In Situ Transformable Supramolecular Nanomedicine Targeted Activating Hippo Pathway for Triple-Negative Breast Cancer Growth and Metastasis Inhibition

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.

Preparation and Properties of Self-Assembling Polypeptide Hydrogels and Their Application in Biomedicine

“…Therefore, both regions play an important role in the self-assembly of MDPs, and peptide sequence length of each block should be specific. 187 Research finding that the sequence length of region B is at least three times that of region A, and it is easier to form secondary structure. that the sequence length of the B region is at least three times that of the A block to stabilize the effect of charge repulsion and form a secondary structure.…”

“…The charged A region is responsible for increasing the solubility of peptides and preventing aggregation. Therefore, both regions play an important role in the self-assembly of MDPs, and peptide sequence length of each block should be specific . Research finding that the sequence length of region B is at least three times that of region A, and it is easier to form secondary structure.…”

Glutathione Depletion‐Induced Versatile Nanomedicine for Potentiating the Ferroptosis to Overcome Solid Tumor Radioresistance and Enhance Immunotherapy

“…The tumor microenvironment plays a crucial role in supporting cancer cells growth and forms multiple barriers to attenuate the therapeutic efficacy of nanomedicines. [ 7 ] Among these barriers, glutathione (GSH) has been proposed as one of the critical factors for tumor initiation, progression, and metastasis. [ 8 ] Furthermore, it is implicated in resistance to many therapeutic approaches, including ferroptosis therapy, [ 9 ] platinum‐based chemotherapy, [ 10 ] photodynamic therapy (PDT), [ 11 ] and radiotherapy.…”

Engineering Diselenide-IR780 Homodimeric Nanoassemblies with Enhanced Photodynamic and Immunotherapeutic Effects for Triple-Negative Breast Cancer Treatment

“…To address these issues, the carrier-free drug delivery system provides an alternative strategy to efficiently deliver hydrophobic drugs or PDT agents to disease sites without additional carriers through systemic circulation. , Compared with carrier-assistant drug delivery systems, a carrier-free drug delivery system with easy preparation and high drug-loading capacities avoids carrier-induced toxicity and immunogenicity, meanwhile. − For designing the carrier-free drug delivery system of hydrophobic small molecules, the common strategy is that the hydrophobic drugs conjugated with carbon chains to endow them with self-aggregation behavior, but the strong intermolecular interactions of drug conjugates induce poor colloidal stability of self-assembly. , It was found that the disulfide bond could improve the spatial flexibility compared with the carbon bond which is beneficial for hydrophobic drugs to form self-assembly and improve its stability. , In addition, since selenium is in the same periodic table family as sulfur, the diselenide bond provides adequate structural flexibility for hydrophobic drug conjugates and forms a more stable self-assembly conformation . Moreover, compared with sulfur, selenium has higher oxidation responsivity owing to a weaker electron binding capacity, and selenium as an important element in the body also is found to be an antitumor agent. , Therefore, dimers conjugated by special bond-containing linkers could be a promising strategy for designing carrier-free self-assemblies of hydrophobic drugs.…”

“…26−28 For designing the carrier-free drug delivery system of hydrophobic small molecules, the common strategy is that the hydrophobic drugs conjugated with carbon chains to endow them with self-aggregation behavior, but the strong intermolecular interactions of drug conjugates induce poor colloidal stability of self-assembly. 29,30 It was found that the disulfide bond could improve the spatial flexibility compared with the carbon bond which is beneficial for hydrophobic drugs to form self-assembly and improve its stability. 30,31 In addition, since selenium is in the same periodic table family as sulfur, the diselenide bond provides adequate structural flexibility for hydrophobic drug conjugates and forms a more stable self-assembly conformation.…”