Synergism of wt-p53 and synthetic material in local nano-TAE gene therapy of hepatoma: comparison of four systems and the possible mechanism

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.

Strategies for Targeting Gene Therapy in Cancer Cells With Tumor-Specific Promoters

“…Transfection efficiency of these nanoparticles was about 26%. Finally, the design of this co-delivery system showed a strong inhibitory effect on angiogenesis in vitro, and in vivo analysis demonstrated a superior anti-tumor effect in a mouse model (181,184,185).…”

Multifunctional nanoplatforms application in the transcatheter chemoembolization against hepatocellular carcinoma

“…The result showed that Rb worked synergistically with p53 in combined therapy mediated by a poly-L-lysine-modified nHAP nano polyplex to augment the antitumoral effect through the downregulated expression of essential genes related to apoptosis, necrosis, growth, differentiation, and multidrug resistance of tumor cells [ 65 ]. Another study also explored the synergism of wt-p53 and synthetic material (such as poly-lysine modified nHAP) in local nano-TAE gene therapy of hepatoma [ 113 ]. These studies created a new gene delivery route using nHAP, which promoted the application of TAE-target gene therapy in HCC.…”