Although administration of anti-cancer drugs in high doses results in serious side effects due to their strong toxicity, many kinds of chemical compounds and recombinant proteins are used against various types of cancer. It would be more beneficial for cancer patients if they could take an effective dose without unexpected and unwanted side effects. Cisplatin (CDDP) is one example. It is one of the most effective anti-cancer agents. It requires an appropriate drug delivery system (DDS). Encapsulation of drug molecules into liposomes is one typical DDS strategy, but it is still necessary to improve the combination of drug and lipids to obtain the best efficiency of incorporation. Our first approach was to establish a highly-efficient method to prepare liposomes incorporating CDDP. We exploited cis-diamminedinitratoplatinum (CDDP3), which is highly soluble in water and labile in the presence of chloride ions converting into CDDP, to prepare liposomes containing CDDP at high concentration, because the insolubility of CDDP in water considerably inhibits incorporation. As expected, the loading efficiency of CDDP into liposomes was dramatically improved with CDDP3 in chloride-ion-free conditions, compared with CDDP used by itself. Furthermore, the liposomes were conferred with the ability to target a specific locus of tumor in vivo, being conjugated with Sialyl Lewis X (SLX) on the surface. The SLX liposome (SLX-Lip) is considered to mimic leucocyte accumulating in the inflammatory region of arthritis and tumors with high affinity to E-selectin expressed on the vascular endothelial cells. CDDP encapsulated into SLX-Lip (CDDP-SLX-Lip) was then evaluated in vivo as a sophisticated active targeting DDS. The acute toxicity of CDDP was markedly reduced by the use of liposome. Intravenous administration of CDDP-SLX-Lip at doses of 18 and 25 mg CDDP/kg weight to normal mice showed a survival rate of 75 % even at 14 days after injection, while CDDP at the same doses showed survival rates of 25 and 0 %. Decrease of body weight was 20 to 25 % for 3 days after administration of these liposomes, but recovered in a couple of days within the loss of 10 %. Histologically, no abnormality was observed in the kidney, spleen or liver of normal mice after administration of CDDP-SLX-Lip at a dose of 25 mg CDDP/kg weight. The anti-tumor effect of CDDP-SLX-Lip or CDDP-Lip administered via tail veins was evaluated in tumor-bearing mice. The amount of CDDP accumulated in tumors at 48 h after injection was 6 times more when CDDP-SLX-Lip was administered than with CDDP-Lip. The anti-tumor effect at the dose of 25 mg/kg weight in lung carcinomabearing mice was shown to be significant when CDDP was actively directed to tumors suppressing the growth. Thus, CDDP at high doses was demonstrated to be incorporated into liposome and specifically directed to tumors in vivo, showing a practical anti-tumor effect. It may be worth doing further evaluation for a clinical study.
|Title of host publication||Cisplatin|
|Subtitle of host publication||Pharmacology, Clinical Uses and Adverse Effects|
|Publisher||Nova Science Publishers, Inc.|
|Number of pages||26|
|Publication status||Published - Feb 2012|
ASJC Scopus subject areas
- Pharmacology, Toxicology and Pharmaceutics(all)