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Current Medicinal Chemistry, 2018, 25, 1-13 1

REVIEW ARTICLE

Polymer Conjugated Gold Nanoparticles in Biomedical Applications

Stanley Anniebell1 and Subash C.B. Gopinath1,2,*

1
School of Bioprocess Engineering, Universiti Malaysia Perlis, 02600 Arau, Perlis, Malaysia; 2Institute of
Nano Electronic Engineering, Universiti Malaysia Perlis, 01000 Kangar, Perlis, Malaysia

Abstract: Background: Research interest on the properties of polymer conjugated gold


nanoparticle (GNP) in biomedicine is rapidly rising because of the extensive evidences for
their unique properties. In the field of biomedicine, GNPs have been widely used because of
their inertness and low levels of cytotoxicity. Therefore, when exposed to cells, they are less
prone to exert damaging effects. GNPs are capable of being functionalized as desired and are
ARTICLE HISTORY ideal as they do not encourage undesired side reactions that might counter react with the in-
tention of the functionalization. Biofouling is an occurrence that takes place at cellular and
Received: August 27, 2016
Revised: September 08, 2016 biological molecular level, binds non-specifically on the detection surface and forms a wrong
Accepted: January 10, 2017
output. This undesired incidence can be avoided by conjugating the surface of biomolecules
DOI: with polymers. Densely packed repeating chains of polymers such as polyethylene glycol are
10.2174/0929867324666170116123633
capable of decreasing non-specific reactions. Applications of polymer conjugated GNPs in
the field of biomedicine are as biosensors, delivery and therapeutic agents.
Conclusion: Therefore, the properties and applications of polymer conjugated GNPs are
studied widely as overviewed here.
Keywords: Polyethylene glycol, gold nanoparticle, biofouling, biomedicine, polymer.

1. INTRODUCTION surface plasmonic nanoparticles can be attributed to the


fact that they have low cytotoxicity, high chemical sta-
Nanoparticles that have unique features such as
bility and high affinity to the molecular elements (Fig.
tunable properties in terms of their size profile in
1). Moreover, it is easier to immobilize various kinds
nanometers have become more utilized in the scientific
of biomolecule (antibody, protein, peptide, and nucleic
field [1-6]. Their application with bottom-up and top-
acids) on the GNP surface through electrostatic interac-
down approaches especially observed in the biotechno-
tion, chemical modification or physical adsorption (Fig.
logical and medical fields are ranging from target de-
2). The immobilized biomolecules on the GNP are
tection to imaging [7-11]. Nanoparticles have also been
quite stable under various conditions, and can be used
formulated in both soluble (e.g. Starch nanoparticle) for different biotechnological applications including
and insoluble (e.g. Metal nanoparticle) forms. Among biosensors, biomedicine, and therapeutics [12-20].
different metal nanoparticles that have been proposed, Biomolecule conjugated GNPs have garnered much
gold nanoparticles (GNP) are well documented due to interest in the field of biomedicine due to its stability
its appealing characteristics such as being biologically under physiological conditions. At the same time, one
non-reactive, cheap and easy to tailor with different of the important focuses is the biofouling on the GNP
sizes [9]. GNPs are considered as surface plasmonic surface because GNPs can easily bind to the bio-
nanoparticles have been used successfully for different molecules non-specifically through electrostatic inter-
functions include targeting the analytes, diagnostics action. To avoid this situation and get the complete
and cancer therapy [12]. The advantages of such benefit of the GNP, researchers use polymer conju-
gated GNPs. Polymer-conjugated GNPs bring more
*Address correspondence to this author at the School of Bioprocess advantage such as stability, reduced biofouling and in-
Engineering, Universiti Malaysia Perlis, 02600 Arau, Perlis, Malay- creased specific targeting of biomolecules. Attributing
sia; Tel: +60125565881; E-mail: subash@unimap.edu.my to these advantages, applications of these conjugations

0929-8673/18 $58.00+.00 © 2018 Bentham Science Publishers


2 Current Medicinal Chemistry, 2018, Vol. 25, No. 00 Anniebell and Gopinath

Table 1. Applications of polymer conjugated GNP.

Target PEG and GNP   Application   Physiological Condition   Reference  

Breast cancer susceptibility gene   GNP on the PEG layer   Biosensor   In vitro   [13]  

Factor IX protein   N6-PEG conjugated GNP   Biosensor   In vitro   [14]  


Coumarin   PEG-thiol conjugated GNP   Imaging   In vivo   [15]  
Trypsin and Urokinase-type plasmino-
SH-PEG   Imaging   In vivo   [16]  
gen activator  
PEGylated CsA-encapsulated
Cyclophilin A (essential for hepatitis
poly (lactic-co-glycolic) acid Drug   In vitro and In vivo   [17]  
C replication)  
(PLGA)  

PLK1-Specific Small Interfering RNA


GNP-polyethyleneimine   Drug   In vitro   [18]  
Transfection  

Hepatocellular carcinoma   GNP-PEG-COOH   cancer Imaging   In vivo   [19]  


