Microspheres prepared by HME combined with wet-milling could achieve a long-term sustained release effect as a novel long-acting formulation strategy.

This paper aimed to develop a novel lipid microsphere delivering cabazitaxel (CTX) using phosphatidylcholine combined with DSPE-PEG2000 as emulsifier, and evaluate its stability, pharmacokinetics, antitumor efficacy, and toxicity. The pegylated cabazitaxel-loaded lipid microspheres (CTX-PLMs) were prepared by high-pressure homogenization methods; the biological samples were analyzed by the UPLC-MS/MS method. CTX-PLMs had a drug concentration of 1.2 mg/ml and a mean particle size of 180.0 ± 51.119 nm. CTX-PLMs showed a superior physical stability as it could remain nearly intact after 1-year storage. The AUC of the CTX-PLMs was 1562.6 ± 520.1 μg h L compared with the CTX-solution of 860.734 ± 312.4 μg h L. CTX-PLMs exhibited a strong antitumor efficacy against NCI-N87 and DU145 tumor models with tumor growth inhibition rates of 93.5 and 88.5%, respectively. The LD50 of CTX-PLMs in rats was 20.89 mg/kg. As for the long-term toxicity, the thymus, mesenteric lymph nodes, and bone marrow were the main toxic target organs and systemic toxicity induced by CTX-PLMs was alleviated relative to that of the CTX-solution. Safety assessment studies including hemolysis test, dermal sensitization test, systemic anaphylaxis, and vascular stimulation test indicated that CTX-PLMs is safe enough for intravenous administration. In a word, CTX-PLMs are a promising carrier for intravenous administration with satisfactory stability, stronger tumor inhibition, and superior safety profile.

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Owing to the modification of PEG, PRG H-NPs can act as safe delivery platforms for sustained-release of drugs with a lower dosage required.

The burst release phase was caused by diffusion of amorphous PRG near the surface, while the second release stage was impacted by PRG-dissolution from crystal depots formed in microspheres. The IVIVC assessment suggests that the in vitro test method used in this study could predict the real situation in vivo and is helpful to study the release mechanism in vivo.