Cancer Therapy with Nanoparticle-Medicated Intracellular Expression of Peptide CRM1-Inhibitor

• Published in: International journal of nanomedicine 2021-01, Vol.16, p.2833-2847
• Main Authors: Sui, Min, Xiong, Meimei, Li, Yuling, Zhou, Qiao, Shen, Xiaofei, Jia, Da, Gou, Maling, Sun, Qingxiang
• Format: Article
• Language: English
• Subjects: A549 Cells; Active Transport, Cell Nucleus - drug effects; Amino Acid Sequence; Cancer; Cancer therapies; Care and treatment; Cell Nucleus - drug effects; Cell Nucleus - metabolism; crm1; crystal structures; Crystals; Deoxyribonucleic acid; DNA; dna nanocomplex; Drug resistance; E coli; Ethylenediaminetetraacetic acid; Exportin 1 Protein; Gene expression; Gene therapy; Gene Transfer Techniques; Glycerol; Green Fluorescent Proteins - metabolism; Health aspects; HeLa Cells; Humans; International trade; Intracellular Space - metabolism; Karyopherins - antagonists & inhibitors; Karyopherins - chemistry; Karyopherins - metabolism; Laboratory animals; Melanoma; Melanoma, Experimental - drug therapy; Melanoma, Experimental - pathology; Mutant Proteins - metabolism; Mutation - genetics; Nanoparticles; Nanoparticles - chemistry; Nanoparticles - ultrastructure; non-covalent inhibitor; Nuclear Export Signals; Original Research; Peptides; Peptides - chemistry; Peptides - pharmacology; Peptides - therapeutic use; Plasmids; Prevention; Protein Binding - drug effects; protein engineering; Proteins; Receptors, Cytoplasmic and Nuclear - antagonists & inhibitors; Receptors, Cytoplasmic and Nuclear - chemistry; Receptors, Cytoplasmic and Nuclear - metabolism; Software; Structure; Viral Nonstructural Proteins - chemistry
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S266398

Peptides can be rationally designed as non-covalent inhibitors for molecularly targeted therapy. However, it remains challenging to efficiently deliver the peptides into the targeted cells, which often severely affects their therapeutic efficiency. Herein, we created a novel non-covalent peptide inhibitor against nuclear export factor CRM1 by a structure-guided drug design method and targetedly delivered the peptide into cancer cells by a nanoparticle-mediated gene expression system for use as a cancer therapy. The nuclear export signal (NES)-optimized CRM1 peptide inhibitor colocalized with CRM1 to the nuclear envelope and inhibited nuclear export in cancer cell lines in vitro. The crystal structures of the inhibitors complexed with CRM1 were solved. In contrast to the covalent inhibitors, the peptides were similarly effective against cells harboring the CRM1 C528S mutation. Moreover, a plasmid encoding the peptides was delivered by a iRGD-modified nanoparticle to efficiently target and transfect the cancer cells in vivo after intravenous administration. The peptides could be selectively expressed in the tumor, resulting in the efficient inhibition of subcutaneous melanoma xenografts without obvious systemic toxicity. This work provides an effective strategy to design peptide-based molecularly targeted therapeutics, which could lead to the development of future targeted therapy.