A paclitaxel-hyaluronan bioconjugate targeting ovarian cancer affords a potent in vivo therapeutic activity
| Autor: | Antonio Rosato, Sara Bobisse, Davide Renier, Alessandra Banzato, Fabio Bettella, Giovanni Esposito, Luigi Quintieri, Maria Rondina, Laura Meléndez-Alafort, Ulderico Mazzi, Paola Zanovello |
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| Jazyk: | angličtina |
| Rok vydání: | 2008 |
| Předmět: |
Cancer Research
Pathology medicine.medical_specialty Biodistribution Paclitaxel Antineoplastic Agents Mice SCID Pharmacology Mice chemistry.chemical_compound Pharmacokinetics In vivo medicine Animals Humans Infusions Parenteral Peripheral blood cell Hyaluronic Acid Ovarian Neoplasms Microscopy Confocal biology business.industry CD44 Cancer Flow Cytometry medicine.disease Xenograft Model Antitumor Assays Oncology chemistry biology.protein Female Ovarian cancer business |
| Popis: | Purpose: This study was designed to evaluate the pharmacologic and biological properties of a paclitaxel-hyaluronan bioconjugate (ONCOFID-P) against IGROV-1 and OVCAR-3 human ovarian cancer xenografts following i.p. administration. Experimental Design: In vitro tumor sensitivity to ONCOFID-P was analyzed by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, whereas bioconjugate interaction with cells was studied cytofluorimetrically and by confocal microscopy. In vivo toxicity was assessed by a single-dose maximum-tolerated dose, peripheral blood cell count determination and by histologic analysis. Biodistribution of the compound was evaluated with a small animal–dedicated scintigraphy gamma camera following injection of 99mTc-labeled ONCOFID-P. Pharmacokinetic analysis was also carried out. Female severe combined immunodeficiency mice implanted with ovarian cancer cells underwent treatment with ONCOFID-P or free paclitaxel starting from day 7 or 14 after tumor injection, and survivals were compared. Results: ONCOFID-P interacted with CD44, entered cells through a receptor-mediated mechanism, and exerted a concentration-dependent inhibitory effect against tumor cell growth. After i.p. administration, the bioconjugate distributed quite uniformly within the peritoneal cavity, was well-tolerated, and was not associated with local histologic toxicity. Pharmacokinetic studies revealed that blood levels of bioconjugate-derived paclitaxel were much higher and persisted longer than those obtained with the unconjugated free drug. Intraperitoneal treatment of tumor-bearing mice with the bioconjugate revealed that ONCOFID-P exerted a relevant increase in therapeutic activity compared with free drug. Conclusions: ONCOFID-P significantly improved results obtained with conventional paclitaxel, in terms of in vivo tolerability and therapeutic efficacy; these data strongly support its development for locoregional treatment of ovarian cancer. |
| Databáze: | OpenAIRE |
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