Synthesis and characterization of HPMA copolymer-aminopropylgeldanamycin conjugates.
Geldanamycin (GDM) is a benzoquinone ansamycin antibiotic with anticancer activity. The use of drug delivery systems based on N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers containing lysosomally degradable oligopeptide (GFLG) spacers results in an increased therapeutic efficacy of anticancer drugs. The objective of this study was to synthesize HPMA copolymer-GDM conjugates with anticancer activity and reduced toxic side-effect of the compound. 17-(3-Aminopropylamino)-17-demethoxygeldanamycin (AP-GDM) was synthesized and converted into a polymerizable GDM derivative, N-methacryloylglycylphenylalanylglycyl-17-(3-aminopropylamino)-17-demethoxygeldanamycin [MA-GFLG-(AP-GDM)]. The structures of AP-GDM and MA-GFLG-(AP-GDM) were validated by mass spectroscopy, elemental analysis, and two-dimensional nuclear magnetic resonance. MA-GFLG-(AP-GDM) was copolymerized with HPMA and N-methacryloyglycylglycine p-nitrophenylester by radical precipitation polymerization. Water-soluble HPMA copolymer-AP-GDM conjugates (M(r)=16 kDa) were obtained. Monoclonal antibody OV-TL16, which recognizes the OA-3 antigen expressed on the OVCAR-3 human ovarian carcinoma cell line, was optionally attached to the HPMA copolymer-AP-GDM conjugate. Cytotoxicity of polymer-bound AP-GDM (both targeted and non-targeted) was determined using OVCAR-3 and another human ovarian carcinoma cell line, A2780. The HPMA copolymer-AP-GDM conjugate was cytotoxic toward A2780 cells. Attachment of OV-TL16 antibody enhanced cytotoxicity of the conjugate toward OVCAR-3 cells.
Kasuya
Y
Y
Department of Pharmaceutics and Pharmaceutical Chemistry/CCCD, University of Utah, Salt Lake City, UT 84112, USA.
Lu
Z R
ZR
Kopecková
P
P
Minko
T
T
Tabibi
S E
SE
Kopecek
J
J
D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology; D016227:Benzoquinones; D004337:Drug Carriers; D005260:Female; D006801:Humans; D047029:Lactams, Macrocyclic; D013058:Mass Spectrometry; D008689:Methacrylates; D008970:Molecular Weight; D010051:Ovarian Neoplasms / Q000188:drug therapy; D011809:Quinones / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000911:Antibodies, Monoclonal; D016227:Benzoquinones; D004337:Drug Carriers; D047029:Lactams, Macrocyclic; D008689:Methacrylates; D011809:Quinones; C032802:hydroxypropyl methacrylate; C001277:geldanamycin