5-poly(amidoamine) (PAMAM)
pDNA   Gene delivery   In vitro   [20]  
dendrimer entrapped GNP  

Estradiol   Imprinted polymer and GNP   Biosensor   In vitro   [21]  


Human retinal cells   PEG protected GNP   Imaging   In vitro   [22]  

GNP modified with poly(ethylene


Colorimetric
Ochratoxin A   glycol) 2-thioethyl ether acetic In vitro   [23]  
assay  
acid and DNA  
Methoxy PEG-Iodine-Capped X-ray CT imag- In vitro and
In vivo blood pool   [24]  
GNPs   ing   In vivo  
Gold nanorods coated PEG-b-
Fibroblast-like L929 cell line   Drug delivery   In vitro   [25]  
poly(N-vinyl caprolactam)  
Gold nanocages covered by smart
Cancer cell   Delivery   In vivo   [26]  
polymers  

Acute mye-
GNP on polymer pillar   Biosensor   In vitro   [27]  
loid leukemia  

are widely used in biomedical applications, which in- nanomaterials. Studies have shown that in delivery ap-
cludes biosensor, imaging, drug delivery and cancer plications, the polymer conjugated GNPs can be used
studies (21-27; Fig. 1). in photodynamic therapy and as a delivery vehicle of
There are different kinds of polymers conjugated cisplatin among others. In imaging functions, it has
with GNPs to produce bioactive nanomaterials, such as proven to amplify the detection of important targets
temperature-sensitive poly(N-isopropyl acrylamide) besides being able to enhance X-ray, Single photon
demonstrated for its pivotal roles in promoting cell in- emission computed tomography (SPECT) and Com-
ternalization, targeted delivery and bioactive modulation puted tomography (CT) imaging. SPECT is utilized for
[28, 29]. Other fantastic applications of polymer-GNP nuclear medicine scans by the injection of a radio-
grafts include recyclable nanocomposites with bacterial pharmaceutical which is then read by a nuclear medi-
specific glycopolymer poly[2-(methacrylamido) glu- cine gamma camera. CT involves an X-ray machine
copyranose] [30] and pH-sensitive poly(methacrylic revolving over a 360˚ arc which produces three-
acid) [31-33] for the controlled release of drugs, biosens- dimensional image reconstructions. Polymer-conju-
ing, and bioactivities. These studies are important to gated GNPs are also contribute to cancer therapy with
produce recyclable and stimuli-responsive GNP- these features and therefore, studies are exploring fur-
conjugated polymers for biomedical applications and ther on the GNP conjugated polymers functions that
they are new ways in preparing controllable bioactive allow the advancement in biomedicine [3,4,9,18,19].
Polymer Conjugated Gold Nanoparticles in Biomedical Applications Current Medicinal Chemistry, 2018, Vol. 25, No. 00 3

2. CHARACTERISTICS OF GOLD NANOPAR-


TICLE
GNPs have been synthesized in various shapes and
sizes by chemical mode using sodium citrate, hydro-
quinone reduction of chloroauric acid or sodium boro-
hydride. Citrate, salt, amine or some leaf extract are to
be used as the reduction agent in these synthesis proc-
esses. GNPs vary in size from one nanometer to several
hundred nanometers. The size and shape of GNP de-
pend on the reducing agent concentration and tempera-
ture [34]. Among various types of GNP structures, the
versatile in the scientific field includes spherical GNP,
gold nanorod, gold nanocube, gold nanostar, gold
nanotriangle, gold nanocage, gold nanowire and nan-
oflower [27,35] (Fig. 4a). The scattering of visible and
near infrared light by GNPs through the process known
as surface plasmon resonance (SPR) is highly depend-
ent on their shape, size, and state of agglomeration
[36]. The color of the GNP is dependent on its size and
the absorbance peak wavelength also varies according
to the shape (Fig. 4b). Due to this, various microscopic
techniques for diagnosis and optical imaging purposes
have been utilized including confocal scanning electron
Fig. (1). Surface chemical functionalization on gold nanopar- microscopy, optical coherence microscopy and third
ticle. Molecular functionalization can be through the chemi- harmonic microscopy. GNPs are also capable of con-
cal linker or by charge-based. verting photons which have been absorbed into thermal
energy at a fast pace.
GNPs have been receiving a widespread attention in
the fields on biomedicine and optoelectronics today
because they have been found to be beneficial in a
number of applications ranging from electrical conduc-
tivity, drug transport, sensing probe functions, and as
carriers in the fields of photovoltaics, biomedicine,
chemical and biological catalysis [37]. This is contrib-
uted by the fact that GNPs are low in cytotoxicity and
has inert properties. This makes GNPs to be less prone
to affect living cells in terms of toxic exposure. So that,
when GNP is functionalized, it is less prone to produce
undesired side reactions that might counter the purpose
of the function [38].
To be able to tune the GNP into the desired physical
and chemical properties, there are number of methods
which can be utilized. Certain physical properties that
can be modified include the shape of the GNP struc-
ture, its chemical surface, and its size. These aspects
can be tuned by modification with polymer, bio-
molecule and small molecular coating [13,14]. The
Fig. (2). Surface biomolecular immobilization on gold
shape of the GNP has unique properties which can be
nanoparticle. Functionalization can be through the chemical
advantageous for various medicinal applications. In the
linker or by charge-based.
case of gold nanocage; biomolecules, drugs or enzymes
are trapped into the cage and released with the proper
4 Current Medicinal Chemistry, 2018, Vol. 25, No. 00 Anniebell and Gopinath

