Taxane conjugate nanoparticles for improved non-small cell lung cancer treatment in a novel orthotopic mouse model.

摘要

The objectives of these studies were to develop lipid-based nanoparticles (NPs) to deliver taxane conjugates for improved non-small cell lung cancer (NSCLC) treatment. The chemotherapy agents Taxol, Abraxane and Taxotere have been limited by severe side effects, sub-optimal pharmacokinetic profile, and moderate therapeutic efficacy. Therefore, Paclitaxel (PX) or Docetaxel (DX) was formulated in lipid-based NPs in these studies to achieve improved therapeutic index for NSCLC treatment. The NPs were engineered from oil-in-water microemulsion precursors with Miglyol as the oil core, and polyoxyl 20-stearyl ether (Brij 78) and D-alpha-tocopheryl polyethylene glycol succinate (TPGS) as the surfactants, and abbreviated as BTM NPs.;A novel orthotopic NSCLC mouse model was established and characterized for in vivo evaluation of the developed formulation. During the effort of developing an orthotopic NSCLC mouse model, three different surgical procedures including intrabronchial injection, chest injection into left lung and dorsal injection into left lung were investigated. The preferred model was established through dorsal side injection of luciferase-expressing A549 cells and then characterized by overall survival, histological staining, bioluminescence imaging and micro PET/CT imaging. The model produced lung tumor with a 94% success rate and a reliable bioluminescence signal for long-term tumor growth monitoring. The therapeutic efficacy of 2'-(2-bromohexadecanoyl)-docetaxel (Br-C16-DX) NPs versus TaxotereRTM was investigated in this model. The results demonstrated longer progression-free survival and median survival of the NP-treated group as compared to the Taxotere group.;For PX delivery, a 2'-(2-bromohexadecanoyl)-paclitaxel (Br-16-PX) conjugate was synthesized and formulated into lipid NPs. The goals were to improve drug entrapment in the drug delivery system and to enhance in vivo pharmacokinetics and conversion to paclitaxel at the tumor site. The developed system was evaluated in luciferase-expressing A549 cells in vitro and in the developed orthotopic NSCLC mouse model. The results demonstrated that the Br-C16-PX NPs had an increased maximum tolerated dose (MTD) and an improved pharmacokinetic profile as compared to TaxolRTM, which resulted in significantly improved antitumor efficacy for the treatment of advanced NSCLC.;In summary, the developed lipid-based NPs with taxane conjugate may serve as a safer and more efficacious treatment options for NSCLC. The developed orthotopic NSCLC model represents a feasible, reproducible, and clinically-relevant experimental mouse model to test current and potential therapies including nanomedicines.