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Antimicrobial Agents and Chemotherapy, November 2004, p. 4342-4348, Vol. 48, No. 11
0066-4804/04/$08.00+0     DOI: 10.1128/AAC.48.11.4342-4348.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Delivery of Granulocyte-Macrophage Colony-Stimulating Factor in Bioadhesive Hydrogel Stimulates Migration of Dendritic Cells in Models of Human Papillomavirus-Associated (Pre)Neoplastic Epithelial Lesions

Pascale Hubert,^1*, Brigitte Evrard,^2, Catherine Maillard,³ Elizabeth Franzen-Detrooz,¹ Luc Delattre,² Jean-Michel Foidart,³ Agnes Noël,³ Jacques Boniver,¹ and Philippe Delvenne¹

Department of Pathology, CRCE,¹ Department of Pharmaceutical Technology,² Laboratory of Tumor and Development Biology, University of Liege, Liege, Belgium³

Received 9 February 2004/ Returned for modification 20 April 2004/ Accepted 29 June 2004

Because of the central role of dendritic cells and/or Langerhans cells(DC/LC) in the induction of cellular immune responses, pharmacological agents that modulate the recruitment of these cells might have a clinical interest. The present study was designed to evaluate the capacity of several pharmaceutical formulations to topically deliver granulocyte-macrophage colony-stimulating factor (GM-CSF) on human papillomavirus (HPV)-associated genital (pre)neoplastic lesions. The formulations were evaluated for their bioactivity and for their potential to recruit DC in organotypic cultures of HPV-transformed keratinocytes. We found that a bioadhesive polycarbophil gel (Noveon) at pH 5.5 is able to maintain the bioactivity of GM-CSF at 4 or 37°C for at least 7 days, whereas a decreased activity of GM-CSF was observed when the molecule is included in other polymer gels. GM-CSF incorporated in the polycarbophil gel was also a potent factor in enhancing the colonization of DC into organotypic cultures of HPV-transformed keratinocytes since the infiltration of DC in the in vitro-formed (pre)neoplastic epithelium was very low under basal conditions and dramatically increased in the presence of GM-CSF gel. We next demonstrated that GM-CSF incorporated in polycarbophil gel induces the recruitment of human DC in a human (pre)neoplastic epithelium grafted into NOD/SCID mice. The efficacy of GM-CSF in this formulation was equivalent to that observed with liquid GM-CSF. These results suggest that GM-CSF incorporated in polycarbophil gel could play an important role in the recruitment of DC/LC in mucosal surfaces and be useful as a new immunotherapeutic approach for genital HPV-associated (pre)neoplastic lesions.

P. Hubert and B. Evrard contributed equally to this work.