title: Riboflavin-targeted polymer conjugates for breast tumor delivery.
abstract: OBJECTIVE
  In breast cancer, a significant decrease in riboflavin (RF) serum levels and increase in RF carrier protein occurs, indicating a potential role of RF in disease progression. To evaluate RF's ability to serve as a targeting agent, mitomycin C (MMC)-conjugated N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers were synthesized and targeted to the RF internalization pathway in human breast cancer cells.
  
  
  METHODS
  Competitive uptake studies were used to determine specificity of RF-targeted conjugates, and an MTT assay established the IC₅₀ for the conjugates. Endocytic mechanisms were investigated by confocal microscopy.
  
  
  RESULTS
  Studies revealed a high-affinity endocytic mechanism for RF-specific internalization of fluorescently-labeled conjugates in both MCF-7 and SKBR-3 cells, whereas folic acid-mediated endocytosis showed high specificity only in SKBR-3 cells. MMC internalization was significantly higher following nontargeted and RF-targeted MMC-conjugate administration compared to that of free MMC. Cytotoxic analysis illustrated potent IC₅₀ values for RF-targeted MMC conjugates similar to free MMC. Maximum nuclear accumulation of MMC resulted from lysosomal release from RF-targeted and nontargeted MMC-conjugates following 6 h incubations, unlike that of free MMC seen within 10 min.
  
  
  CONCLUSIONS
  Targeting polymer-MMC conjugates to the RF internalization pathway in breast cancer cells enabled an increase in MMC uptake and nuclear localization, resulting in potent cytotoxic activity.
authors.affiliation: Department of Pharmaceutical Sciences Center for Nanomedicine and Cellular Drug Delivery, University of Maryland Baltimore, 20 Penn Street, Health Sciences Facility 2, Room 543, Baltimore, Maryland 21201, USA.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Bareford
authors.forename: Brittany R
authors.initials: BR
authors.lastname: Avaritt
authors.forename: Hamidreza
authors.initials: H
authors.lastname: Ghandehari
authors.forename: Anjan
authors.initials: A
authors.lastname: Nan
authors.forename: Peter W
authors.initials: PW
authors.lastname: Swaan
mesh_terms: D000178:Acrylamides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D001940:Breast / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D016503:Drug Delivery Systems; D004705:Endocytosis; D005260:Female; D006801:Humans; D016685:Mitomycin / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D012256:Riboflavin / Q000378:metabolism*
chemical_list: D000178:Acrylamides; D000903:Antibiotics, Antineoplastic; D016685:Mitomycin; C032976:N-(2-hydroxypropyl)methacrylamide; D012256:Riboflavin