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Targeted Selenium Nanoparticles as Carriers of Anticancer Drugs and Their Apoptosis-Inducing Activities

Author: LiuZuo
Tutor: ZhengWenJie; ChenTianFeng
School: Jinan University
Course: Inorganic Chemistry
Keywords: Selenium nanoparticles 5-Fluorouracil Doxorubicin Transferrin Apoptosis
CLC: TQ463
Type: Master's thesis
Year: 2012
Downloads: 173
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Abstract


Selenium nanopaticles (SeNPs), a novel Se species with low toxicity andexcellent biological performance, could be modified through coupling or adsorptionof molecules to the surface of the nanoparticles. In order to develop the function ofSeNPs as anticancer drug carrier, and to enhance their targetting effects against cancercells, in this study, we designed a drug delivery system by using SeNPs as a carrier ofanticancer drugs, including5-fluorouracil and doxorubicin. Moreover, the preparationof targetting SeNPs and the in vitro anticancer activity were also examined. The size,morphology and stability of the as-prepared products were examined by SEM, TEM,HR-TEM and Nano-ZS. The interaction pattern and modulation mechanism betweenSeNPs and the anticancer drugs or targeting molecules were examined by SEM-EDX,FTIR and XPS. The in vitro anticancer activity and the underlying mechanisms ofSeNPs against human cancer cells were also examined by MTT assay against anumber of human cancer and normal cell lines, flow cytometric analysis, PI doublestaining, TUNEL-DAPI co-staining assay.(1) Selenium nanoparticles as a carrier of5-fluorouracil to achieve anticancersynergism5-Fluorouracil (5FU) surface-functionalized Se nanoparticles (5FU-SeNPs) werepreparation by redox reaction of selenite with vitamin C. SeNPs were capped with5FU through formation of Se-O and Se-N bonds and physical adsorption, leading tothe highly stable structure of the conjugates.5FU-SeNPs presented monodisperse andhomogeneous spherical structure with an average diameter of about100nm andmaintained stable until the time of160h in aqueous solutions. A panel of five humancancer cell lines was shown to be susceptible to5FU-SeNPs, with IC50values rangingfrom6.2to14.4μM. Despite this potency,5FU-SeNPs possessed great selectivitybetween cancer and normal cells. According to the results of flow cytometry,TUNEL-DAPI co-staining assay, Western blot analysis, we showed that,5FU-SeNPsinduced caspase-dependent apoptosis in cancer cells by triggering the intrinsicapoptotic pathway with the involvement of ROS generation. Moreover, the growthinhibitory effect of5FU-SeNPs against cancer cells was strongly synergistic.Therefore,5FU-SeNPs may be a candidate for further evaluation as achemopreventive and chemotherapeutic agent for human cancers, especially melanoma.(2) Chitosan as the surface decorator of doxorubicin-loaded SeNPs to enhancecellular uptake and anticancer activitiesIn this study, chitosan was used as stabilizer and coated agent ofdoxorubicin-loaded SeNPs to enhance their cellular uptake and anticancer activities.The results revealed that SeNPs-DOX-CS formed more compact and stable globularand high drug loadings nanocomposites after CS surface decoration. A panel of threehuman cancer cell lines was shown to be susceptible to SeNPs-DOX-CS, with IC50values ranging from7.54to13.01μM. Despite this potency, SeNPs-DOX-CSpossessed great selectivity between cancer and normal cells. Moreover, flowcytometric analysis, caspase activity and Western blot analysis were employed toexamine the action mechanisms of SeNPs-DOX-CS. The results revealed thatSeNPs-DOX-CS inhibited cancer cell growth through induction of caspase-mediatedapoptosis by triggering both of the intrinsic and extrinsic apoptotic pathways.SeNPs-DOX-CS may be a candidate for further evaluation as a chemotherapeuticagent for human breast cancer.(3) Design and preparation of cancer-targeting SeNPsIn this study, cancer-targeted SeNPs were prepared conjugation of transferrin tochitosan-stabilized SeNPs (TF-SeNPs) through formation of chemical bonds. The size,morphology and stability of TF-SeNPs were examined by SEM, TEM and Nano-ZS.The interaction pattern and modulation mechanism between SeNPs with chitosan andTF were examined by SEM-EDX and FTIR. Our results revealed that the dehydrationreaction between the-NH2group of CS and carboxyl of TF resulted in the conjugationof TF to SeNPs, and thus led to formation of the highly stable structure of theconjugates. Furthermore, we showed that, TF conjugation significantly enhanced thecellular uptake of SeNPs in cancer cells, and lowered their uptake in normal cells.There results indicate the achievement of selectivity of SeNPs between human cancerand normal cells by conjugation of TF.

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