Targeted PDT agent eradicates TrkC expressing tumors via photodynamic therapy (PDT)
Chin Siang Kue1, Anyanee Kamkaew, Hong Boon Lee
1Department of Pharmacology, Faculty of Medicine, University of Malaya , 50603 Kuala Lumpur, Malaysia.
Abstract:
This contribution features a small molecule that binds TrkC (tropomyosin receptor kinase C) receptor that tends to be overexpressed in metastatic breast cancer cells but not in other breast cancer cells. A sensitizer for (1)O2 production conjugated to this structure gives 1-PDT for photodynamic therapy. Isomeric 2-PDT does not bind TrkC and was used as a control throughout; similarly, TrkC- cancer cells were used to calibrate enhanced killing of TrkC+ cells. Ex vivo, 1- and 2-PDT where only cytotoxic when illuminated, and 1-PDT, gave higher cell death for TrkC+ breast cancer cells. A 1 h administration-to-illumination delay gave optimal TrkC+/TrkC--photocytotoxicity, and distribution studies showed the same delay was appropriate in vivo. In Balb/c mice, a maximum tolerated dose of 20 mg/kg was determined for 1-PDT. 1- and 2-PDT (single, 2 or 10 mg/kg doses and one illumination, throughout) had similar effects on implanted TrkC- tumors, and like those of 2-PDT on TrkC+ tumors. In contrast, 1-PDT caused dramatic TrkC+ tumor volume reduction (96% from initial) relative to the TrkC- tumors or 2-PDT in TrkC+ models. Moreover, 71% of the mice treated with 10 mg/kg 1-PDT (n = 7) showed full tumor remission and survived until 90 days with no metastasis to key organs.
Insights
A novel small molecule photodynamic therapy agent, 1-PDT, targets TrkC+ metastatic breast cancer cells. This targeted therapy demonstrated significant tumor reduction and long-term remission in preclinical models.
Area of Science:
- Oncology
- Photodynamic Therapy
- Molecular Targeting
Background:
- Metastatic breast cancer often overexpresses the tropomyosin receptor kinase C (TrkC) receptor.
- Targeted therapies are crucial for improving treatment efficacy and reducing side effects in metastatic breast cancer.
Purpose of the Study:
- To develop and evaluate a novel photodynamic therapy (PDT) agent, 1-PDT, for targeted killing of TrkC-overexpressing metastatic breast cancer cells.
- To assess the efficacy and safety of 1-PDT in preclinical models of breast cancer.
Main Methods:
- Synthesis of a small molecule that binds TrkC, conjugated to a photosensitizer for 1-PDT.
- Utilized an isomeric control (2-PDT) that does not bind TrkC and TrkC- cancer cells for comparative studies.
- Evaluated photocytotoxicity ex vivo and in vivo in Balb/c mice with TrkC+ and TrkC- tumors.
Main Results:
- 1-PDT demonstrated selective cytotoxicity against TrkC+ breast cancer cells upon illumination, with enhanced cell death compared to the control 2-PDT.
- A 1-hour administration-to-illumination delay optimized TrkC+/TrkC- photocytotoxicity both ex vivo and in vivo.
- 1-PDT treatment resulted in a 96% reduction in TrkC+ tumor volume, with 71% of mice achieving complete remission and surviving 90 days without metastasis.
Conclusions:
- Targeted photodynamic therapy with 1-PDT is a promising strategy for treating TrkC-overexpressing metastatic breast cancer.
- 1-PDT exhibits significant efficacy in reducing tumor burden and achieving long-term remission in preclinical models.
- The developed targeted PDT agent offers a potential new therapeutic avenue with high specificity and minimal off-target effects.
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