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Self-Assembled Multivalent Aptamer Drug Conjugates: Enhanced Targeting and Cytotoxicity for HER2-Positive Gastric
Wenjuan Ma1,2,3, Yuting Yang1,2, Zhiqiang Liu1,2
1State Key Laboratory of Oral Diseases, National Center for Stomatology, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, P. R. China.
Abstract:
Antibody drug conjugates (ADCs) have shown promise to be the mainstream chemotherapeutics for advanced HER2-positive cancers, yet the issues of poor drug delivery efficiency, limited chemotherapeutic effects, severe immune responses, and drug resistance remain to be addressed before the clinical applications of ADCs. The DNA aptamer-guided drug conjugates (ApDCs) are receiving growing attention for specific tumors due to their excellent tumor affinity and low cost. Therefore, developing a multivalent ApDC nanomedicine by combining anti-HER2 aptamer (HApt), tetrahedral framework nucleic acid (tFNA), and deruxtecan (Dxd) together to form HApt-tFNA@Dxd might help to address these concerns. In this study, the HER2-targeted DNA aptamer modified DNA tetrahedron (HApt-tFNA) was employed as a system for drug delivery, and the adoption of tFNA could effectively enlarge the drug-loading rate compared to aptamer-guided ApDCs previously reported. Compared with free Dxd and tFNA@Dxd, HApt-tFNA@Dxd showed better structural stability, excellent targeted cytotoxicity to HER2-positive gastric cancer, and increased tissue aggregation ability in tumors. These features and superiorities make HApt-tFNA@Dxd a promising chemotherapeutic medicine for HER2-positive tumors. Our work developed a new targeting nanomedicine by combining DNA nanomaterials and chemotherapeutic agents, which represents a critical advance toward developing novel DNA-based nanomaterials and promoting their potential applications for HER2-positive cancer therapy.
Insights
Researchers developed a novel DNA aptamer-guided drug conjugate (ApDC) called HApt-tFNA@Dxd. This nanomedicine shows improved delivery and efficacy for HER2-positive cancers, addressing limitations of traditional antibody drug conjugates (ADCs).
Area of Science:
- Biotechnology
- Nanomedicine
- Cancer Therapeutics
Background:
- Antibody drug conjugates (ADCs) show promise for HER2-positive cancers but face challenges in drug delivery, efficacy, and resistance.
- DNA aptamer-guided drug conjugates (ApDCs) offer specific tumor targeting with high affinity and lower cost.
Purpose of the Study:
- To develop a multivalent ApDC nanomedicine combining anti-HER2 aptamer (HApt), tetrahedral framework nucleic acid (tFNA), and deruxtecan (Dxd) to overcome ADC limitations.
- To enhance drug loading capacity and targeted delivery for HER2-positive cancers.
Main Methods:
- Constructed HApt-tFNA@Dxd by integrating HER2-targeting DNA aptamers with a DNA tetrahedron nanocarrier loaded with deruxtecan.
- Evaluated the structural stability, targeted cytotoxicity, and tumor tissue aggregation of HApt-tFNA@Dxd compared to free Dxd and tFNA@Dxd.
Main Results:
- HApt-tFNA@Dxd demonstrated superior structural stability and enhanced targeted cytotoxicity against HER2-positive gastric cancer cells.
- The nanomedicine exhibited increased tissue aggregation within tumors, indicating improved drug delivery efficiency.
- The DNA tetrahedron carrier facilitated a higher drug-loading rate compared to previously reported aptamer-guided ApDCs.
Conclusions:
- HApt-tFNA@Dxd represents a promising nanomedicine for treating HER2-positive tumors, offering improved efficacy and targeted delivery.
- This study advances the development of DNA-based nanomaterials for cancer therapy by combining DNA nanostructures with chemotherapeutics.
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