Fig. (3). Applications of GNP-polymer conjugates. Examples are biosensor, imaging, drug delivery and cancer study.

Fig. (4). (a) Types of gold nanostructures. Spherical, nanorods, nanocubes, nanostars, nanotriangles, nanocage, nanowire and
nanoflower are displayed; (b) Peak wavelength and color changes with different sized GNPs. Larger sized GNP tends to aggre-
gate more rather than smaller sizes. Line explains the increment in the wavelength. Spheres explain the color changes from red
to purple.

control [39]. Different shapes of GNPs have similar ple and colors of GNP are dependent on the size of the
behaviors but the light scattering properties of each nanoparticles and the colors of the gold nanocage is
shape are different. It was found that gold nanorods dependent on the thickness of the cage wall and size of
enter the tumor cells more efficiently than gold spheres the pores. Once the suitable GNP surface has been suc-
[40]. Apart from that, colloidal gold suspended liquid is cessfully modified as intended, we are able to function-
commonly used in various medical, sensor applications alize the GNP for the various interdisciplinary fields of
and also to be used for making colored stained glasses. research including medicine, chemistry, biology and
The gold colloid colors can transition from red to pur- engineering. The unique properties of GNP open up a
Polymer Conjugated Gold Nanoparticles in Biomedical Applications Current Medicinal Chemistry, 2018, Vol. 25, No. 00 5

world of possibilities with the usage of GNP in bio- For GNPs with charge that has been stabilized, the zeta
medical applications for the years to come. potential is the measurement of its stability. Conven-
tionally, GNPs have enough electrostatic repulsion to
3. PHYSICAL PROPERTIES OF GOLD NANO- maintain their stability in a solution when their zeta
PARTICLES potential is in the range of 20 to -20 mV. When intro-
The small size of GNP contributes to their unique duced to highly basic or acidic solutions, the nanoparti-
properties. GNPs have extremely high surface area to cles are also able to dissolute into an ionic state that
volume ratio [41]. The nature of GNP surface deter- can deposit further on the preexisting nanoparticles
mines their physical properties such as their stability which eventually modifies its size distribution and av-
and solubility. Although the surface area to volume erage diameter.
ratio is important for catalytic applications, the GNP’s To functionalize the GNPs, in the biological field it
actual properties are analyzed to be dissimilar at the is usually coated with proteins, peptides, oligonucleo-
nanoscale level. This can be showed by the particle’s tides and polyethylene glycol (PEG). This process can
phenomenal visible light scattering ability by the plas- be accomplished by physioadsorption or by utilizing
mon resonance of spherical GNPs. The size and shape the interaction potential with the thiol bond that is
of GNPs are determined by the production method. highly stable. The conformation of these immobilized
Anisotropic shaped GNPs are the conventional shaped molecules on the GNP is an essential criterion for the
that formed in the presence of a polymer with stabiliz- downstream applications and to generate high-
ing properties which selectively binds to the single performance biosensors [13, 14, 34, 43, 44]. The activ-
crystal face and forms a single crystal direction grows ity of biomolecules with a proper orientation on the
quicker than others. nanoparticles especially at the interfaces is vital and
With GNPs are in a solution, the prevention of ag- plays a major role [43]. Once the GNPs have been
gregation takes place when charged molecules interact functionalized with the respective molecules, it will
on the GNP surface and bind to them to develop a dou- then flip from being neutral, positively or negatively
ble layer of charge. Among the main challenges faced charged surface to the intended charge. These GNPs
by the studies for the development of GNPs are the en- can also be functionalized to have terminal reactive
dosomal capping in an environment that is purely groups such as carboxyl or amine terminated surfaces
physiological. Unsuitable capping can results in the for further desired conjugation. To encapsulate the
declined functionality and targeting limitation of the GNP, suppliers conventionally utilize dielectric shells
nano-constructs. Suppliers usually cap GNPs with cit- such as silica and aluminum oxide which allows the
rate, tannic acid or poly(vinyl pyrrolidone) (PVP) tuning of optical properties or the incorporation of fluo-
agents. According to Untener et al. [42], after explor- rescent dyes. The unique properties of GNP have al-
ing the surface chemistries on GNPs, only tannic acid lowed it to be applied in a number of sensors including
illustrated the integrity retention of GNPs in a localized surface plasmon resonance, Surface En-
hanced Raman Spectroscopy (SERS), colorimetric sen-
keratinolytic cell when exposed to endocytosis. This is
sors and various imaging purposes [13,14,36]. The dy-
contributed by the strong protein based corona matrix
namic physical properties of GNP allow it to be incor-
that functions to protect the particles that it contains.
porated with various scientific functions and continue
Citrate will bind weakly to the surface on the GNP and
to be a topic of interest among biomedical scientists of
is the most commonly used solution as its capping
the day.
which is weakly bound, generate GNPs which are sta-
ble for a longer term and allows them to be readily at- 4. CONJUGATION OF POLYMERS WITH GOLD
tached to the molecules such as polymers, proteins, NANOPARTICLE
antibodies, thiols and amines [13,14]. In addition,
Gold is originally neutrally charged and when it is a
GNPs are affected differently in varying conditions.
particle (having surface charge) or during particle forma-
Salt solutions such as NaCl will cause the double layer
tion, it can be simply conjugated with polymers by elec-
of charge to collapse and result in its aggregation.
trostatic attraction [14]. The polymers that will be dis-
When reacted with proteins and other biomolecules cussed further in our study are polyethylene glycol
however, the GNP will stabilize. (PEG)-based polymer. PEG is a water soluble and non-
In reality, the prevention of nanoparticle aggrega- toxic neutral polymer, commonly used as surfactant in
tion can be extensively challenging. GNPs by its own industry and in the biomedicine field. It was proved that
are either stabilized sterically or charge stabilized [36]. PEG-modified nanoparticles are easily soluble in various
6 Current Medicinal Chemistry, 2018, Vol. 25, No. 00 Anniebell and Gopinath

