title: Systemic Lipoplatin infusion results in preferential tumor uptake in human studies.
abstract: 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.
authors.affiliation: Regulon, Inc., 715 North Shoreline Blvd, Mountain View, California 94043, USA. teni@regulon.org
authors.forename: Teni
authors.initials: T
authors.lastname: Boulikas
authors.forename: Georgios P
authors.initials: GP
authors.lastname: Stathopoulos
authors.forename: Nikolaos
authors.initials: N
authors.lastname: Volakakis
authors.forename: Maria
authors.initials: M
authors.lastname: Vougiouka
mesh_terms: D000273:Adipose Tissue / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism; D002945:Cisplatin / Q000008:administration & dosage* / Q000493:pharmacokinetics; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism; D004067:Digestive System Neoplasms / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary; D008297:Male; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; C503131:lipoplatin; D002945:Cisplatin