2. Academic Validation
  3. An anti-GD2 aptamer-based bifunctional spherical nucleic acid nanoplatform for synergistic therapy targeting MDM2 for retinoblastoma

An anti-GD2 aptamer-based bifunctional spherical nucleic acid nanoplatform for synergistic therapy targeting MDM2 for retinoblastoma

  • Biomed Pharmacother. 2024 Mar 22:174:116437. doi: 10.1016/j.biopha.2024.116437.
Shijing Wang 1,  Yan Zhao 2,  Fei Yao 1,  Pengxue Wei 3,  Lan Ma 4,  Shaochong Zhang 5
Affiliations

Affiliations

  • 1 Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, 18 Zetian Road, Futian District, Shenzhen 518040, China; Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, University Town of Shenzhen, Nanshan District, Shenzhen 518055, China.
  • 2 Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Guangqiao Road, Guangming District, Shenzhen 518107, China.
  • 3 Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, 18 Zetian Road, Futian District, Shenzhen 518040, China.
  • 4 Institute of Biopharmaceutical and Health Engineering, Tsinghua Shenzhen International Graduate School, Tsinghua University, University Town of Shenzhen, Nanshan District, Shenzhen 518055, China; Institute of Biomedical Health Technology and Engineering, Shenzhen Bay Laboratory, Guangqiao Road, Guangming District, Shenzhen 518107, China. Electronic address: malan@sz.tsinghua.edu.cn.
  • 5 Shenzhen Eye Hospital, Jinan University, Shenzhen Eye Institute, 18 Zetian Road, Futian District, Shenzhen 518040, China. Electronic address: zhangshaochong@gzzoc.com.
PMID: 38522240 DOI: 10.1016/j.biopha.2024.116437
Abstract

Retinoblastoma (RB) is a type of pediatric solid tumor in the fundus. The lack of precision therapies combined with the difficulty of delivering small interfering RNA (siRNA) into the eyes means that there is currently no nucleic acid-based therapy for RB in clinical practice. Here, we reported on anti-GD2 and glutathione-responsive spherical nucleic acids (SNAs), loaded with siRNA and the inhibitor NVP-CGM097, which jointly blocked the oncogenic factor n in RB cells (Y79 and WERI-RB-1). The SNAs were formed through the self-assembly of bifunctional Cholesterol amphiphiles containing Aptamers that specifically targeted GD2-positive RB cells, allowing for the formation of an SNA with a dense DNA shell. The aptamer/siRNA component functioned both as a carrier and a payload, enhancing the specific recognition and delivery of both components and constituting an active agent for MDM2 regulation. Following SNA endocytosis by RB cells, siRNA and NVP-CGM097 were released from the SNA particles by glutathione, which synergistically blocked the MDM2-p53 pathway, increasing p53 protein content and inducing cell Apoptosis. This study showed a potent antitumor effect following intravitreal injection of SNAs in Y79 tumor-bearing mice through clinical manifestation and tumor pathological analysis. In hematological analysis and hepatotoxicity assays, SNAs were safer for mice than melphalan, the favored drug for treating RB in clinical practice. Our results illustrated the potential of intravitreally injected SNAs as a precision medicine for treating RB.

Keywords

RNA interference; Self-assembly; retinoblastoma; specific therapy; spherical nucleic acids.

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