betadex and Osteosarcoma

Combination therapy is a promising and prevalent strategy for osteosarcoma treatment. Curcumin (CUR), as a chemosensitizer, improves the antitumor effect of first‑line chemotherapy drugs. However, due to its poor solubility and instability in physiological conditions, the bioavailability of CUR is limited. In order to improve the physicochemical properties of natural CUR, β‑cyclodextrin was adopted to generate a β‑cyclodextrin curcumin (CD‑CUR) inclusion complex. A thermosensitive hydrogel, poly(D,L‑lactide‑co‑glycolide)-poly(ethylene‑glycol)‑poly(D,L‑lactide‑co‑glycolide), was selected and synthesized to co‑deliver doxorubicin (DOX) and CD‑CUR to tumor sites. The dual‑drug delivery system (gel+DOX+CD‑CUR) was prepared by mixing drugs with hydrogels and had a perfect sol‑gel phase transition temperature (18.3˚C for 20% concentration). Both DOX and CUR were released from hydrogels in a sustained manner in PBS (pH 7.4) medium. The combination therapy based on DOX+CD‑CUR exhibited higher antitumor activity than monotherapies in vitro. Combined CD‑CUR therapy significantly downregulated Bcl‑2 expression and upregulated caspase‑3 expression, suggesting that DOX combined with CD‑CUR treatment has a higher apoptosis‑inducing efficiency. The antitumor efficiency of the gel+DOX+CD‑CUR strategy was evaluated in K‑7 tumor‑bearing mice, and this localized combination therapy demonstrated a higher antitumor efficiency compared with free DOX+CD‑CUR or single‑drug strategies. There were no significant differences in body weight and histological changes of major organs in each group. Therefore, the present combination treatment based on hydrogel may be a feasible approach to co‑deliver DOX and CD‑CUR to osteosarcoma tumor sites in clinical practice.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; beta-Cyclodextrins; Bone Neoplasms; Cell Line, Tumor; Curcumin; Disease Models, Animal; Doxorubicin; Drug Carriers; Drug Compounding; Feasibility Studies; Female; Humans; Hydrogels; Injections, Intralesional; Mice; Nanoparticles; Osteosarcoma; Polyesters; Polyethylene Glycols

The complex Ru([9]aneS(3))(gly)Cl (gly = glycine) was obtained from the reaction of the precursor Ru([9]aneS(3))dmsoCl(2) with glycine and encapsulated into native beta-CD, a hydroxypropylated derivative HPbetaCD, and the methylated cyclodextrins TRIMEB and CRYSMEB. All four inclusion compounds were obtained with a 1:1 host:guest stoichiometry and characterised in the solid-state by powder X-ray diffraction, thermogravimetric analysis (TGA), and (13)C{(1)H} CP/MAS NMR and FTIR spectroscopies. The cytostatic and antiproliferative activity of the complex Ru([9]aneS(3))(gly)Cl and its four CD inclusion compounds was tested on the human osteosarcoma MG-63 cell line and the results compared to the inhibitory effect exerted by the pure cyclodextrins.

Topics: Antineoplastic Agents; beta-Cyclodextrins; Bone Neoplasms; Cell Line, Tumor; Cell Proliferation; Coordination Complexes; Glycine; Humans; Osteosarcoma

The in vitro osteogenic effects of fluoride have not always been consistently observed in human bone cells. The present study sought to test if dexamethasone (Dex) could potentiate the action of fluoride to increase the detectability of the stimulatory effects of fluoride on [3H]thymidine incorporation, alkaline phosphatase (ALP) specific activity, collagen synthesis, and osteocalcin secretion in human TE85 osteosarcoma cells. Neither Dex at 10(-10)-10(-6) M or fluoride at a mitogenic dose (100 microM) had any consistent stimulatory effects on thymidine incorporation. When the cells were treated with both agents simultaneously, significant and highly reproducible stimulations were observed. The mitogenic effects of the two agents were confirmed with cell number counting. Analysis of variance (ANOVA) revealed a significant interaction (P < 0.001) between fluoride and Dex on cell proliferation. The enhancing effect of Dex on [3H]thymidine incorporation was not due to a shift of the optimal dose response of fluoride. Though fluoride alone or Dex alone also had no consistent effect on ALP specific activity, the co-treatment with fluoride and Dex for 24 hours produced significant (P < 0.001, ANOVA) stimulation in ALP specific activity. Fluoride alone had no consistent effect on collagen synthesis and on 1, 25(OH)2D3-dependent osteocalcin secretion, whereas Dex treatment consistently inhibited these two osteoblastic parameters in a dose-dependent manner. However, both the collagen synthesis and osteocalcin secretion rates were significantly higher (P < 0.001 ANOVA for each) when the cells were co-treated with Dex and fluoride (100 microM) than when they were treated with Dex alone. Thus, these data indicate that the response in collagen synthesis and osteocalcin secretion to fluoride stimulation was more readily observed in the presence of Dex than in its absence. ANOVA analysis revealed that the interaction between fluoride and Dex on collagen synthesis, but not the 1,25(OH)2D3-dependent osteocalcin secretion, was significant (P < 0.02). In summary, we have demonstrated for the first time that in TE85 cells (1) Dex potentiated the effects of fluoride on cell proliferation, ALP specific activity, and collagen synthesis; (2) while Dex at 10(-7)-10(-6) M alone inhibited the collagen synthesis and at 10(-9)-10(-6) M reduced osteocalcin secretion, Dex at 10(-8)-10(-6) M significantly stimulated the proliferation of TE85 cells; and (3) Dex interacted with fluoride t

Topics: Alkaline Phosphatase; beta-Cyclodextrins; Calcitriol; Cell Division; Collagen; Cyclodextrins; Dexamethasone; Dose-Response Relationship, Drug; Drug Synergism; Fluorides; Glucocorticoids; Humans; Osteocalcin; Osteogenesis; Osteosarcoma; Thymidine; Tritium; Tumor Cells, Cultured