Targeted Nanotherapeutics Using LACTB Gene Therapy Against Melanoma

• Published in: International journal of nanomedicine 2021-01, Vol.16, p.7697-7709
• Main Authors: Liu, Jinlu, Yang, Ling, Yuan, Xin, Xiong, Meimei, Zhu, Jiao, Wu, Wenbi, Ren, Min, Long, Jianlin, Xu, Xuewen, Gou, Maling
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic Agents - pharmacology; Apoptosis; Beta lactamases; beta-Lactamases - pharmacology; beta-Lactamases - therapeutic use; Biotechnology industry; Breast cancer; Cancer; Cancer therapies; Care and treatment; Cell cycle; Cell growth; Cell Line, Tumor; Flow cytometry; Gene therapy; Genes; Genetic Therapy; Humans; lactb；nanocomplexes；gene therapy; Melanoma; Melanoma, Experimental - drug therapy; Membrane Proteins - genetics; Mice; Mice, Inbred C57BL; Mitochondrial Proteins - genetics; Nanoparticles; Original Research; Patients; Plasmids; Prevention; Proteins; RNA; Skin cancer; Tumor proteins; Vectors (Biology)
• ISSN: 1178-2013; 1176-9114; 1178-2013
• DOI: 10.2147/IJN.S331519

β-lactamase (LACTB) is a tumor suppressor gene in various tumors including melanoma. However, it remains challenging to efficiently deliver the LACTB gene into melanoma. Recently, we designed a nonviral nanocarrier iRGD/DOTAP/MPEG-PDLLA (iDPP) that could deliver gene targetedly to melanoma efficiently without obvious adverse effects. In this study, the tumor-targeted nanoparticle iDPP was prepared to deliver LACTB gene to treat melanoma in vitro and in vivo. First, the expression level of LACTB in 6 clinical specimens of melanoma patients was evaluated. Subsequently, the characteristics of iDPP/ nanocomplexes were studied. Afterwards, the in vitro and in vivo anti-tumor efficacy of the iDPP/ nanocomplexes were explored utilizing the B16-F10 mouse melanoma cell line and the B16-F10 subcutaneous melanoma model. Compared with the normal epithelium, the expression level of LACTB in melanoma tissues was significantly downregulated. In vitro B16-F10 cell tests showed iDPP/ nanocomplexes could increase the mRNA levels of P21, Bid, Bax, Pidd1, and Sival genes and up-regulate the p53 signaling pathway of melanoma cells, thus promoting cell apoptosis and blocking the cell cycle. Injected intravenously, iDPP nanoparticles could deliver DNA to the subcutaneous melanoma targetedly. Based on in vivo mouse xenograft model, iDPP/ nanocomplexes could effectively inhibit tumor proliferation and induce tumor apoptosis, thus significantly inhibiting melanoma growth (tumor inhibition rate is about 68%) in the subcutaneous B16-F10 melanoma model. The downregulated LACTB might be a potential target for melanoma therapy. The iDPP/ nanocomplexes could inhibit the growth of the mouse melanoma without obvious side effects, which provide a new option for melanoma gene therapy research.