organic solvents and water, and yields optimal condi- compressed which causes a steric repulsion towards
tions for specific binding. PEG-modified GNP can be protein molecules. Secondly, PEG functions as a bar-
prepared by electrostatic interaction or chemical modifi- rier, formed when PEG comes into contact with the
cation through thiol link. PEG has been used with GNP undesired protein. This interaction causes the formation
to improve its ability under in vitro and in vivo condi- of water like structure that causes repulsion towards the
tions. PEG conjugated GNPs are very stable in biologi- protein element. The reaction of the PEG towards these
cal media especially in avoiding the reticular endothelial undesired molecules which cause biofouling is highly
uptake [45]. Moreover, it was found that GNP is more determined by its molecular weight and the amount of
stable with a longer PEG chain and with smaller sized impurity that they contain. Studies for PEG have paved
nanoparticles [46]. PEG with high molecular weights the way for the further conjugation of other polymers
has also shown more stability compared with low mo- with GNP to enhance the development of biosensors to
lecular weight PEG [47]. Miyamoto et al. [48] have improve the quality of biomedical studies.
modified the GNP with the polymer, poly(ethylene
glycol)-block-poly(2-N,N-dimethylamino) ethyl metha-
crylate) and found that the GNPs show excellent disper-
sion and also avoid coagulation. PEG blocks copolymers
such as PEG-b-polyanions and PEG-b-polycations.
PEG-b-hydrophobic polymers have been shown in
previous studies to be extremely versatile materials [49-
51]. According to the previous study, PEG-b-polyamine
is effective in the modification of GNP surface for
targeted bio-analyte recognition. This is assisted by the
amino group lone pair that coordinates to the surface of
the GNP via an electrostatic attraction. The main reason
as to why polymers such as PEG are utilized allows for
Fig. (5). Display for polymer arrangements on sensing sur-
the decrement of biofouling in biorecognition especially
face. Polymer facilitates right immobilization of bio-
in biosensors. Therefore, the joint properties of GNP and
molecules.
polymers are believed to mediate non-fouling
biorecognition event and is to be studied further.
6. APPLICATION OF PEG CONJUGATED
5. ANTI-BIOFOULING MECHANISMS OF GOLD NANOPARTICLES
POLYMER CONJUGATED GOLD NANOPAR- 6.1. Analytical Sensing
TICLES
The application of polymer conjugated gold
Previous reports have proven that polymer is film/GNPs can be observed in a number of researches
densely packed, capable of highly resisting the published (Fig. 6a & b) [14,49,54,55]. These PEG-
phenomenon of biofouling. This is because of its conjugated gold surfaces were widely used to detect
densely tethered chain will reduce non-specific various biomolecules including protein, DNA, RNA,
adsorption of proteins or other biomolecules onto the peptide and also whole virus and cancer cells. There
surface of the gold that has been immobilized with the are two methods of conjugations which have been used
antibody for the detection of appropriate antigen (Fig. for the sensitive detection, the first being the direct
5). According to Wisniewski and Reichert (2000) [52], immobilization of the conjugated GNP on the sensor
biofouling is a phenomenon that occurs when biologi- surface with proper orientation to minimize the signal
cal components including cells and proteins assemble to noise ratio. The second method is to conjugate with
on the biosensing surface non-specifically. Among the the detection probe to improve the limit of detection.
many cross-linked polymers available in the market, PEG conjugated GNPs have been previously used in
PEG has been used highly for many fields of research. the study for the enhanced biorecognition of the factor
This is contributed to the fact that it can prevent bio- IX (FIX) in serum sample. In that study, PEG-b-PAAc
fouling due to its polymer chains that are highly resis- was assembled on the amine surface and used as an
tant to the adsorption of protein [53]. agent for blocking the non-specific binding of the pro-
This is assisted by two different anti-biofouling tein FIX. The positive charged PEG-b-PAAc bound to
mechanisms of PEG. The first mechanism that has the negatively charged amine surface, so it reduced the
been studied is when polymeric chains of PEG are signal to noise ratio. The interaction of analyte with
Polymer Conjugated Gold Nanoparticles in Biomedical Applications Current Medicinal Chemistry, 2018, Vol. 25, No. 00 7

