No abstract

Allergic reactions and severe systemic toxicity are two major challenges for the clinical application of docetaxel (DTX) for treatment of non-small-cell lung cancer (NSCLC). We developed a novel lung-targeted DTX-loaded liposome (DTX-LP), an efficient drug delivery system, with a patented DBaumNC technology to overcome these deficiencies. In the present study, we describe the targeting activity, tumor inhibition rate (TIR), survival, pathology, tumor apoptosis and metabolism of DTX after intravenous injection of DTX-LP compared to the DTX injection (DTX-IN) formulation based on the VX2 orthotopic lung cancer rabbit model. Biodistribution studies revealed the highest accumulation in lung and tumor within 12 h after the injection of DTX-LP. The increased TIR indicates that the growth of tumor was slowed. Pathology tests demonstrated that DTX-LP can reduce metastasis and toxicity to non-targeted organs, leading to greatly extended survival time and improved survival of tumor-bearing rabbits. Flow cytometry and immunohistochemistry confirmed that DTX-LP is highly efficacious in tumor tissue, leading to a significant increase of tumor apoptosis and decrease of proliferation and angiogenesis. The results from this study demonstrate the increased intrapulmonary tumor targeting activity, enhanced antitumor effect and reduced toxicity of DTX-LP compared to DTX-IN and highlight its clinical prospects for NSCLC therapy.

The application of chemotherapeutics with chemical drugs is always challenged by their high toxicities throughout the body in clinical trials. Here, we reported a smart formulation of docetaxel developed by solid dispersion and effervescent techniques for efficient and safe delivery of chemical drug to lung tissue. To achieve a high delivery to lung with reduced systemic toxicity, docetaxel was loaded into a kind of lecithoid nanoparticles (DTX-LN) which were prepared by a solid dispersion and effervescent method. After intravenous administration of DTX-LN to rabbit, the docetaxel level in lung was approximately 37-fold higher than that of docetaxel injection (DTX-INJ, a commercial injection preparation of DTX/polysorbate 80 micelles) group at 0.5 h and showed the highest tissue distribution among all the organs. Besides, the targeting parameter R e value of total increased amount of DTX in lung (AUC 0-t ) ratio (DTX-LN to DTX-INJ) is about 16.69, indicating a significantly enhanced lung targeting ability of DTX-LN. In subacute toxicity study, DTX-LN displayed a reduced hematotoxicity, especially for the negative impacts on white blood cells, lymphocyte and granulocyte when compared with DTX-INJ during both weekly and 3-weekly schedules administration. In addition, histopathological analysis demonstrated that DTX-LN showed less tissue damages on rabbit heart and kidney compared to DTX-INJ. Hence, this work would provide an insight for improving lung delivery efficacy of drugs with reduced systemic toxicity. Key words lecithoid nanoparticle; lung targeting; docetaxel; solid dispersionChemotherapy with cytotoxic drugs represents one of the major categories of therapeutic regimen for many kinds of cancers. However, the therapeutic activities of most anticancer drugs in clinical use are limited by their concomitant side effects for which these cytotoxic drugs always lack of the capability of discriminating the targeted tissues from the normal counterparts. 1) Docetaxel (DTX), a potent inhibitor of cell division, is one of the most effective members of the taxane drug class that represents a major class of antitumor agents, 2) and also is one of the most extensive used antitumor drugs because of its broad spectrum of antitumor activity, including breast, lung, prostate, gastric, head and neck, and ovarian cancer.3) The anti-tumor potency of DTX is dose-dependent, 4) and the in vivo efficacy of DTX is highly related to its concentration in tumor lesion. However, pharmacokinetic studies revealed that docetaxel injection (DTX-INJ, docetaxel/ polysorbate80 micelles injection) showed a wide-spread tissue distribution throughout the whole body, and thus needed a relative high dose to maintain the therapeutic efficacy in clinic. 5)Furthermore, the accumulation of DTX in non-related tissues contributed to most of clinical adverse reactions reported in patients (e.g., febrile neutropenia, fluid retention, peripheral neurotoxicity and musculoskeletal toxicity).6,7) Besides, due to its poor solubility in aqueous phase, the solu...