Hyaluronic acid-decorated liposomal nanoparticles for targeted delivery of 5-fluorouracil into HT-29 colorectal cancer cells.

The use of liposomes as drug carriers improves the therapeutic efficacy of anticancer drugs, while at the same time reducing side effects. Hyaluronic acid (HA) is recognized by the CD44 receptor, which is overexpressed in many cancer cells. In this study, we developed HA-modified liposomes encapsulating 5-fluorouracil (5-FU) and tested them against a CD44 expressing colorectal cell line (HT29) and a non-CD44 expressing hepatoma cell line. The average size of 5-FU-lipo and 5-FU-lipo-HA nanoparticles were 112 ± 28 and 144 ± 77 nm, respectively. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium (MTT) assay showed selective cancer cell death depending on the CD44 expression in a time-dependent manner. Apoptosis assays and cell-cycle analysis indicated that G0/G1 arrest occurred. The colony formation study revealed that cells treated with 5-FU-lipo and 5-FU-lipo-HA had reduced colony formation. Quantitative reverse-transcription polymerase chain reaction study showed that the oncogenic messenger RNA and microRNA levels were significantly reduced in the 5-FU-lipo-HA-treated group, while tumor suppressors were increased in that group. We suggest that optimal targeted delivery and release of 5-FU into colorectal cancer cells, renders them susceptible to apoptosis, cell-cycle arrest, and decreased colony formation.

Silencing of HMGA2 by siRNA Loaded Methotrexate Functionalized Polyamidoamine Dendrimer for Human Breast Cancer Cell Therapy.

The transcription factor high mobility group protein A2 (HMGA2) plays an important role in the pathogenesis of some cancers including breast cancer. Polyamidoamine dendrimer generation 4 is a kind of highly branched polymeric nanoparticle with surface charge and highest density peripheral groups that allow ligands or therapeutic agents to attach it, thereby facilitating target delivery. Here, methotrexate (MTX)- modified polyamidoamine dendrimer generation 4 (G4) (G4/MTX) was generated to deliver specific small interface RNA (siRNA) for suppressing HMGA2 expression and the consequent effects on folate receptor (FR) expressing human breast cancer cell lines (MCF-7, MDA-MB-231). We observed that HMGA2 siRNA was electrostatically adsorbed on the surface of the G4/MTX nanocarrier for constructing a G4/MTX-siRNA nano-complex which was verified by changing the final particle size and zeta potential. The release of MTX and siRNA from synthesized nanocomplexes was found in a time- and pH-dependent manner. We know that MTX targets FR. Interestingly, G4/MTX-siRNA demonstrates significant cellular internalization and gene silencing efficacy when compared to the control. Besides, the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay demonstrated selective cell cytotoxicity depending on the folate receptor expressing in a dose-dependent manner. The gene silencing and protein downregulation of HMGA2 by G4/MTX-siRNA was observed and could significantly induce cell apoptosis in MCF-7 and MDA-MB-231 cancer cells compared to the control group. Based on the findings, we suggest that the newly developed G4/MTX-siRNA nano-complex may be a promising strategy to increase apoptosis induction through HMGA2 suppression as a therapeutic target in human breast cancer.