title: Poly(lactic-co-glycolic acid) nanoparticles conjugated with CD133 aptamers for targeted salinomycin delivery to CD133+ osteosarcoma cancer stem cells.
abstract: BACKGROUND
  Cancer stem cells (CSCs) possess the characteristics associated with normal stem cells and are responsible for cancer initiation, recurrence, and metastasis. CD133 is regarded as a CSCs marker of osteosarcoma, which is the most common primary bone malignancy in childhood and adolescence. Salinomycin, a polyether ionophore antibiotic, has been shown to kill various CSCs, including osteosarcoma CSCs. However, salinomycin displayed poor aqueous solubility that hinders its clinical application. The objective of this study was to develop salinomycin-loaded nanoparticles to eliminate CD133(+) osteosarcoma CSCs.
  
  
  METHODS
  The salinomycin-loaded PEGylated poly(lactic-co-glycolic acid) nanoparticles (SAL-NP) conjugated with CD133 aptamers (Ap-SAL-NP) were developed by an emulsion/solvent evaporation method, and the targeting and cytotoxicity of Ap-SAL-NP to CD133(+) osteosarcoma CSCs were evaluated.
  
  
  RESULTS
  The nanoparticles are of desired particle size (~150 nm), drug encapsulation efficiency (~50%), and drug release profile. After 48 hours treatment of the Saos-2 CD133(+) osteosarcoma cells with drugs formulated in Ap-SAL-NP, SAL-NP, and salinomycin, the concentrations needed to kill 50% of the incubated cells were found to be 2.18, 10.72, and 5.07 μg/mL, respectively, suggesting that Ap-SAL-NP could be 4.92 or 2.33 fold more effective than SAL-NP or salinomycin, respectively. In contrast, Ap-SAL-NP was as effective as SAL-NP, and less effective than salinomycin in Saos-2 CD133(-) cells, suggesting that Ap-SAL-NP possess specific cytotoxicity toward Saos-2 CD133(+) cells. Ap-SAL-NP showed the best therapeutic effect in Saos-2 osteosarcoma xenograft mice, compared with SAL-NP or salinomycin. Significantly, Ap-SAL-NP could selectively kill CD133(+) osteosarcoma CSCs both in vitro and in vivo, as reflected by the tumorsphere formation and proportion of Saos-2 CD133(+) cells.
  
  
  CONCLUSIONS
  Our results suggest that CD133 is a potential target for drug delivery to osteosarcoma CSCs and that it is possible to significantly inhibit the osteosarcoma growth by killing CD133(+) osteosarcoma CSCs. We demonstrated that Ap-SAL-NP have the potential to target and kill CD133(+) osteosarcoma CSCs.
authors.affiliation: Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Miaozhong
authors.initials: M
authors.lastname: Ni
authors.affiliation: Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Min
authors.initials: M
authors.lastname: Xiong
authors.affiliation: Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Xinchao
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Guoping
authors.initials: G
authors.lastname: Cai
authors.affiliation: International Joint Cancer Institute, The Second Military Medical University, Shanghai, People's Republic of China.
authors.forename: Huaiwen
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Qingmin
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: Department of Orthopedics, Jinshan Hospital, Fudan University, Shanghai, People's Republic of China.
authors.forename: Zuochong
authors.initials: Z
authors.lastname: Yu
mesh_terms: D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D052157:Aptamers, Nucleotide / Q000737:chemistry / Q000235:genetics / Q000493:pharmacokinetics / Q000494:pharmacology; D045744:Cell Line, Tumor; D006023:Glycoproteins / Q000235:genetics / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry*; D051379:Mice; D053758:Nanoparticles / Q000737:chemistry*; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism; D012516:Osteosarcoma / Q000378:metabolism*; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011714:Pyrans / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D023041:Xenograft Model Antitumor Assays; D000095662:Polyether Polyketides
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D052157:Aptamers, Nucleotide; D006023:Glycoproteins; D019344:Lactic Acid; D010455:Peptides; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011714:Pyrans; C000606024:Prom1 protein, mouse; C000606025:Prom1 protein, rat; C010327:salinomycin; D000095662:Polyether Polyketides
keywords: cancer initiating cells; ligand-conjugated nanomedicines; targeted therapy
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