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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, 3-hydroxy-16-hydroxymino-androst-5-en-17-one (A) and 3,17-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: d(50) = 138 nm for A-loaded HAp/ChOSL and d(50) = 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 dire

Mechanical milling of commercial ZnO and SnO2 was used to produce a ZnO/SnO2 composite with a high density of surface defects; in particular, zinc interstitials (Zni) and oxygen vacancies (VO). To determine the impact of surface defects on photocatalytic activity, the relative concentration ratio of bulk defects to surface defects was modified by annealing at 400 and 700 degrees C. The possible application of the ZnO/SnO2 composite as a natural sunlight and UV- light driven photocatalyst was revealed via de-colorization of methylene blue. In both cases the ZnO/SnO2 composite exhibited enhanced photocatalytic activity as compared to the pristine ZnO. In order to investigate the origin of the enhancement, the pristine metal oxides and composites were characterized using a variety of techniques, including X-ray diffraction (XRD), Raman and Fourier transform infrared (FTIR) spectroscopy, field emission scanning electron microscopy (FESEM), laser diffraction particle size analysis, Brunauer-Emmett-Teller, UV-Vis diffuse reflectance and photoluminescence spectroscopy. High-resolution transmission electron microscopy (HRTEM) and elemental mapping analyses were used to reveal the presence of SnO2 nanocrystallites on the surface of larger ZnO particles. The enhanced photocatalytic activity of the composite can be attributed to the synergetic effect of the surface defects and the ZnO/SnO2 heterojunction particles, which facilitated charge separation, thereby hindering the recombination of photogenerated carriers. This study draws attention to mechanical activation as an inexpensive and environmentally friendly technique for the large-scale production of the composite with an enhanced photocatalytic activity under illumination of either UV or sunlight.

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 17 beta-hydroxy-17 alpha-picolyl-androst-5-en-3 beta-yl-acetate (A), a chemotherapeutic derivative of androstane and a novel compound with a selective anticancer activity against lung cancer cells. H-1 NMR and C-13 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 d(50) = 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.

Doktorska disertacija obuhvata istraţivanja fundamentalnih aspekata i strategija sinteze koloidnih nanokristala, nanostruktura i submikronskih kristala nekoliko neorganskih oksidnih materijala i zlata, hidrotermalnim i solvotermalnim procesima. Motivacija za istraţivanja je opšti nauĉni interes za poznavanjem mehanizama sinteze koloidnih nanokristala i rasta kristala u hidrotermalnim i solvotermalnim uslovima u cilju uspostavljanja metoda kontrolisane sinteze homogenih i heterogenih funkcionalnih nanostruktura. Dalja istraţivanja su voĊena u dva pravca, formiranje razliĉitih struktura višeg reda supramolekulskim interakcijama i potencijalna implementacija sintetisanih materijala u praksi. Materijal koji je po obimu najviše bio zastupljen u istraţivanjima koja su obuhvaćena doktorskom disertacijom je kalcijum hidroksiapatit (HAp) i njegovi parcijalno supstituisani derivati sa jonima Co2+ (CoHAp) i Zr4+/ZrO2 (ZrHAp). Ispitana je sinteza HAp, CoHAp i ZrHAp u hidrotermalnom sistemu bez prisustva organskih supstanci. UraĊena je detaljna karakterizacija uzoraka metodama kao što su rendgenska difrakcija na prahu (XRD), laserska difrakcija (LD), atomska spektroskopija (ICP AS) i skanirajuća elektronska mikroskopija (SEM). U nastavku istraţivanja, ekstenzivno su ispitani HAp i CoHAp sa razliĉitim udelima supstituisanog kobalta u strukturi u in vitro i in vivo biološkim uslovima kao funkcionalnog materijala za reparaciju oštećenog koštanog tkiva mandibule pacova. Dobijeni rezultati pokazuju da sinergistiĉki efekti u biološkim sistemima prilikom implantacije CoHAp materijala, omogućavaju iznenaĊujuće brzu regeneraciju i povećanje gustine koštanog tkiva..., The PhD thesis includes research of the fundamental aspects and the synthetic strategies of colloidal nanocrystals, nanostructures and submicron crystals of several inorganic oxide materials and gold element obtained by hydrothermal and solvothermal processes. The motivation for the research was the general scientific interest for understanding the mechanisms of the colloidal nanocrystals synthesis and the crystal growth in hydrothermal and solvothermal conditions, in order to establish controlled synthesis of homogeneous and heterogeneous functional nanostructures. The following investigations were conducted in two directions, the first one was the formation of various structures of higher orders by supramolecular interactions, and the other was the potential implementation of the synthesized materials in practice. The most used materials in the research included in this thesis were calcium hydroxyapatite (HAp) and its derivates, the partial substituent with Co2+ (CoHAp) and Zr4+/ZrO2 (ZrHAp). The synthesis of HAp, CoHAp and ZrHAp were investigated in hydrothermal system without any presence of organic compounds. The detailed characterization of samples was performed using methods such as X – ray powder diffraction (XRD), the laser diffraction (LD), atomic spectroscopy (ICP AS) and scanning electron microscopy (SEM). In addition, the extensive study of HAp and CoHAp was conducted in vitro and in vivo in the biological environment to examine functional properties of these materials for bone damage reparation in rat’s mandible. Obtained results shows that synergistic effects in biological systems, when implanting CoHAp material, enable unexpectedly fast regeneration and improve density of bone tissue...

