RESUMO
Osteosarcoma describes a tumor of mesenchymal origin with an annual incidence rate of four to five people per million. Even though chemotherapy treatment has shown success in non-metastatic osteosarcoma, metastatic disease still has a low survival rate of 20%. A targeted therapy approach is limited due to high heterogeneity of tumors, and different underlying mutations. In this review, we will summarize new advances obtained by new technologies, such as next generation sequencing and single-cell sequencing. These new techniques have enabled better assessment of cell populations within osteosarcoma, as well as an understanding of the molecular pathogenesis. We also discuss the presence and properties of osteosarcoma stem cells-the cell population within the tumor that is responsible for metastasis, recurrence, and drug resistance.
RESUMO
The aim of this work was to prepare bimetallic chitosan microgels with high sphericity and investigate the influences of metal-ion type and content on the size, morphology, swelling, degradation and biological properties of microgels. Amino and hydroxyl groups of chitosan (deacetylation degree, DD, of 83.2% and 96.9%) served as ligands in the Cu2+-Zn2+/chitosan complexes with various contents of cupric and zinc ions. The electrohydrodynamic atomization process was used to produce highly spherical microgels with a narrow size distribution and with surface morphology changing from wrinkled to smooth by increasing Cu2+ ions' quantity in bimetallic systems for both used chitosans. The size of the bimetallic chitosan particles was estimated to be between 60 and 110 µm for both used chitosans, and FTIR spectroscopy indicated the formation of complexes through physical interactions between the chitosans' functional groups and metal ions. The swelling capacity of bimetallic chitosan particles decreases as the DD and copper (II) ion content increase as a result of stronger complexation with respect to zinc (II) ions. Bimetallic chitosan microgels showed good stability during four weeks of enzymatic degradation, and bimetallic systems with smaller amounts of Cu2+ ions showed good cytocompatibility for both used chitosans.
RESUMO
Polymer hydrogels crosslinked by therapeutic metal ions have attracted increased interest in recent years due to their unique and versatile properties. Chitosan hydrogels are widely investigated for various biomedical applications such as tissue engineering and drug delivery. Copper and zinc ions are considered as therapeutic metal ions, that have important roles in bone regeneration. The aim of this study was to investigate the physicochemical and biological properties of bimetallic-chitosan complex hydrogels with different cupric and zinc ions content. Scanning electron microscopy (SEM) revealed changes in the morphology from the microstructure with larger, tubular pores for aerogels with higher Zn content, to the sheets-like structure with long pores for samples with higher Cu content. FTIR analysis indicated the formation of bimetallic-chitosan aerogels. The obtained X-ray diffraction patterns showed a broadening of chitosan's characteristic diffraction maximum, while characterization of physical properties showed decreased swelling ability and increased shear modulus with higher Cu content. ICP-MS results showed a negligible amount of copper and zinc ions released under physiological conditions during 24 h indicating a strong physical crosslink between metal ions and chitosan chains. Furthermore, accelerated in vitro degradation showed that hydrogels maintained good stability during four weeks of lysozyme activity. The MTT assay indicated that the cytotoxicity of Cu2+-Zn2+/chitosan complexes could be adjusted by the amount of cupric ions. All results imply that Cu2+ and Zn2+ ions act as physical crosslinkers of the polymer network. Also, results are in agreement with the prediction of density functional theory (DFT) which indicated stronger chitosan-Cu tetrahedral aqua complex interactions in comparison to the chitosan-[Zn(H2O)4]2+ interactions.
RESUMO
Biologically compatible chitosan-based scaffolds have been considered a promising platform for tissue regeneration, tumor treatment, and targeted drug delivery. Chitosan-based scaffolds can be utilized as pH-sensitive drug carriers with targeted drug delivery resulting in less invasive tumor treatments. Further improvement with bioactive ions, such as borate ions, can result in the dual functionality of chitosan carriers provided by simultaneous antitumor efficacy and tissue regeneration. Here, boric acid-containing crosslinked chitosan scaffolds were prepared as delivery systems of doxorubicin, a chemotherapy drug used in the treatment of osteosarcoma. The encapsulation of boric acid was indicated by FTIR spectroscopy, while the ICP-MS analysis indicated the rapid release of boron in phosphate buffer (pH 6.0) and phosphate-buffered saline solution (pH 7.4). The obtained chitosan-boric acid scaffolds exhibit a highly porous and interconnected structure responsible for high swelling capacity, while enzymatic degradation indicated good scaffolds stability during four weeks of incubation at pH 6.0 and 7.4. Furthermore, the release of doxorubicin investigated in phosphate buffers indicated lower doxorubicin concentrations at pH 7.4 with respect to pH 6.0. Finally, the cytotoxicity of prepared doxorubicin-encapsulated scaffolds was evaluated on human sarcoma cells indicating the scaffolds' potential as cytostatic agents.