Background: Poly(lactic-co-glycolic acid) (PLGA) is a biodegradable and biocompatible polymer which is widely used as a matrix to incorporate therapeutic agents. The anticancer activity of targeted folate-modified docetaxel-loaded PLGA nanoparticles (F-NP-Doc) was studied in vitro. Methods: Nanoparticles were prepared by a single-emulsion solvent-evaporation technique and characterized by physico-chemical methods. Cell survival was measured by the MTT assay and the sulforhodamine B assay. Folate receptor α expression, particle uptake and apoptosis were assessed by flow cytometry. Results: Folate-modified docetaxel-loaded PLGA nanoparticles showed high anticancer activity in vitro against HeLa cervical carcinoma cells and MCF7 breast adenocarcinoma cells overexpressing folate receptors. Targeted F-NP-Doc nanoparticles were more active compared to free docetaxel and non-targeted NP-Doc nanoparticles; in contrast, the activity of targeted nanoparticles against human fibroblasts (negative control) was significantly lower. F-NP-Doc particles, like free docetaxel, induced apoptosis in cancer cells. F-NP-Doc, but not unmodified docetaxel-loaded PLGA nanoparticles, reversed multidrug resistance of MCF7 R breast adenocarcinoma cells. High antitumor activity of F-NP-Doc has also been proven in in vivo experiments. Conclusions: The summarized experimental data brought us to the conclusion that the incorporation of docetaxel into the targeted PLGA nanoparticles dramatically improves its selectivity against cancer cells.
Purpose: To study the possibility of malignant transformation of control and irradiated mesenchymal stromal stem cells (MSC) from the bone marrow (BM) and brain (BR) and from the adipose tissue (AT) of mice and some cytokines secretion after mixed γ,neutron (γ, n) irradiation and γ-irradiation. Material and methods: MSCs were isolated and cultured according to generally accepted protocols. γ, n-irradiation was carried out by a collimated beam of neutrons and gamma rays at a special station of the nuclear reactor IR-8. MSCs were irradiated at the 29th passage at doses of 0.05; 0.5 and 2 Gy, were cultured for 10 passages and transplanted subcutaneously 1×106 cells to C57BL/6 syngeneic mice. MSCs AT were irradiated at the facility GUT-200M (60Co) at doses 1–6 Gy. The level of cytokines in the culture medium of MSC was measured by an ELISA. Results: A decrease in RBE was observed after radiation dose increasing from 0.5 to 4.0 Gy. The maximum of RBE for all MSCs, equal to 5.5, was observed at a dose of 0.5 Gy. After the dose increasing to 2 Gy an average RBE decreased to 2.5, and at dose 4.0 Gy RBE it was 2.0. Tumors were detected after 5 months after transplantation into syngeneic mice of MSC BM irradiated at doses of 0.05; 0.5 and 2 Gy. After transplantation of control MSCs BM and of control and irradiated MSCs BR and MSC AT, no tumors were detected. After subcutaneous injection of γ-irradiated at doses of 0.1; 1 and 6 Gy MSC AT, unlike MSCs BM, no tumors were detected. Histological examination of tumors revealed signs of a low-grade fibrosarcoma with active proliferation and a high degree of malignancy. Tumors contained inclusions from the derivatives of several tissues of mesenchymal origin – muscular, fatty, cartilaginous and bone. In the case of a tumor that developed after transplantation of MSCs BM exposed to γ,n-radiation at a dose of 0.05 Gy, the contact metastasis was detected in the shoulder with the penetration of tumor cells between the muscle fibers. From the tumors, the mouse fibrosarcoma cell lines were obtained. The highest level of cytokines VEGF, HGF and IL6was found in the culture medium of MSC AT. The level of TGFβ secretion was practically the same in all studied MSCs. After γ,n-irradiation an increase of VEGF secretion in MSC BM, a decrease of IL6 secretion in MSC BM and MSC BR, and an increase in its secretion in MSC AT were detected. Conclusions: The obtained results testify the high sensitivity of MSC BM to malignant transformation after ionizing irradiation and the much higher resistance of mouse MSC BR and MSC AT. The mechanisms of these differences are yet not known. The highest level of cytokines VEGF, HGF and IL6 was found in the culture medium of MSC AT. After the action of γ,n-radiation, as well as after the action of γ-radiation, the secretion profile of the investigated cytokines was changed, depending both on the dose and on the type of radiation.
Using poly(lactic-co-glycolic) acid we developed a polymeric form of niclosamide (PFN) and investigated molecular mechanisms underlying its antitumor activity against human colorectal cancer cell lines (SW837, Caco-2, COLO 320 HSR). PFN was shown to be more cytotoxic against cancer cells and less cytotoxic against normal cells (human embryonic lung fibroblasts) as compared to niclosamide. Both niclosamide and its polymeric form caused mitochondrial damage (evaluated as a decrease in rhodamine 123 accumulation) and increased the levels of reactive oxygen species, particularly mitochondrial superoxide, resulting in the oxidative damage to biomolecules. Furthermore, niclosamide and PFN induced G0/G1 cell cycle arrest.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.