Abstract
In recent years, active targeting strategies by ligand modification have emerged to enhance tumor accumulation of NP, but their clinical application was strictly restricted due to the complex preparation procedures, poor stability and serious toxicity. An effective and clinical translational strategy is required to satisfy the current problems. Interestingly, the internalization of NP is intimately related with cell cycle and the expression of receptors is not only related with cancer types but also cell cycle progression. So the cellular uptake of ligand modified NP may be related with cell cycle. However, few investigations were reported about the relationship between cell cycle and the internalization of ligand modified NP. Herein, cellular uptake of folic acid (FA) modified NP after utilizing chemotherapeutic to retain the tumor cells in G2/M phase was studied and a novel strategy was designed to enhance the active targeting effect. In our study, docetaxel (DTX) notably synchronized cells in G2/M phase and pretreatment with DTX highly improved in vitro and in vivo tumor cell targeting effect of FA decorated NP (FANP). Since FA was a most common used tumor active targeting ligand, we believe that this strategy possesses broader prospects in clinical application for its simplicity and effectiveness.
Highlights
Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No 17, Block 3, Southern Renmin Road, Chengdu 610041, China. *These authors contributed to this work
Low dosage of DTX arrested more cells in G2/M phase[18], we evaluated the influence of DTX on cellular uptake of NP and FA conjugated PEG-PCL NP (FANP) (Fig. 2)
To clarify the universal mechanism, we evaluated the cellular uptake of LIP and FA modified liposome (FA-LIP) (Supplementary Figs S4 and 5)
Summary
Key Laboratory of Drug Targeting and Drug Delivery Systems, West China School of Pharmacy, Sichuan University, No 17, Block 3, Southern Renmin Road, Chengdu 610041, China. *These authors contributed to this work. In this study, FA was employed to functionalize the NP for active tumor targeting, and the cellular uptake of FA conjugated PEG-PCL NP (FANP) during different cell cycles was studied. We would combine the G2/M phase retention effect of DTX and tumor active targeting effect of FANP to evaluate whether this novel strategy could further improve the tumor targeting delivery. The cellular uptake on FR positive A549 cells and negative L929 cells of FANP after pretreated with DTX was studied. This study may open up the possibility of increasing targeting delivery efficacy through combining active targeting nanomedicines with clinical available G2/M phase retained chemotherapeutics and provided appeal for the development of novel therapeutic strategies by application of the existing formulations in clinic
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