A Biomimic Reconstituted High-Density-Lipoprotein-Based Drug and p53 Gene Co-delivery System for Effective Antiangiogenesis Therapy of Bladder Cancer.

Qiaohong Ouyang,Zhongxiang Duan,Guangli Jiao,Jixiao Lei

doi:10.1186/s11671-015-0965-5

Qiaohong Ouyang, Zhongxiang Duan + Show 2 more

Open Access

https://doi.org/10.1186/s11671-015-0965-5

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Abstract

A biomimic reconstituted high-density-lipoprotein-based drug and p53 gene co-delivery system (rHDL/CD-PEI/p53 complexes) was fabricated as a targeted co-delivery nanovector of drug and gene for potential bladder cancer therapy. Here, CD-PEI was utilized to effectively condense the p53 plasmid, to incorporate the plasmid into rHDL, and to act as an antitumor drug to suppress tumor angiogenesis. The rHDL/CD-PEI/p53 complexes exhibited desirable and homogenous particle size, neutral surface charge, and low cytotoxicity in vitro. The results of confocal laser scanning microscopy and flow cytometry confirmed that SR-BI-targeted function induced specific cytoplasmic delivery and high gene transfection efficiency in MBT-2 murine bladder cells. In addition, rHDL/CD-PEI/p53 complexes co-delivering CD and p53 gene achieved synergistic angiogenesis suppression by more effectively downregulating the expression of vascular endothelial growth factor (VEGF) messenger RNA (mRNA) and protein via different pathways in vitro. In vivo investigation on C3H/He mice bearing MBT-2 tumor xenografts revealed that rHDL/CD-PEI/p53 complexes possessed strong antitumor activity. These findings suggested that rHDL/CD-PEI/p53 complexes could be an ideal tumor-targeting system for simultaneous transfer of drug and gene, which might be a new promising strategy for effective bladder cancer therapy.

Highlights

Bladder cancer is one of the most common cancers
Compared with the spectrum of PEI, the proton peaks of –NHCH2CH2– from CD-PEI appeared at 2.2–3.3 ppm, whereas PEI only appeared at about 2.7 ppm
Downregulated the vascular endothelial growth factor (VEGF) secretion from cells induced by Ang II and endogenous mutant p53 compared with an untargeting delivery system (Lipos/CD-PEI/p53) or a mono-delivery system, which was consistent with the abovementioned quantitative reverse transcription PCR (qRT-PCR) and western blotting assays. All these results strongly demonstrated that effective co-delivery of CD and p53 gene into MBT-2 cells using Reconstituted high-density lipoprotein (rHDL)/CD-PEI/p53 complexes achieved synergistic effect in suppressing overexpression of the angiogenesis-related gene VEGF, which might restrain tumor-associated angiogenesis

Summary

Introduction

There were approximately 70,980 cases diagnosed with bladder cancer in the USA in 2009, of which 14,330 patients would likely succumb to the disease [1]. Gene therapy has garnered significant attention as a therapeutic approach for bladder cancer. From a clinical point of view, this disease is an ideal target for gene therapy [2]. Efficient delivery of genetic material to the required cells within a patient without significant toxicity and side effect in gene therapy requires an ideal delivery vector, which has been extensively studied for several decades [3]. Reconstituted high-density lipoprotein (rHDL) is the synthetic form of the endogenous human HDL. Both rHDL and endogenous human HDL possess similar physicochemical properties. RHDL has been successfully developed as a scavenger receptor class B type 1 (SR-BI)-targeting gene carrier [4], which displayed promising application potential in vivo

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