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Specifically Eliminating Tumor-Associated Macrophages with an Extra- and Intracellular Stepwise-Responsive
Ningning Guo1, Yi Zhou1, Tiantian Wang1
1Institution of Pharmaceutics, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
Abstract:
Metastasis is the primary cause of death for most cancer patients, in which tumor-associated macrophages (TAMs) are involved through several mechanisms. While hitherto there is still a lack of study on exclusive elimination of TAMs to inhibit metastasis due to the difficulties in specific targeting of TAMs, we construct an extra- and intracellular stepwise-responsive delivery system p-(aminomethyl)benzoic acid (PAMB)/doxorubicin (DOX) to achieve specific TAM depletion for the first time, thereby preventing tumor metastasis. Once accumulated into the tumor, PAMB/DOX would stepwise responsively (hypoxia and reactive oxygen species (ROS) responsively) disintegrate to expose the TAM-targeting ligand and release DOX sequentially, which depletes TAMs effectively in vivo. Owing to the inhibition of extracellular matrix (ECM) degradation, neovascularization, and tumor invasion contributed by TAM depletion, lung metastasis was successfully inhibited. Furthermore, PAMB/DOX showed efficient inhibition against tumor growth as well as spontaneous metastasis formation when combined with additional chemotherapy, representing a safe and efficient nanoplatform to modulate the adverse tumor microenvironment via TAM elimination.
Insights
This study introduces a novel drug delivery system to target and eliminate tumor-associated macrophages (TAMs), a key factor in cancer metastasis. This approach successfully inhibited tumor growth and spread, offering a new strategy for cancer treatment.
Area of Science:
- Oncology
- Nanomedicine
- Cancer Biology
Background:
- Metastasis is the leading cause of cancer-related death.
- Tumor-associated macrophages (TAMs) play a crucial role in promoting metastasis.
- Targeting TAMs presents a promising therapeutic strategy, but specific depletion remains challenging.
Purpose of the Study:
- To develop a novel stepwise-responsive delivery system for specific TAM depletion.
- To investigate the efficacy of this system in preventing tumor metastasis and growth.
Main Methods:
- Constructed a stepwise-responsive delivery system (PAMB/DOX) that responds to tumor microenvironment cues (hypoxia and ROS).
- The system sequentially releases doxorubicin (DOX) and exposes a TAM-targeting ligand.
- Evaluated the system's ability to deplete TAMs, inhibit ECM degradation, neovascularization, and tumor invasion in vivo.
Main Results:
- Achieved specific TAM depletion for the first time using the PAMB/DOX system.
- Successfully inhibited lung metastasis by modulating TAM-driven processes.
- Demonstrated efficient inhibition of tumor growth and spontaneous metastasis when combined with chemotherapy.
Conclusions:
- The PAMB/DOX system is a safe and effective nanoplatform for eliminating TAMs.
- Modulating the tumor microenvironment via TAM elimination offers a promising strategy to combat cancer metastasis.
- This approach holds potential for combination therapy to improve cancer treatment outcomes.
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