Synthesis of efficient gene delivery systems by grafting pegylated alkylcarboxylate chains to PAMAM dendrimers: Evaluation of transfection efficiency and cytotoxicity in cancerous and mesenchymal stem cells.
The applications of polyamidoamine (PAMAM) dendrimers have attracted much attention in biomedicine specially non-viral gene delivery because of thier unique characteristics including hyperbranching, multivalency, and well-defined uniform globular three-dimensional structures. In the current study, in order to enhance the transfection efficiency and reduce the cytotoxicity of PAMAMs, bromoalkylcarboxylates with different chain length (2-bromoacetic, 6-bromohexanoic, 10-bromodecanoic and 16-bromohexadecanoic acids) were covalently conjugated with 10% and 30% of primary amines of generation 4 and 5 (G4 and G5) of PAMAM dendrimers to increase the hydrophobicity of the carrier. At the next stage, the alkylcarboxylate-PAMAMs were pegylaed to further modify the PAMAM structures for biological applications. Obtained results demonstrated that the prepared PAMAM derivatives had particle size around 140 nm with net-positive surface charge. None of the prepared PAMAM-based non-viral vactors exhibited significant hemolytic activity and also cytotoxicity. Meanwhile decahexanoate-PAMAM G4 [G4(16C-10%)] and decanoate-PAMAM G4 conjugated to polyethylene glycol (PEG) (G4[(10C-30%)(10C-PEG)]) showed highest transfection efficiency in murine neuroblastoma (Neuro-2a) cell line, interestingly only the latter had improved transfection efficiency in mesenchymal stem cells (MSCs). This study proved the potential utility of alkylcarboxylate-grafted PAMAM dendrimers (G4 and G5) with or without PEG modification for efficient gene transfer into cancerous cells as well as MSCs.
Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Sara
S
Ayatollahi
Nanotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Maryam
M
Hashemi
Department of Modern Sciences and Technologies, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Reza Kazemi
RK
Oskuee
Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Zahra
Z
Salmasi
School of Medicine, Gonabad University of Medical Sciences, Gonabad, Iran Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Ahad
A
Mokhtarzadeh
Biotechnology Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Mona
M
Alibolandi
Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran.
Khalil
K
Abnous
Pharmaceutical Research Center, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran ramezanim@mums.ac.ir abnouskh@mums.ac.ir.
Mohammad
M
Ramezani
D000818:Animals; D002264:Carboxylic Acids / Q000737:chemistry / Q000633:toxicity; D002460:Cell Line; D045744:Cell Line, Tumor; D050091:Dendrimers / Q000737:chemistry* / Q000633:toxicity; D018014:Gene Transfer Techniques; D017930:Genes, Reporter; D006461:Hemolysis / Q000187:drug effects; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000378:metabolism*; D051379:Mice; D009447:Neuroblastoma / Q000235:genetics; D011092:Polyethylene Glycols / Q000737:chemistry* / Q000633:toxicity; D014162:Transfection / Q000379:methods
D002264:Carboxylic Acids; D050091:Dendrimers; C104700:PAMAM Starburst; D011092:Polyethylene Glycols
Polyamidoamine; alkylcarboxylate chain; gene delivery; mesenchymal stem cell; polyethylene glycol