Docetaxel-loaded Solid Lipid Nanoparticles Suppress Breast Cancer Cells Growth With Reduced Myelosuppression Toxicity

Docetaxelisawidelyusedantitumordrugthatissemi-synthesizedfrom10-deacetylbaccatin III, an inactive taxoid precursor prepared from needles of the European yew, Taxus baccata.It has been used to treat a broad spectrum of solid tumorssuch as advanced ovarian cancer, non-small-cell lung cancer, locally advancedor metastatic breast cancer, and androgen-independent prostate cancer.Docetaxel belongs to the taxane family that can promote assembly of free tubulin into microtubules and stabilize them by binding to tubulin to inhibit disassembly of microtubules.Therefore,docetaxel can suppresses tumor cell growth.However, because ofdocetaxel’s the solubility is low, the current commercially available docetaxel that increaseits solubility and adda lot of Tween-80 or ethanol of composite solvent. In clinical applications, This drug dosage’sdocetaxel can cause a lot of serious side effects,such as, such as neutropenia, myelosuppression, anemia, and hypersensitivity reaction, which limit its clinical applications.However, Some of these side effects are simply induced by the formulation vehicles that are added to improve poor solubility of docetaxel, such as surfactant polysorbate 80.So far,a lot of effort has been put into improving the formulation to simultaneously reduce its side effects and enhance its antitumor activity, loaded solid lipid nanoparticles, however, as a new excellent carrier of antitumor drugs have many advantages.For example, increasing of the drug, to improve its stability, and reduceing the side effects.In addition, loaded solid lipid nanoparticles will Pay more attention,bacause it can delay the release of drugs and targeting drug releasive of advantages.To date, loaded solid lipid nanoparticles was used in a variety of anti-cancer drug research and development. We producted docetaxel -loaded solid lipid nanoparticles, Aimed at improving docetaxel’s anti-tumor activity, lower toxicity and increaseingits stability, at the same time we studied docetaxel that has the internal mechanism of anti-tumor.Docetaxel is an adjuvant chemotherapy drug widely used to treat multiple solid tumors; however, its toxicity and side effects limit its clinical efficacy. Herein, docetaxel-loaded solid lipid nanoparticles (DSNs) were developed to reduce systemic toxicity of docetaxel while still keeping its anticancer activity. To evaluate its anticancer activity and toxicity, and to understand the molecular mechanisms of DSNs, different cellular, molecular, and whole genome transcription analysis approaches were utilized. The DSNs showed lower cytotoxicity compared with the commercial formulation of docetaxel (Taxotere(?)) and induced more apoptosis at 24 hours after treatment in vitro. DSNs can cause the treated cancer cells to arrest in the G2/M phase in a dose-dependent manner similar to Taxotere. They can also suppress tumor growth very effectively in a mice model with human xenograft breast cancer. Systemic analysis of gene expression profiles by microarray and subsequent verification experiments suggested that both DSNs and Taxotere regulate gene expression and gene function, including DNA replication, DNA damage response, cell proliferation, apoptosis, and cell cycle regulation. Some of these genes expressed differentially at the protein level although their messenger RNA expression level was similar under Taxotere and DSN treatment. Moreover, DSNs improved the main side effect of Taxotere by greatly lowering myelosuppression toxicity to bone marrow cells from mice. Taken together, these results expound the antitumor efficacy and the potential working mechanisms of DSNs in its anticancer activity and toxicity, which provide a theoretical foundation to develop and apply a more efficient docetaxel formulation to treat cancer patients.