Citation: Lei Ji, Xue-hao Zhang, Zi-xin Yang, Zeng-ying Qiao, Hao Wang. Microenvironment-induced in situ Self-assembly of Polymer-Peptide Conjugates[J]. Acta Polymerica Sinica, ;2019, 50(6): 642-652. doi: 10.11777/j.issn1000-3304.2019.19039 shu

Microenvironment-induced in situ Self-assembly of Polymer-Peptide Conjugates

Lei Ji ^1,2 ,
Xue-hao Zhang ^1,2 ,
Zi-xin Yang ^1,, ,
Zeng-ying Qiao ² ,
Hao Wang ^2,,

1.
College of Science, Huazhong Agricultural University, Wuhan 430070
2.
The National Center for Nanoscience and Technology, Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, CAS Center for Excellence in Nanoscience and Technology, Beijing 100190

Corresponding author: Zi-xin Yang, zixinyang@mail.hzau.edu.cn Hao Wang, wanghao@nanoctr.cn
Received Date: 25 February 2019
Revised Date: 25 March 2019
Available Online: 5 May 2019

The " in vivo self-assembly” strategy was adopted to improve the efficacy of polymer-peptide conjugates (PPCs) in tumor destruction. Briefly, a pH-sensitive PPC was designed and synthesized, which could penetrate deep into the solid tumors as a single chain. Such single chain would subsequently respond to the mildly acidic environment inside the solid tumor and assemble into a ball, thereby acquiring higher internalization capacity and achieving an enhanced therapeutic function. The major work in this research is as follows. First, several β-thioester polymers were synthesized via a condensation polymerization, and two peptides were produced by solid-phase peptide synthesis. One of the peptides was modified with a pH-sensitive group, cis-aconitic anhydride, and then as-designed polymer-peptide conjugates were prepared by coupling the peptides with polymers through the Michael addition. The PPC products remained stable in a single stranded form under the neutral aqueous condition but aggregated at pH = 6.5. According to TEM observation, the size of PPCs in a pH = 6.5 solution increased from 17 nm to 88 nm in 12 h due to self-assembly, while no obvious size change was noticed under the pH = 7.4 condition. The PPCs modified with DBD group (PS-KFx-CAA-DBD) were dissolved in PBS at different pHs for FL measurement; the FL intensity was significantly increased at pH = 6.5 but barely changed at pH = 7.4, which verified acid-induced aggregation. The mechanism of peptide cytotoxicity is rooted in the destructive effect of α-helix structure on mitochondria membranes. Within 12 h, the content of α-helix structure increased slightly from 19.5% to 25.8% at pH = 7.4 but markedly to 58.9% at pH = 6.5. Based on the rapid hydrolysis of PPCs at pH = 6.5, the better recovery of α-helix structure implied a higher therapeutic activity. Therefore, this in vivo self-assembly strategy enables the peptide nanomaterials to penetrate deeper into the tumor cells and thus endows them with enhanced therapeutic efficacy.
- In vivo self-assembly,
- pH-sensitive,
- Polymer-peptide conjugates,
- Tumour
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