Enhancement of both intracellular uptake and antitumor action of cisplatinum on human neuroblastoma cells by encapsulation in liposomes.

Phospholipid vesicles (phosphatidylcholine:phosphatidylserine:cholesterol = 6:2:3 in molar ratio) with a small unilamellar structure were used as drug carriers for introducing cis-diamminedichloroplatinum (CDDP) into human neuroblastoma cells, IMR-32, GOTO, Nagai, and TGW. DNA synthesis of IMR-32 cells among the human neuroblastoma cell lines was inhibited most strongly by CDDP-liposomes. CDDP-liposomes dose-dependently inhibited the DNA synthesis of IMR-32 in a similar fashion to that observed with free CDDP, but the drug concentration required to induce 50% inhibition of DNA synthesis for CDDP-liposomes (IC50: 0.7 micrograms CDDP/ml) was 1/3 of the IC50 for free CDDP (2.0 micrograms CDDP/ml). In support of the marked growth-inhibitory action of CDDP-liposomes, the intracellular incorporation rate of CDDP-liposomes was 3-fold higher when liposomes were used as carriers than when free CDDP was directly applied. CDDP-liposomes showed a stronger growth inhibition on IMR-32 cells at a high cell density than at a low density in culture. CDDP-liposomes were rapidly incorporated by IMR-32 cells within 5 min, resulting in the inhibition of DNA synthesis to 40% of the control. Swiss albino mouse 3T3 cells were less inhibited by CDDP-liposomes than by free CDDP, suggesting that encapsulation of CDDP in liposomes decreases cytotoxicity to normal cells.