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Receptor and Microenvironment Dual-Recognizable Nanogel for Targeted Chemotherapy of Highly Metastatic Malignancy
Jinjin Chen1,2, Jianxun Ding1, Weiguo Xu1
1Key Laboratory of Polymer Ecomaterials, Changchun Institute of Applied Chemistry, Chinese Academy of Sciences , Changchun 130022, People's Republic of China.
Abstract:
Targeted delivery of chemotherapeutic drugs to the desired lesion sites is the main objective in malignancy treatment, especially in highly metastatic malignancies. However, extensive studies around the world on traditional targeting strategies of recognizing either overexpressed receptors or microenvironments in tumors show great limitations, owing to the off-target effect and tumor homogeneity. Integration of both receptor-mediated targeting (RMT) and environment-mediated targeting (EMT) enhances the tumor accumulation and subsequent cell uptake at the same time, which may avoid these limitations. Herein, a dual targeting nanogel of PMNG engineered with both phenylboronic acid (PBA) and morpholine (MP) was reported for not only RMT via specific recognition of sialyl (SA) epitopes but also EMT toward extracellular acidity. Further engineering the nanoparticles via loading doxorubicin (DOX) brought a novel dual targeting system, that is, PMNG/DOX. PMNG/DOX demonstrated a greater targeting effect to both primary and metastatic B16F10 melanoma than the single PBA-modified nanogel (PNG) with only RMT in vitro and in vivo. Moreover, PMNG/DOX was also proved to be highly potent on inhibiting primary tumor growth as well as tumor metastasis on B16F10 melanoma-grafted mouse model. The results demonstrated the dual targeting design as a translational approach for drug delivery to highly metastatic tumor.
Insights
This study introduces a dual-targeting nanogel (PMNG/DOX) for enhanced chemotherapy delivery. It effectively targets both primary and metastatic melanoma, improving treatment outcomes and reducing off-target effects.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Cancer Therapy
Background:
- Targeted chemotherapy delivery is crucial for treating metastatic cancers.
- Traditional targeting methods face limitations due to off-target effects and tumor heterogeneity.
- Combining receptor-mediated targeting (RMT) and environment-mediated targeting (EMT) offers a promising strategy.
Purpose of the Study:
- To develop and evaluate a dual-targeting nanogel (PMNG/DOX) for enhanced delivery of doxorubicin to melanoma.
- To investigate the combined RMT and EMT capabilities of the nanogel for improved tumor accumulation and cell uptake.
- To assess the efficacy of the dual-targeting system in inhibiting primary tumor growth and metastasis.
Main Methods:
- Engineered a dual-targeting nanogel (PMNG) with phenylboronic acid (PBA) for RMT and morpholine (MP) for EMT.
- Loaded doxorubicin (DOX) into the nanogel to create the PMNG/DOX system.
- Evaluated targeting efficiency, tumor inhibition, and metastasis suppression in vitro and in vivo using B16F10 melanoma models.
Main Results:
- PMNG/DOX exhibited superior targeting of primary and metastatic B16F10 melanoma compared to single-targeting nanogels.
- The dual-targeting system demonstrated significant inhibition of primary tumor growth.
- PMNG/DOX effectively suppressed tumor metastasis in a mouse model.
Conclusions:
- Dual targeting using RMT and EMT represents a translational approach for improving chemotherapy delivery in highly metastatic cancers.
- The developed PMNG/DOX nanogel shows potential as an effective therapeutic strategy for melanoma.
- This strategy overcomes limitations of traditional targeting methods, offering enhanced efficacy and reduced side effects.
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