Self‐Assembly of Therapeutic Peptide into Stimuli‐Responsive Clustered Nanohybrids for Cancer‐Targeted Therapy

Abstract

Clinical translation of therapeutic peptides, particularly those targeting intracellular protein–protein interactions (PPIs), has been hampered by their inefficacious cellular internalization in diseased tissue. Therapeutic peptides engineered into nanostructures with stable spatial architectures and smart disease targeting ability may provide a viable strategy to overcome the pharmaceutical obstacles of peptides. This study describes a strategy to assemble therapeutic peptides into a stable peptide–Au nanohybrid, followed by further self‐assembling into higher‐order nanoclusters with responsiveness to tumor microenvironment. As a proof of concept, an anticancer peptide termed β‐catenin/Bcl9 inhibitors is copolymerized with gold ion and assembled into a cluster of nanohybrids (pCluster). Through a battery of in vitro and in vivo tests, it is demonstrated that pClusters potently inhibit tumor growth and metastasis in several animal models through the impairment of the Wnt/β‐catenin pathway, while maintaining a highly favorable biosafety profile. In addition, it is also found that pClusters synergize with the PD1/PD‐L1 checkpoint blockade immunotherapy. This new strategy of peptide delivery will likely have a broad impact on the development of peptide‐derived therapeutic nanomedicine and reinvigorate efforts to discover peptide drugs that target intracellular PPIs in a great variety of human diseases, including cancer.

A general-purpose Nanohybrid fabricated by Polymeric Au(I)-peptide precursor to wake the function of Peptide Therapeutics

“…As previous report, the dodecameric peptide PMI is designed for competitive antagonism MDM2 to restore p53, thereby reactivating the anti-cancer function of p53 to kill cancer cells (Figure 5 A) 47 . The 20-mer BBI was dedicated to targeting β-catenin toward disturbing the β-catenin/Bcl9 interaction and as a result of the blockage of the cancerogenic Wnt signaling pathway (Figure 5 B) 48 . Besides, dextrorotary peptide DPA has similar functions as PMI to restore p53 (Figure 5 C) 45 .…”

“…To address them, we turn our gaze to a de novo synthesis of nanoparticle by Au(I) thiolate precursors 32 , 33 . By this approach, previous reports successfully fabricated size-tuned gold nanoparticles via reducing Au(I)-glutathione precursors 32 , 34 . But that reaction, in which thiol peptide strains the conversion of the ionic gold precursor into metallic gold nuclei, has to be driven by strong reducing agent, such as sodium borohydride (NaBH 4 ) 33 .…”

A lanthanide-peptide-derived bacterium-like nanotheranostic with high tumor-targeting, -imaging and -killing properties

“…After synthesis, peptides were cleaved by a reagent cocktail, which is consist of TFA (88%), phenol (5%), H2O (5%) and TIPS (2%). Next, products were identified and purified by C18 or C4 reversed-phase HPLC [49]. ESI-MS was used to ascertain the molecular weights of peptides.…”

Nanomaterials Enhance the Immunomodulatory Effect of Molecular Targeted Therapy

“…In another study, He et al fabricated Au-peptide nanohybrids (pParticles) via the copolymerization of HAuCl 4 and a β-catenin/Bcl9 inhibitor (BBI). 60 Then, the pParticle self-assembled into a size-switchable and pH-responsive nanocluster (pCluster) triggered by poly-L-lysine. In the acidic TME, pCluster accumulated at the tumor site due to the EPR effect and disintegrated into small nanoparticles, which contributed to deep penetration and cellular internalization.…”