Dual-Ligand Synergistic Targeting Anti-Tumor Nanoplatforms with Cascade-Responsive Drug Release
Fang Luo1,2, Ting Zhong1,2, Ying Chen1,3
1State Key Laboratory of Functions and Applications of Medicinal Plants, School of Pharmaceutical Sciences, Guizhou Medical University, University Town, Guian New District, Guiyang 550025, China.
Abstract:
Dual-ligand targeting drug delivery nanoplatforms are considered a promising tool for enhancing the specificity of chemotherapy. However, serious off-target delivery has been observed in current dual-ligand targeting nanoplatforms, as each ligand can independently recognize receptors on the cell membrane surface and guide drug nanocarriers to different cells. To overcome this barrier, a dual-ligand synergistic targeting (DLST) nanoplatform is developed, which can guide chemotherapy treatment specifically to cancer cells simultaneously overexpressing two receptors. This nanoplatform consists of a singlet oxygen (1O2) photosensitizer-loaded nanocarrier and a drug-loaded nanocarrier with 1O2 responsiveness, which were, respectively, decorated with a pair of complementary DNA sequences and two different ligands. For cancer cells overexpressing both receptors, two nanocarriers can be internalized in larger quantities to cause DNA hybridization-induced nanocarrier aggregation, which further activates 1O2-triggered drug release under light irradiation. For cells overexpressing a single receptor, only one type of nanocarrier can be internalized in a large quantity, leading to blocked drug release due to the ultrashort action radius of 1O2. In vivo evaluation showed this DLST nanoplatform displayed highly specific tumor treatment with minimized long-term toxicity. This is a highly efficient drug delivery system for DLST chemotherapy, holding great potential for clinical applications.
Insights
A novel dual-ligand synergistic targeting (DLST) nanoplatform precisely targets cancer cells overexpressing two receptors, enhancing chemotherapy specificity and reducing off-target toxicity.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- Dual-ligand targeting nanoplatforms aim to improve chemotherapy specificity.
- Current systems suffer from off-target delivery due to independent ligand action.
- A new approach is needed to ensure simultaneous targeting of multiple receptors.
Purpose of the Study:
- To develop and evaluate a dual-ligand synergistic targeting (DLST) nanoplatform for precise cancer chemotherapy.
- To overcome the limitations of off-target delivery in existing dual-ligand systems.
- To achieve targeted drug release specifically in cancer cells overexpressing two distinct receptors.
Main Methods:
- Designed a DLST nanoplatform comprising a singlet oxygen (¹O₂) photosensitizer-loaded nanocarrier and a drug-loaded ¹O₂-responsive nanocarrier.
- Decorated nanocarriers with complementary DNA sequences and two different ligands for synergistic targeting.
- Investigated DNA hybridization-induced nanocarrier aggregation and ¹O₂-triggered drug release upon light irradiation.
- Evaluated in vivo tumor treatment efficacy and toxicity.
Main Results:
- The DLST nanoplatform demonstrated specific internalization and aggregation in cancer cells overexpressing both target receptors.
- ¹O₂-triggered drug release was activated specifically upon light irradiation in the presence of both receptors.
- Cells overexpressing only one receptor showed blocked drug release due to the limited range of ¹O₂.
- In vivo studies confirmed highly specific tumor treatment with significantly reduced long-term toxicity.
Conclusions:
- The developed DLST nanoplatform offers a highly efficient and specific drug delivery system for dual-receptor-positive cancers.
- This synergistic targeting strategy effectively minimizes off-target effects and associated toxicities.
- The DLST nanoplatform holds significant potential for clinical translation in targeted cancer chemotherapy.
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