Article pubs.acs.org/molecularpharmaceutics
Nucleolin Targeting AS1411 Modified Protein Nanoparticle for Antitumor Drugs Delivery Jinhui Wu,*,†,‡ Chenchen Song,†,‡ Chenxiao Jiang,† Xin Shen,† Qian Qiao,† and Yiqiao Hu*,† †
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, China S Supporting Information *
ABSTRACT: Over recent years, cell surface nucleolin as an anticancer target has attracted many researchers’ attentions. To improve the antitumor efficacy, we developed a nucleolin targeted protein nanoparticle (NTPN) delivery system in which human serum albumin (HSA) was used as drug carrier and a DNA aptamer named AS1411, which had high affinity to nucleolin, was used as a bullet. The HSA nanoparticles (NPsPTX) were fabricated by a novel self-assembly method and then modified with AS1411 (Apt-NPs-PTX). The resulted Apt-NPs-PTX were spherical. Compared with NPs-PTX, the uptake of Apt-NPs-PTX displayed a significant increase in MCF-7 cells while there was a decrease in nontumor cell lines such as MCF10A and 3T3 cells. In a cytotoxic study, Apt-NPs-PTX displayed an enhanced cytotoxicity in MCF-7 tumor cells while there was almost no cytotoxicity in MCF-10A cells. Endostatin, a nucleolin inhibitor, could significantly decrease the internalization of AptNPs-PTX, suggesting nucleolin mediates the transmembrane process of Apt-NPs-PTX. Therefore, the AS1411 modified NTPN delivery system might be a promising targeted drug delivery system. KEYWORDS: aptamer AS1411, nucleolin targeting, nanoparticle, paclitaxel, antitumor therapy
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INTRODUCTION
As a delivery vehicle, protein is nontoxic and is able to degrade into amino acids which could be utilized by peripheral tissue.6 Protein-based nanoparticles hold advantages such as decreased clearance and degradation of free drugs. By avoiding solvent-based toxicities and exploiting endogenous pathways, protein-based drug delivery can potentially result in higher intratumor concentrations of the drug.7 Human serum albumin (HSA) is the most abundant protein in blood plasma. HSA is a global molecule with more hydrophobic domains in the inner core and more hydrophilic domains in the surface layer.8 After unfolding, the disulfide bonds are reduced and hydrophobic domains are exposed, which makes it possible to interact with hydrophobic PTX and cause self-assembly into nanoparticles. Aptamers are short, structured DNA or RNA oligonucleotides or peptides that can precisely target surface markers on cancer cells with high affinity and specificity. AS1411, a 26-mer DNA oligonucleotides, is one of the most fully studied aptamers which has been evaluated in phase II clinical trials.9,10 AS1411 was developed for clinical use based on early observations that guanosine-rich oligonucleotides (GRO) possessed antiproliferative properties in vitro.11 Early studies revealed that AS1411 could form a G-quartet-containing structure that remained remarkably stable in serum-containing medium. This makes the AS1411 resistant to nuclease degradation.12 Furthermore, studies showed that AS1411
Paclitaxel (PTX), isolated from the bark of Pacific Yew, is believed to be one of the best antineoplastic drugs discovered from nature. In clinical trials, PTX is used in the treatment of various types of cancer such as prostate, breast, melanoma, esophageal cancer, and Kaposi’s sarcoma,1,2 but its clinical use is limited due to its low solubility (
