Facile Formation of PAMAM Dendrimer Nanoclusters for Enhanced Gene Delivery and Cancer Gene Therapy.
Shewaye Lakew MekuriaJin LiCong SongYue GaoZhijun OuyangXiangyang ShiXiangyang ShiPublished in: ACS applied bio materials (2021)
Preparation of versatile and safe nanovectors for efficient cancer gene therapy remains to be challenging in the current nanomedicine. Herein, we report the formation of dendrimer nanoclusters for enhanced gene delivery toward gene therapy of cancer. Here, poly(amidoamine) (PAMAM) dendrimers of generation 3 (G3) were cross-linked with 4,4'-dithiodibutryic acid (DA) to form nanoclusters (NCs) through 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride-induced covalent bonding. The synthesized G3-DA NCs having a hydrodynamic size of 219.3 nm possess good colloidal stability and can condense pDNA, encoding both enhanced green fluorescent protein and tumor suppressor p53 gene to form polyplexes with good cytocompatibility. Strikingly, the created NCs/pDNA polyplexes enable 2.3 and 2.1 times higher gene transfection to cancer cells than the counterpart materials of single G3 and G5 PAMAM dendrimers, respectively, under the same conditions. Furthermore, polyplex-treated cancer cells have upregulated p53 and p21 protein and mRNA expression levels and downregulated Cyclin-D1 and CDK-4 protein and mRNA expressions, thus arresting the cell cycle to the G1 phase in vitro to achieve cancer cell gene therapy. The gene delivery efficiency of the polyplexes was further validated through the in vivo tumor therapy without systemic toxicity. The synthesized highly efficient dendrimer NC-based vector system with low cytotoxicity may be extended to tackle various types of diseases related to genetic disorders.
Keyphrases
- gene therapy
- cell cycle
- highly efficient
- papillary thyroid
- squamous cell
- genome wide
- cell proliferation
- copy number
- sensitive detection
- binding protein
- protein protein
- quantum dots
- label free
- fluorescent probe
- stem cells
- young adults
- mesenchymal stem cells
- high glucose
- signaling pathway
- oxide nanoparticles
- transcription factor
- single molecule
- reduced graphene oxide