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Biocompatible Chemotherapy for Leukemia by Acid-Cleavable, PEGylated FTY720.
Bioconjugate Chemistry ( IF 4.7 ) Pub Date : 2020-01-27 , DOI: 10.1021/acs.bioconjchem.9b00822 Jessica A Kemp , Andrew Keebaugh , Julius A Edson , David Chow , Michael T Kleinman , Yap Ching Chew 1 , Alison N McCracken , Aimee L Edinger , Young Jik Kwon
Bioconjugate Chemistry ( IF 4.7 ) Pub Date : 2020-01-27 , DOI: 10.1021/acs.bioconjchem.9b00822 Jessica A Kemp , Andrew Keebaugh , Julius A Edson , David Chow , Michael T Kleinman , Yap Ching Chew 1 , Alison N McCracken , Aimee L Edinger , Young Jik Kwon
Affiliation
Targeting the inability of cancerous cells to adapt to metabolic stress is a promising alternative to conventional cancer chemotherapy. FTY720 (Gilenya), an FDA-approved drug for the treatment of multiple sclerosis, has recently been shown to inhibit cancer progression through the down-regulation of essential nutrient transport proteins, selectively starving cancer cells to death. However, the clinical use of FTY720 for cancer therapy is prohibited because of its capability of inducing immunosuppression (lymphopenia) and bradycardia when phosphorylated upon administration. A prodrug to specifically prevent phosphorylation during circulation, hence avoiding bradycardia and lymphopenia, was synthesized by capping its hydroxyl groups with polyethylene glycol (PEG) via an acid-cleavable ketal linkage. Improved aqueous solubility was also accomplished by PEGylation. The prodrug reduces to fully potent FTY720 upon cellular uptake and induces metabolic stress in cancer cells. Enhanced release of FTY720 at a mildly acidic endosomal pH and the ability to substantially down-regulate cell-surface nutrient transporter proteins in leukemia cells only by an acid-cleaved drug were confirmed. Importantly, the prodrug demonstrated nearly identical efficacy to FTY720 in an animal model of BCR-Abl-driven leukemia without inducing bradycardia or lymphopenia in vivo, highlighting its potential clinical value. The prodrug formulation of FTY720 demonstrates the utility of precisely engineering a drug to avoid undesirable effects by tackling specific molecular mechanisms as well as a financially favorable alternative to new drug development. A multitude of existing cancer therapeutics may be explored for prodrug formulation to avoid specific side effects and preserve or enhance therapeutic efficacy.
中文翻译:
酸可裂解的聚乙二醇化FTY720对白血病的生物相容性化学疗法。
针对癌细胞无法适应新陈代谢的压力,是常规癌症化疗的有希望的替代方法。FTY720(Gilenya)是FDA批准的用于治疗多发性硬化症的药物,最近被证明可通过下调必需营养素转运蛋白来抑制癌症进展,从而选择性地使癌细胞饿死。但是,由于FTY720在给药后被磷酸化时具有诱导免疫抑制(淋巴细胞减少)和心动过缓的能力,因此禁止将其用于癌症治疗。通过经由酸可裂解的缩酮键用聚乙二醇(PEG)封端羟基,合成了一种在循环过程中特异性防止磷酸化从而避免心动过缓和淋巴细胞减少的前药。通过PEG化也改善了水溶性。细胞吸收后,前药还原为完全有效的FTY720,并在癌细胞中诱导代谢应激。证实了FTY720在中等酸性的内体pH值下的增强释放以及仅通过酸裂解的药物即可实质上下调白血病细胞中细胞表面营养转运蛋白的能力。重要的是,在BCR-Abl驱动的白血病动物模型中,前药显示出与FTY720几乎相同的功效,而不会在体内引起心动过缓或淋巴细胞减少,从而突出了其潜在的临床价值。FTY720的前药制剂展示了通过解决特定的分子机理以及对新药开发的经济上有利的替代方案,对药物进行精确工程化以避免不良影响的实用性。
更新日期:2020-01-29
中文翻译:
酸可裂解的聚乙二醇化FTY720对白血病的生物相容性化学疗法。
针对癌细胞无法适应新陈代谢的压力,是常规癌症化疗的有希望的替代方法。FTY720(Gilenya)是FDA批准的用于治疗多发性硬化症的药物,最近被证明可通过下调必需营养素转运蛋白来抑制癌症进展,从而选择性地使癌细胞饿死。但是,由于FTY720在给药后被磷酸化时具有诱导免疫抑制(淋巴细胞减少)和心动过缓的能力,因此禁止将其用于癌症治疗。通过经由酸可裂解的缩酮键用聚乙二醇(PEG)封端羟基,合成了一种在循环过程中特异性防止磷酸化从而避免心动过缓和淋巴细胞减少的前药。通过PEG化也改善了水溶性。细胞吸收后,前药还原为完全有效的FTY720,并在癌细胞中诱导代谢应激。证实了FTY720在中等酸性的内体pH值下的增强释放以及仅通过酸裂解的药物即可实质上下调白血病细胞中细胞表面营养转运蛋白的能力。重要的是,在BCR-Abl驱动的白血病动物模型中,前药显示出与FTY720几乎相同的功效,而不会在体内引起心动过缓或淋巴细胞减少,从而突出了其潜在的临床价值。FTY720的前药制剂展示了通过解决特定的分子机理以及对新药开发的经济上有利的替代方案,对药物进行精确工程化以避免不良影响的实用性。