Protein degradation targeted chimera (PROTAC) can efficiently degrade disease-causing proteins to treat varieties of diseases and has been widely investigated by global researchers. Despite of its promising prospects, the pharmacokinetic behavior of traditional PROTAC small molecules is barely satisfactory and lacks tumor specificity. Its continuous catalytic degradation can not control the degradation of POI protein in normal tissues, thus resulting in serious side effects, which greatly limits its clinical application.
Therefore, the accurate delivery of PROTAC molecules to the tumor site and effective degradation of target proteins are very core factors shaping the development of PROTAC antineoplastic drugs.
Researchers from Chinese Academy of Sciences, Zhongshan Hospital affiliated to Fudan University, and East China Normal University published a research paper entitled “Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy” in the journal Nature Communications.
Based on the diverse intelligent drug delivery systems for tumor microenvironment response developed by the team led by Haijun Yu from Chinese Academy of Sciences, a polymerized PROTAC (POLY-PROTAC) nanotherapy strategy was innovatively proposed to achieve tumor-specific PROTAC delivery and protein degradation. The study results show the accurate degradation of target protein by POLY-PROTAC and the prospect of efficient tumor therapy based on PROTAC.
To achieve accurate tumor delivery, the team first synthesized a series of PROTACs based on von Hipel-Lindau (VHL) ligands, and then attached the disulfide modified precursor PROTACs to amphiphilic polymers by covalent reversible addition-fragmentation chain transfer polymerization (RAFT).
The polymer can be self-assembled to form uniform and stable nanoparticles, and has the responsiveness of tumor extracellular enzyme environment, intracellular acid environment, and reduction environment, so that the nanoparticles can achieve specific aggregation and efficient infiltration of tumor tissue.
In addition, the research team optimized the nanoparticles by azide-modification to further increase the accumulation and retention of nanoparticles in tumor tissue through biological orthogonal strategy. To this end, the research team designed pre-targeted nanoparticles containing DBCO groups in response to the extracellular microacid environment of tumor cells, which can dissociate and expose DBCO groups in the extracellular acid environment of tumor cells, thus capturing azide-modified POLY-PROTAC nanoparticles by click reaction. The retained N3@POLY-PROTAC nanoparticles exfoliate PEG under the action of MMP-2 enzyme overexpressed in tumor microenvironment, which makes it easier to penetrate into tumor tissue and be absorbed by tumor cells. After entering the cells, the response of the microacid environment in the tumor cells of the nanoparticles dissociated and restored the fluorescence activity of its loaded photosensitizer pyromagnesium chlorophyll a (PPa). Simultaneously, the overexpressed glutathione (GSH) cut off the disulfide bond connecting the PROTAC molecule and released it to degrade the target protein.
The research team demonstrated that the bioorthogonal POLY-PROTAC nanoparticles combined with photodynamic therapy can effectively activate the apoptotic protein caspase-3, thus achieving a highly effective anti-tumor effect. The findings of this study proposed a universal nano-platform for specific delivery of PROTAC molecules to tumor sites and confirmed its anti-tumor potential.