A GD2-aptamer-mediated, self-assembling nanomedicine for targeted multiple treatments in neuroblastoma theranostics

Liyu Zhang; Meng Wang; Zeen Zhu; Shengquan Chen; Haibin Wu; Ying Yang; Fengyu Che; Qiao Li; Hui Li

doi:10.1016/j.omtn.2021.08.021

A GD2-aptamer-mediated, self-assembling nanomedicine for targeted multiple treatments in neuroblastoma theranostics

Mol Ther Nucleic Acids. 2021 Aug 26:26:732-748. doi: 10.1016/j.omtn.2021.08.021. eCollection 2021 Dec 3.

Authors

Liyu Zhang^{1

2}, Meng Wang³, Zeen Zhu⁴, Shengquan Chen¹, Haibin Wu², Ying Yang², Fengyu Che², Qiao Li⁵, Hui Li^{1

6}

Affiliations

¹ Department of Neonatology, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
² Shaanxi Institute of Pediatric Diseases, Affiliated Children's hospital of Xi'an Jiaotong University, Xi'an 710002, Shaanixi, China.
³ Department of Emergency Surgery, Shaanxi Provincial People's Hospital, Xi'an 710068, Shaanxi, China.
⁴ Department of Hepatobiliary Surgery, the First Affiliated Hospital of Xi'an Jiaotong University, Xi'an 710061, Shaanxi, China.
⁵ Department of clinical laboratory, Affiliated Children's hospital of Xi'an Jiaotong University, Xi'an 710002, China.
⁶ Department of Neonatology, Affiliated Children's hospital of Xi'an Jiaotong University, Xi'an 710002, China.

Abstract

Because current mainstream anti-glycolipid GD2 therapeutics for neuroblastoma (NB) have limitations, such as severe adverse effects, improved therapeutics are needed. In this study, we developed a GD2 aptamer (DB99) and constructed a GD2-aptamer-mediated multifunctional nanomedicine (ANM) with effective, precise, and biocompatible properties, which functioned both as chemotherapy and as gene therapy for NB. DB99 can bind to GD2⁺ NB tumor cells but has minimal cross-reactivity to GD2^- cells. Furthermore, ANM is formulated by self-assembly of synthetic aptamers DB99 and NB-specific MYCN small interfering RNA (siRNA), followed by self-loading of the chemotherapeutic agent doxorubicin (Dox). ANM is capable of specifically recognizing, binding, and internalizing GD2⁺, but not GD2^-, NB tumor cells in vitro. Intracellular delivery of ANM activates Dox release for chemotherapy and MYCN-siRNA-induced MYCN silencing. ANM specifically targets, and selectively accumulates in, the GD2⁺ tumor site in vivo and further induces growth inhibition of GD2⁺ tumors in vivo; in addition, ANM generates fewer or no side effects in healthy tissues, resulting in markedly longer survival with fewer adverse effects. These results suggest that the GD2-aptamer-mediated, targeted drug delivery system may have potential applications for precise treatment of NB.

Keywords: GD2; Neuroblastoma; aptamer; self-assembling nanomedicine; targeted multiple treatments.