Functionalization of Octacalcium Phosphate Bone Graft with Cisplatin and Zoledronic Acid: Physicochemical and Bioactive Properties.

Bones are the fourth most frequent site of metastasis from malignant tumors, including breast cancer, prostate cancer, melanoma, etc. The bioavailability of bone tissue for chemotherapy drugs is extremely low. This requires a search for new approaches of targeted drug delivery to the tumor growth zone after surgery treatment. The aim of this work was to develop a method for octacalcium phosphate (OCP) bone graft functionalization with the cytostatic drug cisplatin to provide the local release of its therapeutic concentrations into the bone defect. OCP porous ceramic granules (OCP ceramics) were used as a platform for functionalization, and bisphosphonate zoledronic acid was used to mediate the interaction between cisplatin and OCP and enhance their binding strength. The obtained OCP materials were studied using scanning electron and light microscopy, high-performance liquid chromatography, atomic emission spectroscopy, and real-time PCR. In vitro and in vivo studies were performed on normal and tumor cell lines and small laboratory animals. The bioactivity of initial OCP ceramics was explored and the efficiency of OCP functionalization with cisplatin, zoledronic acid, and their combination was evaluated. The kinetics of drug release and changes in ceramics properties after functionalization were studied. It was established that zoledronic acid changed the physicochemical and bioactive properties of OCP ceramics and prolonged cisplatin release from the ceramics. In vitro and in vivo experiments confirmed the biocompatibility, osteoconductivity, and osteoinductivity, as well as cytostatic and antitumor properties of the obtained materials. The use of OCP ceramics functionalized with a cytostatic via the described method seems to be promising in clinics when primary or metastatic tumors of the bone tissue are removed.

Human Platelet Lysate Sustains the Osteogenic/Adipogenic Differentiation Potential of Adipose-Derived Mesenchymal Stromal Cells and Maintains Their DNA Integrity in vitro.

Human platelet lysate (HPL) is a promising alternative to fetal calf serum (FCS) for the expansion of adipose tissue mesenchymal stromal cells (AT-MSCs) for translational medicine applications. However, some biological effects of HPL are still to be elucidated. We aimed to compare complex characteristics, such as cell morphology, proliferative activity, differentiation potential, and especially monolayer recovery, DNA integrity, and the gene expression pattern, between AT-MSCs cultured with HPL or FCS. Primary AT-MSC cultures were expanded in medium containing FCS or pooled HPL. Cell growth and proliferation were estimated by cell doubling time and the monolayer formation rate, while migration was assessed by wound-healing assay. The capacity for adipogenic and osteogenic differentiation was evaluated by alkaline phosphatase and Oil Red O staining. DNA integrity was evaluated by comet assay, and analysis of gene expression by real-time PCR. Media supplemented with HPL or FCS provided a similar surface immunophenotype, cell morphology (except some cell dimensions and a bigger colony size in HPL), DNA integrity, and rate of wound healing. Meanwhile, AT-MSC proliferated more intensively in HPL-supplemented media (especially at 5% HPL) and had a reduced doubling population time. AT-MSC in HPL had increased adipogenic potential and similar osteogenic potential in comparison with FCS. Our results indicate the feasibility and evident prospects for the use of pooled HPL as an alternative to FCS and safe non-xenogenic growth supplement for ex vivo expansion of clinical-grade AT-MSCs for regenerative medicine purposes.

Breast cancer organoid model allowed to reveal potentially beneficial combinations of 3,3'-diindolylmethane and chemotherapy drugs.

Epigenetic alterations represent promising therapeutic targets in cancer treatment. Recently it was revealed that small molecules have the potential to act as microRNA silencers. Capacity to bind the discrete stem-looped structure of pre-miR-21 and prevent its maturation opens opportunities to utilize such compounds for the prevention of initiation, progression, and chemoresistance of cancer. Molecular simulations performed earlier identified 3,3'-diindolylmethane (DIM) as a potent microRNA-21 antagonist. However, data on DIM and microRNA-21 interplay is controversial, which may be caused by the limitations of the cell lines.