Inverse gas chromatography at infinite dilution was applied to determine the thermodynamic interactions of poly(l-lactide) (PLLA) and the composite of biphasic calcium phosphate and PLLA (BCP/PLLA). The specific retention volumes, , of 11 organic compounds of different chemical nature and polarity (non-polar, donor or acceptor) were determined in the temperature range of 308-378 K for PLLA and 308-398 K for BCP/PLLA. The weight fraction activity coefficients of test sorbates, , and the Flory-Huggins interaction parameters, , were estimated and discussed in terms of interactions of the sorbates with PLLA and BCP/PLLA. Also, the partial molar free energy, , the partial molar heat of mixing, , the sorption molar free energy, , the sorption enthalpy, , and the sorption entropy, , were analyzed. A different chromatographic behavior of the two investigated samples, PLLA and BCP/PLLA, was observed. The values of indicated n-alkanes, diethyl ether, tetrahydrofurane (THF), cyclohexane, benzene, dioxane (except for 338 K), and ethyl acetate (EtAc) (except for 338 K) as non-solvents, and chloroform (CHCl3) as good solvent (except for 378 K) for PLLA. For BCP/PLLA, CHCl3, EtAc (for 378 K), dioxane (except for 378 K), and THF were indicated as good solvents.

Development of a material for simultaneous sustained and localized delivery of antibiotics and induction of spontaneous regeneration of hard tissues affected by osteomyelitis stands for an important clinical need. In this work, a comparative analysis of the bacterial and osteoblastic cell response to two different nanoparticulate carriers of clindamycin, an antibiotic commonly prescribed in the treatment of bone infection, one composed of calcium phosphate and the other comprising poly-(D,L-lactide-co-glycolide)-coated calcium phosphate, was carried out. Three different non-cytotoxic phases of calcium phosphate, exhibiting dissolution and drug release profiles in the range of one week to two months to one year, respectively, were included in the analysis: monetite, amorphous calcium phosphate and hydroxyapatite. Spherical morphologies and narrow size distribution of both types of nanopowders were confirmed in transmission and scanning electron microscopic analyses. The antibiotic-containing powders exhibited sustained drug release contingent upon the degradation rate of the carrier. Assessment of the antibacterial performance of the antibiotic-encapsulated powders against Staphylococcus aureus, the most common pathogen isolated from infected bone, yielded satisfactory results both in broths and on blood agar plates for all the analyzed powders. In contrast, no cytotoxic behavior was detected upon the incubation of the antibiotic powders with the osteoblastic MC3T3-E1 cell line for up to three weeks. The cells were shown to engage in a close contact with the antibiotic-containing particles, irrespective of their internal or surface phase composition, polymeric or mineral. At the same time, both types of particles upregulated the expression of osteogenic markers osteocalcin, osteopontin, Runx2 and protocollagen type I, suggesting their ability to promote osteogenesis and enhance remineralization of the infected site in addition to eliminating the bacterial source of i

Silver nanoparticles (AgNps) were prepared by modified chemical reduction with poly (alpha, gamma, L-glutamic acid) (PGA) as capping agent. These Ag/PGA nanoparticles (AgNpPGAs) were highly stable over long periods of time without signs of precipitation. In addition to obtaining stable AgNpPGAs, a further aim was to examine their encapsulation in the poly(L-lactide-co-glycolide) (PLGA) polymer matrix. The current interest of polymer-AgNps in biomedical applications is because a versatile system must have antimicrobial activity upon target contact, without the release of toxic biocides. The synthesis of these PLGA/AgNpPGAs used physicochemical methods with solvent/non-solvent systems. Degradation of these PLGA/AgNpPGAs and the release rate of their AgNPs were studied in physiological solution over three months. The antimicrobial activity of the samples was investigated towards six laboratory control strains from the American Type Culture Collection (ATCC) and one clinical isolate methicillin-resistant Staphylococcus aureus strain by the broth microdilution method and the results showed superior and extended activity of PLGA/AgNpPGAs. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay indicated good biocompatibility of these PLGA/AgNpPGAs. The formation of intracellular reactive oxygen species was measured spectrophotometrically using a fluorescent probe, which showed that these PLGA/AgNpPGAs are not inducers of such species. The samples were characterized by UV-VIS spectrometry, X-ray diffraction, zeta potential measurements, field-emission scanning electron microscopy, and transmission electron microscopy.

