The Application of Nanoparticles for Gene Vector in Tumor Gene Therapy

 

Nian-Feng Sun, Zhan-Ao Liu, San-Yuan Hu

 

Nian-Feng Sun, Zhan-Ao Liu, San-Yuan Hu, Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, China

Nian-Feng Sun, Zhan-Ao Liu, Department of the Surgery, Affiliated Jinan Central Hospital of Shandong University, Jinan 250013, China

Correspondence to: Nian-Feng Sun, Department of General Surgery, Qilu Hospital of Shandong University, Jinan 250012, China. sunnianfeng@163.com

Tel: +86-15806416654                  Fax: +86-0531-85695754    

Received: June 1, 2013                Revised: August 19, 2013

Accepted: August 20, 2013

Published online: October 18, 2013

 

 

ABSTRACT

Development of safe and effective carriers is one of the major difficulties for gene therapy. Commonly used carriers for gene delivery can be classified into two categories: viral carriers and non-viral carriers. Nanoparticles gene carrier of various different kinds of materials, which belong to non-viral carriers, are paid attentions widely for its advantages such as low toxicity and immunogenicity, good biocompatibility, easy to produce, and a promising perspective for application in tumor  gene  therapy.  The nanoparticles have a high stability in organisms and cells, which was difficult to be degraded. Nanoparticles can improve transfection efficiency. As a nonviral gene vector, the application of nanoparticles in gene therapy became research focus. In this article, we mainly reviewed the recent studies of the characteristics of nanoparticles,  characteristics and transport mechanism of nanoparticles as gene vector, the progress on nanoparticles as gene vector in tumor  gene  therapy.

 

© 2013 ACT. All rights reserved.

 

Key words: Nanoparticles; Gene vectors; Transfection efficiency; Tumor

 

Sun NF, Liu ZA, Hu SY. The Application of Nanoparticles for Gene Vector in Tumor Gene Therapy. Journal of Tumor 2013; 1(5): 24-27 Available from: URL: http://www.ghrnet.org/index.php/JT/article/view/487

 

 

INTRODUCTION

Nowadays the morbidity and mortality of tumors are increasing year by year and seriously threaten the health of human. Traditional surgery can resect the lesion but the residue cancer cells can be the origins of the recurrence and metastasis of malignant tumors. And chemotherapy and radiotherapy are greatly restricted in clinical use for their serious side effects and multidrug resistance[1]. In recent years with the development of molecular biology the application of gene therapy can completely clear the lesion without serious toxic and side effects and these reasons make it become the development trend in the treatment of tumors.

    Gene therapy is a major advance in modern medicine and it is also the hotspot of tumor therapy research. The key to successful realization of gene therapy is the gene delivery mode, so it's important to choose a suitable gene delivery system that can make the plasmid DNA distributed in specific nucleus and inserted into specific DNA site. Scholars have done large numbers of studies on tumor gene therapy over the years, but influenced by many factors gene therapy effect is not ideal till the present time. It is still a very urgent and difficult problem about how to improve the efficiency of gene transfer, efficiently, targeted and harmlessly deliver the gene into a target site to achieve its therapeutic effect on the molecular level[2].

 

 

TYPES, MATERIALS AND MECHANISM OF NANOPARTICLE GENE VECTOR

At present there are two existent gene vectors defined as viral vectors and non-viral vectors[3-4]. Although retrovirus and adenovirus have high transfection efficiencies as representatives of the viral vectors,  there were existed problems such as complex preparation, immunogenicity, serious security hidden danger and can’t be repeatedly used in vivo so they can’t become the satisfactory gene vectors[5-6]. And the non-viral vectors use the synthetic nonbiological materials to bring the nucleic acids into the cells, have some good properties like non-toxic, easy to design and low immunologic reaction while the transformation efficiency is low[7-8].

    Nano-gene vector is usually some kind of nanocapsule or nanoparticles that prepared from biocompatible material, it can form nano-carrier gene complex by encapsulated or absorbed nucleic acid molecules like exogenous DNA. The particle size of the nanoparticles carrier is usually 10-100 NM and chemistry activity from the huge specific surface area makes it has outstanding adsorption, concentration and protection ability, this is one of the main causes for nano-gene carrier exerts its adsorption, transport function on exogenous genes[9-10]. The nano gene carrier materials are divided into organic and inorganic materials two. Organic materials are mainly high molecular polymer including dendritic polymers, cationic liposome, PLGA and Chitosan, inorganic nano material stability, with good dispersion behavior, easy preparation, easy to control the particle size, large loading quantity, no immunogenicity, low cytotoxicity and easy to achieve targeted delivery with coupling specific molecules on the surface to improve transaction efficiency. Inorganic materials mainly include silica, iron oxide and gold nanoparticles[11-15]. The advantages and disadvantages of various gene nanoparticle carrier as shown in table 1.

