Optimizing Antitumor Efficacy and Adverse Effects of Pegylated Liposomal Doxorubicin by Scheduled Plasmapheresis: Impact of Timing and Dosing.

Abstract

Background: Nanoscale drug delivery systems accumulate in solid tumors preferentially by the enhanced permeation and retention effect (EPR-effect). Nevertheless, only a miniscule fraction of a given dosage reaches the tumor, while >90% of the given drug ends up in otherwise healthy tissues, lead-ing to the severe toxic reactions observed during chemotherapy. Once accumulation in the tumor has reached its maximum, extracorporeal elimination of circulating nanoparticles by plasmapheresis can dimin-ish toxicities.Objective: In this study, we investigated the effect of dosing and plasmapheresis timing on adverse events and antitumor efficacy in a syngeneic rat tumor model.Methods: MAT-B-III cells transfected with a luciferase reporter plasmid were inoculated into female Fisher rats, and pegylated liposomal doxorubicin (PLD) was used for treatment. Plasmapheresis was performed in a discontinuous manner via centrifugation and subsequent filtration of isolated plasma.Results: Bioluminescence measurements of tumor growth could not substitute caliper measurements of tumor size. In the control group, raising the dosage above 9 mg PLD/kg body weight did not increase therapeutic efficacy in our fully immunocompetent animal model. Plasmapheresis was best done 36 h after injecting PLD, leading to similar antitumor efficacy with significantly less toxicity. Plasmapheresis 24 h after injection interfered with therapeutic efficacy, while plasmapheresis after 48 h led to fewer side effects but also to increased weight loss.Conclusion: Long-circulating nanoparticles offer the unique possibility to eliminate the excess of circulat-ing particles after successful accumulation in tumors by EPR, thereby reducing toxicities and likely toxici-ty-related therapeutic limitations