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:
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Oncology, Ljubljana, Slovenia.
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