PEGylated lipid microspheres loaded with cabazitaxel for intravenous administration: stability, bioavailability, antitumor efficacy, and toxicity

Abstract

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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“…At present, various nano-drug delivery systems have been used to reduce side effects and prolong the circulation time of CBZ, mainly including nanoparticles, micelles, and lipid microspheres. [34][35][36][37] However, most of these studies are still in the basic research stages and cannot effectively achieve clinical transformation. Albumin nanoparticles have the advantages of safety, non-toxicity, and good biocompatibility.…”

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“…Cabazitaxel lipid nanoparticles also can use targeting factors to increase drug accumulation near the tumor tissue, leading to better therapeutic effects. Numerous studies have demonstrated targeted lipid nanoparticles, including passive targeting (EPR effects; Y. Liu et al, 2018), as well as active targeting, by targeting molecule (bombesin; W. Chen et al, 2016), aptamer‐peptide (Y. Chen et al, 2020) and cell‐penetrating peptide (Hu et al, 2018). d ‐Oligoarginine peptide (r9) is a cell‐penetrating peptide, that has shown to have advantages like high intracellular transport efficiency and good penetrating effect, suitable for lymph metastasis targeting (Copolovici et al, 2014; Ruoslahti, 2012).…”

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