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  • a Institute of Biopathology and Regenerative Medicine IBIM

    2019-10-22

    a Institute of Biopathology and Regenerative Medicine (IBIM9090325ER), Center of Biomedical Research (CIBM), University of Granada, 18100 Granada, Spain
    b Department of Anatomy and Embriology, Faculty of Medicine, University of Granada, 18071 Granada, Spain
    c Biosanitary Institute of Granada (ibs.GRANADA), SAS-University of Granada, 18014 Granada, Spain
    d Department of Pharmacy and Pharmaceutical Technology, Faculty of Pharmacy, University of Seville, 41012 Sevilla, Spain
    e Department of Pharmacology, Institute of Neuroscience, Biomedical Research Center (CIBM), University of Granada, 18100, Granada, Spain
    Keywords:
    Paclitaxel
    PLGA
    Lung cancer
    Drug resistance
    Neurotoxicity
    Biodistribution 
    Paclitaxel (PTX), a chemotherapy agent widely used to treat lung cancer, is characterised by high toxicity, low bioavailability and the need to use of excipients with serious side effects that limit its use. Paclitaxel en-capsulation into nanoparticles (NPs) generates drug pharmacokinetic and pharmacodynamic advantages com-pared to free PTX. In this context, a NP carrier formed from a copolymer of lactic (±)-Baclofen and glycolic acid (PLGA) has demonstrated high biocompatibility and low toxicity and therefore being approved by FDA to be used in humans. We synthesised a new PLGA NP and loaded it with PTX to improve drug efficacy and reduce side effects. This nanoformulation showed biocompatibility and no toxicity to human immune system. These NPs favor the intracellular uptake of PTX and enhance its antitumor effect in human and murine lung cancer cells, with up to 3.6-fold reductions in the PTX’s IC50. Although PLGA NPs did not show any inhibitory capacity against P-glycoprotein, they increased the antitumor activity of PTX in cancer stem cells. Treatment with PLGA-PTX NPs increased apoptosis and significantly reduced the volume of the tumorspheres derived from A549 and LL2 cells by up to 36% and 46.5%, respectively. Biodistribution studies with PLGA-PTX NPs revealed an increase in drug circulation time, as well as a greater accumulation in lung and brain tissues compared to free PTX. Low levels of PTX were detected in the dorsal root ganglion with PLGA-PTX NPs, which could exert a protective effect against peripheral neuropathy. In vivo treatment with PLGA-PTX NPs showed a greater decrease in tumor volume (44.6%) in immunocompetent mice compared to free PTX (24.4%) and without increasing the toxicity of the drug. These promising results suggest that developed nanosystem provide a potential strategy for improving the chemotherapeutic effect and reducing the side effects of PTX.
    1. Introduction
    Lung cancer is the leading cause of cancer death worldwide [1]. Paclitaxel (PTX), a drug of choice in lung cancer chemotherapy [2,3], is a diterpene alkaloid that promotes polymerisation and microtubule assembly by specifically binding to the β-tubulin subunit of tubulin causing the kidnapping in the G2 phase of the cell cycle [4,5]. However, the administration of PTX has several disadvantages which limit its antitumor activity and result in treatment failure. In fact, the two most common chronic toxicities associated with PTX are painful peripheral
    neuropathy [6,7] and haematological toxicity due to bone marrow depression, which affect more than 60% of treated patients and lead to treatment suspension (temporarily or permanently) or dose reduction and therefore decreased antitumor efficacy [7,8]. In addition, PTX shows low solubility in water (˜ 0.4 μg/ml), so the drug formulation requires the use of Cremophor® EL and ethanol which induce hy-persensitivity reactions, neutropenia or peripheral neuropathy [8,9]. Finally, PTX also undergoes rapid elimination and has a low bioavail-ability [10,11] and drug resistance may develop mediated by several mechanisms including P-glycoprotein (P-gp) which considerably