Harnessing the Folding of Antitumor Peptides for Controlled Carrier-Free Drug Delivery.
TL;DR
An antitumor peptide-based delivery platform in which both termini of a stapled p53 α-helix are linked via a disulfide bond, thereby repurposing nonpolar residues originally involved in target protein (hDM2) binding as a hydrophobic block that drives co-assembly with doxorubicin.
Abstract
The development of nanocarriers using therapeutic molecules is a rational strategy to enhance treatment efficacy despite limited drug delivery efficiency. Herein, we devised an antitumor peptide-based delivery platform in which both termini of a stapled p53 α-helix are linked via a disulfide bond, thereby repurposing nonpolar residues originally involved in target protein (hDM2) binding as a hydrophobic block that drives co-assembly with doxorubicin. Upon exposure to the reductive intracellular environment of cancer cells, cleavage of the disulfide bond induces α-helix refolding, which triggers nanostructure disassembly and the coordinated release of both the antitumor peptide and doxorubicin. Furthermore, an RGD sequence was conjugated to the peptide terminus to confer cancer targeting functionality and enhance amphiphilicity owing to its high polarity. Within this platform, the resulting spherical nanocomplexes were well-defined and exhibited pronounced protease resistance, efficient cellular internalization, and robust antitumor activity in vitro. In a xenograft colorectal cancer model, the nanocomplexes exhibited significantly enhanced antitumor efficacy with reduced off-target toxicity compared to free doxorubicin, based on the complementary contribution of the peptide as both a therapeutic component and a delivery scaffold. This approach provides a versatile carrier-free delivery platform based on its broad applicability to diverse small-molecule drugs and peptide sequences.
