Nenad L Ignjatović1, Katarina M Penov-Gaši2, Victoria M Wu3, Jovana J Ajduković2, Vesna V Kojić4, Dana Vasiljević-Radović5, Maja Kuzmanović1, Vuk Uskoković6, Dragan P Uskoković7. 1. Institute of Technical Sciences of the Serbian Academy of Science and Arts, Knez Mihailova 35/IV, P.O. Box 377, 11000 Belgrade, Serbia. 2. University of Novi Sad, Faculty of Sciences, Department of Chemistry, Biochemistry and Environmental Protection, Trg Dositeja Obradovića 3, 21000 Novi Sad, Serbia. 3. Advanced Materials and Nanobiotechnology Laboratory, Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, 9401 Jeronimo Road, Irvine, CA 92618-1908, USA. 4. University of Novi Sad, Faculty of Medicine, Oncology Institute of Vojvodina, Dr Goldmana 4, 21204 Sremska Kamenica, Serbia. 5. University of Belgrade, Institute for Chemistry, Technology and Metallurgy, Njegoševa 12, Belgrade, Serbia. 6. Advanced Materials and Nanobiotechnology Laboratory, Department of Biomedical and Pharmaceutical Sciences, School of Pharmacy, Chapman University, 9401 Jeronimo Road, Irvine, CA 92618-1908, USA; Department of Bioengineering, University of Illinois, 851 South Morgan Street, Chicago, IL 60607-7052, USA. Electronic address: uskokovi@chapman.edu. 7. Institute of Technical Sciences of the Serbian Academy of Science and Arts, Knez Mihailova 35/IV, P.O. Box 377, 11000 Belgrade, Serbia. Electronic address: dragan.uskokovic@itn.sanu.ac.rs.
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 7.47wt.%. 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=168nm. 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.
In an earlier study we demonstrated that hydroxyapatite nanoparticles n class="Chemical">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. 1HNMR and 13CNMR 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 7.47wt.%. 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=168nm. 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 A549humanlung carcinoma cell line (46±2%), while simultaneously preserving high viability (83±3%) of regular MRC5human 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.
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