Antitumor Efficacy, Pharmacokinetics, and Toxicity Studies of Novel Estrogen Receptors Targeted PEGylated Liposomes Encapsulating Paclitaxel and Cisplatin in SKOV-3 Tumor-Bearing Nude Mice, ICR Mice, and SD Rats.

Abstract

Ovarian malignancies overexpress estrogen receptors (ERs), offering a therapeutic avenue for targeted drug delivery. Here, we developed a novel ER-targeted PEGylated liposome (ES-SSL-PTX/CDDP) coencapsulating paclitaxel (PTX) and cisplatin (CDDP) to enhance therapeutic efficacy and mitigate systemic toxicity. ES-SSL-PTX/CDDP exhibited a spherical shape with a hydrodynamic diameter of around 150 nm, a negative zeta potential of about -20 mV, and high encapsulation efficiencies of 83.7% for PTX and 41.1% for CDDP. ES-SSL-PTX/CDDP showed a sustained release pattern, with release rates of <60% for both drugs within 12 h. Meanwhile, ES-SSL-PTX/CDDP demonstrated excellent storage and serum stability, with the leakage rates less than 30% when stored at either 4 or 25 °C. ES-SSL-PTX/CDDP exhibited a strong antitumor effect in athymic mice with the tumor volume 8.50 times smaller than that in the control group on the 27th day, and the tumor inhibition rate reached 87.3%. Pharmacokinetic studies revealed prolonged circulation of ES-SSL-PTX/CDDP, with elimination half-lives (t_1/2β) of 13.84 h (PTX) and 7.18 h (CDDP), which were 8.82- and 1.83-fold higher than those of PTX/CDDP, and clearance rates reduced to 0.01 L/h/kg (PTX) and 0.02 L/h/kg (CDDP), being 18.0- and 4.0-fold lower than those of PTX/CDDP. Acute toxicity results demonstrated a 2.12-fold increase in the LD₅₀ of ES-SSL-PTX/CDDP (27.82 mg/kg for PTX; 19.87 mg/kg for CDDP) versus PTX/CDDP. Long-term toxicity studies demonstrated that ES-SSL-PTX/CDDP attenuated myelosuppression and nephrotoxicity, with no histopathological abnormalities observed across 32 tissues after 16 weeks of administration. This study highlights the potential of ES-SSL-PTX/CDDP to improve the efficacy and reduce the toxicity of platinum-taxane regimens in the treatment of ovarian cancer.