A Therapeutic Pretargeting Strategy for Triple-Negative Breast Cancer Based on a Bioorthogonal Reaction and a Self-Assembled Peptide

Feb 16, 2024·
Chen Zhang
,
Junqiao Wang
,
Hui Chen
Muzi Ouyang (Mia)
Muzi Ouyang (Mia)
,
Yuanheng Li
,
Chunyan Tan
,
Yuyang Jiang
,
Ying Tan
· 0 min read
DOI
Abstract
Triple‐negative breast cancer (TNBC), a disease with a poor prognosis and high mortality, is difficult to targeted therapy, due to the metastatic nature of TNBC cells and their lack of estrogen, progesterone, and Her‐2/Neu receptor targets. Here, a novel pretargeting strategy involving self‐assembled peptides and a bioorthogonal reaction are described. This process generates nanofibers on TNBC cell surface that prevent them migration and invasion and deliver untargeted anticancer drugs (e.g., doxorubicin) that synergistically eliminates TNBC cells. The self‐assembled peptide contains four modules: i) an aromatic group‐rich tetraphenylethylene (TPE) unit for promoting self‐assembly and nanofiber formation, ii) a GFFY peptide motif that supports self‐assembly of nanofibers into peptide scaffolds, iii) a targeting RGD motif that binding with the abundant integrin molecules present on TNBC cell surface, and iv) an azide group acting as the bioorthogonal reaction site that reacts with drugs or probes containing the dibenzocyclooctyne (DBCO) group. Results of in vitro and in vivo experiments indicate that the self‐assembled peptide inhibits tumor invasion and metastasis, while also pretargeting and killing TNBC cells with superior effectiveness and lower toxicity to that of current chemotherapies. In conclusion, this novel bioorthogonal pretargeting strategy holds promise as an effective anticancer therapeutic approach.
Type
Publication
Advanced Functional Materials, 34(24), 2313090
Status
Peer-reviewed
publications
Bioorthogonal Chemistry Self-Assembled Peptides Triple-Negative Breast Cancer
Muzi Ouyang (Mia)
Authors
Muzi Ouyang (Mia)
PhD Candidate

I am Muzi Ouyang (欧阳木子) — I go by Mia. I am a PhD candidate in Chemistry at Tsinghua University, advised by Prof. Ying Tan (谭英) at the Institute of Biopharmaceutical and Health Engineering (iBHE) in Shenzhen. I work on targeted protein degradation: designing bioPROTACs that recruit E3 ligases to destroy proteins small molecules struggle to drug — and working out why that degradation sometimes fails.

My dissertation has two halves. The first is a dual-target bioPROTAC that co-degrades ERα and PI3K p85α, re-sensitizing tamoxifen-resistant breast cancer cells to endocrine therapy. The second is a KRAS-targeting degrader, where I found a resistance mutation in the hypervariable region that lets KRAS escape a multimerization-dependent platform, and used all-atom molecular dynamics to trace the conformational mechanism behind the escape.

Alongside the wet lab I work in computational protein design — Rosetta, ProteinMPNN and AlphaFold2 — including an end-to-end reproduction of the CLAIRE de novo binder-design pipeline, published openly with its debugging narrative. My training spans animal science, basic medicine and chemistry, which is why I move between wet-lab mechanism and computational design rather than choosing between them.

I expect to defend in June 2027 and am seeking postdoctoral positions starting in late 2027. If my work overlaps with your group’s, I’d be glad to hear from you — I’ll gladly send my CV. Write to me at mumumia.1009@gmail.com, or oymzmia@163.com if you are corresponding from within China.