Rationally designed mitochondria-impairing small molecule-enabled chemo-phototherapy to potentiate apoptosis and
Asima Sahu1, Phanindra Kumar1, Anushka Kochar1
1Department of Chemistry, Indian Institute of Technology (IIT) Gandhinagar, Palaj, Gandhinagar, Gujarat, 382355, India. Sudipta.basu@iitgn.ac.in.
Abstract:
Mitochondria, central regulators of cellular bioenergetics, biosynthesis, and stress signaling, represent an attractive yet challenging target for cancer therapy. Although phototherapy offers a non-invasive approach with high spatiotemporal control, the development of small-molecule systems capable of precise mitochondrial targeting for combined chemo and phototherapeutic modalities remains limited. Here, we report a rationally engineered small-molecule platform that integrates a cationic heptamethine cyanine scaffold with non-steroidal anti-inflammatory drugs (NSAIDs) to enable multifunctional chemo-phototherapy. The heptamethine cyanine unit acts as a mitochondrial targeting vector, intrinsic fluorescent reporter, and phototherapeutic module, while the NSAID component provides chemotherapeutic activity through inhibition of mitochondrial cyclooxygenase-2 (Cox-2). Biological evaluation identified the indomethacin-conjugated derivative 7a as a lead candidate that self-assembles into nanoscale structures and selectively accumulates in the mitochondria of HCT-116 colon cancer cells. Near-infrared light activation induces photothermal heating and reactive oxygen species generation (ROS), causing mitochondrial membrane depolarization, structural disruption, and oxidative stress. This mitochondrial damage triggers apoptosis via inhibition of Bcl-2, Cas-3/9, PARP and Cox-2, as well as upregulation of BAX, alongside inducible autophagy that can be pharmacologically regulated. This heptamethine cyanine-NSAID conjugate establishes a versatile mitochondria-targeted chemo-phototherapeutic system and advances light-activated organelle-directed chemical biology as a promising strategy for minimally invasive cancer therapy.
Insights
This study presents a new small-molecule drug that targets cancer cell mitochondria. Combining chemotherapy and phototherapy, it effectively kills cancer cells using light activation for minimally invasive treatment.
Area of Science:
- Biochemistry and Molecular Biology
- Nanotechnology
- Cancer Therapeutics
Background:
- Mitochondria are key regulators of cellular functions and a challenging target for cancer therapy.
- Phototherapy offers non-invasive cancer treatment but lacks effective mitochondrial targeting systems for combined modalities.
- Developing small-molecule systems for precise mitochondrial targeting is crucial for advanced cancer therapy.
Purpose of the Study:
- To engineer a small-molecule platform for multifunctional chemo-phototherapy targeting mitochondria.
- To develop a system integrating a heptamethine cyanine scaffold with NSAIDs for combined therapeutic effects.
- To evaluate the efficacy of a lead indomethacin-conjugated derivative (7a) in colon cancer cells.
Main Methods:
- Conjugation of a cationic heptamethine cyanine scaffold with NSAIDs.
- Self-assembly of the conjugate into nanoscale structures for mitochondrial accumulation.
- Evaluation of photothermal heating, ROS generation, and apoptosis induction upon near-infrared light activation.
- Assessment of effects on mitochondrial membrane potential, Bcl-2, Cas-3/9, PARP, BAX, and autophagy.
Main Results:
- The indomethacin-conjugated derivative 7a selectively accumulated in mitochondria of HCT-116 colon cancer cells.
- Near-infrared light triggered photothermal heating and ROS generation, leading to mitochondrial damage and apoptosis.
- The conjugate inhibited Cox-2 and modulated apoptosis-related proteins (Bcl-2, Cas-3/9, PARP, BAX).
- Inducible autophagy was observed and found to be pharmacologically regulable.
Conclusions:
- The developed heptamethine cyanine-NSAID conjugate is a versatile mitochondria-targeted chemo-phototherapeutic system.
- This approach advances light-activated, organelle-directed chemical biology for minimally invasive cancer therapy.
- The system demonstrates potential for combined chemo-phototherapy by targeting mitochondrial dysfunction.
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