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.
Highlights
Lung cancer is a primary malignancy of the lungs and the leading cause of cancer-related deaths worldwide[1,2,3]
DTX is a conventional chemotherapeutic of choice for many cancers including non-small-cell lung cancer (NSCLC), but its effectiveness in lung cancer therapy is limited due to significant side effects resulting from toxicity after intensive therapy
DTX-loaded liposome (DTX-LP) offers both increased antitumor efficacy and reduced toxicity compared to DTX injection (DTX-IN) since more DTX can be delivered directly into intrapulmonary tumors after intravenous injection of DTX-LP compared to DTX-IN
Summary
Lung cancer is a primary malignancy of the lungs and the leading cause of cancer-related deaths worldwide[1,2,3]. 80–85% of lung cancer patients have NSCLC4. DTX, a semisynthetic taxane, acts by binding to the β-subunit of tubulin, and promotes stabilization of microtubules, causing G2/M cell cycle arrest[7]. It is the only drug with demonstrated activity approved by the FDA for both first- and second-line therapy for treatment of advanced NSCLC8, 9. It has been reported that new formulations of DTX, such as nanoparticles[16], intravenous lipid emulsions[17], nanostructured liposomes[18], microemulsions[19], chitosan-anchored liposomes[20] and PEGylated immunoliposomes[21], may increase the efficacy of targeted delivery to specific tumor cells without obvious toxic side effects. The purpose of this study was to evaluate targeting activity, TIR, survival, pathology, and tumor apoptosis after intravenous injection of DTX-LP compared
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