drug delivery applications of gold...

BIOTECHNOLOGY, MOLECULAR BIOLOGY AND NANOMEDICINE VOL.1 NO.1 OCTOBER 2013

ISSN: 2330-9318 (Print) ISSN: 2330-9326 (Online) http://www.researchpub.org/journal/bmbn/bmbn.html

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Abstract—During the last decade, due to advances in

functionalization chemistry, novel nano-biomaterials with

applications in the therapy of various human diseases have

been developed. Nanotechnology might be crucial for drug

delivery and nanoparticles (NPs) are of high importance,

with many potential applications in clinical medicine and

research. These novel materials with their unique physical

and chemical properties are bioactive hierarchical

structures that hold great hopes as support for future

development of human diseases. NPs emerge as the future

of drug delivery technology as they might be future crucial

diagnostic and therapeutic tools. Of these, gold

nanoparticles with their unique chemical and physical

properties properties have emerge as promising carrier for

delivery of various molecules with therapeutic properties.

This paper illustrates the latest achievements in the

applications of gold nanoparticles as drug delivery tools for

the therapy of human diseases.

Keywords — Gold; Therapy; Drug delivery; Nanoparticles;

Target; Release

I. INTRODUCTION

here has been immense interest in targeted drug delivery as

it is one of the main drawbacks of pharmaceutics and

biotechnology.[1] In a few words, drug delivery is the

release of bioactive agents at specific rates and specific sites,

but the use of these new therapeutics is limited by toxicity

issues.[2] Biotechnology advances help discovering and

designing many new drug classes, as it is very important to

improve specific drug-delivery methods to turn them into

clinical realities. Most drugs are limited by their

pharmacodynamics properties as well as cytotoxicity and

aggregation due to poor solubility, nonspecific delivery, in vivo

short circulating half-lives.[3, 4] Drug delivery has also drew

attention to biopharmaceutical companies as these new delivery

nanomediated systems could represent a feasabile replacing

therapy for traditional drugs thus inhibiting competition from

generics.[5] These novel nanomediated drug delivery systems

can yield a more effective drug accumulation in tissues and

body fluids than classic ones, with minimal side effects,

increasing patient quality of life with high socio-economic

benefits.[3, 4, 6] Moreover, novel drug-delivery systems would

offer protection and would enhance the pharmacokinetics of

easily degradable peptides and proteins that often have short

half-lives in vivo.[7] Thus, today, drug research aims to

improve those techniques that could selectively deliver drugs to

the pathological sites.[8] Nanotechnology might be crucial for

drug delivery and nanoparticles (NPs) are of high importance,

with many potential applications in clinical medicine and

research. NPs emerge as the future of drug delivery technology

as they might be future crucial diagnostic and therapeutic tools.

Nanotechnology implies the design and use of materials, tools

and systems through the manipulation of matter on nanometric

scale that is atomic, molecular and supramolecular scales.

Nanotechnology applications in multiple fields and mostly are

becoming to be tested in clinical trials on humans.[9] Drug

delivery nanomediated systems are based on biocompatible

nanocarriers, such as gold nanoparticles, carbon nanotubes,

nanovesicles, micellar systems and dendrimers.[10, 11]

Additionally, one of the major benefits of nanotechnology is

the targeted drug delivery at the site of the disease by passive

targeting of drugs to the site of action or by selective active

targeting of the active pharmaceutic agent. Nanotechnology

also tries to find potential applications of nanoparticles for

efficient drug delivery. Of these, gold nanoparticles with their

unique chemical and physical properties properties have

emerge as promising carrier for delivery of various molecules

with therapeutic properties. This paper illustrates the latest

achievements in the applications of gold nanoparticles as drug

delivery tools for the therapy of human diseases.

Peptide delivery using GNPs

Various methods employing carriers for drug delivery have

been developed during the past one and a half decade in order to

ease the uptake of plasmids, peptides, short oligonucleotides

and proteins. The discovery of the Antennapedia home

domain[12] brought great enthusiasm regarding the ability of

short cationic peptides to translocate cell membrane without

disruption. These were called cell-penetrating peptides

(CPPs).[13] Various CPPs have been detailed since then,

including Tat, Sweet Arrow peptide, transportan and

polyarginines, together with their controversed method of

internalization.[14-16]

Drug Delivery Applications of Gold

Nanoparticles

Lucian Mocan, MD, PhD,

T



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Fig 1.Schematic illustration of potential applications of gold nanoparticles in Biology and Medicine

Briefly, CPPs use more mechanisms of endocytosis in order to

translocate across the plasma membrane. Vizualization of Tat

peptide-conjugated quantum dots in live cells revealed that

peptide-conjugated nanomaterials penetrate cells via

macropinocytosis. [13, 17] Data records show that the quantum

dot-loaded vesicles were actively carried by molecular vehicles

to an asymmetric perinuclear region.[18] Even if this study

employed quantum dots, the same mechanisms may occur

when using gold nanoparticles. Direct membrane translocation

of CPPs was also indicated when they appear in larger

concentrations and in association with endocytotic inhibitors.

