Abstract
BackgroundTAE-gene therapy for hepatoma, incorporating the tumor-targeted therapeutic efficacy of trans-arterial embolization, hydroxyapatite nanoparticles (nHAP) and anti-cancer wild-type p53 gene (wt-p53), was presented in our former studies (Int J Nanomedicine 8:3757-68, 2013, Liver Int 32:998-1007, 2012). However, the incompletely antitumoral effect entails defined guidelines on searching properer materials for this novel therapy.MethodsUnmodified nHAP, Ca(2+) modified nHAP, poly-lysine modified nHAP and liposome were separately used to form U-nanoplex, Ca-nanoplex, Pll-nanoplex, L-nanoplex respectively with wt-p53 expressing plasmid. The four nanoplexs were then applied in vitro for human normal hepacyte L02 and hepatoma HePG2 cell line, and in vivo for rabbits with hepatic VX2 tumor by injection of nanoplexs/lipiodol emulsion into the hepatic artery in a tumor target manner. The distribution, superficial potential, physical structure, morphology and chemical compositions of nanoplexs were evaluated by TEM, SEM, EDS etc., with the objective of understanding their roles in hepatoma TAE-gene therapy.ResultsIn vitro, L-nanoplex managed the highest gene transferring efficiency. Though with the second highest transfection activity, Pll-nanoplex showed the strongest tumor inhibition activity while maintaining safe to the normal hepacyte L02. In fact, only Pll-nanoplex can combine both the antitumoral effect to HePG2 and safe procedure to L02 among the four systems above. In vivo, being the only one with successful gene transference to hepatic VX2 tumor, Pll-nanoplex/lipiodol emulsion can target the tumor more specifically, which may explain its best therapeutic effect and hepatic biologic response. Further physical characterizations of the four nanoplexs suggested particle size and proper electronic organic surface may be crucial for nano-TAE gene therapy.ConclusionPll-nanoplex is the most proper system for the combined therapy due to its selectively retention in liver cancer cells, secondary to its morphological and physico-chemical properties of nanometric particle size, steady emulsion, proper organic and electronic surface.
Highlights
transcatheter arterial embolization (TAE)-gene therapy for hepatoma, incorporating the tumor-targeted therapeutic efficacy of trans-arterial embolization, hydroxyapatite nanoparticles and anti-cancer wild-type p53 gene, was presented in our former studies (Int J Nanomedicine 8:3757-68, 2013, Liver Int 32:998-1007, 2012)
Optimal dosage for safe procedure and antitumoral effect of nHAP based nanoplexs in vitro In general, cell viability of both cell lines decreased with increased concentration of nanoplexs
Slight L02 normal liver cell viability was decreased, whereas much more HepG2 tumor cell viability was decreased when both treated by same concentration of Pll-nHAP-PEGFP-C2 (Pll-nanoplex)
Summary
TAE-gene therapy for hepatoma, incorporating the tumor-targeted therapeutic efficacy of trans-arterial embolization, hydroxyapatite nanoparticles (nHAP) and anti-cancer wild-type p53 gene (wt-p53), was presented in our former studies (Int J Nanomedicine 8:3757-68, 2013, Liver Int 32:998-1007, 2012). Wild-type p53 (wt-p53) is a housekeeping tumour suppressor that is frequently mutated and disfunctional in more than 50% of HCCs. Former study [1, 9, 10] successfully combined wt-p53 gene therapy, transcatheter arterial embolization (TAE) and antitumoral nanoparticle for hepatoma by exploiting poly-lysine modified hydroxyapatite nanoparticles (Pll-nHAP) to serve as both embolic material and therapeutic target gene vector at the same time. We conclude the necessary similarities and propose basic guidelines for selecting synthetic inorganic materials in novel strategy of nano-TAE gene therapy
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