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,
leading 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
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 circulating
particles after successful accumulation in tumors by EPR, thereby reducing toxicities and likely
toxicity-related therapeutic limitations.