A mRNA-Responsive G-Quadruplex-Based Drug Release System

Sensors

Hidenobu Yaku¹  Takashi Murashima²  Daisuke Miyoshi²  Naoki Sugimoto² 

[1] Advanced Research Division, Panasonic Corporation, 3-4 Hikaridai, Seika-cho, Soraku-gun, Kyoto 619-0237, Japan; E-Mail:;Faculty of Frontiers of Innovative Research in Science and Technology (FIRST), Konan University, 7-1-20 Minatojima-Minamimachi, Chuo-ku, Kobe 650-0047, Japan; E-Mails:

关键词: drug delivery carrier;    G-quadruplex;    anionic phthalocyanine;    cancer;    mRNA;    telomerase;   

DOI  :  10.3390/s150409388

来源: mdpi

【 摘 要 】

G-quadruplex-based drug delivery carriers (GDDCs) were designed to capture and release a telomerase inhibitor in response to a target mRNA. Hybridization between a loop on the GDDC structure and the mRNA should cause the G-quadruplex structure of the GDDC to unfold and release the bound inhibitor, anionic copper(II) phthalocyanine (CuAPC). As a proof of concept, GDDCs were designed with a 10-30-mer loop, which can hybridize with a target sequence in epidermal growth factor receptor (EGFR) mRNA. Structural analysis using circular dichroism (CD) spectroscopy showed that the GDDCs form a (3 + 1) type G-quadruplex structure in 100 mM KCl and 10 mM MgCl₂ in the absence of the target RNA. Visible absorbance titration experiments showed that the GDDCs bind to CuAPC with K_a values of 1.5 × 10⁵ to 5.9 × 10⁵ M⁻¹ (K_d values of 6.7 to 1.7 μM) at 25 °C, depending on the loop length. Fluorescence titration further showed that the G-quadruplex structure unfolds upon binding to the target RNA with K_a values above 1.0 × 10⁸ M⁻¹ (K_d values below 0.01 μM) at 25 °C. These results suggest the carrier can sense and bind to the target RNA, which should result in release of the bound drug. Finally, visible absorbance titration experiments demonstrated that the GDDC release CuAPC in response to the target RNA.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.