title: Lipid-functionalized dextran nanosystems to overcome multidrug resistance in cancer: a pilot study.
abstract: BACKGROUND
  The toxicity of anticancer agents and the difficulty in delivering drugs selectively to tumor cells pose a challenge in overcoming multidrug resistance (MDR). Recently, nanotechnology has emerged as a powerful tool in addressing some of the barriers to drug delivery, including MDR in cancer, by utilizing alternate routes of cellular entry and targeted delivery of drugs and genes. However, it is unclear whether doxorubicin (Dox) can be delivered by nanotechnologic approaches.
  
  
  OBJECTIVE
  We asked whether (1) Dox-loaded lipid-functionalized dextran-based biocompatible nanoparticles (Dox/NP) can reverse MDR, (2) Dox/NP has more potent cytotoxic effect on MDR tumors than poly(ethylene glycol)-modified liposomal Dox (PLD), and (3) multidrug resistance protein 1 (MDR1) small interfering RNA loaded in these nanoparticles (siMDR1/NP) can modulate MDR.
  
  
  METHODS
  To create stable Dox/NP and siMDR1/NP, we used two different lipid-modified dextran derivatives. The effect of Dox or Dox/NP was tested on drug-sensitive osteosarcoma (KHOS) and ovarian cancer (SKOV-3) cell cultures in triplicate and their respective MDR counterparts KHOS(R2) and SKOV-3(TR) in triplicate. We determined the effects on drug retention, transfection efficacy of siMDR1/NP, and P-glycoprotein expression and the antiproliferative effect between Dox/NP and PLD in MDR tumor cells.
  
  
  RESULTS
  Fluorescence microscopy revealed efficient uptake of the Dox/NP and fluorescently tagged siMDR1/NP. Dox/NP showed five- to 10-fold higher antiproliferative activity at the 50% inhibitory concentration than free Dox in tumor cells. Dox/NP showed twofold higher activity than PLD in MDR tumor cells. siMDR1/NP (100 nM) suppressed P-glycoprotein expression in KHOS(R2).
  
  
  CONCLUSIONS
  Dextran-lipid nanoparticles are a promising platform for delivering Dox and siRNAs.
  
  
  CONCLUSIONS
  Biocompatible dextran-based nanoparticles that are directly translatable to clinical medicine may lead to new potential therapeutics for reversing MDR in patients with cancer.
authors.affiliation: Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, 100 Blossom St, Jackson 1115, Boston, MA 02114, USA.
authors.forename: Eisuke
authors.initials: E
authors.lastname: Kobayashi
authors.forename: Arun K
authors.initials: AK
authors.lastname: Iyer
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Hornicek
authors.forename: Mansoor M
authors.initials: MM
authors.lastname: Amiji
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Duan
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics / Q000378:metabolism; D000903:Antibiotics, Antineoplastic / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002626:Chemistry, Pharmaceutical; D003911:Dextrans / Q000737:chemistry*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D004337:Drug Carriers; D018432:Drug Resistance, Multiple / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D006801:Humans; D008055:Lipids / Q000737:chemistry*; D008856:Microscopy, Fluorescence; D036103:Nanotechnology; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D010865:Pilot Projects; D011092:Polyethylene Glycols / Q000737:chemistry; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000737:chemistry / Q000378:metabolism; D013997:Time Factors; D014162:Transfection
chemical_list: C513055:ABCB1 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000903:Antibiotics, Antineoplastic; D003911:Dextrans; D004337:Drug Carriers; D008055:Lipids; D034741:RNA, Small Interfering; D011092:Polyethylene Glycols; D004317:Doxorubicin