title: CD44-tropic polymeric nanocarrier for breast cancer targeted rapamycin chemotherapy.
abstract: In contrast with the conventional targeting of nanoparticles to cancer cells with antibody or peptide conjugates, a hyaluronic acid (HA) matrix nanoparticle with intrinsic-CD44-tropism was developed to deliver rapamycin for localized CD44-positive breast cancer treatment. Rapamycin was chemically conjugated to the particle surface via a novel sustained-release linker, 3-amino-4-methoxy-benzoic acid. The release of the drug from the HA nanoparticle was improved by 42-fold compared to HA-temsirolimus in buffered saline. In CD44-positive MDA-MB-468 cells, using HA as drug delivery carrier, the cell viability was significantly decreased compared to free rapamycin and CD44-blocked controls. Rat pharmacokinetics showed that the area under the curve of HA nanoparticle formulation was 2.96-fold greater than that of the free drug, and the concomitant total body clearance was 8.82-fold slower. Moreover, in immunocompetent BALB/c mice bearing CD44-positive 4T1.2neu breast cancer, the rapamycin-loaded HA particles significantly improved animal survival, suppressed tumor growth and reduced the prevalence of lung metastasis.
  
  
  BACKGROUND
  This study demonstrates increased efficiency of rapamycin delivery and consequential treatment effects in a breast cancer model by hyaluronic acid - L-rapamycin conjugates with intrinsic tropism for CD44-positive cells.
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, USA.
authors.forename: Yunqi
authors.initials: Y
authors.lastname: Zhao
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, USA.
authors.forename: Ti
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, USA.
authors.forename: Shaofeng
authors.initials: S
authors.lastname: Duan
authors.affiliation: Faculty of Pharmacy, The University of Manitoba, Winnipeg Manitoba, Canada.
authors.forename: Neal M
authors.initials: NM
authors.lastname: Davies
authors.affiliation: Department of Pharmaceutical Chemistry, The University of Kansas, Lawrence, KS, USA. Electronic address: mforrest@ku.edu.
authors.forename: M Laird
authors.initials: ML
authors.lastname: Forrest
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use; D001940:Breast / Q000187:drug effects / Q000473:pathology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D004337:Drug Carriers / Q000378:metabolism*; D016503:Drug Delivery Systems; D005260:Female; D018960:Hyaluronan Receptors / Q000378:metabolism*; D006820:Hyaluronic Acid / Q000378:metabolism*; D008807:Mice, Inbred BALB C; D053758:Nanoparticles / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000627:therapeutic use
chemical_list: D000903:Antibiotics, Antineoplastic; D004337:Drug Carriers; D018960:Hyaluronan Receptors; D006820:Hyaluronic Acid; D020123:Sirolimus
keywords: Breast cancer; CD44; Hyaluronic acid; Rapamycin