CPPs may be employed in transfection as they only require

incubation, without any other physical disruption and

manipulation of the membrane.

CPP functionalized GNPs have been supplied, examining their

efficiency for delivery. CPPs are believed to enhance

intracellular uptake, but their subcellular location and efflux out

of endosomes is contradictory. Electron microscopy indicated

the presence of Tat peptide functionalized gold nanoparticles (3

nm) in the nucleus and cytoplasm.[19] On the other hand,

studies employing Tat, penetratin peptide (10 nm gold

nanoparticles) or amphipathic proline-rich peptide (12 nm gold

nanoparticles, SAP) functionalized gold nanoparticles

indicated that nanoparticles are trapped in endosomes.[19] The

inconsistency of these studies might be related to the type of

cell lines used, the cargo size[20, 21] the chemical content of

the cover layers, and can also be due to artifacts resulted from

the fixation imposed by electron microscopy.[22] Cell shape

and cell viability must also be strongly considered. Several

studies assert intracellular absorption and nuclear localization,

but visualize dead or dying cells. Therefore, these studies are

not notable, as membrane permeability clearly indicates cell

death.

Feldherr et al. successfully achieved nuclear localization using

the microinjection of gold nanoparticles (∼ 20 nm) covered

with nucleoplasmin (containing NLS), but observed no nuclear

import with the NLS sequence alone.[23] Tkachenko et al.

detected endosomal trapping, without nuclear localization,

using the same NLS sequence from the SV40 large T antigen

with 20 nm GNPs nurtured on HepG2 cells.[24] Using

video-enhanced color differential interference contrast

(VEC-DIC) microscopy, the authors could visualize nuclear

delivery of gold nanoparticles with an adenoviral fiber protein

exhibiting receptor-mediated endocytosis (RME) and nuclear

localization sequences (NLS). The single cell showing

evidence of successful delivery does not seem very healthy and

it might be involved in a death program. This stresses one more

time the importance of assessing cell shape and cell viability in

such experiments, in order to prevent the appearance of

artifacts. Altogether, except several studies observing nuclear

localization in dead cells, NLS could not achieve nuclear

localization under any conditions, proving that endosomal

escape is mandatory for a successful intracellular delivery.[25]

Transferrin-receptor mediated drug delivery

Vectors enabling gold nanoparticle delivery also include

proteins. Transferrin-receptor interactions have represented

potential drug and gene uptake pathways.[26-28] Transferrin is

of major importance in iron transport for the synthesis of

hemoglobin. It was successfully used for a better internalization

of gold nanoparticles, 20 nm in size, covered with transferrin

(96 nm hydrodynamic radius) as imaged by atomic force

microscopy (AFM). The absorption of 25 nm

transferrin-coupled gold nanoparticles was also assessed by

laser scanning confocal microscopy. AFM indicated receptor

mediated endocytosis and confocal microscopy observed a

spotty fluorescent signal, suggesting endosomal localization. In

a third study employing differently sized and shaped particles,

TEM and fluorescence imaging also exhibited endosomal

localization.[29]

Nowadays, various functional molecular linkers and

passivating agents are used in functionalized gold nanoparticles

employed in biomedical applications. Nevertheless, the main

groups used for molecule-gold conjugation usually include:

thiolate [30, 31], [21, 29, 32] dithiocarbamate amine[33],

carboxylate, isothiocyanate or phosphine [34-37] moieties.

Recent studies show that direct gold–C binding may be

provided by trimethyltin leaving group. Still, there is need for

further tests in order to use it in biomedical or

nanoparticle-based applications. Chosing a particular

molecular anchor depends on the desired molecule adaptability

to a specific application, with trends in bonding strength

usually following hard–soft acid–base (HSAB) theory

developed by Pearson for soft gold surfaces. Non-adaptable

applications most often involve thiol-based anchoring groups

while adaptable applications employ amine or carboxylate

surface anchors. Burda et al. demonstrated the importance of

using more adaptable amino linkers than stronger thiol groups

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215206/#CIT0077



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for the therapeutic results obtained after gold

nanoparticle-mediated delivery of photodynamic therapy

agents.

