title: In vivo tumor targeting and anti-tumor effects of 5-fluororacil loaded, folic acid targeted quantum dot system.
abstract: In this study, we modulated the anti-cancer efficacy of 5-Fluorouracil (5-FU) using a carrier system with enhanced targeting efficacy towards folate receptors (FRs) expressing malignant tissues. The 5-FU drug was loaded onto Mn-ZnS quantum dots (QDs) encapsulated with chitosan (CS) biopolymer and conjugated with folic acid (FA) based on a simple wet chemical method. The formation of 5-FU drug loaded composite was confirmed using Fourier transform infrared spectroscopy (FTIR), thermo gravimetric analysis (TGA) and differential scanning calorimetry (DSC). Furthermore, the in vivo biodistribution and tumor targeting specificity of the 5-FU@FACS-Mn:ZnS in the tumor-bearing mice was conducted based on the Zn(2+) tissue bioaccumulation using inductively coupled plasma (ICP) spectroscopy. In addition to the characterization, the in vitro release profile of 5-FU from the conjugates investigated under diffusion controlled method demonstrated a controlled release behaviour as compared against the release behaviour of free 5-FU drug. The as-synthesized 5-FU@FACS-Mn:ZnS nanoparticle (NP) systemically induced higher level of apoptosis in breast cancer cells in vitro as compared to cells treated with free 5-FU drug following both cell cycle and annexin assays, respectively. Also, the in vivo toxicity assessment of the 5-FU@FACS-Mn:ZnS NPs as compared to the control did not cause any significant increase in the activities of the liver and kidney function biomarkers, malondialdehyde (MDA) and nitric oxide (NO) levels. However, based on the FA-FRs chemistry, the 5-FU@FACS-Mn:ZnS NPs specifically accumulated in the tumor of the tumor-bearing mice and thus contributed to the smaller tumor size and less event of metastasis was observed in the lungs when compared to the tumor-bearing mice groups treated with the free 5-FU drug. In summary, the results demonstrated that the 5-FU@FACS-Mn:ZnS QDs exhibits selective anti-tumor effect in MDA-MB231 breast cancer cells in vitro and 4TI breast cancer cells in vivo, providing a blueprint for improving the 5-FU efficacy and tumor targeting specificity with limited systemic toxicity.
authors.affiliation: Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia.
authors.forename: Ibrahim Birma
authors.initials: IB
authors.lastname: Bwatanglang
authors.affiliation: Institute of Advanced Technology, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia. Electronic address: farooqm1983@gmail.com.
authors.forename: Faruq
authors.initials: F
authors.lastname: Mohammad
authors.affiliation: Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia; Institute of Advanced Technology, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia. Electronic address: azahy@upm.edu.my.
authors.forename: Nor Azah
authors.initials: NA
authors.lastname: Yusof
authors.affiliation: Department of Chemistry, Faculty of Science, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia.
authors.forename: Jaafar
authors.initials: J
authors.lastname: Abdullah
authors.affiliation: Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia.
authors.forename: Noorjahan Banu
authors.initials: NB
authors.lastname: Alitheen
authors.affiliation: Institute of Advanced Technology, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia.
authors.forename: Mohd Zubir
authors.initials: MZ
authors.lastname: Hussein
authors.affiliation: Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia.
authors.forename: Nadiah
authors.initials: N
authors.lastname: Abu
authors.affiliation: Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia.
authors.forename: Nurul Elyani
authors.initials: NE
authors.lastname: Mohammed
authors.affiliation: Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia.
authors.forename: Noraini
authors.initials: N
authors.lastname: Nordin
authors.affiliation: Department of Cell and Molecular Biology, Faculty of Biotechnology and Biomolecular Science, Universiti Putra Malaysia, Serdang, Selangor 43400, Malaysia.
authors.forename: Nur Rizi
authors.initials: NR
authors.lastname: Zamberi
authors.affiliation: Institute of Bioscience, University Putra Malaysia, Serdang, Selangor, Malaysia.
authors.forename: Swee Keong
authors.initials: SK
authors.lastname: Yeap
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005472:Fluorouracil / Q000737:chemistry / Q000494:pharmacology*; D005492:Folic Acid / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D045663:Quantum Dots; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D005492:Folic Acid; D005472:Fluorouracil
keywords: 5-Fluorouracil delivery; Anti-tumor; Folic acid; Mn:ZnS quantum dots; Targeted delivery; Theranostics