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Peptide-Induced Self-Assembly of Therapeutics into a Well-Defined Nanoshell with Tumor-Triggered Shape and Charge Switch

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journal contribution
posted on 2018-09-21, 00:00 authored by Wangxiao He, Jin Yan, Wei Jiang, Shichao Li, Yiping Qu, Fan Niu, Yuwei Yan, Fang Sui, Simeng Wang, Yi Zhou, Liang Jin, Yujun Li, Meiju Ji, Peter X. Ma, Min Liu, Wuyuan Lu, Peng Hou
Peptide-tuned self-assembly of macromolecular agents (>500 Da) such as therapeutic peptides offers a strategy to improve the properties and biofunctions of degradable nanomaterials, but the tough requirement of macromolecular therapeutics delivery and a lack of understanding of peptide-based self-assembly design present high barriers for their applications. Herein, we developed a new strategy for nanoengineering macromolecular drugs by an elaborate peptide, termed PSP (VVV­VVH­HRG­DC), capable of directly conjugating with cargo to be a PSP-cargo monomer as building block tending to self-assemble into a well-defined nanoshell with tumor-triggered shape and charge switch. As a proof of concept, conjugation PSP to a D-peptide activator of tumor suppressor p53 termed DPMI (1492.5 Da) generated hollow spheres ∼80 nm in diameter named PSP-DPMI that disintegrated only in the acidic microenvironment of tumor tissues, followed by integrin-mediated cellular uptake of PSP-DPMI monomers. Importantly, PSP-based self-assembly successfully endowed the DPMI with long circulation time and high cancer-cell-specific intracellular accumulation. PSP-DPMI nanoshells potently inhibited tumor growth in vitro and in vivo by the p53 restoration, while maintaining a highly favorable in vivo safety profile. Out of conventional encapsulation and conjugation, our study showcases a clinically viable novel method to nanoengineer macromolecular agents such as peptide for anticancer therapy and provides a hazard-free alternative strategy for the theranostics delivery.