Sequential treatment of oxaliplatin-containing PEGylated liposome together with S-1 improves intratumor distribution of subsequent doses of oxaliplatin-containing PEGylated liposome.

We recently reported that combination therapy with metronomic S-1 dosing and oxaliplatin (l-OHP)-containing PEGylated liposomes improved antitumor activity in a murine colorectal tumor model. However, little is known about the mechanism underlying such improved therapeutic efficacy. Here we investigated the impact of combined treatment on biodistribution, tumor accumulation and intratumor distribution of test PEGylated liposomes and on the structure of tumor vasculature in a solid tumor. The combined treatment clearly enhanced tumor accumulation and intratumor distribution of a subsequent test dose of PEGylated liposome as a result of on the one hand prolonging blood circulation of test liposome and on the other hand the alteration in tumor microenvironment. The l-OHP-containing PEGylated liposomes contributed predominantly to the enhanced tumor accumulation and altered tumor distribution of test liposome. On the other hand, metronomic S-1 dosing contributed to the altered tumor distribution but not the tumor accumulation of test liposome. The antitumor effect of the combined treatment, reflected by the proportion of apoptotic cells in the tumor, was approximately equally accounted for by each of the two treatments, leading to a roughly additive effect. In conclusion, 1-OHP-containing PEGylated liposome together with S-1 enhanced intratumor influx, leading to improved antitumor activity of subsequently injected 1-OHP-containing PEGylated liposomes and/or S-1. This strategy we propose, which is clinically applicable, may overcome the problems related to the use of EPR effect-based nanocarrier systems.