ligand can accomplish the improvement in measuring GNP is generally used as a quenching material in
sensitivity up to 100 pM. It also proved that the conju- the Raman spectroscopy. GNP combined polymer is
gation of streptavidin-conjugated GNPs with N6-PEG more attractive in the field of SERS technology to en-
[pentaethylenehexamine-terminated poly(ethylene gly- hance the limit of detection. Simultaneous detection of
col)] is also enabled the prevention of biofouling effec- multiple genes was carried out on the polymer piller
tively and enhanced the sensitivity due to co- coated GNP by SERS technology and lowered the limit
immobilization of polymer and streptavidin on the of detection to 2 pM [27]. Zhang et al. [21] used im-
GNPs, which could achieve the limit of detection to printed polymer and GNP for the detection in milk
100 fM [14]. The same group has studied the utility of samples and results were demonstrated the limit of de-
dual polymers on gold film and enhanced the sensitiv- tection as 1.28 × 10−12 mg/mL. The above examples
ity using GNP in surface plasmon resonance (SPR) sys- have clearly proved the contribution of polymer conju-
tem. In their study, initially PEG-b-poly[2-(N,N- gated GNP in the field of analytical sensing. Similarly,
dimethylamino)ethyl methacrylate] (PEG-b-PAMA) PEG-coated gold nanorod monoclonal antibody conju-
was intended to be immobilized to the biomolecules in gates are also used for the quantitative analyses of
the proper orientation. Furthermore, with the applica- CD33 and HER2 in the cancer cell lines. It was evident
tion of N6-PEG, there was a complete reduction in bio- that gold nanorod conjugated PEG improved the effi-
fouling [50]. These conjugations were not only used in ciency in detecting tumor [56].
the detection of protein, however they are also used to
detect the cancer due to its high improvement in detec- 7. CONTROLLED ASSEMBLY AND DISASSEM-
tion. Wang et al. (2015) [13] found that the highly effi- BLY ON GOLD NANOPARTICLE
cient detection of breast cancer susceptibility gene GNP has a surface charge that induces a condition
(BRCA1) was possible with GNP coated PEG-polymer for repulsion against them. This leads to a dispersed
film whereby the limit of detection of down to 1.72 fM orientation and the solution is seen to be red in color.
was achieved. This dispersed orientation of the red colored solution
can be turned into an aggregated orientation in the
presence of salts such as NaCl. Ions in the salts can
neutralize the particles which will turn the solution into
purple due to aggregation. This strategy is commonly
in use to analyze the aptamer and target interaction [57]
and can be altered using polymers. In the GNP-based
colorimetric assay, purple colored solution with the
aggregated particle orientation can be observed in the
presence of NaCl. However, when the aptamer is im-
mobilized on the GNP, the same cannot be observed
due to the occupation of aptamer molecules on the
GNP. Conversely, in the abundance of the target, ap-
tamer will be released due to complex formation (ap-
tamer and target) and GNP will return to an aggregated
condition in the presence of NaCl. If polymers are con-
jugated on the GNP, they can occupy the surface of the
GNP as in the case of aptamer though not easily re-
moved (Fig. 6c). As shown in the Fig. (6c), the poly-
mer detachment on GNP was tested using NaCl. The
condition remained the same and GNP maintained it’s
dispersed state in red. Even at a higher concentration of
NaCl (1 M), conditions remained the same. When this
test was performed spectrophotometrically, it attested
Fig. (6). Anti-biofouling properties of polyethylene glycol to show no peak shift before and after treatment of
(PEG). a) Attachment of PEGylated GNP for aptamer detec- GNP with polymers in the presence of NaCl. Due to
tion; b) Application of PEG on gold surface. c) Wavelength the high absorbance of GNP around 520 nm, both con-
of GNP remains at 520 nm with the addition of PEG due to ditions showed peaks at the same wavelength (520
disability to aggregate. nm). This result delineates, with the proper optimiza-
8 Current Medicinal Chemistry, 2018, Vol. 25, No. 00 Anniebell and Gopinath

