Center for Bionanoengineering and the State Key Laboratory for Chemical Engineering, Department of Chemical and Biological Engineering, Zhejiang University, Hangzhou, China 310027.
J Am Chem Soc. 2010 Mar 31;132(12):4259-65. doi: 10.1021/ja909475m.
Anticancer drugs embedded in or conjugated with inert nanocarriers, referred to as nanomedicines, show many therapeutic advantages over free drugs, but the inert carrier materials are the major component (generally more than 90%) in nanomedicines, causing low drug loading contents and thus excessive uses of parenteral excipients. Herein, we demonstrate a new concept directly using drug molecules to fabricate nanocarriers in order to minimize use of inert materials, substantially increase the drug loading content, and suppress premature burst release. Taking advantage of the strong hydrophobicity of the anticancer drug camptothecin (CPT), one or two CPT molecule(s) were conjugated to a very short oligomer chain of ethylene glycol (OEG), forming amphiphilic phospholipid-mimicking prodrugs, OEG-CPT or OEG-DiCPT. The prodrugs formed stable liposome-like nanocapsules with a CPT loading content as high as 40 or 58 wt % with no burst release in aqueous solution. OEG-DiCPT released CPT once inside cells, which showed high in vitro and in vivo antitumor activity. Meanwhile, the resulting nanocapsules can be loaded with a water-soluble drug-doxorubicin salt (DOX.HCl)-with a high loading efficiency. The DOX.HCl-loaded nanocapsules simultaneously delivered two anticancer drugs, leading to a synergetic cytotoxicity to cancer cells. The concept directly using drugs as part of a carrier is applicable to fabricating other highly efficient nanocarriers with a substantially reduced use of inert carrier materials and increased drug loading content without premature burst release.
抗癌药物嵌入或与惰性纳米载体结合，称为纳米药物，与游离药物相比具有许多治疗优势，但惰性载体材料是纳米药物的主要成分（通常超过 90%），导致载药量低，因此需要过多地使用注射用赋形剂。在此，我们提出了一个新概念，即直接使用药物分子来制备纳米载体，以最小化惰性材料的使用、大幅度提高载药量并抑制早期突释。利用抗癌药物喜树碱（CPT）的强疏水性，将一个或两个 CPT 分子与非常短的乙二醇（OEG）寡聚物链连接，形成两亲性磷脂类似物前药，OEG-CPT 或 OEG-DiCPT。前药在水溶液中形成具有高达 40 或 58wt%载药量且无突释的稳定类脂质体纳米胶囊。OEG-DiCPT 一旦进入细胞内就会释放 CPT，表现出高的体外和体内抗肿瘤活性。同时，所得纳米胶囊可以高载药量负载水溶性药物-盐酸多柔比星（DOX.HCl）。载 DOX.HCl 的纳米胶囊同时递送两种抗癌药物，导致对癌细胞产生协同细胞毒性。该概念直接使用药物作为载体的一部分，适用于制备其他高效纳米载体，可大大减少惰性载体材料的使用并提高载药量，同时避免早期突释。
