Temporary suppression the sequestrated function of host macrophages for better nanoparticles tumor delivery

Abstract

Orchestration of nanoparticles to achieve targeting has become the mainstream for efficient delivery of antitumor drugs. However, the low delivery efficiency becomes the biggest barrier for clinical translation of cancer nanomedicines, as most of them are sequestrated in the liver where more macrophages located in are responsible for capture of systemic administrated nanoparticles. In this study, we found that the depletion of the liver macrophages could lead to a superior improvement in the nanoparticles delivery. Firstly, we developed clodronate-containing liposomes (clodrolip) to transiently suppress the phagocytic function of macrophages, the residual macrophages in liver only accounted for less than 1% when the mice were treated with clodrolip in advance. In addition, the pharmacokinetics results of treatment with paclitaxel-poly(lactic-co-glycolic acid) (PTX-PLGA) nanoparticles disclosed that the AUC of PTX in the macrophages depletion group increased 2.11-fold. These results meant that the removal of macrophages would decrease the nanoparticles accumulation in the liver and better the biodistribution and bioavailability of nanoparticles delivery systems. Moreover, treatment of mice with melanoma by the combination of clodrolip and PTX-PLGA nanoparticles resulted in an elevated anti-tumor efficacy, the tumor inhibition ratio was nearly reached to 80%. Furthermore, these combinatorial regimens have demonstrated negligible toxicity in incidence of adverse effects. In conclusion, the encouraging results from this study inspire the generation of a rational strategy to focus on microenvironmental priming for modulation of innate immunity and to improve delivery efficiency of nanoparticles.

Keywords

• macrophages depletion
• paclitaxel
• plga nanoparticles
• clodrolip
• antitumor effect