title: Double targeting and aptamer-assisted controlled release delivery of epirubicin to cancer cells by aptamers-based dendrimer in vitro and in vivo.
abstract: Clinical use of epirubicin (Epi) in the treatment of cancer has been limited, due to its cardiotoxicity. Targeted delivery of chemotherapeutic agents could increase their efficacy and reduce their off-target effects. High drug loading and excellent stability of DNA dendrimers make these DNA nanostructures unique candidates for biological applications. In this study a modified and promoted dendrimer using three kinds of aptamers (MUC1, AS1411 and ATP aptamers) was designed for targeted delivery of Epi and its efficacy was evaluated in target cells including MCF-7 cells (breast cancer cell) and C26 cells (murine colon carcinoma cell). Aptamers (Apts)-Dendrimer-Epi complex formation was analyzed by fluorometric analysis and gel retardation assay. Release profiles of Epi from the designed complex were assessed at pHs 5.4 and 7.4. For MTT assay (cytotoxic study) MCF-7 and C26 cells (target cells) and CHO cells (Chinese hamster ovary cell, nontarget) were treated with Epi, Apts-Dendrimer-Epi complex and Apts-Dendrimer conjugate. Internalization was evaluated using flow cytometry analysis. Finally, the developed complex was used for inhibition of tumor growth in vivo. 25μM Epi was efficiently intercalated to 1μM dendrimer. Epi was released from the Apts-Dendrimer-Epi complex in a pH-sensitive manner (more release at pH 5.5). The results of flow cytometry analysis indicated that the designed complex was efficiently internalized into target cells, but not into control cells. The internalization data were confirmed by the results of MTT assay. Apts-Dendrimer-Epi complex had less cytotoxicity in CHO cells compared to Epi alone. The complex had more cytotoxicity in C26 and MCF-7 cells compared to Epi alone. Moreover, the Apts-Dendrimer-Epi complex could efficiently prohibit tumor growth in vivo. In conclusion, the designed targeted drug delivery system inherited characteristics of pH-dependent drug release, high drug loading and tumor targeting in vitro and in vivo.
authors.affiliation: Targeted Drug Delivery Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Seyed Mohammad
authors.initials: SM
authors.lastname: Taghdisi
authors.affiliation: Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Research Institute of Sciences and New Technology, Mashhad, Iran.
authors.forename: Noor Mohammad
authors.initials: NM
authors.lastname: Danesh
authors.affiliation: Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: ramezanim@mums.ac.ir.
authors.forename: Mohammad
authors.initials: M
authors.lastname: Ramezani
authors.affiliation: Academic Center For Education, Culture and Research (ACECR)-Mashhad Branch, Mashhad, Iran; Department of Chemistry, Ferdowsi University of Mashhad, Mashhad, Iran.
authors.forename: Parirokh
authors.initials: P
authors.lastname: Lavaee
authors.affiliation: Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran; Academic Center For Education, Culture and Research (ACECR)-Mashhad Branch, Mashhad, Iran.
authors.forename: Seyed Hamid
authors.initials: SH
authors.lastname: Jalalian
authors.affiliation: Department of Pharmaceutical Biotechnology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
authors.forename: Rezvan Yazdian
authors.initials: RY
authors.lastname: Robati
authors.affiliation: Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran. Electronic address: abnouskh@mums.ac.ir.
authors.forename: Khalil
authors.initials: K
authors.lastname: Abnous
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000737:chemistry*; D052157:Aptamers, Nucleotide / Q000008:administration & dosage / Q000737:chemistry*; D016466:CHO Cells; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000737:chemistry*; D050091:Dendrimers / Q000008:administration & dosage / Q000737:chemistry*; D016503:Drug Delivery Systems / Q000379:methods; D015251:Epirubicin / Q000008:administration & dosage* / Q000737:chemistry*; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D049329:Nanostructures / Q000008:administration & dosage / Q000737:chemistry
chemical_list: D000970:Antineoplastic Agents; D052157:Aptamers, Nucleotide; D003692:Delayed-Action Preparations; D050091:Dendrimers; D015251:Epirubicin
keywords: Aptamer; Cancer; Dendrimer; Epirubicin; Targeted delivery