Cattel Luigi, Ceruti Maurizio, Dosio Franco
Dipartimento di Scienza e Tecnologia del Farmaco, Università degli Studi di Torino, Italy.
Tumori. 2003 May-Jun;89(3):237-49. doi: 10.1177/030089160308900302.
Many attempts have been made to achieve good selectivity to targeted tumor cells by preparing specialized carrier agents that are therapeutically profitable for anticancer therapy. Among these, liposomes are the most studied colloidal particles thus far applied in medicine and in particular in antitumor therapy. Although they were first described in the 1960s, only at the beginning of 1990s did the first therapeutic liposomes appear on the market. The first-generation liposomes (conventional liposomes) comprised a liposome-containing amphotericin B, Ambisome (Nexstar, Boulder, CO, USA), used as an antifungal drug, and Myocet (Elan Pharma Int, Princeton, NJ, USA), a doxorubicin-containing liposome, used in clinical trials to treat metastatic breast cancer. The second-generation liposomes ("pure lipid approach") were long-circulating liposomes, such as Daunoxome, a daunorubicin-containing liposome approved in the US and Europe to treat AIDS-related Kaposi's sarcoma. The third-generation liposomes were surface-modified liposomes with gangliosides or sialic acid, which can evade the immune system responsible for removing liposomes from circulation. The fourth-generation liposomes, pegylated liposomal doxorubicin, were called "stealth liposomes" because of their ability to evade interception by the immune system, in the same way as the stealth bomber was able to evade radar. Actually, the only stealth liposome on the market is Caelyx/Doxil (Schering-Plough, Madison NJ, USA), used to cure AIDS-related Kaposi's sarcoma, resistant ovarian cancer and metastatic breast cancer. Pegylated liposomal doxorubicin is characterized by a very long-circulation half-life, favorable pharmacokinetic behavior and specific accumulation in tumor tissues. These features account for the much lower toxicity shown by Caelyx in comparison to free doxorubicin, in terms of cardiotoxicity, vesicant effects, nausea, vomiting and alopecia. Pegylated liposomal doxorubicin also appeared to be less myelotoxic than doxorubicin. Typical forms of toxicity associated to it are acute infusion reaction, mucositis and palmar plantar erythrodysesthesia, which occur especially at high doses or short dosing intervals. Active and cell targeted liposomes can be obtained by attaching some antigen-directed monoclonal antibodies (Moab or Moab fragments) or small proteins and molecules (folate, epidermal growth factor, transferrin) to the distal end of polyethylene glycol in pegylated liposomal doxorubicin. The most promising therapeutic application of liposomes is as non-viral vector agents in gene therapy, characterized by the use of cationic phospholipids complexed with the negatively charged DNA plasmid. The use of liposome formulations in local-regional anticancer therapy is also discussed. Finally, pegylated liposomal doxorubicin containing radionuclides are used in clinical trials as tumor-imaging agents or in positron emission tomography.
人们已进行了许多尝试，通过制备对抗癌治疗具有治疗益处的特殊载体来实现对靶向肿瘤细胞的良好选择性。其中，脂质体是迄今为止在医学尤其是抗肿瘤治疗中研究最多的胶体颗粒。尽管它们在20世纪60年代首次被描述，但直到20世纪90年代初，第一批治疗性脂质体才出现在市场上。第一代脂质体（传统脂质体）包括含两性霉素B的脂质体安必素（Nexstar，美国科罗拉多州博尔德），用作抗真菌药物，以及含多柔比星的脂质体麦道可兰（美国新泽西州普林斯顿的Elan Pharma Int），用于治疗转移性乳腺癌的临床试验。第二代脂质体（“纯脂质方法”）是长循环脂质体，如柔红霉素脂质体Daunoxome，在美国和欧洲被批准用于治疗与艾滋病相关的卡波西肉瘤。第三代脂质体是用神经节苷脂或唾液酸进行表面修饰的脂质体，可逃避负责从循环中清除脂质体的免疫系统。第四代脂质体，聚乙二醇化脂质体多柔比星，因其能够像隐形轰炸机躲避雷达一样逃避免疫系统的拦截而被称为“隐形脂质体”。实际上，市场上唯一的隐形脂质体是凯素灵/多喜（美国新泽西州麦迪逊的先灵葆雅公司），用于治疗与艾滋病相关的卡波西肉瘤、耐药卵巢癌和转移性乳腺癌。聚乙二醇化脂质体多柔比星的特点是循环半衰期非常长、药代动力学行为良好且在肿瘤组织中特异性蓄积。这些特性使得凯素灵与游离多柔比星相比，在心脏毒性、发泡作用、恶心、呕吐和脱发方面表现出低得多的毒性。聚乙二醇化脂质体多柔比星的骨髓毒性似乎也比多柔比星小。与之相关的典型毒性形式是急性输注反应、粘膜炎和手足红斑感觉异常，尤其在高剂量或短给药间隔时发生。通过将一些抗原导向的单克隆抗体（单克隆抗体或单克隆抗体片段）或小蛋白质和分子（叶酸、表皮生长因子、转铁蛋白）连接到聚乙二醇化脂质体多柔比星中聚乙二醇的远端，可以获得活性和细胞靶向脂质体。脂质体最有前景的治疗应用是作为基因治疗中的非病毒载体，其特点是使用与带负电荷的DNA质粒复合的阳离子磷脂。还讨论了脂质体制剂在局部区域抗癌治疗中的应用。最后，含放射性核素的聚乙二醇化脂质体多柔比星在临床试验中用作肿瘤成像剂或正电子发射断层扫描剂。
