Abstract 3633: Evauation of doxorubicin-thanine co-loaded nanoparticles for cancer chemotherapy

Abstract

[Purpose] Novel nanoparticles have the potential to increase the efficacy of cancer chemotherapy. Recently, the use of two chemotherapeutic drugs load to liposomes has been studied. In particular, cytarabine-daunorubicin (1:5) co-loaded liposome (CPX-351) has high therapeutic efficacy against acute myelocytic leukemia. We previously reported that a combination of theanine (a specific amino acid of green tea) with doxorubicin (DOX) had a stronger antitumor effect than DOX alone. The effect is caused by the competitive inhibition of glutamate transport by theanine as a glutamate derivative via glutamate transporters in tumor cells. Subsequently, decreased glutamate levels in tumor cells result in lower glutathione, which makes efflux of DOX from cells difficult. Thus, it was speculated that specific accumulation of DOX, caused by theanine, increases the therapeutic index. In the present study, we examined the availability of a DOX-theanine co-loaded liposome as drug carrier for cancer chemotherapy. [Methods] DOX-theanine co-loaded liposome (DT-lip) was prepared using the thin-lipid method. DOX and theanine were loaded at the lipid membrane layer and internal water layer, respectively. P388 leukemia cells were used to study the influence of DT-lip on DOX influx and efflux. The cell suspension was incubated with DT-lip at 37°C, and the DOX concentration in tumor cells was determined. In the antitumor effect study in vivo, tumor-bearing mice were intravenously administered DT-lip (DOX 2.5 mg/kg) at 17th, 20th, and 23rd days after tumor cell implant. Tumors and normal tissue were removed 48 h after last administration. Tumor weight and DOX concentration in tissue were measured. [Results and Discussion] DT-lip was prepared with three ratios of DOX to theanine (1:0.5, 1:1, and 1:4, w/w). In the influx study, the DOX concentration in tumor cells was the same for the different ratios. DOX influx into tumor cells in the DT-lip group was enhanced compared to liposomes loaded with DOX only (D-lip). At 30 min, the intracellular DOX concentration in the DT-lip was 1.4 fold higher than that in the D-lip group. Conversely, there was no practical difference in DOX efflux from tumor cells between the D-lip and DT-lip group. In other words, DT-lip had an influence on influx system, and this phenomenon differed from the previous results for theanine′s role in the DOX efflux system. This findings suggest that liposomalization of theanine + DOX changed the theanine connected integrated mechanism in tumor cells. In vivo, the antitumor effect of DT-lip was superior to combined administration of both solutions. The adverse effects of DT-lip treatment on normal tissue did not increase because DOX concentration in tissue was comparable across group. In conclusion, the DT-lip, a liposome co-loaded DOX and theanine, is a novel antitumor formulation for cancer chemotherapy. Citation Format: Ikumi Sugiyama, Yasuyuki Sadzuka. Evauation of doxorubicin-thanine co-loaded nanoparticles for cancer chemotherapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3633.