Liposomal irinotecan: formulation development and therapeutic assessment in murine xenograft models of colorectal cancer.
OBJECTIVE
The purpose is to demonstrate whether an appropriately designed liposomal formulation of irinotecan is effective in treating mice with liver-localized colorectal carcinomas.


METHODS
Irinotecan was encapsulated in 1,2-distearoyl-sn-glycero-3-phosphocholine/cholesterol (55:45 molar ratio) liposomes using an ionophore (A23187)-generated transmembrane proton gradient. This formulation was evaluated in vivo by measuring plasma elimination of liposomal lipid and drug after i.v. administration. Therapeutic activity was determined in SCID/Rag-2M mice bearing s.c. LS180 tumors or orthotopic LS174T colorectal metastases.


RESULTS
Drug elimination from the plasma was significantly reduced when irinotecan was administered in the liposomal formulation. At 1 hour after i.v. administration, circulating levels of the liposomal drug were 100-fold greater than that of irinotecan given at the same dose. High-performance liquid chromatographic analysis of plasma samples indicated that liposomal irinotecan was protected from inactivating hydrolysis to the carboxylate form. This formulation exhibited substantially improved therapeutic effects. For the LS180 solid tumor model, it was shown that after a single injection of liposomal irinotecan at 50 mg/kg, the time to progress to a 400-mg tumor was 34 days (as compared with 22 days for animals treated with free drug at an equivalent dose). In the model of colorectal liver metastases (LS174T), a median survival time of 79 days was observed after treatment with liposomal irinotecan (50 mg/kg, given every 4 days for a total of three doses). Saline and free drug treated mice survived for 34 and 53 days, respectively.


CONCLUSIONS
These results illustrate that liposomal encapsulation can substantially enhance the therapeutic activity of irinotecan and emphasize the potential for using liposomal irinotecan to treat liver metastases.
British Columbia Cancer Agency, Department of Advanced Therapeutics, Vancouver, Canada.
Corrie Lynn
CL
Messerer
Euan C
EC
Ramsay
Dawn
D
Waterhouse
Rebecca
R
Ng
Eva-Maria
EM
Simms
Natashia
N
Harasym
Paul
P
Tardi
Lawrence D
LD
Mayer
Marcel B
MB
Bally
D000818:Animals; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000627:therapeutic use*; D002214:Capsules; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007275:Injections, Intravenous; D000077146:Irinotecan; D008081:Liposomes; D008113:Liver Neoplasms / Q000517:prevention & control / Q000556:secondary; D008297:Male; D051379:Mice; D016513:Mice, SCID; D016019:Survival Analysis; D013997:Time Factors; D016896:Treatment Outcome; D023041:Xenograft Model Antitumor Assays / Q000379:methods*
D002214:Capsules; D008081:Liposomes; D000077146:Irinotecan; D002166:Camptothecin