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Published on: September 13, 2022
Development of Novel Aptamer-Based Targeted Chemotherapy for Bladder Cancer
Yao Wang1,2, Yang Zhang2,3, Peng-Chao Li4
1State Key Laboratory of Coordination Chemistry, Department of Biomedical Engineering, College of Engineering and Applied Sciences, Jiangsu Key Laboratory of Artificial Functional Materials, Nanjing University, Nanjing, Jiangsu, China.
Abstract:
Bladder cancer is common worldwide, with most patients presenting with nonmuscle invasive disease. Multiple intravesical recurrences lead to reduced quality of life and high costs for patients with this form of bladder cancer. Intravesical chemotherapy aimed at reducing recurrence is the standard-of-care but has significant side effects from nonspecific cytotoxicity to normal urothelium. Importantly, toxicity limits doses that can be administered. Thus, tumor-specific drug targeting could reduce toxicity and enhance effectiveness by allowing higher doses. Here, using cell internalization systematic evolution of ligands by exponential enrichment (SELEX), we identify a novel bladder cancer-specific, chemically modified nucleic acid aptamer that can be preferentially internalized into tumor cells but not normal urothelial cells. The 35-nucleotide B1 aptamer is internalized into bladder cancer cells through clathrin-mediated endocytosis and macropinocytosis. As proof of principle, a B1-guided DNA nanotrain delivery vehicle for epirubicin was constructed as a targeted intravesical chemotherapy. The B1-nanotrain-epirubicin construct exhibited selective cytotoxicity towards bladder cancer cells and outperformed epirubicin in murine orthotopic xenograft models of human bladder cancer. This aptamer-based delivery system makes targeted chemotherapy possible for bladder cancer, providing a compelling rationale for clinical development.
Significance:
These findings identify a bladder cancer-specific aptamer that can be used for targeted delivery of chemotherapy, potentially reducing toxicity and enhancing therapeutic efficacy.
Insights
Researchers developed a novel bladder cancer-specific aptamer for targeted chemotherapy delivery. This aptamer selectively targets tumor cells, reducing side effects and improving treatment efficacy for bladder cancer patients.
Area of Science:
- Biotechnology
- Oncology
- Nanomedicine
Background:
- Bladder cancer is a prevalent malignancy, often recurring after initial treatment.
- Current intravesical chemotherapy for nonmuscle invasive bladder cancer causes significant side effects due to non-specific toxicity.
- There is a critical need for targeted therapies to reduce toxicity and improve treatment effectiveness.
Purpose of the Study:
- To identify a novel bladder cancer-specific aptamer for targeted drug delivery.
- To develop an aptamer-guided nanocarrier system for intravesical chemotherapy.
- To evaluate the efficacy and safety of the targeted delivery system in preclinical models.
Main Methods:
- Systematic evolution of ligands by exponential enrichment (SELEX) was used to identify a bladder cancer-specific aptamer (B1 aptamer).
- The B1 aptamer's internalization mechanism (clathrin-mediated endocytosis and macropinocytosis) into bladder cancer cells was investigated.
- A DNA nanotrain delivery vehicle was engineered to carry epirubicin, guided by the B1 aptamer, for targeted intravesical chemotherapy.
Main Results:
- A novel 35-nucleotide B1 aptamer was identified, showing preferential internalization into bladder cancer cells over normal urothelial cells.
- The B1 aptamer-guided DNA nanotrain-epirubicin construct demonstrated selective cytotoxicity against bladder cancer cells.
- In murine orthotopic xenograft models, the B1-nanotrain-epirubicin construct significantly outperformed free epirubicin.
Conclusions:
- A bladder cancer-specific aptamer has been identified, enabling targeted chemotherapy delivery.
- The aptamer-based nanocarrier system shows potential for reducing chemotherapy toxicity and enhancing therapeutic efficacy.
- This aptamer-guided delivery approach offers a promising strategy for the clinical development of targeted bladder cancer therapies.
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