The first liposomal formulation of
cisplatin to be evaluated clinically was
SPI-077. Although the formulation demonstrated enhanced
cisplatin tumor accumulation in preclinical models it did not enhance clinical efficacy, possibly due to limited
cisplatin release from the formulation localized within the
tumor. We have examined a series of liposomal formulations to address the in vivo relationship between
cisplatin release rate and formulation efficacy in the P388 murine
leukemia model. The base formulation of
phosphatidylcholine:
phosphatidylglycerol:
cholesterol was altered in the C18 and C16
phospholipid content to influence membrane fluidity and thereby impacting drug circulation lifetime and drug retention. Phase transition temperatures (T(m)) ranged from 42-55°C. The high T(m) formulations demonstrated enhanced drug retention properties accompanied by low antitumor activity while the lowest T(m) formulations released the drug too rapidly in the plasma, limiting drug delivery to the
tumor which also resulted in low antitumor activity. A formulation composed of DSPC : DPPC : DSPG : Chol; (35 : 35 : 20 : 10) with an intermediate drug release rate and a
cisplatin plasma half-life of 8.3 hours showed the greatest antitumor activity. This manuscript highlights the critical role that drug release rates play in the design of an optimized drug delivery vehicle.