GNP as anti-infective agents

In addition to antitumor substances, antibiotics and other

antibacterial agents are also used for GNP delivery. [26-28] Gu

et al. [38] prepared stable water soluble vancomycin

(Van)-covered gold nanoparticles as polyvalent inhibitors and

demonstrated their effectiveness towards various

enteropathogenic strains (including vancomycin-resistant ones),

such as vancomycin-resistant strains (VRE) and

Gram-negative bacteria. In this experiment, gold nanoparticles

(4-5 nm, obtained in toluene) were functionalized with

bis(vancomycin) cystamide (in H2O), under dynamic stirring

for 12 hours, to generate Gold-S bonds that link Van to gold. A

small excess of gold nanoparticles was employed to secure

complete consumption of all Van molecules. When the reaction

was completed, Gold-Van nanoparticles were dissolved in the

aqueous solution and then removed from the organic phase.

Rosemary et al.[39] obtained similar results using a complex

made of ciprofloxacin and gold nanoshells with high

antibacterial activity against E. coli. Drug delivery research

regarding Ciprofloxacin@SiO2 (cip@SiO2) was conducted

employing E. coli DH5R and L. lactis MG 1363 using the agar

dilution method, results being compared to those of free

ciprofloxacin. Hydrophobicity studies on cip@SiO2 presented

a different penetration pathway compared to the free drug.

FITC@SiO2 helped perform nanoshell/bacteria interaction

studies. The fluorescence image indicated shell internalization

into the microorganism. Studies regarding transmission

electron microscopy were carried out on cip@SiO2-treated E.

Coli and showed that bacterial morphology is unharmed by

nanoshell therapy, even if the shells were not observed.

In a study conducted by Selvaraj and Alagar,[40] a colloidal

gold conjugate of the antileukemic drug 5-fluorouracil

exhibited observable antibacterial and antifungal activities

against Staphylococcus aureus, Micrococcus luteus,

Pseudomonas aeruginosa, E. coli, Aspergillus fumigatus and A.

niger. The 5FU-colloidal gold complex, obtained by means of

the imino (–NH) group, was assessed using different analytical

techniques (UV–vis spectroscopy, FT-IR, cyclic voltammetry,

transmission electron microscopy, fluorescence). The type of

interaction was determined using fluorescence and

electrochemical studies. The results indicated that the

association between anticancer drugs and gold nanoparticles

determines a much powerful reaction against Gram-negative

bacterial infections. The mechanisms involved in this improved

ativity are still not clear.

In the experiment carried out by Burygin et al.[41] free

gentamicin and its combination with GNPs proved not to differ

in their antimicrobial activity in assays on solid and liquid

nutrient media. They examined the influence of gold NPs

(16-nm in size) on the antibacterial activity exhibited by

gentamicin. No differences appeared within experimental error

limits between the antibacterial activity of gentamicin and that

of a gentamicin–gold NP mixture in different gentamicin and

particle concentrations. GNPs sedimented from the conjugates

exhibited no antibacterial activity, but the supernatant liquids

from gentamicin–NP complexes and free gentamicin displayed

the same activity. Electron microscopy and extinction spectra

changes demonstrated the presence of NP aggregates that were

unable to enter the gel. This explains the absence of growth

inhibition following addition of NP sediment. Moreover, the

same degree of activity of free gentamicin and the mixture

indicates the small amount of antibiotic that could bind to the

particles. The CFU method indicated that the bacteria-killing

action of a gentamicin–NP complex is not different from that of

free gentamicin within error limits. The parameters inhibiting

bacterial growth in liquid bacterial culture (MIC and MTC)

were also similar for gentamicin and for the gentamicin–NP

mixture. There were no significant differences between the free

antibiotic and the mixture in terms of antibacterial activity, on

neither solid nor liquid nutrient medium, in any of the studies.

The increased antibacterial activity due to the presence of NPs

indicates that there must be at least two conditions (still not

enough) to detect such effects. Firstly, antibiotic–NP

complexes need to be stabilized and their spectrum and color

should correlate with those of single-particle nonaggregated

colloids. Secondly, the amount of antibiotic capping the

particle surface should be large enough to guarantee an increase

in local antibiotic concentration at the site of bacterium–

particle contact. Therefore, even though gold NPs alone do not

employ any antimicrobial activity, they may behave as drug

curriers. In conclusion, GNPs increase the surface area and

carry large amounts of drug on it.

Rai et al.[42] particularly suggested the direct use of cefaclor

antibiotic in the synthesis of GNPs. They have defined a simple

way to synthesise 52 to 22 nm spherical gold nanoparticles

using cefaclor (a second-generation cephalosporin antibiotic) at

different temperatures. Additionally, they acquired robust

antimicrobial coatings on glass slides that maintain their

antimicrobial activity even under unfavorable conditions. The

rate of gold ion reduction in solution was essential in

determining synthesized gold nanoparticle size. The authors

demonstrated that the amino group on cefaclor behaves as both

reducing and coating agent and thus, the antibacterial activity

of cefaclor is retained because of the presence of free blactam

rings available on nanoparticle surface. Moreover, cefaclor

reduced GNPs proved to have effective antimicrobial activity

on both Gram-positive (S. aureus) and Gram-negative (E. coli)

bacteria, compared to cefaclor and gold nanoparticles alone.

