cabazitaxel and Carcinoma--Lewis-Lung

Pluronic (Poloxomer) micelles can solubilize cabazitaxel (CTX), a second-generation taxane, and then be subjected to low-temperature "surfactant-stripping" to selectively remove loose and free surfactant, thereby increasing the drug-to-surfactant ratio. We previously found that the addition of certain other co-loaded hydrophobic cargo to the micelles can result in stabilized, surfactant-stripped cabazitaxel (sss-CTX) micelles, which resist drug aggregation in aqueous storage, a common challenge for taxanes. Here, we show that elevated temperatures can accelerate the aggregation of sss-CTX micelles, thereby enabling rapid optimization of formulations with respect to the type and ratio of co-loader used for stabilization. A sss-CTX micelle formulation was developed using mifepristone as the co-loader, at a 60% mass ratio to the CTX. Drug release, hemolysis and complement activation were investigated

Topics: Animals; Antineoplastic Agents; Carcinoma, Lewis Lung; Drug Stability; Drug Storage; Excipients; Humans; Hydrophobic and Hydrophilic Interactions; Lung Neoplasms; Male; Mice; Mice, Inbred C57BL; Micelles; Poloxamer; Polysorbates; Surface-Active Agents; Taxoids; Xenograft Model Antitumor Assays

Lung cancer is a leading cause of cancer deaths worldwide, chemotherapy has improved overall survival but remains limited at <12 months median overall survival. Cabazitaxel is hopeful to do the same in advanced lung cancer as well as in metastatic prostate cancer. However, its clinical application was restricted due to its high hydrophobicity and severe side effects. To overcome these problems, we developed self-assembled micelle loading cabazitaxel (CBZ-PM) for therapy of lung cancer. The CBZ-PM has high drug loading (10.52%) and encapsulation efficiency (99.30%) with particle size of 28.77 ± 0.52 nm and polydisperse index of 0.114 ± 0.012. The transmission electron microscope image presented its spherical and homogeneous appearance. In vitro release profile showed CBZ-PM has a sustained-release behavior. Furthermore, the result of cell proliferation assays proved that CBZ-PM could induce the Lewis lung carcinoma (LLC) cells death through G2/M arrest more effectively than free CBZ. In vivo anti-tumor activity of CBZ-PM was further studied in mice model of LLC. The tumor inhibitory rate of CBZ-PM was more than 50% and the survival time of LLC bearing mice was efficiently prolonged following administration of CBZ-PM. In addition, the immunohistochemical study showed that more apoptosis cells were detected in the tumor tissue of CBZ-PM group than that of the positive control group. All these indicated that CBZ-PM served as a potential anti-lung cancer agent.

Topics: Animals; Antineoplastic Agents; Apoptosis; Carcinoma, Lewis Lung; Cell Proliferation; Delayed-Action Preparations; Hydrophobic and Hydrophilic Interactions; Lung Neoplasms; Mice; Mice, Inbred C57BL; Micelles; Microscopy, Electron, Transmission; Particle Size; Survival Rate; Taxoids