In this paper, the mechanical properties of polymer matrix phase (modulus of elasticity, yield stress and work hardening rate) have been determined using combined methods such as nanoindentation, finite element modelling and artificial neural networks. The approach of neural modelling has been employed for the functional approximation of the nanoindentation load-displacement curves. The data obtained from finite element analyses have been used for the artificial neural networks training and validating. The neural model of polymer matrix phase of poly-L-lactide (PLLA) polymer in hydroxyapatite (HAp)/PLLA mechanical behaviour has been developed and tested versus unknown data related to the load-displacement curves that were not used during the neural network training. Based on this neural model, the nanoindentation matrix phase properties of PLLA polymer in HAp/PLLA composite have been predicted.

Poster presented at the 9th Conference of the Yugoslav Materials Research Society - YUCOMAT 2007, Herceg Novi, Crna Gora, September 10-14, 2007.

In this work, a combination of nanoindentation experiment and finite element modeling is proposed in order to obtain approximate material behavior of PLLA polymer in hydroxyapatite (HAp)/poly-L-lactide (PLLA) composite. Knowing these properties is important since the processing conditions used in hot pressing of composites with thermoplastic matrix strongly influence final mechanical properties of material in the solid state. A bi-linear material behavior is adopted for the polymer phase of the HAp/PLLA composite. Material behavior model, stress-strain curve, is determined by modulus of elasticity, yield stress and work-hardening rate. This combined method is proposed to determine material behavior before (modulus of elasticity) and after yield point (work hardening rate) of polymer phase after the hot-pressing of the composite. .

In order to obtain more accurate properties after compaction of hydroxyapatite (HAp)/poly-L-lactide (PLLA) composite, high-resolution measurement of mechanical properties method is proposed to determine the properties of each phase separately, leading to information that are valuable for the development of new materials as well as for predictive modeling purposes. The PLLA polymer processing conditions used in hot pressing of the composite strongly influence final mechanical properties of the material in the solid state. Since the aim was to measure PLLA material properties, acceptable findings could only be made using unconstrained, cured in situ nanoindentation tests. A finite element analysis of the in situ indentation experiment was performed to determine required size of plain polymer area, needed for indentation test, which would minimize the particle influence on the matrix elastic behavior.

A three-dimensional (31)) finite element (FE) unit cell model is applied to studies on the elastic properties of ceramic spherical particle-polymer composite. In this model, hydroxyapatite particles (HAp) are assumed to be spherical and are arranged on a face-centered cubic (FCC) array in poly-L-lactide (PLLA) matrix surrounding. The three dimensionality of the proposed model enables simulation of elastic properties as well as developed stress states. The FE calculations provide estimates of compressive elastic modulus, shear modulus, Poisson's ratio and stress state of the composite for a range of particle volume fractions. The FCC unit cell FE models are evaluated by comparison to available experimental results, simple cubic (SC) unit cell FE calculations and Halpin-Tsai equations. In applying unit cell models for predicting elastic properties of particle-filled composites, the FCC arrangement can be observed to be more accurate compared with the SC arrangement.

Na osnovu usvojenog numeričkog modela, primenom metode konačnih elemenata (MKE), analiziran je uticaj oblika, zapreminskog udela i rasporeda keramičkih čestica (HAp) u polimernoj matrici (PLLA) na modul elastičnosti kompozita. Razmatrana su tri oblika i dva rasporeda čestica u matrici. Izvršeno je poređenje tako dobijenih rezultata sa poluempirijskom metodom Halpin-Tsai i eksperimentalnim podacima. Rezultati istraživanja pokazuju da Jangov modul elastičnosti ne zavisi mnogo od oblika čestice. Sa druge strane, raspored čestica značajno utiče na modul elastičnosti (krutost) kompozita. Primećuje se da površinsko centrirani kubni (FCC) raspored čestica oblika sfere daje rezultate koji su najpribližniji eksperimentalnim podacima., The influence of particle geometry, volume fraction and particle distribution on the modulus of elasticity of a hydroxyapatite (HAp) particulate reinforced polymer (poly -L-lactide) matrix composite biomaterial was investigated through finite element (FE) analysis. Three various shapes and two types of particle distribution were considered. Calculated stiffness values from FE analysis were compared to the experimental results available in the literature and with predictions from the semi-empirical Halpin-Tsai method. The compressive Young's modulus was found to be slightly dependent on particle shape, but very sensitive to volume fraction and particle distribution. Comparisons of available experimental data of the HAp/PLLA composites with the FE model results of spherical particles with face centered cubic (FCC) array, give very good agreement.