A New Approach to Decrease the RES Uptake of Nanodrugs by Pre-administration with Intralipid® Resulting in a Reduction of Toxic Side Effects

Abstract

The number of different nanoparticle drug-delivery systems currently being developed is increasing rapidly. A major limitation for the translation of nanodrugs to clinical applications is their rapid uptake by the cells of the reticuloendothelial system (RES), in particular liver and spleen. This can reduce the efficacy at the target tissue and increase the nano-toxicity to these off-target organs. Unfortunately, the accumulation of nanodrugs in tumors represents a small fraction of total injected dose (1–10 %). The majority (40–80 %) of injected nanodrugs end up in the RES. Many studies have been conducted to try to decrease the RES uptake and to increase the tumor targeting of nanodrugs by modifying nanoparticle characteristics, such as size, shape, charge, surface property, and composition. Our new strategy is to temporarily blunt the uptake of nanodrugs by the RES using Intralipid® 20 %, which has been used as a safe nutrition source for four decades. We have found that, in rodents, pre-treatment with Intralipid® 20 % (using a clinical route and dosage, 2 g/kg) can change the pharmacokinetic/pharmacodynamic profile of nanoparticles. A single dose of Intralipid® can reduce RES uptake by ~50 % and increase blood half-life by ~3-fold of nano- and micron-sized iron-oxide particles. Recently, we have applied this finding to the delivery of a platinum (Pt)-containing anti-cancer nanodrug. Pre-administration with Intralipid® can increase the bioavailability of the Pt-nanodrug and reduce the toxicity in liver, spleen, and kidney. Our method is a general one applicable to any approved and in-development nanodrugs without additional modification of the nano-carriers.