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A Supramolecular, Triple Negative Breast Cancer-Targeting Avidin-Photosensitizer
Bingjie Gao1, Charlotte Schäfers1,2, Seah Ling Kuan1
1Department of Synthesis of Macromolecules, Max Planck Institute for Polymer Research, 55128, Mainz, Germany.
Abstract:
The potential of photodynamic therapy (PDT) in combination with chemotherapy to improve treatment outcomes for triple-negative breast cancer (TNBC), for which no targeted therapy is available, is the subject of considerable investigation. In PDT, photosensitizers (PSs) are frequently administered directly but do not selectively target cancer cells. To address the delivery of a PS to TNBC and enhance cellular uptake, the Ru-NH2-modified avidin bioconjugate (RuAvi) via Tyr-specific modification using the Mannich reaction is prepared. The RuAvi is further assembled with the cinnamoyl peptide-F(D)LF(D)LFK-NH2 (FK), which binds to formyl peptide receptor 1, overexpressed in TNBC. Notably, the modified Avi still possesses the ability to efficiently bind biotin for the assembly of up to four copies of the FK peptides. The resultant FK4-RuAvi exhibited an IC50 value of 0.36 ± 0.08 µM, which is ≈3.5-fold lower than that of RuAvi (1.25 ± 0.09 µM), upon irradiation in the triple-negative MDA-MB-231 breast cancer cells. FK4-RuAvi also shows efficient uptake in MDA-MB-231 tumor spheroids and exhibited significant toxicity after irradiation compared to the control RuAvi. The presented strategy has the potential to improve the efficacy of targeted PDT to meet the high demand for targeted therapies to treat TNBC, such as targeted adjuvant treatment after breast cancer surgery.
Insights
Researchers developed a targeted photodynamic therapy (PDT) delivery system for triple-negative breast cancer (TNBC). This new method enhances photosensitizer uptake and toxicity in cancer cells, offering a promising new treatment strategy for TNBC.
Area of Science:
- Bioconjugate chemistry
- Cancer therapy
- Nanomedicine
Background:
- Triple-negative breast cancer (TNBC) lacks targeted therapies, necessitating novel treatment approaches.
- Photodynamic therapy (PDT) shows potential but suffers from poor photosensitizer selectivity and cellular uptake.
- Targeted delivery of photosensitizers is crucial for enhancing PDT efficacy in TNBC.
Purpose of the Study:
- To develop a targeted delivery system for photosensitizers in TNBC.
- To enhance cellular uptake and phototoxicity of photosensitizers in TNBC cells.
- To create a novel bioconjugate for targeted photodynamic therapy.
Main Methods:
- Preparation of a Ru-NH2-modified avidin bioconjugate (RuAvi) via Tyr-specific modification.
- Assembly of RuAvi with a cinnamoyl peptide (FK) that targets the formyl peptide receptor 1 overexpressed in TNBC.
- Evaluation of the bioconjugate's binding affinity, cellular uptake, and phototoxicity in TNBC cells and tumor spheroids.
Main Results:
- The assembled FK4-RuAvi bioconjugate demonstrated enhanced binding and significantly lower IC50 values (0.36 µM) compared to RuAvi alone (1.25 µM) in MDA-MB-231 cells upon irradiation.
- FK4-RuAvi showed efficient uptake in MDA-MB-231 tumor spheroids.
- Irradiated FK4-RuAvi exhibited significant toxicity in TNBC models.
Conclusions:
- The developed FK4-RuAvi bioconjugate effectively targets TNBC cells by leveraging the formyl peptide receptor 1.
- This targeted delivery strategy enhances photosensitizer uptake and photodynamic therapy efficacy.
- The approach holds promise for developing targeted adjuvant treatments for TNBC.