tion of polymers on the GNP; a wide range of assays hours. More importantly, in 10 minutes the 125 I-
can be designed for sensing purposes with higher non- labeled cRGD-PEG-GNP probe could target the tumor
fouling for high-performance analyses. site in vivo by SPECT/CT imaging. It is necessary to
have cRGD functionality which is vital for effective
8. IMAGING STUDIES and stable tumor-targeted imaging. Besides that,
Single-molecule imaging is possible with the mole- Transmission Electron Microscopy and radio Thin
cules conjugated with GNP [58]. Kim et al. [59] in his Layer Chromatography analyses showed that these
study have made evident the function of polymer nanoprobes can be excreted from the body after renal
coated GNP as a contrast agent in the imaging of vivo filtration. These results illustrate that image probing for
X-ray for the conventional computed tomography (CT) angiogenesis and tumor SPECT/CT can be conducted
imaging. A contrast agent is defined as the CT or X-ray successfully by radioactive iodine and RGD-PEG-
imaging enhancer which improves the internal anat- functionalized GNPs which will then be useful for the
omic structure visibility. Polymer-conjugated GNPs applications in therapy and diagnosis.
have said to be suitable for this purpose because it can According to Kawde and Wang (2004) [60], the us-
overcome the challenges brought by usual contrast age of polymeric beads with GNP tags have also shown
agents due to its low cytotoxicity. It prevents renal sys- to amplify the electrical transduction of DNA hybridi-
tem intoxication and vascular system perfusion. Also, zation. In their study, a novel strategy was developed to
after the imaging has been carried out, the renal func- amplify the electrical DNA detection on particles using
tions are cleared immediately. oligonucleotide that has been functionalized with car-
To allow for the longevity of GNP in the blood rier polymeric beads containing a large number of GNP
stream, the GNP is coated with a fine layer of PEG. tags. The preparation of the GNP tags was done by
This simultaneously eliminated the occurrence of GNP- binding streptavidin-coated polystyrene spheres to the
mediated biofouling in the system [14]. In the field of biotinylated metal nanoparticles. This amplification
biomedicine, the usage of conjugated GNP was tested platform based on a carrier sphere is combined with the
on rats with hepatoma as a contrast agent. When imag- enhancement of numerous gold tags catalytically and
ing was conducted, it was observed that a contrast with an ultrasensitive electrochemical stripping detection of
2 fold could be observed on the affected liver tissue in the GNP tags. The GNP-loaded beads and the eventual
contrast to the unaffected liver tissue. Therefore, the DNA linked assembly were analyzed by Scanning
amalgamation of PEG and GNP is seen to be effective Electron Microscopy and Transmission Electron Mi-
to improve CT imaging especially in hepatoma identi- croscopy. With the optimization of the performance
fication. affecting factors, the amplified electrical transduction
paves the way for the DNA detection targets down to a
Another function of polymer conjugated nanoparti- lower level and promises a prospect for the ultrasensi-
cles is to produce tumor-specific Single Photon Emis- tive detection of biorecognition.
sion Computed Tomography (SPECT)/CT imaging
probes with stability. SPECT scan combines two tech- The selective and sensitive detection of cysteine by
nologies to visualize the flow of blood into the tissues fluorescent conjugated polymer stabilized GNPs has
and organs. The two technologies that used are CT and also been studied [61]. According to the study, a one-
a radioactive material as a tracer. SPECT scan usually step preparation of fluorescent conjugated polymer sta-
uses radioactive isotope to facilitate its function by bilized GNPs were used to facilitate an innovative fluo-
labeled tracer. The common radioisotopes used are rescent detection. The fluorescence resonance energy
technetium-99m, iodine-123, thallium-201, xenon-133 transfer between the GNPs and fluorophore contribute
and fluorine-18. SPECT is able to visualize the blood to a weak fluorescence of the fluorescent conjugated
flow through the arteries or veins in the brain for pre- polymer stabilized GNPs. Cysteine is an amino acid
surgical analysis of seizures that are uncontrolled by which contains thiol and upon addition into the conju-
medicine. It was proved that 125 I-labeled cyclic Arg- gated GNP, the colloidal solution exhibits an increased
Gly-Asp-polyethylene glycol conjugated GNPs level of fluorescence. This proves that modulation of
(cRGD-PEG-GNP) probe can specifically target α vβ 3 energy transfer between GNP and fluorophore can be
integrin expressing tumor cells via integrin α vβ 3- conducted by cysteine. Following this, the sensitive
receptor-mediated endocytosis with no cytotoxicity. In detection of cysteine with a limit of 25 nM is permissi-
different pH and high concentration of salts, the conju- ble. 5 x 10-8 to 4 x 10-5 was found to be the linear range
gated probes showed an approximate stability for 20 for the determination of cysteine. Other amino acids
Polymer Conjugated Gold Nanoparticles in Biomedical Applications Current Medicinal Chemistry, 2018, Vol. 25, No. 00 9

