Study on in Vivo Safety and Anti-tumor Pharmacodynamics of Paclitaxel-loaded PEGylated Rhein Conjugate Micelles

OBJECTIVE To investigate the safety of paclitaxel(PTX)-loaded PEGylated carboxymethyl chitosan-rhein (CRmP) polymeric micelles(PTX/CRmP PMs) as intravenous drug delivery preparations, and to investigate the anti-tumor effect of PTX/CRmP PMs in mice. METHODS The pH value and osmotic pressure of PTX/CRmP PMs were measured. The hemolysis was detected using the blood cells of New Zealand Rabbit. New Zealand rabbits were injected with PTX/CRmP PMs and CRmP conjugate solutions via the auricle vein. The vessels along with surrounding tissue sections were examined histologically under light microscopy. H-22 tumor-bearing mice models were established and divided into 0.9% sodium chloride injection group, paclitaxel liposome for injection group, paclitaxel injection group, PTX/CRmP PMs groups in low, medium and high dose(5, 10, 15 mg·kg^-1). The mice were administered via tail vein. During administration, the activity was observed every day. Changes of body weight and tumor volume were measured. The body weight change curve and tumor inhibition rate were plotted. Morphological changes in tumor tissues were observed by HE staining. RESULTS The pH values of PTX/CRmP PMs at different concentrations were similar to blood, with an osmotic pressure of 286-292 mOsm·kg^-1. In the concentration range of 0.01~0.05 mg·mL^-1 the hemolysis of CRmP conjugate and PTX/CRmP PMs were <5%. After intravenous injection via the auricle vein, no irritation phenomena were observed in the blood vessels at the injection site, and no obvious pathological changes were observed in the blood vessels. Tumor growth and metastasis were inhibited in PTX/CRmP PMs group, and the tumor-inhibiting effect showed dose-dependent. At the administered dose was 10 mg·kg^-1, the tumor inhibition rate of PTX/CRmP PMs reached 52.11%, better than that of paclitaxel liposome for injection group and paclitaxel injection group. Moreover, the mice in the PTX/CRmP PMs group gained weight, and no apparent whole-body diffusion was observed at the tumor site. During the treatment, the mice were in a good mental state. Pathological tissue sections indicated that the degree of tumor tissue necrosis was the greatest in the PTX/CRmP PMs high-dose group. CONCLUSION PTX/CRmP PMs have good biosafety and can be used for intravenous administration to effectively inhibit tumor growth, while reducing the toxic side effects of PTX and improving the anti-tumor effect of PTX, providing a reference for clinical application.