Abstract LB-196: A folate receptor-targeted nanoparticle minimizes multidrug resistance in human cancer xenograft model

Resistance to chemotherapy is a major obstacle in cancer therapy. Intrinsic or acquired drug resistance occurs frequently in most cancers. In this report, we developed a novel nanoparticle formulation with the intent of significantly increasing the bioavailability and enhancing the efficacy of chemotherapeutic agent, paclitaxel in the experimental model of resistant human squamous cell carcinama. The targeted nanoparticle (HFT-T) was loaded with paclitaxel in its hydrophobic core, which is composed of Heparin-Folate-Paclitaxel (HFT) conjugates (Wang X., et al. ACS Nano 2009 , 3, 3165–3174). In vitro cytotoxicity of nanoparticle HFT-T was assessed on a resistant human squamous cancer cell line KB-8–5 (ten time resistant to paclitaxel compare to the sensitive cell line KB-3–1). The targeted nanoparticle HFT-T was more effective in inhibiting cell growth, when compared with non-targeted nanoparticle (HT-T) or free paclitaxel in multidrug resistance cells. In vitro cellular uptake, retention, and efflux of HFT-T nanoparticles studies suggested that the HFT-T formulation may counteract the transporter-mediated drug resistance in KB-8–5 cells, thereby increasing intracellular concentrations of paclitaxel and enhancing its cytotoxicity. Compared to free paclitaxel, HFT-T was found to be capable of effectively delivering and maintaining markedly higher concentrations (by 2∼3-fold) of paclitaxel in KB-8–5 cells when added to the cultures at various times. To test the in vivo efficacy of HFT-T particles, nude mice bearing subcutaneous human KB-8–5 tumors were randomly divided into four groups (n=8 per group), and treated with HFT-T, free paclitaxel, HT-T or PBS (control), respectively. The drugs (at a dose of 40 mg/kg paclitaxel or equivalent) were administrated intravenously via tail vein once a week for 3 weeks (3 injections in total). At the end of the experiment, the tumor volume in the HFT-T-treated group were significantly reduced compared with all other treatment groups including the control (p=0.0075), free paclitaxel (p=0.0155), and HT-T (p=0.0381) treated groups. In contrast, tumor volumes in paclitaxel (p=0.2287) or HT-T-treated (P=0.1423) groups were not significantly different from the control group. The results indicated that the therapeutic efficacy of targeting HFT-T nanoparticle is significantly superior to free paclitaxel and non-targeted nanoparticle in drug-resistant xenograft models. In conclusion, this study provides a novel strategy using targeted nanoparticle as drug deliver system to minimize the drug resistance in human cancers. (Supported by NCI P50 CA128613 and U54CA119338–04) Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-196. doi:10.1158/1538-7445.AM2011-LB-196