Boulikas Teni, Stathopoulos Georgios P, Volakakis Nikolaos, Vougiouka Maria
Regulon, Inc., 715 North Shoreline Blvd, Mountain View, California 94043, USA.
Anticancer Res. 2005 Jul-Aug;25(4):3031-9.
Lipoplatin, a liposomal formulation of cisplatin, was developed with almost negligible nephrotoxicity, ototoxicity and neurotoxicity, as demonstrated in preclinical and Phase I human studies. A polyethylene-glycol coating of the liposome nanoparticles is supposed to result in tumor accumulation of the drug by extravasation through the altered tumor vasculature. We explored the hypothesis that intravenous infusion of Lipoplatin results in tumor targeting in four independent patient cases (one with hepatocellular adenocarcinoma, two with gastric cancer and one with colon cancer) who underwent Lipoplatin infusion followed by a prescheduled surgery approximately 20 h later. Direct measurement of the platinum levels in specimens from the excised tumors and normal tissues showed that the total platinum levels were on average 10-50 times higher in malignant tissue compared to the adjacent normal tissue specimens; most effective targeting was observed in colon cancer, with an accumulation up to 200-fold higher in colon tumors compared to normal colon tissue. Of the several surgical specimens, gastric tumors displayed the highest levels of total platinum suggesting Lipoplatin as a candidate anticancer agent for gastric tumors; gastric tumor specimens had up to 260 micrograms platinum /g tissue, that was higher than any tissue level in animals treated at much higher doses. Fat tissue displayed a high accumulation of total platinum in surgical specimens in three different patients, correlating to the lipid capsule of cisplatin in its Lipoplatin formulation. It was also inferred that normal tissue had more platinum trapped in the tissue but not reacted with macromolecules, whereas tumor tissue displayed platinum that reacted with cellular macromolecules; the data were consistent with a model where Lipoplatin damages more tumor compared to normal cells. In conclusion, Lipoplatin has the ability to preferentially concentrate in malignant tissue both of primary and metastatic origin following intravenous infusion to patients. In this respect, Lipoplatin emerges as a very promising drug in the arsenal of chemotherapeutics.
脂质体顺铂（Lipoplatin）是顺铂的脂质体制剂，临床前研究和I期人体研究表明，其肾毒性、耳毒性和神经毒性几乎可以忽略不计。脂质体纳米颗粒的聚乙二醇涂层被认为可使药物通过改变的肿瘤脉管系统外渗而在肿瘤中蓄积。我们探讨了以下假设：对4例独立患者（1例肝细胞腺癌、2例胃癌和1例结肠癌）静脉输注脂质体顺铂后，约20小时后进行预定手术，观察脂质体顺铂是否具有肿瘤靶向性。对切除肿瘤和正常组织标本中的铂水平进行直接测量发现，恶性组织中的总铂水平平均比相邻正常组织标本高10 - 50倍；在结肠癌中观察到最有效的靶向性，结肠肿瘤中的蓄积量比正常结肠组织高200倍。在多个手术标本中，胃肿瘤的总铂水平最高，表明脂质体顺铂是胃肿瘤的候选抗癌药物；胃肿瘤标本的铂含量高达260微克/克组织，高于以高得多的剂量治疗的动物的任何组织水平。在3例不同患者的手术标本中，脂肪组织显示出总铂的高蓄积，这与脂质体顺铂制剂中顺铂的脂质包膜有关。还推断正常组织中有更多铂被困在组织中但未与大分子反应，而肿瘤组织中显示的铂与细胞大分子发生了反应；这些数据与脂质体顺铂对肿瘤细胞的损伤大于正常细胞的模型一致。总之，静脉输注脂质体顺铂后，它有能力优先在原发性和转移性恶性组织中蓄积。在这方面，脂质体顺铂成为化疗药物库中一种非常有前景的药物。