Cefaclor inhibited peptidoglycan synthesis resulting in porous

cell walls. As a result, gold nanoparticles produced holes in the

cell wall, followed by leakage of cell contents and cell death.

The authors demonstrated that gold nanoparticles attach to

bacterial DNA and inhibit DNA uncoiling and transcription,

thus supporting bacterial death.

The high antioxidant activity of GNPs conjugated with

salvianic acid A was demonstrated by Du et al. who proposed

potential applications using this complex. The synthesis of a

novel salvianic acid A-coated gold nanoparticle (Au@PEG3SA)

was achieved using a layer-by-layer self-assembly method. The

DPPH radical-scavenging assay showed that the constant value

for DPPH radical - Au@PEG3SA reaction was about nine



4

times higher than with salvianic acid A monomer. The authors

also showed that the mechanism for the kinetic enhancement of

Au@PEG3SA resulted from the transition state variation in

DPPH radical-scavenging reaction and possibly, from the pi–pi

stacking interactions among adjacent phenolic groups located

on the surface of GNPs. Another major discovery was the

dramatic increase in the kinetics for the ROS scavenging

process in living cells, as well as in vivo, enhancing cellular

antioxidant status.[43]

Data provided by Bowman et al. showed that GNP complexes

involving[44] TAK-779 display a more pronounced activity

against HIV than the native preparation at the cost of the high

local concentration. The synthesis of SDC-1721, a potent HIV

inhibitor TAK-779 fragment, was accompanied by its

conjugation to gold nanoparticles of 2.0 nm in diameter.

Phytohemagglutinin (PHA)-stimulated peripheral blood

mono-nuclear cells (PBMCs) were infected with the

CCR5-tropic HIV-1 clone JR-CSF, in the presence or absence

of test compounds, in order to assess the antiviral activity of

nanoparticle conjugates. On the 7th day after infection,

supernatants were collected and HIV-1 capsid p24 antigen was

assessed using ELISA test. TAK-779 proved to inhibit the

replication of HIV-1 with an IC50 of 10 nM. The IC50 for

TAK-779 against four different CCR5-tropic viral isolates

varied between 1.6 and 3.7 nM. Nevertheless, JR-CSF was not

one of the analyzed viruses. With a similar virus, JR-FL,

TAK-779 indicated a 20 nM IC50. Responsiveness to CCR5

penetration inhibitors is influenced by receptor expression

levels and HIV-1 envelope/receptor affinity, mediated by both

cellular and viral determinants. Thus, JR-CSF appears to be

naturally less sensitive to TAK-779.

GNPS as drug delivery platform for the therapy of

metabolic diseases

Joshi et al. noted hormone[45] insulin functionalized gold

nanoparticles and their application in transmucosal delivery for

diabetes mellitus treatment. Insulin was load onto bare gold

nanoparticles and aspartic acid-coated gold nanoparticles and

administered in diabetic Wistar rats by means of both oral and

intranasal (transmucosal) administration. Much lower blood

glucose levels (postprandial hyperglycemia) were noticed when

insulin was delivered using gold nanoparticle carriers by

transmucosal administration. Moreover, the management of the

intranasal delivery protocol for postprandial hyperglycemia

was similar to that obtained by the conventional subcutaneous

administration used for type I diabetes mellitus.

Chamberland et al.[46] noted the therapeutic effect of

etanercept, an antirheumatic drug, conjugated to gold nanorods.

The authors have estimated the potential of a developing hybrid

imaging technology for use in noninvasive monitoring of

anti-TNF drug delivery (photoacoustic tomography). After

preparing the contrast agent made of etanercept-conjugated

gold nanorods, ELISA tests were performed in order to validate

the conjugation and to indicate that the conjugated anti-TNF-α

drug was biologically active. PAT of ex vivo rat tail joints with

the joint connective tissue increased by intra-articularly

injected contrast agent was carried out to analyze PAT

performance in visualizing the distribution of the

gold-nanorod-conjugated drug in articular tissues. This system

helped visualize gold nanorods of <1 pM concentration in

phantoms or 10 pM concentration in biological tissues, with

good signal-to-noise ratio and high spatial resolution,

indicating the feasibility of binding TNF antagonist

pharmaceutical compounds to gold nanorods, the preservation

of the tumor necrosis factor antagonist mechanism of action

together with the preliminary assessment of the new PAT

technology for the detection of optical contrast agents

conjugated with antirheumatic drugs.

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