Ming Zhu, Juan Jia, Huan Tang, Yizhuo Xie, Zhe Lv, Han Bao, Yan Zhang, Dongfanghui Miao, Xin Guo, Kejia Chen, Shanshan Wang, Liangping Yu, Jin Pei
{"title":"新型雌激素受体靶向聚乙二醇脂质体包封紫杉醇和顺铂在SKOV-3裸鼠、ICR小鼠和SD大鼠中的抗肿瘤疗效、药代动力学和毒性研究","authors":"Ming Zhu, Juan Jia, Huan Tang, Yizhuo Xie, Zhe Lv, Han Bao, Yan Zhang, Dongfanghui Miao, Xin Guo, Kejia Chen, Shanshan Wang, Liangping Yu, Jin Pei","doi":"10.1021/acs.molpharmaceut.4c01457","DOIUrl":null,"url":null,"abstract":"<p><p>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 (<i>t</i><sub>1/2β</sub>) 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 LD<sub>50</sub> 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.</p>","PeriodicalId":52,"journal":{"name":"Molecular Pharmaceutics","volume":" ","pages":""},"PeriodicalIF":4.5000,"publicationDate":"2025-05-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"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.\",\"authors\":\"Ming Zhu, Juan Jia, Huan Tang, Yizhuo Xie, Zhe Lv, Han Bao, Yan Zhang, Dongfanghui Miao, Xin Guo, Kejia Chen, Shanshan Wang, Liangping Yu, Jin Pei\",\"doi\":\"10.1021/acs.molpharmaceut.4c01457\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Ovarian malignancies overexpress estrogen receptors (ERs), offering a therapeutic avenue for targeted drug delivery. 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Pharmacokinetic studies revealed prolonged circulation of ES-SSL-PTX/CDDP, with elimination half-lives (<i>t</i><sub>1/2β</sub>) 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 LD<sub>50</sub> 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. 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引用次数: 0
摘要
卵巢恶性肿瘤过度表达雌激素受体（er），为靶向给药提供了一条治疗途径。在这里，我们开发了一种新的er靶向聚乙二醇脂质体（ES-SSL-PTX/CDDP），共包覆紫杉醇（PTX）和顺铂（CDDP），以提高治疗效果并减轻全身毒性。ES-SSL-PTX/CDDP呈球形，水动力直径约为150 nm，负zeta电位约为-20 mV， PTX和CDDP的包封效率分别为83.7%和41.1%。ES-SSL-PTX/CDDP呈缓释模式，其t1/2β释放率分别为13.84 h （PTX）和7.18 h (CDDP)，分别是PTX/CDDP的8.82和1.83倍，清除率分别降至0.01 L/h/kg （PTX）和0.02 L/h/kg (CDDP)，分别比PTX/CDDP低18.0和4.0倍。急性毒性结果显示ES-SSL-PTX/CDDP的LD50增加2.12倍(PTX为27.82 mg/kg；19.87 mg/kg (CDDP) vs . PTX/CDDP。长期毒性研究表明，ES-SSL-PTX/CDDP减轻了骨髓抑制和肾毒性，在给药16周后，32个组织未观察到组织病理学异常。本研究强调了ES-SSL-PTX/CDDP在提高铂紫杉烷方案治疗卵巢癌的疗效和降低毒性方面的潜力。
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.
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 (t1/2β) 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.
期刊介绍：
Molecular Pharmaceutics publishes the results of original research that contributes significantly to the molecular mechanistic understanding of drug delivery and drug delivery systems. The journal encourages contributions describing research at the interface of drug discovery and drug development.
Scientific areas within the scope of the journal include physical and pharmaceutical chemistry, biochemistry and biophysics, molecular and cellular biology, and polymer and materials science as they relate to drug and drug delivery system efficacy. Mechanistic Drug Delivery and Drug Targeting research on modulating activity and efficacy of a drug or drug product is within the scope of Molecular Pharmaceutics. Theoretical and experimental peer-reviewed research articles, communications, reviews, and perspectives are welcomed.
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