Purpose: This study was designed to evaluate the pharmacologic and biological properties of a paclitaxel-hyaluronan bioconjugate (ONCOFID-P) against IGROV-1and 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 animald edicated 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 tumorbearing 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.Ovarian cancer is the most common cause of death from gynecologic malignancy and is the fifth leading cause of cancerrelated death (1). Intravenous administration of taxane-and platinum-based chemotherapy represents the current standard of postoperative care for patients with advanced neoplasia. This therapeutic regimen is also considered for high-risk patients with early stage tumors in an adjuvant setting, to eradicate residual disease following surgical debulking. Despite these approaches having resulted in improved survival over the last decade, nonetheless, relapses still occur in the majority of cases and represent the major problem for patients with advanced disease (2).A potential solution to these obstacles takes into consideration the biological behavior of ovarian cancer, which is mainly confined to the peritoneal cavity for most of its initial natural course. The biology of the tumor offers the possibility of delivering drugs directly within the peritoneum to achieve a theoretical potential for increased exposure of the tumor to the antineoplastic agen...

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