Effect of expansile paclitaxel-loaded nanoparticles on growth of lung cancer in vivo

Abstract

7593 Background: Surgical resection remains the most effective treatment for patients with non-small cell lung cancer; however, even in early stage diagnoses the presence of occult microscopic disease at the surgical resection margin significantly impacts long-term patient survival. Thus, the focus of this study is to establish proof of concept that locoregional growth of microscopic tumor burden can be prevented through the application of a novel “expansile” nanoparticle drug delivery system. Methods: Biocompatible polymer nanoparticles that enter tumor cells and swell 300 fold in response to pH were loaded with paclitaxel (Pax-NP) and assessed for efficacy against murine Lewis lung carcinoma (LLC) cells using cell viability assays in vitro and tumor implantation in vivo. Paclitaxel-loaded non-expansile nanoparticles (Pax-neNP) that are not sensitive to pH variation were also produced. For the in vivo studies, 7.5 x 105 LLC tumor cells were co-injected with 0.25 mg unloaded control (expansile) NP, Pax-NP, Pax-neNP or paclitaxel alone in 100μL Cremophor EL/ethanol (each equivalent to a 2.5 μg dose of paclitaxel) subcutaneously in C57Bl/6 mice. Results: In vitro assays demonstrated that co-culture of LLC cells and Pax-NP results in significant inhibition of tumor growth (p<0.01, t-test vs control). In contrast, LLC incubated with unloaded NP did not inhibit tumor growth. Moreover, Pax-NP prevented tumor growth in vivo. Whereas LLC alone (n=11) or LLC with 0.25mg unloaded NP (n=14) or Pax-neNP (n=12) resulted in the development of tumors with volumes of 388±86, 382±82 and 268±63 mm3, respectively (mean ± SE), only one mouse (n=15) developed a small tumor (2±2 mm3) following the injection of LLC and Pax-NP (p<0.05 via ANOVA). Further, injection with an equivalent dose of paclitaxel did not significantly reduce tumor growth (225±95, n=6). Conclusions: These results establish that locoregional growth of microscopic tumor burden can be inhibited by intracellular nanoparticle-mediated drug delivery. These early results suggest that Pax-NP, which undergo cellular uptake with resultant drug release, may afford enhanced local drug delivery aimed at preventing the growth of occult microscopic disease present at the resection margin following parenchyma-sparing surgery for lung cancer. No significant financial relationships to disclose.