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Targeting treatment of bladder cancer using PTK7 aptamer-gemcitabine conjugate
Wei Xiang1, Yongbo Peng2, Hongliang Zeng1,3
1Department of Urology, The Third Xiangya Hospital of Central South University, No.138, Tongzipo Road, Changsha, Hunan, 410013, China.
Background:
Gemcitabine (GEM) is one of the first-line chemotherapies for bladder cancer (BC), but the GEMs cannot recognize cancer cells and have a low long-term response rate and high recurrence rate with side effects during the treatment of BC. Targeted transport of GEMs to mediate cytotoxicity to tumor and avoid the systemic side effects remains a challenge in the treatment of BC.
Methods:
Based on a firstly confirmed biomarker in BC-protein tyrosine kinase 7 (PTK7), which is overexpressed on the cell membrane surface in BC cells, a novel targeting system protein tyrosine kinase 7 aptamer-Gemcitabine conjugate (PTK7-GEMs) was designed and synthesized using a specific PTK7 aptamer and GEM through auto-synthesis method to deliver GEM against BC. In addition, the antitumor effects and safety evaluation of PTK7-GEMs was assessed with a series of in vitro and in vivo assays.
Results:
PTK7-GEMs can specifically bind and enter to BC cells dependent on the expression levels of PTK7 and via the macropinocytosis pathway, which induced cytotoxicity after GEM cleavage from PTK7-GEMs respond to the intracellular phosphatase. Moreover, PTK7-GEMs showed stronger anti-tumor efficacy and excellent biosafety in three types of tumor xenograft mice models.
Conclusion:
These results demonstrated that PTK7-GEMs is a successful targeted aptamer-drug conjugates strategy (APDCs) to treat BC, which will provide new directions for the precision treatment of BC in the field of biomarker-oriented tumor targeted therapy.
Insights
A new targeted therapy, protein tyrosine kinase 7 aptamer-Gemcitabine conjugate (PTK7-GEMs), effectively targets bladder cancer (BC) cells. This approach enhances chemotherapy efficacy while minimizing side effects for improved BC treatment.
Area of Science:
- Oncology
- Biotechnology
- Nanomedicine
Background:
- Gemcitabine (GEM) is a first-line chemotherapy for bladder cancer (BC) but lacks specificity, leading to low response rates, high recurrence, and systemic side effects.
- Targeted delivery of GEM to cancer cells to enhance efficacy and reduce toxicity remains a significant challenge in BC treatment.
Purpose of the Study:
- To design and synthesize a novel targeted drug delivery system, protein tyrosine kinase 7 aptamer-Gemcitabine conjugate (PTK7-GEMs), for bladder cancer treatment.
- To evaluate the in vitro and in vivo antitumor effects and safety of the PTK7-GEMs conjugate.
Main Methods:
- A specific aptamer targeting protein tyrosine kinase 7 (PTK7), which is overexpressed in BC cells, was conjugated with Gemcitabine (GEM) via auto-synthesis.
- In vitro and in vivo assays were performed to assess the binding specificity, cellular uptake, drug release mechanism, antitumor efficacy, and biosafety of PTK7-GEMs.
Main Results:
- PTK7-GEMs specifically binds to and enters BC cells through PTK7-dependent macropinocytosis.
- Intracellular phosphatase-triggered cleavage of GEM from PTK7-GEMs induces targeted cytotoxicity.
- PTK7-GEMs demonstrated superior antitumor efficacy and excellent biosafety in preclinical models of bladder cancer.
Conclusions:
- PTK7-GEMs represents a successful aptamer-drug conjugate (APDC) strategy for targeted bladder cancer therapy.
- This approach offers a promising new direction for biomarker-oriented, precision treatment of bladder cancer.
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