title: CD44 targeted chemotherapy for co-eradication of breast cancer stem cells and cancer cells using polymeric nanoparticles of salinomycin and paclitaxel.
abstract: This combinational therapy is mainly aimed for complete eradication of tumor by killing both cancer cells and cancer stem cells. Salinomycin (SLM) was targeted towards cancer stem cells whereas paclitaxel (PTX) was used to kill cancer cells. Drug loaded poly (lactic-co-glycolic acid) nanoparticles were prepared by emulsion solvent diffusion method using cationic stabilizer. Size of the nanoparticles (below 150nm) was determined by dynamic light scattering technique and transmission electron microscopy. In vitro release study confirmed the sustained release pattern of SLM and PTX from nanoparticles more than a month. Cytotoxicity studies on MCF-7 cells revealed the toxicity potential of nanoparticles over drug solutions. Hyaluronic acid (HA) was coated onto the surface of SLM nanoparticles for targeting CD44 receptors over expressed on cancer stem cells and they showed the highest cytotoxicity with minimum IC50 on breast cancer cells. Synergistic cytotoxic effect was also observed with combination of nanoparticles. Cell uptake studies were carried out using FITC loaded nanoparticles. These particles showed improved cellular uptake over FITC solution and HA coating further enhanced the effect by 1.5 folds. CD44 binding efficiency of nanoparticles was studied by staining MDA-MB-231 cells with anti CD44 human antibody and CD44(+) cells were enumerated using flow cytometry. CD44(+) cell count was drastically decreased when treated with HA coated SLM nanoparticles indicating their efficiency towards cancer stem cells. Combination of HA coated SLM nanoparticles and PTX nanoparticles showed the highest cytotoxicity against CD44(+) cells. Hence combinational therapy using conventional chemotherapeutic drug and cancer stem cell inhibitor could be a promising approach in overcoming cancer recurrence due to resistant cell population.
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad 500037, India.
authors.forename: Eameema
authors.initials: E
authors.lastname: Muntimadugu
authors.affiliation: UGC Centre of Excellence in Applications of Nanomaterials, Nanoparticles, and Nanocomposites, Panjab University, Chandigarh 160014, India.
authors.forename: Rajendra
authors.initials: R
authors.lastname: Kumar
authors.affiliation: Department of Pharmaceutical Analysis, National Institute of Pharmaceutical Education and Research, Hyderabad 500037, India.
authors.forename: Shantikumar
authors.initials: S
authors.lastname: Saladi
authors.affiliation: Biochemistry, Cellular and Molecular Biology Laboratories, Central Research Institute of Unani Medicine (CRIUM), Hyderabad 500038, India.
authors.forename: Towseef Amin
authors.initials: TA
authors.lastname: Rafeeqi
authors.affiliation: Department of Pharmaceutics, National Institute of Pharmaceutical Education and Research, Hyderabad 500037, India. Electronic address: wahid.niperhyd@gov.in.
authors.forename: Wahid
authors.initials: W
authors.lastname: Khan
mesh_terms: D000906:Antibodies / Q000737:chemistry; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D004337:Drug Carriers; D004339:Drug Compounding; D065546:Drug Liberation; D005260:Female; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D015870:Gene Expression; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry* / Q000235:genetics / Q000276:immunology; D006820:Hyaluronic Acid / Q000737:chemistry; D019344:Lactic Acid / Q000737:chemistry; D061986:MCF-7 Cells; D058990:Molecular Targeted Therapy / Q000379:methods*; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D017239:Paclitaxel / Q000737:chemistry / Q000494:pharmacology*; D010316:Particle Size; D011100:Polyglycolic Acid / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011714:Pyrans / Q000737:chemistry / Q000494:pharmacology*; D000095662:Polyether Polyketides
chemical_list: D000906:Antibodies; D000970:Antineoplastic Agents; D004337:Drug Carriers; D016650:Fluorescein-5-isothiocyanate; D005456:Fluorescent Dyes; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D019344:Lactic Acid; D017239:Paclitaxel; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011714:Pyrans; C497483:CD44 protein, human; C010327:salinomycin; D000095662:Polyether Polyketides
keywords: CD44 receptors; Cancer stem cells; Combinational chemotherapy; Hyaluronic acid; Paclitaxel; Polymeric nanoparticles; Salinomycin