contained in proteins do not interfere with the determi- usage of water soluble PEG enables the stabilization of
nation. Fluorescent conjugated polymers have a re- the GNP steric repulsion to constrain the aggregation of
markable protecting ability which allows the one-step colloids in physiological conditions. Exceptional pro-
synthesis and modification of GNPs with fluorophores. tein adsorption resistance is shown because of the PEG
This simplifies this particular method compared to molecules which are randomly coiled and its high de-
other conventional methods. It is also expected that gree of hydration. The PEG-conjugated GNPs dramati-
other analytes which are equally important biologically cally improved the delivery of the drug by being well
can also be detected by using the fluorescent conju- dispersed in solutions. Silicon phthalocyanine 4 (Pc 4)
gated polymer-stabilized GNPs. This concludes that when injected into in vivo PDT normally reaches the
conjugated GNPs are capable of enhancing imaging tumor site at a sufficient concentration in 1 or 2 days
systems in the detection or targeting the cells or other and is eventually prepared for therapy by 672 nm irra-
analytes by their unique characteristics. diation. However, when Pc 4 is conjugated with PEG-
conjugated GNPs; the maximum accumulation of drugs
9. DELIVERY SYSTEMS is decreased to less than 2 hours compared to the 2
According to a drug delivery study [62], in develop- days required by free Pc 4.
ing a suitable drug vector for the applications in pho- Another application of polymer conjugated GNPs is
todynamic therapy (PDT), PEGylated GNP conjugates as delivery vehicles for the battle against cancer cells
was synthesized. PDT is an adept method for treating [63,64] (Fig. 7a & b). In this research, the derivative of
various forms of cancer by utilizing light, tissue oxygen polyvalent oligonucleotide GNPs functionalized with
and photosensitizers. Some of these photosensitizing amine was produced by the reaction with a cisplatin
agents such as phthalocyanines and porphyrins contain prodrug. The resulting conjugation was then employed
hydrophobic properties and localize with the preference to internalize into various platinum centers. The suc-
in sites which are apolar including the bilayer lipid cell cess of cisplatin as an anticancer drug has been a step-
membranes. When intravenous injection is introduced ping stone for the evolution of cancer-fighting drugs in
and these agents amass at the target tissue, they will un- medicine. This drug has proved to manage a number of
dergo excitation with exposure to the light and will cancers including ovarian, testicular, head and neck,
transfer energy to the oxygen in the surrounding tissue. bladder, cervical, small cell lung and esophageal can-
This produces an oxygen species that is highly reactive cer. As with other agents of chemotherapy, the side
and encourages direct necrosis or apoptosis. Therefore, effects of cisplatin include irreversible peripheral nerve
there are certain conditions that PDT drugs need to damage, nausea, kidney toxicity and hearing impair-
fulfill such as the requirement to be lipophilic and able ments. To counter these issues, synthetic delivery sys-
to penetrate lipophilic membranes for the incorporation tems such as platinum-based treatment may be used.
into the relevant sites which might include Endoplasmic Polyvalent oligonucleotide GNP conjugates are a fa-
reticulum, Golgi apparatus and Mitochondria. This will vorable option for this purpose due to its high cellular
ensure that the oxidative damage at the initial stage will uptake, non-existent damaging toxicity to the conjugate
take place on the proteins that reside in the membranes and high resistance to enzymatic degradation. Research
of organelles. Secondly, there is a need for the PDT drug has amalgamated the properties of polyvalent oligonu-
to have the solubility in physiological conditions cleotide GNP and Platinum (IV) prodrugs to perform as
whereby the lack of solubility might contribute a prob- a delivery agent. The study utilized the GNPs function-
lem for in vivo intravenous PDT drug delivery. Without alized with thiolated 28 mer oligonucleotides with a
proper solubility, the photosensitizers might take ~24 terminal dodecyl amine for appropriate conjugation.
hours to reach the maximum accumulation in the sites of This combination has created to release a dose of cyto-
tumor which gives the side effects and cytotoxicity. toxic cisplatin when reduced intracellularly.
With this in mind, a delivery vector able to convene A good PT (IV) conjugate should be able to with-
hydrophilicity during the drug delivery is required stand decomposition as it travels through the
without extinguishing the hydrophobic properties of the bloodstream until it reaches the target tumor cell. Upon
chosen drug. Comparatively, PEGylated GNPs illus- reaching the cell, this delivery agent should contain a
trate prospects to be a functional and efficient delivery suitable reduction potential for it to be reduced and re-
platform for PDT drugs. Owing to their inertness, lease its cytotoxic payload. These are features shown
minimum toxicity and the ability to fine tune its size in by the polyvalent oligonucleotide GNP conjugates. The
a range of 2 to 100 nm with corresponding higher sur- PT (IV) complex, which by its own is inactive, known
face to volume ratio, they are deemed suitable. The to be activated when attached to the polyvalent oli-
10 Current Medicinal Chemistry, 2018, Vol. 25, No. 00 Anniebell and Gopinath

