Medium-Term Culture of Primary Oral Squamous Cell Carcinoma in a Three- Dimensional Model: Effects on Cell Survival Following Topical 5-Fluororacile Delivery by Drug-Loaded Matrix Tablets

Giuseppina      Campisi; Libero      Italo Giannola; Alberto      Fucarino; Antonella      Marino Gammazza; Alessandro      Pitruzzella; Vito      Marciano; Viviana      De Caro; Maria      Gabriella Siragusa; Giulia      Giandalia; Domenico      Compilato; Stephen      T. Holgate; Donna      E. Davies; Felicia      Farina; Giovanni      Zummo; Carlo      Paderni; Fabio      Bucchieri

doi:10.2174/138161212803307536

Abstract

Since the activity of several conventional anticancer drugs is restricted by resistance mechanisms and dose-limiting sideeffects, the design of formulations for local application on malignant lesions seems to be an efficient and promising drug delivery approach.

In this study, the effect of locally applied 5-FU on cell death was evaluated both in a SCC4/HEK001 model and in a newly proposed 3D outgrowth model of oral squamous cell carcinoma (OSCC). Initially, the optimal drug dose was established by delivery of solutions containing different amounts of 5-FU. The solution containing 1% (w/v) of 5-FU resulted effective in inducing cell death with complete eradication of cell colonies.

Buccal tablets were designed to deliver 5-FU locoregionally to the cancer lesions of the oral cavity. Tablets were prepared using a drug loaded matrix of acrylic/methacrylic acid copolymer containing 1% (w/w) of 5-FU and applied on 3D outgrowths. The drug release from tablets appeared to be sufficient to induce cell death as confirmed by transmission electron microscopy and enzymatic assay (TUNEL). After 120 h of treatment, when about 90% of the drug had been discharged from the tablets into the culture environment, 5-FU caused loss of cell-cell communications and apoptotic cell death. After 192 h, a complete disaggregation of the 3D oral outgrowths and the death of all the cells was observed.

Buccal matrix tablets could be considered a promising new approach to the locoregional treatment of OSCC. Risks of systemic toxicity are avoided since very low drug doses are delivered.

Keywords: 5-Fluorouracil, Locoregional drug delivery, Oral squamous cell carcinoma, Buccal tablets, Tissue engineering, 3D oral outgrowths, malignant lesions, cell death, oral cavity, systemic toxicity.