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In spite of recent advances in targeted tumor therapy, systemic chemotherapy with cytotoxic agents remains a vital cancer treatment modality. Gemcitabine is a nucleoside analog commonly used in the treatment of various solid tumors, but an oral gemcitabine dosage form remain unavailable. Previously, we developed the 4-( N )-stearoyl gemcitabine solid lipid nanoparticles (GemC18-SLNs) by incorporating 4-( N )-stearoyl gemcitabine (GemC18), an amide prodrug of gemcitabine, into solid lipid nanoparticles. GemC18-SLNs, when administered intravenously, showed strong antitumor activity against various human and mouse tumors in mouse models. In the present study, we defined the plasma pharmacokinetics of gemcitabine when GemC18-SLNs were given orally to healthy mice and evaluated the antitumor activity of GemC18-SLNs when given orally in mouse models of lung cancer. In mice orally gavaged with GemC18-SLNs, plasma gemcitabine concentration followed an absorption phase and then clearance phase, with a T max of ~2 h. The absolute oral bioavailability of gemcitabine in the GemC18-SLNs was ~70% (based on AUC 0-24 h values). In mice with pre-established tumors (i.e. mouse TC-1 or LLC lung cancer cells), oral GemC18-SLNs significantly inhibited the tumor growth and increased mouse survival time, as compared to the molar equivalent dose of gemcitabine hydrochloride or GemC18 in vegetable oil or in Tween 20. Immunohistostaining revealed that oral GemC18-SLNs also have significant antiproliferative, antiangiogenic, and proapoptotic activity in LLC tumors. Formulating a lipophilic amide prodrug of gemcitabine into solid lipid nanoparticles may represent a viable approach toward developing a safe and efficacious gemcitabine oral dosage form.

Oral 4-(N)-stearoyl gemcitabine nanoparticles inhibit tumor growth in mouse models