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Self‐Assembly of an Amphiphilic Janus Camptothecin–Floxuridine Conjugate into Liposome‐Like Nanocapsules for More Efficacious Combination Chemotherapy in Cancer
Advanced Materials ( IF 29.4 ) Pub Date : 2017-09-11 , DOI: 10.1002/adma.201703135
Xiaolong Liang 1 , Chuang Gao 2 , Ligang Cui 1 , Shumin Wang 1 , Jinrui Wang 1 , Zhifei Dai 2
Affiliation  

The combination of camptothecin (CPT) and fluoropyrimidine derivatives acts synergistically at a 1:1 molar ratio. Practically, the greatest challenge is the development of a single liposomal formulation that can both encapsulate and maintain this drug combination at an exact 1:1 ratio to achieve coordinated pharmacokinetics. Consequently, a new type of liposome‐like nanocapsule (NC) is developed from a highly symmetric Janus camptothecin–floxuridine conjugate (JCFC) amphiphile, which is synthesized by coupling two hydrophobic CPT molecules and two hydrophilic floxuridine (FUDR) molecules to multivalent pentaerythritol via a hydrolyzable ester linkage. JCFC NCs possess remarkably high drug‐loading contents, and no premature release because of the highly stable co‐delivery of the drug combination without the need for any carrier. It is shown that JCFC NCs consistently provide synergy and avoid antagonism in a broad panel of tumor cell lines. In vivo delivery of JCFC NCs leads to longer blood retention half‐life, higher tumorous accumulation and cellular uptake of drugs, and greatly enhanced efficacy in murine tumor models compared to CPT, FUDR, and CPT + FUDR. This liposomal strategy can be extended to other hydrophilic and hydrophobic anticancer drugs that are coupled to pentaerythritol to self‐assemble into nanocapsules for drug self‐delivery, pointing to potential clinical translation in near future.

中文翻译:

将两亲性喜树碱喜树碱-氟尿嘧啶的自组装物缀合到脂质体样纳米胶囊中,以更有效地联合治疗癌症

喜树碱(CPT)和氟嘧啶衍生物的组合以1:1的摩尔比协同作用。实际上,最大的挑战是开发一种脂质体制剂,该制剂既可以以精确的1:1比例封装和维持这种药物组合,又可以实现协调的药代动力学。因此,从高度对称的喜树碱喜树碱-氟尿苷共轭物(JCFC)两亲物开发了一种新型的脂质体状纳米胶囊(NC),该两亲物是通过将两个疏水性CPT分子和两个亲水性氟尿苷(FUDR)分子通过多价季戊四醇偶联而合成的可水解的酯键。JCFC NC具有非常高的载药量,并且由于不需要任何载体就可以高度稳定地共同输送药物组合,因此不会过早释放。结果表明,JCFC NC在多种肿瘤细胞系中始终提供协同作用,并避免了拮抗作用。与CPT,FUDR和CPT + FUDR相比,JCFC NCs的体内递送可延长血液滞留半衰期,提高肿瘤累积和细胞摄取药物的能力,并大大增强了在鼠肿瘤模型中的功效。这种脂质体策略可以扩展到其他与季戊四醇偶联的亲水性和疏水性抗癌药物,以自组装成纳米胶囊以实现药物自我传递,并指出在不久的将来可能进行临床翻译。与CPT,FUDR和CPT + FUDR相比,在鼠类肿瘤模型中的功效大大提高。这种脂质体策略可以扩展到其他与季戊四醇偶联的亲水性和疏水性抗癌药物,以自组装成纳米胶囊以实现药物自我传递,并指出在不久的将来可能进行临床翻译。与CPT,FUDR和CPT + FUDR相比,在鼠类肿瘤模型中的功效大大提高。这种脂质体策略可以扩展到其他与季戊四醇偶联的亲水性和疏水性抗癌药物,以自组装成纳米胶囊以实现药物自我传递,并指出在不久的将来可能进行临床翻译。
更新日期:2017-09-11
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