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Updated: Aug 30, 2025
Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?
Published on: June 13, 2014
In Situ Transformable Supramolecular Nanomedicine Targeted Activating Hippo Pathway for Triple-Negative Breast Cancer
Zhilong Wang1, Cuihong Yang1, Hao Zhang2
1Key Laboratory of Radiopharmacokinetics for Innovative Drugs, Chinese Academy of Medical Sciences, and Institute of Radiation Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin 300192, People's Republic of China.
Abstract:
As it is closely associated with tumor proliferation, metastasis, and the immunosuppressive microenvironment, the dysfunctional Hippo pathway has become an extremely attractive target for treating multiple cancers. However, to date, the corresponding chemotherapeutic nanomedicines have not been developed. Herein, a supramolecular self-delivery nanomedicine with in situ transforming capacity was tailor-constructed for Hippo-pathway restoration, and its inhibitory effect against tumor growth and metastasis was investigated in a highly aggressive triple-negative breast cancer (TNBC) model. Stimulated by overexpressed glutathione (GSH) and esterase in cancer cells, the self-assembled nanomedicine transformed from inactive nanospheres to active nanofibers conjugating tyrosvaline and spatiotemporally synchronously released the covalently linked flufenamic acid in situ, together activating the maladjusted Hippo pathway by simultaneously acting on different targets upstream and downstream. The transcriptional expression of Yes-associated protein (YAP) and related growth-promoted genes were significantly reduced, finally significantly repressing the proliferation and metastasis of cancer cells. Additionally, the Hippo-pathway restoration showed an excellent radiosensitization effect, making the targeted therapy combined with radiotherapy display a prominent synergistic in vivo anticancer effect against TNBC. This work reports a specifically designed smart nanomedicine to restore the function of the Hippo pathway and sensitize radiotherapy, providing an attractive paradigm for targeted drug delivery and cancer combination therapy.
Insights
A novel nanomedicine restores the Hippo pathway in triple-negative breast cancer (TNBC) by transforming and releasing drugs. This approach inhibits tumor growth, metastasis, and enhances radiotherapy effectiveness.
Area of Science:
- Biomedical Engineering
- Nanotechnology
- Oncology
Background:
- The Hippo pathway is crucial in cancer, regulating cell proliferation and metastasis.
- Dysfunctional Hippo signaling is implicated in aggressive cancers like triple-negative breast cancer (TNBC).
- Effective nanomedicines for Hippo pathway restoration are currently lacking.
Purpose of the Study:
- To develop and evaluate a supramolecular self-delivery nanomedicine for Hippo pathway restoration.
- To investigate the nanomedicine's efficacy against tumor growth and metastasis in a TNBC model.
- To assess the potential of Hippo pathway restoration in enhancing radiotherapy.
Main Methods:
- Constructed a supramolecular nanomedicine that self-assembles and transforms in situ.
- Utilized stimuli-responsive elements (glutathione and esterase) for drug release.
- Administered flufenamic acid covalently linked to the nanomedicine.
- Evaluated the nanomedicine's effect on Hippo pathway targets (YAP) and cancer progression in a TNBC model.
- Assessed radiosensitization effects in combination therapy.
Main Results:
- The nanomedicine transformed from nanospheres to nanofibers, releasing flufenamic acid in cancer cells.
- Successfully activated the Hippo pathway by targeting upstream and downstream components.
- Significantly reduced Yes-associated protein (YAP) expression and downstream oncogenes.
- Demonstrated significant inhibition of TNBC proliferation and metastasis in vivo.
- Observed a synergistic anticancer effect when combined with radiotherapy.
Conclusions:
- Developed a smart nanomedicine for targeted Hippo pathway restoration in TNBC.
- The nanomedicine effectively inhibits tumor growth, metastasis, and enhances radiosensitivity.
- This approach offers a promising strategy for advanced cancer therapy and targeted drug delivery.
