Less is More: Preorganization Leads to Better Tumor Retention and Therapeutic Efficacy

• Published in: Advanced functional materials 2022-12, Vol.32 (49), p.n/a
• Main Authors: Xie, Limin, Ding, Yinghao, Wang, Yuhan, Li, Xinxin, Yang, Zhimou, Hu, Zhi‐Wen
• Format: Article
• Language: English
• Subjects: Affinity; Alkaline phosphatase; alkaline phosphatase (ALP); Binding; Cell death; Kinases; Materials science; Peptides; Phosphorylation; preorganization; programmed cell death ligand‐1 (PD‐L1); self‐assembling peptide; Tumors; Tyrosine
• ISSN: 1616-301X; 1616-3028
• DOI: 10.1002/adfm.202206969

Protein preorganization is ubiquitous in nature and enables subtle structural rearrangements and precise function executions, making it an attractive approach for generating functional peptide materials. Here, a phosphorylation‐dependent pre‐organization approach to optimize the therapeutic outcomes of a self‐assembling peptide targeting programmed cell death ligand 1 (PD‐L1) is reported. Upon incorporating the imaging probe cyanine 5.5 (Cy5.5) and therapeutic drug 10‐hydroxycamptothecin (HCPT), three phosphorylated precursors (1P, 2P, and 3P) containing identical peptide sequences with different tyrosine phosphorylation sites are constructed. The presence of a phosphate group can stabilize the self‐assembling peptide in a well‐defined, preorganized state. Moreover, variations in the phosphorylation sites lead to different preorganized secondary structures, dephosphorylation rates, and PD‐L1 binding affinities. Responding to alkaline phosphatase dephosphorylation, subtle structural transformation to more ordered states, an increase in binding affinity against PD‐L1, and rapid cellular internalization are observed. Compared with the unphosphorylated control (0P), the preorganization of 1P, 2P, and 3P can optimize tumor retention and resultant therapeutic performance, of which 3P maximizes the final therapeutic outcomes, leading to a 70.3% tumor inhibition rate. This study highlights the great potential to control the subtle structural transformation and therapeutic effects of self‐assembling peptides by preparing their preorganized entities. Phosphorylation serves as a regulatory switch to stabilize peptide nanomedicines in a well‐preorganized state. The subsequent dephosphorylation response to alkaline phosphatase enabled subtle structural transformation, resulting in better tumor retention and therapeutic outcomes compared with the unphosphorylated control. This study proposes a generic strategy to optimize the therapeutic efficacy of peptide nanomedicines by preparing their preorganized entities.