gonucleotide GNP. These conjugates are then taken by PEG chains also observed that cell lines have less can-
cells and undergo reduction to release the sufficient cer cell entry. By hyperspectral imaging, a reasonable
concentration of cisplatin. This takes place when 1,2-d confirmation was given for these quantitative results.
(GpG) intrastrand cross-links are formed with DNA An increased cellular uptake and a heightened adsorp-
upon the entry of the drug into the nucleus. The ability tion of non-specific protein were shown when PEG was
of GNP conjugates to retain certain properties as deliv- grafted at lower densities. The most favorable grafting
ery vectors and facilitate efficient drug delivery has identified was grafts with higher density with short
piqued the interests of scientists to further investigate lengths of PEG chains. This eventually managed to
their properties. lead the decreased adsorption of non-specific proteins
and increased the uptake of nanoparticles into the cells
compared to the other combinations of low-density
grafting and longer chains of PEG. Using PEG grafting
onto GNP have therefore been proved to enhance can-
cer therapy to make it more efficient.

11. CHALLENGES OF POLYMER CONJU-


GATED GNP
The application of GNPs in biomedicine is found to
be relatively costly and not suitable for increased us-
age. This may be a limitation factor that can be faced in
its implementation. Besides that, the inaccurate attach-
ment of polymers on GNP can also cause the reverse of
anti-biofouling and affect the initial functions of the
polymer conjugated GNP. Pre-existing studies also do
not exemplify the optimized conditions for the conju-
gation of polymers with GNPs which can be a chal-
lenge for the further utilization of GNP is the field of
biomedicine.
Fig. (7). a) Polyvalent oligonucleotide GNP conjugates as In the functions of cancer therapy, the disadvantage
delivery vehicles for selective targeting and cell destruction; of using high-density polymers coverage on GNPs is
b) PEGylated GNP enhances Computed Tomography (CT) reducing the uptake by cancer cells. This is a negative
imaging in hepatoma identification. side for applications that focus on nanoparticle local-
ization. However, when reduced polymer density is
10. CANCER STUDIES used, it may leads to the increased adsorption of non-
Cancer therapy applications in the field of medicine specific protein. When non-specific proteins are ad-
are mandatory and PEG conjugated nanoparticles have sorbed it can cause the entry of cancer cell or the mark-
also been utilized widely [65]. The surface modifica- ing of inorganic GNPs for clearance from the body.
tions of GNP with PEG have been highly encouraged The benefits of polymer conjugated GNP surpass the
for this purpose. The interaction of the surface of GNPs challenges that it poses. This stimulates further re-
with the environment can be reduced significantly by search to enhance their properties and overcome the
PEG in this functionalization when it undergoes high- challenges at hand.
density grafting. This minimizes its detection in the
11.1. Alternatives to Polymer Conjugated GNP
immune system of the living organism. In this study,
GNP with spherical diameter of 50 nm was studied as a Instead of conjugating polymers with GNP, we
model to analyze the effects of the PEG properties on may also attach other functional groups for biomedical
the reduction of non-specific adsorption of proteins by functions. We may conjugate peptides to the GNPs
GNPs and its subsequent uptake by MCF-7, MDA- with ligands or carrier molecules such as amyloid in-
MB-231 and HeLa cells. When the PEG was grafted hibitory peptide, octreotide peptide, sweet arrow pep-
onto the GNP at higher densities it was found to facili- tide, cell surface receptors and antibodies. The key fea-
tate less protein adsorption and decrease the uptake of ture is capable of cytoplasmic and nuclear transloca-
nanoparticles by the cell lines. The usage of longer tion, targeting carcinoma cells, adjuvant and analogue
Polymer Conjugated Gold Nanoparticles in Biomedical Applications Current Medicinal Chemistry, 2018, Vol. 25, No. 00 11

of somatostatin. This can be applied in imaging cancer novel bioactive nanomaterials. Overall, it is justified to
cells, pro-inflammatory cytokine elicitation and macro- note that the contribution of polymer conjugated GNPs
phage and cellular and intracellular targeting. Accord- is still an open book with endless horizons of applica-
ing to the prior study, there have been a number of tions in biomedicine that will improve the lifestyle and
modifications that have been done to a biosensor in the health quality.
effort to reduce biofouling. Among the methods are the
treatment of the sensor’s topological surface, systems CONSENT FOR PUBLICATION
which are based on flow, covalent binding of materials, Not applicable.
biological mimicry with a phospholipid base, overlay-
ing of hydrogels, Nafion, materials attained from natu- CONFLICT OF INTEREST
ral sources, surfactant based integrations and carbons
The authors declare no conflict of interest, financial
similar to diamond structures [24]. However, these
or otherwise.
researches do not conclude on a specific modification
which is useful for the alleviation of biofouling in bio- ACKNOWLEDGEMENTS
sensors. Therefore, it is necessary to explore newly fo-
cused approaches on polymer conjugated nanoparticles Declared none.
to mediate non-fouling performance of a biosensor.
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