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Combination chemotherapy and photodynamic therapy with fab' fragment targeted HPMA copolymer conjugates in human ovarian carcinoma cells.

Abstract
The biological activities of sequential combinations of anticancer drugs, SOS thiophene (SOS) and mesochlorin e 6 monoethylenediamine (Mce 6), in the form of free drugs, nontargeted N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-drug conjugates, P-GFLG-Mce 6 and P-GFLG-SOS (P is the HPMA copolymer backbone and GFLG is the glycylphenylalanylleucylglycine spacer), and Fab'-targeted HPMA copolymer-drug conjugates, P-(GFLG-Mce 6)-Fab' and P-(GFLG-SOS)-Fab' (Fab' from OV-TL16 antibodies complementary to CD47), were evaluated against human ovarian carcinoma OVCAR-3 cells. Mce 6, SOS, P-GFLG-Mce 6, P-GFLG-SOS, P-(GFLG-Mce 6)-Fab', and P-(GFLG-SOS)-Fab', when used as single agents or in binary combination, exhibited cytotoxic activities against OVCAR-3 cells, as determined using a modified MTT assay. The binding and internalization of P-(GFLG-Mce 6)-Fab' and P-(GFLG-SOS)-Fab' by OVCAR-3 cells were visualized by confocal microscopy and flow cytometry. The results confirmed an enhanced biorecognition by OVCAR-3 cells of Fab'-targeted HPMA copolymer conjugates over nontargeted conjugates. The median-effect analysis and the determination of the combination index (CI) were used to describe the drug interaction and quantify the synergism, antagonism, or additivity in anticancer effects. The sequential combinations of SOS+Mce 6 and P-GFLG-SOS+P-GFLG-Mce 6 displayed very strong synergism to synergism in the entire range of cell inhibition levels ( f a = 0.5 - 0.95). The P-(GFLG-SOS)-Fab'+P-(GFLG-Mce 6)-Fab' exhibited a strong synergism for f a values up to about 0.85, but showed synergistic effect and nearly additive effect at f a = 0.9 and 0.95, respectively. These observations support the continuation of in vivo investigations of these conjugates for the treatment of ovarian cancer.
AuthorsJarunee Hongrapipat, Pavla Kopecková, Jihua Liu, Sompol Prakongpan, Jindrich Kopecek
JournalMolecular pharmaceutics (Mol Pharm) 2008 Sep-Oct Vol. 5 Issue 5 Pg. 696-709 ISSN: 1543-8384 [Print] United States
PMID18729468 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Acrylamides
  • Drug Carriers
  • Immunoglobulin Fab Fragments
  • Immunotoxins
  • Mesoporphyrins
  • Thiophenes
  • meso-chlorin e(6) monoethylene diamine
  • N-(2-hydroxypropyl)methacrylamide
  • Fluorescein
Topics
  • Acrylamides (chemistry, pharmacokinetics, pharmacology)
  • Antineoplastic Combined Chemotherapy Protocols (pharmacology)
  • Carcinoma (drug therapy, immunology)
  • Cell Line, Tumor
  • Cell Proliferation (drug effects)
  • Combined Modality Therapy
  • Dose-Response Relationship, Drug
  • Drug Carriers (chemical synthesis, chemistry)
  • Drug Delivery Systems
  • Drug Screening Assays, Antitumor
  • Female
  • Flow Cytometry
  • Fluorescein (chemistry)
  • Humans
  • Immunoglobulin Fab Fragments (chemistry, pharmacology)
  • Immunotoxins (chemistry, pharmacokinetics, pharmacology)
  • Inhibitory Concentration 50
  • Mesoporphyrins (chemistry, pharmacokinetics, pharmacology)
  • Microscopy, Confocal
  • Molecular Structure
  • Ovarian Neoplasms (drug therapy, immunology)
  • Photochemotherapy
  • Thiophenes (chemistry, pharmacokinetics, pharmacology)

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