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Adrenomedullin Antagonist Nanoparticles Inhibit Breast Cancer Brain Metastasis by Immunomodulating
Yifan Zhao1, Yanfeng Dai2,3, Xiang Yu2,3
1MOE Key Laboratory for Biomedical Photonics, Wuhan National Laboratory for Optoelectronics-Huazhong University of Science and Technology, Wuhan 430074, China.
Abstract:
Breast cancer brain metastasis (BCBM) is a devastating disease with limited treatment options, largely due to the presence of the blood-brain barrier (BBB) in the central nervous system (CNS), and thus, the development of effective alternative therapies for BCBM remains a significant unmet clinical challenge. Herein, we found that monocytes, M2 macrophages, and adrenomedullin (AM) were abundantly present in human BCBM. Therefore, we innovatively proposed monocytes/macrophages as promising immunomodulatory targets for effective immunotherapy of BCBM in mice models. The high-density lipoprotein-mimicking peptide-phospholipid scaffold (HPPS) nanoparticle efficiently targets monocytes/macrophages. Meanwhile, the adrenomedullin antagonist (AMA)-carrying HPPS (AMA-HPPS) nanoparticle has the potential to target and immunomodulate monocytes/macrophages into antitumor effector cells due to the pro-inflammatory polarization ability of AMA. Given this, AMA-HPPS effectively targeted and modulated circulating monocytes after intravenous injection, enabling the delivery of nanoparticle to brain metastasis sites. Incorporating immunomodulatory CpG into AMA-HPPS (forming AMA-HPPS-CpG) further enhanced monocyte targeting and immunomodulation. Thus, AMA-HPPS-CpG further inhibited the BCBM and prolonged the survival of mice by modulating the differentiation of infiltrating monocytes/macrophages into M1 macrophages and promoting the infiltration of CD8+ T cells into the brain. This effect was attributed to the activation of the NF-κB pathway in monocytes/macrophages following the uptake of nanoparticles, which reprogrammed the immunosuppressive tumor microenvironment. Therefore, this study highlights a promising immunotherapy strategy for brain metastasis by AMA-HPPS nanodrugs eliciting the pro-inflammatory polarization of monocytes/macrophages that have infiltrated the CNS as effector cells rather than considering monocytes/macrophages merely as a drug delivery system across the BBB.
Insights
This study developed novel nanoparticles (AMA-HPPS-CpG) to reprogram immunosuppressive cells in the brain, effectively inhibiting breast cancer brain metastasis and improving survival in mice.
Area of Science:
- Neuro-oncology
- Immunotherapy
- Nanomedicine
Background:
- Breast cancer brain metastasis (BCBM) presents a significant clinical challenge due to the blood-brain barrier (BBB).
- Monocytes, M2 macrophages, and adrenomedullin (AM) are prevalent in BCBM, suggesting their potential as therapeutic targets.
- Current treatment options for BCBM are limited, highlighting the need for novel therapeutic strategies.
Purpose of the Study:
- To investigate monocytes/macrophages as immunomodulatory targets for BCBM immunotherapy.
- To develop and evaluate adrenomedullin antagonist (AMA)-carrying high-density lipoprotein-mimicking peptide-phospholipid scaffold (HPPS) nanoparticles (AMA-HPPS) for targeting and reprogramming these cells.
- To assess the efficacy of AMA-HPPS combined with CpG (AMA-HPPS-CpG) in inhibiting BCBM and enhancing antitumor immunity.
Main Methods:
- Development of HPPS nanoparticles for efficient monocyte/macrophage targeting.
- Functionalization of HPPS with AMA to induce pro-inflammatory polarization of monocytes/macrophages.
- Incorporation of CpG into AMA-HPPS nanoparticles (AMA-HPPS-CpG) to enhance targeting and immunomodulation.
- Evaluation of nanoparticle delivery, immune cell modulation, and therapeutic efficacy in mouse models of BCBM.
Main Results:
- AMA-HPPS nanoparticles successfully targeted and modulated circulating monocytes, delivering to brain metastasis sites.
- AMA-HPPS-CpG nanoparticles enhanced monocyte targeting and polarization towards M1 macrophages.
- AMA-HPPS-CpG treatment significantly inhibited BCBM, promoted CD8+ T cell infiltration, and prolonged survival in mice.
- Nanoparticle uptake activated the NF-κB pathway in monocytes/macrophages, reprogramming the immunosuppressive tumor microenvironment.
Conclusions:
- AMA-HPPS-CpG nanoparticles represent a promising immunotherapy strategy for BCBM.
- Targeting monocytes/macrophages for pro-inflammatory polarization offers a novel approach to combat brain metastasis.
- This strategy effectively reprograms the CNS tumor microenvironment, shifting from immunosuppression to an antitumor immune response.
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