual Conference YUCOMAT 2016, Herceg Novi, September 5-10, 2016
T1  - Tumor-selective hybrid system based on hydroxyapatite nanocarrier, chitosan, poly(lactic-co-glycolic acid) and androstan derivate
SP  - 27
EP  - 27
UR  - https://hdl.handle.net/21.15107/rcub_dais_896
ER  - 

@conference{
author = "Ignjatović, Nenad and Penov Gaši, Katarina and Wu, Victoria and Ajduković, Jovana and Kojić, Vesna V. and Vasiljević-Radović, Dana and Uskoković, Vuk and Uskoković, Dragan",
year = "2016",
abstract = "The applicative potential of synthetic calcium phosphates, especially hydroxyapatite (HAp), has become intensely broadened in the past 10 years, from bone tissue engineering to multiple other fields of biomedicine. Previously we have shown that hydroxyapatite nanoparticles coated with chitosan-poly(D,L)-lactide-co-glycolide (HAp/Ch-PLGA) target lungs following their intravenous administration into mice. For this purpose radioactive 125-Iodine (125I), a low energy gamma emitter, was used to develop a novel in situ method for radiolabeling of particles and investigation of their biodistribution. In this study we utilize an emulsification process and freeze drying to load the composite particles based on hydroxyapatite nanocarrier, chitosane and poly(lactic-co-glycolic acid) with 17β- hydroxy-17α-picolyl-androst-5-en-3β-acetate (A), a chemotherapeutic derivative of androstane. The picolyl androstane derivatives showed high potency in the cell inhibitors of hormonedependent cancers (adenocarcinoma, prostate cancer, cervix carcinoma, colon cancer, etc.). 1H NMR, 13C NMR and high-resolution time-of-flight mass spectrometry (MS) techniques confirmed the intact structure of the derivative A following its entrapment within HAp/Ch-PLGA particles. The synthesized particles of A-loaded HAp/Ch-PLGA were found to be spherical in shape with a uniform size distribution of d50=168 nm. The release of A from HAp/Ch-PLGA was sustained, with no burst release or plateauing after three weeks. The obtained results of the DET and MTT tests show that the particles of A-loaded HAp/Ch-PLGA exhibit almost three times higher cytotoxicity towards lung adenocarcinoma cells (A549) than towards healthy cells (MRC5), while at the same time allowing twice as fast recovery of healthy cells. We have also analyzed the period of recovery of healthy, as well as cancer cells, following the treatment with A-loaded HAp/Ch-PLGA. After treatment with A-loaded HAp/Ch-PLGA, healthy cells recover twice as fast as the malignant ones. Immunofluorescent staining of primary fibroblasts interacting with HAp/Ch-PLGA and A-HAp/Ch-PLGA particles demonstrates no negative morphological or proliferative effects on cells.",
publisher = "Belgrade : Materials Research Society of Serbia",
journal = "Programme and The Book of Abstracts / Eighteenth Annual Conference YUCOMAT 2016, Herceg Novi, September 5-10, 2016",
title = "Tumor-selective hybrid system based on hydroxyapatite nanocarrier, chitosan, poly(lactic-co-glycolic acid) and androstan derivate",
pages = "27-27",
url = "https://hdl.handle.net/21.15107/rcub_dais_896"
}

Ignjatović, N., Penov Gaši, K., Wu, V., Ajduković, J., Kojić, V. V., Vasiljević-Radović, D., Uskoković, V.,& Uskoković, D.. (2016). Tumor-selective hybrid system based on hydroxyapatite nanocarrier, chitosan, poly(lactic-co-glycolic acid) and androstan derivate. in Programme and The Book of Abstracts / Eighteenth Annual Conference YUCOMAT 2016, Herceg Novi, September 5-10, 2016
Belgrade : Materials Research Society of Serbia., 27-27.
https://hdl.handle.net/21.15107/rcub_dais_896

Ignjatović N, Penov Gaši K, Wu V, Ajduković J, Kojić VV, Vasiljević-Radović D, Uskoković V, Uskoković D. Tumor-selective hybrid system based on hydroxyapatite nanocarrier, chitosan, poly(lactic-co-glycolic acid) and androstan derivate. in Programme and The Book of Abstracts / Eighteenth Annual Conference YUCOMAT 2016, Herceg Novi, September 5-10, 2016. 2016;:27-27.
https://hdl.handle.net/21.15107/rcub_dais_896 .

Ignjatović, Nenad, Penov Gaši, Katarina, Wu, Victoria, Ajduković, Jovana, Kojić, Vesna V., Vasiljević-Radović, Dana, Uskoković, Vuk, Uskoković, Dragan, "Tumor-selective hybrid system based on hydroxyapatite nanocarrier, chitosan, poly(lactic-co-glycolic acid) and androstan derivate" in Programme and The Book of Abstracts / Eighteenth Annual Conference YUCOMAT 2016, Herceg Novi, September 5-10, 2016 (2016):27-27,
https://hdl.handle.net/21.15107/rcub_dais_896 .