    Nano gene vectors have the ability to combine and concentrate DNA and RNA then efficiently import them into various cells. Then enter the cytoplasm through the interaction between the surface cation and the glycoproteins and phospholipid in the membrane with negative charge, the number of cations and their gene transfer rate is positively correlated[16]. The nanoparticles can combine with DNA to form complexes and nanoparticles coupling with DNA molecules through electrostatic adsorption or their chemical bond. This combination can effectively protect the exogenous DNA that combined with nano particles from various enzyme digestions, and improve the transfection efficiency[17]. Endocytosis is the main mechanism of the complex entered into the cells. Meanwhile, coupling specific targeted molecules such as specific antibodies or monoclonal antibodies on the surface of the nanoparticles and binding to specific receptors by targeting molecular on a cell membrane, under the action of the cell uptake the particles the gene into the cell and so that the gene transaction can be safe and effective targeted. Nanoparticles can mediate the DNA integrate into the nuclear genome and obtain the stable expression of exogenous gene.

Nano gene vectors have the ability to combine and concentrate DNA and RNA then efficiently import them into various cells. Then enter the cytoplasm through the interaction between the surface cation and the glycoproteins and phospholipid in the membrane with negative charge, the number of cations and their gene transfer rate is positively correlated[16]. The nanoparticles can combine with DNA to form complexes and nanoparticles coupling with DNA molecules through electrostatic adsorption or their chemical bond. This combination can effectively protect the exogenous DNA that combined with nano particles from various enzyme digestions, and improve the transfection efficiency[17]. Endocytosis is the main mechanism of the complex entered into the cells. Meanwhile, coupling specific targeted molecules such as specific antibodies or monoclonal antibodies on the surface of the nanoparticles and binding to specific receptors by targeting molecular on a cell membrane, under the action of the cell uptake the particles the gene into the cell and so that the gene transaction can be safe and effective targeted. Nanoparticles can mediate the DNA integrate into the nuclear genome and obtain the stable expression of exogenous gene.

 

 

THE APPLICATION OF POLYMER MATERIALS NANOMETER GENE VECTOR IN TUMOR TREATMENT

Baker, University of Michigan Medical School immunologist and Nanomedicine technology authority, developed a nanoscale dendritic polymer, after injecting the carrying DNA dendritic polymer into the tissue its size is fit to enter the cell by endocytosis and then the DNA molecules released and into the nucleus to achieve gene integration[18-19]. Nian-Feng Sun et al[20-23] prepared the cationic nano-liposome and tested its phenotype then using it as a gene carrier to study the mechanism of the colon carcinoma, indicating that it has advantage than the viral vector in cytotoxicity but the gene transfection efficiency is still lower. Kaul et al using the PCMV-beta gene polyethylene gel nanoparticles and PCMV-beta gene were transfected into Lewis lung cancer cells respectively with nearly 100% encapsulation efficiency and 200 nm average diameter, high efficient transfection and expression was in control group, and in vivo studies on female C57BL/6J rats transplanted Lewis lung cancer found that both vein or intratumoral injection all have significant differences in gene expression between PCMV-beta gene polyethylene gel nanoparticles and the control group, and this provide new ideas for tumor gene therapy[24].

