title: Influence of the structure of drug moieties on the in vitro efficacy of HPMA copolymer-geldanamycin derivative conjugates.
abstract: OBJECTIVE
  To optimize the structure of geldanamycin (GDM) derivative moieties attached to N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers via an enzymatically degradable spacer.
  
  
  METHODS
  HPMA copolymers containing different AR-GDM (AR = 3-aminopropyl (AP), 6-aminohexyl (AH), and 3-amino-2-hydroxypropyl AP(OH)) were synthesized and characterized. Their cytotoxicity towards the A2780 human ovarian carcinoma cells was evaluated.
  
  
  RESULTS
  The cytotoxic efficacy of HPMA copolymer-AR-GDM conjugates depended on the structure of AR-GDM. Particularly, HPMA copolymer-bound AH-GDM, which possessed the longest substituent at the 17-position, demonstrated the highest efficacy among the polymer-bound GDM derivatives; however the activity of free AH-GDM was lower than that of the other free AR-GDMs. The relative increase of the activity of macromolecular AH-GDM when compared to AP-GDM or AP(OH)-GDM correlated with the enhanced recognition of AH-GDM terminated oligopeptide side-chains by the active site of the lysosomal enzyme, cathepsin B. Drug stability and further stabilization upon binding to HPMA copolymer also contributed to the observed phenomena.
  
  
  CONCLUSIONS
  AH-GDM was found to be a suitable GDM derivative for the design of a drug delivery system based on HPMA copolymers and enzymatically-degradable spacers.
authors.affiliation: Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City 84112, USA.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kasuya
authors.forename: Zheng-Rong
authors.initials: ZR
authors.lastname: Lu
authors.forename: Pavla
authors.initials: P
authors.lastname: Kopecková
authors.forename: S Esmail
authors.initials: SE
authors.lastname: Tabibi
authors.forename: Jindrich
authors.initials: J
authors.lastname: Kopecek
mesh_terms: D000178:Acrylamides / Q000737:chemistry*; D000903:Antibiotics, Antineoplastic / Q000737:chemistry* / Q000494:pharmacology*; D016227:Benzoquinones; D002401:Cathepsin B / Q000037:antagonists & inhibitors; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D004355:Drug Stability; D005079:Excipients; D005260:Female; D006801:Humans; D006868:Hydrolysis; D047029:Lactams, Macrocyclic; D008247:Lysosomes / Q000201:enzymology; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D011809:Quinones / Q000737:chemistry* / Q000494:pharmacology*; D012995:Solubility; D014407:Tumor Cells, Cultured
chemical_list: D000178:Acrylamides; D000903:Antibiotics, Antineoplastic; D016227:Benzoquinones; D015853:Cysteine Proteinase Inhibitors; D005079:Excipients; D047029:Lactams, Macrocyclic; D011809:Quinones; D002401:Cathepsin B; C032976:N-(2-hydroxypropyl)methacrylamide; C001277:geldanamycin