A novel multifunctional nanoparticles formed by molecular recognition between AS1411 aptamer and redox-responsive paclitaxel-nucleoside analogue prodrug for combination treatment of β-lapachone and paclitaxel

Despite its high antitumor activity , the clinical application of chemotherapy is greatly impeded by lacking of specific accumulation and poor solubility. To address the above challenges, we designed a AS1411 aptamer modified nanoparticles based on molecular recognition of nucleobases . Firstly, a redox sensitive Paclitaxel-SS-Zidovudine (PZ) prodrug was synthesized. Then PZ/β-lapachone/AS1411/DSPE-PEG nanoparticles were prepared and AS1411 aptamer was connected through molecular recognition between the nucleoside analogue Zidovudine (ZDV) and the thymine on aptamer. DSPE-PEG (DP) was incorporated into nanoparticles to prolong the residence time of nanoparticles in the blood circulation . Furthermore, to realize the combination treatment, β-lapachone (LAP) has been incorporated into nanoparticles with high drug loading efficiency through the interaction of π-π stacking force and H-bonding between LAP and Paclitaxel (PTX). LAP can generate abundant exogenous reactive oxygen species (ROS) via the bioactivation of NAD(P)H: quinone oxidoreductase-1 (NQO1). Moreover, the connection of Zidovudine (ZDV) and AS1411 through molecular recognition of nucleobases further optimized the nanoparticles with high affinity to nucleolin which overexpressed on tumor cell membrane , thereby inducing the specific accumulation of nanoparticles in tumor sites. In vivo and in vitro studies showed that the obtained nanoparticles of PZ/LAP/AS1411/DP exhibited better tumor growth inhibition and lower systemic side effects. Herein, we have rationally conducted a novel self-codelivery system for effectively synergistic antitumor treatment.