 

 

THE APPLICATION OF MAGNETIC NANOMETER GENE VECTOR IN TUMOR TREATMENT

Now with the development of bionanotechnology the applications of nano-magnetic particles and gold nanoparticles in biomedical field have increasingly become one of the hot spots and they have obvious advantages in cell targeting transfection efficiency especially[25]. Nano-magnetic particles' application in gene transfection is a new emerging multi-subjects research field, its proposition and development is built on the basis of nano-magnetic particles' materials science research results and non-viral gene transfection biological research[26]. The study showed that during the process of magnetofection the magnetic field can't pull the magnetic particles into the cells directly and also did not change the mechanism of gene complexes' endocytosis, but accelerated gene complexes' sedimentation to the cell surface so as to promote the phagocytosis of gene complexes greatly, thereby enhanced gene transfection[27]. Through the force of external magnetic field in the process of magnetofection the  magnetic gene particle’s sedimentation to the cell surface can be accelerated, thus promoted the phagocytosis of gene complexes and achieved the enhancement of gene transfection. The results of experiment showed that magnetofection is a kind of high efficiency, low toxicity and widely applied gene transfection method, and a plasmid DNA harboring target genes or a synthesized small interference RNAs (siRNA) all can be efficiently transfected into cells through it in a short time, thus overcomes the defect of  the lack  of targeted without external magnetic field in gene transfection and makes more DNA enriched to the surface of a target cell, these all let it become the best choice for local targeted gene therapy in vivo[28-30].

 

 

THE APPLICATION OF GOLD  NANOMETER GENE VECTOR IN TUMOR TREATMENT

Gold nanoparticle is a kind of new material with many biological functions, mainly metabolized via urine and has no apparent cytotoxicity. The study showed that the unmodified gold nanoparticles had poor ability to carry DNA but the gene transfection efficiency can be improved after the superficial modification. Due to the gold nanoparticles have characteristics such as good stability, high surface activity, strong ability to carry genes and special biological affinity so they have been applied to some areas' exploring research like DNA testing, rapid immunodiagnosis, biosensor and targeted drug carrier in the world at present[31-35].

    With the development of Bio-nanotechnology more and more researches showed that superficial modified gold nanoparticles can greatly improve the gene transfection efficiency and have incomparable advantages in carrying genes for gene therapy[36]. Now in using nano material as an assembly system structure unit, the latest research hotspot is the assemblies of multi-functional materials for that gold nanoparticles and nano-magnetic particles have excellent genes carrying capacity and targeting functions. Some studies have reported that the polyethylenimine (PEI) on the surface of nano-magnetic particles can prepare gold nanoparticles by reduction of chloroauric acid so goldmag bifunctional nanocomposite system is expected to become a good gene vector material[37].

 

 

CONCLUSION

As a new drug and gene carrier nano-gene vector has some characteristics such as controlled released, target directed and higher bioavailability, and shows very good efficacy to some tumor animal model. But most of the current studies are still in vitro and in an animal experimental stage that need to be further researched and do some human experiments to improve targeted therapy efficacy and the rate of early cancer diagnosis. In order to improve the transfection efficiency of nano particles /DNA, some substances holding a positive charge such as poly-l-lysine and PEG can be modified on the surface of the nanoparticles, this will be more conducive to the formation of nano-particles / DNA complexes. As gene vector nanoparticle targeted relatively poor in gene therapy, but with coupling specific targeted molecules on the surface and through targeted molecules binding to specific surface receptors can achieve targeted and efficient gene transportation. Although the tumor-targeting gene therapy research has a long way to go, but I believe that tumor targeted therapy has a bright future under the efforts of numerous researchers.

 

 

FUTURE PERSPECTIVES

Currently, Gene therapy is essentially a question of purpose gene, vectors and transfection, gene delivery way is the key to the success of gene therapy . Ideal gene delivery carrier will be at the same time high transfection activity and good biocompatibility. Here, we present an overview of the clinically used and tested nanoparticles for imaging and treatment of cancer. Both clinical and preclinical studies show a variety of the type of nanoparticles developed for cancer. There are more types of nanoparticles currently at an early design step that may progress in the future to preclinical development for cancer imaging and therapy. Nanoparticles for cancer imaging and therapy have evolved rapidly during the last decade and it is expected that more and more will become clinical practise. Their controlled size and multi-functionality are the main reasons for their increasing applications as anticancer agents.

    With the continuous development of biotechnology and interdisciplinary penetration and cross each other, also gradually in-depth research on nanometer gene carrier, in the near future, as a new nanometer gene carrier gene delivery carrier will be in medical research and treatment play a bigger role. From all these nanoparticles, we would like to highlight the potential value of theragnostic nanoparticles in both imaging (diagnosis) and therapy (i.e.chemotherapy or genetic therapy).

 

 

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Peer reviewer: Gregor Sersa, Institute of Oncology Ljubljana, Department of Experimental Oncology, Ljubljana, Slovenia.

 

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