Nanoparticles as platforms of molecular delivery in diagnosis and therapy

Abstract

Introduction Nanoparticles are polymeric colloidal systems ranging from 10 to 1000 nm, which are able to deliver compounds to the cells. Their size, shape and surface determine the activity of the molecules incorporated. Two main groups of nanoparticles are applied as drug delivery systems: the polymeric nanoparticles, such as liposomes, dendrimers and micelles, and the inorganic particles, including gold, iron oxide, silica and graphene. The aim of this review is to discuss nanoparticles as platforms of molecular delivery in diagnosis and therapy.

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Page 1 of 6
Compeng interests: none declared. Conict of interests: none declared.
All authors contributed to the concepon, design, and preparaon of the manuscript, as well as read and approved the nal manuscript.
All authors abide by the Associaon for Medical Ethics (AME) ethical rules of disclosure.
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: Cordon CS, Piva MBR, Melo CM, Pinhal MAS, Suarez ER. Nanoparticles as platforms of molecular
delivery in diagnosis and therapy. OA Cancer 2013 Dec 01;1(2):15.
* Corresponding author
Email: eloahrabello@yahoo.com.br
1
Department of Biochemistry, Faculdade de
Medicina do ABC, Santo André, SP, Brazil
2 Department of Biochemistry, Universidade
Federal de São Paulo, São Paulo, SP, Brazil
Review
Novel Therapies
Nanoparticles as platforms of molecular delivery
in diagnosis and therapy
CS Cordon1, MBR Piva2, CM Melo2, MAS Pinhal1,2, ER Suarez1,2*
Abstract
Introduction
Nanoparticles are polymeric colloidal
systems ranging from 10 to 1000 nm,
which are able to deliver compounds
to the cells. Their size, shape and
surface determine the activity of the
molecules incorporated. Two main
groups of nanoparticles are applied as
drug delivery systems: the polymeric
nanoparticles, such as liposomes,
dendrimers and micelles, and the
inorganic particles, including gold,
iron oxide, silica and graphene.
The aim of this review is to discuss
nanoparticles as platforms of molecular
delivery in diagnosis and therapy.
Discussion
Dendrimers and liposomes incor-
porate hydrophobic and hydrophilic
agents, but present low biodegra-
dation and leaking of the agents,
respectively. Micelles are suitable for
hydrophobic molecules, but may use
toxic materials. Superparamagnetic
     
magnetic resonance and easily bio-
degradable; however, at high doses
this particle promotes intense oxi-
dative stress. Gold particles are very
useful as sensor particles, but they
are immunogenic. Silica particles are
easy to synthesise and functionalise;
however, very less information about
their biodegradation is available. The
graphene structures, such as carbon
nanotubes, have many interesting
properties; however, they are very
toxic and accumulative.
Conclusion
Nanoparticles are very promising as
new diagnosis and pharmacotherapy
tools. However, the disadvantages
associated with them must be over-


Introduction
Nanoparticles are polymeric colloidal
systems ranging from 10 to 1000 nm,
which are able to deliver compounds
to the cells1. They can be used alone
or associated to several molecules
for the treatment and diagnosis of
cancer, autoimmune and congenital
diseases. For example, showing
      
drugs and, mainly, minimising the
adverse events. The nanoparticles
     
nanocapsules and nanospheres.
The nanocapsules have a polymeric
membrane and a cavity where the
therapeutic agent can be incorporated,
while nanospheres have a polymeric
matrix where the therapeutic agent
can be adsorbed or dispersed2.
The size, shape and surface of the
nanoparticles are important factors
to determine the pharmacological
activity of the therapeutic agents
incorporated. Particles less than
5–10 nm in size are quickly removed
from circulation and eliminated by
the kidney, while particles sized
15 µm or more tend to accumulate in
organs, such as liver, spleen and bone
marrow. Micelles, as an exception,
have a reduced size and a half-life of
5 days, due to their ability to escape
 3. The biodistribu-
tion and uptake of nanoparticles by
    
by the type of cell4. In addition, cells
capture particles less than 20 nm by
pinocytosis and less than 100 nm by
phagocytosis. The immune response
is affected by the capture mechanism
   
to the target tissue5. Particles ranging
from 10 to 200 nm have shown better
      
distribution systems6.
Discussion
Two main groups of nanoparticles,
the polymeric and inorganic particles,
are applied as drug delivery systems
(DDS). Polymeric nanoparticles include
liposomes, dendrimers and micelles.
Inorganic nanoparticles include gold,
iron oxide, silica and grapheme7. These
systems will be described below.
Delivery systems
Micelles
Micelles are colloidal dispersions of
5–100 nm formed by amphipathic
molecules that present a hydrophilic
exterior and a hydrophobic interior
(Figure 1)8. The hydrophobic nucleus
allows storage of a large dose of hydro-
phobic compounds, which would
require toxic amounts of organic
solvents/surfactants to be diluted9.
Micelles preferentially accumulate
in tumours because of the leaky vas-
culature of these tissues and poor
drainage; this is called the enhanced
permeability and retention effect9. It
helps to concentrate the therapeutic
substance in the target tissue. Another


molecules to the micelles surface9.
Lipid nanoparticles are synthe-
   
technique consists of prior fusion
of the lipid, incorporating the active
principle by dissolution or disper-
sion. Then, the lipid phase is emulsi-
   
a surfactant. The emulsion prepared

Page 2 of 6
Review
Compeng interests: none declared. Conict of interests: none declared.
All authors contributed to the concepon, design, and preparaon of the manuscript, as well as read and approved the nal manuscript.
All authors abide by the Associaon for Medical Ethics (AME) ethical rules of disclosure.
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: Cordon CS, Piva MBR, Melo CM, Pinhal MAS, Suarez ER. Nanoparticles as platforms of molecular
delivery in diagnosis and therapy. OA Cancer 2013 Dec 01;1(2):15.
is maintained at room temperature
10.
Liposomes
Liposomes are vesicles constituted
by a concentric phospholipid bilayer
(Figure 2), which involves an aqueous
central compartment of 50–100 nm11.
Due to its larger size, when com-
pared to most particles, liposomes
can carry larger amounts of drugs8.
The organisation of this system is
based on the presence of water, since
the orientation of the bilayer may
be determined by the nature of the
polar groups and carbonic chains.
The amphipathic nature of liposomes
allows transportation of hydrophobic
compounds bounded to the carbonic
chains of their phospholipids and
also of hydrophilic molecules in the
interior aqueous cavity. The mainte-
nance of the drug inside the liposome
is dependent on the concentration,
chemical nature, electric charge of
the phospholipid, ionic strength of
the media and the size of the drug12.
Liposomes are non-toxic and bio-
degradable, have high circulation
time and have the possibility of high-
scale production. However, like other
DDS, liposomes have the disadvantage
of leaking the encapsulated agent4.
Some liposome systems recog-
nise some characteristics of tumour
microenvironment, such as hypoxia
and low pH, releasing the therapeutic
agent only inside the tumour4. Some
structures are formulated to suffer
an acid-catalysed hydrolysis of the
vinyl ether group with polyethyl-
ene glycol (PEG) removal leading to
liposome destabilisation and drug
release13. Liposomes are also widely
used in cosmetic formulations due to
their structural similarity with cell
membranes, which allows an easy
interaction with the skin11.
Dendrimers
Dendrimers are macromolecules
(1–12 nm) with high molecular
-

by monomeric or oligomeric units
of polyamidoamine (PAMAM), poly-
propylenimine (PPI) or poly--lysine
(PLL), for example. These particles
are formed by a central nucleus sur-
rounded by several concentric layers,
called generations, where therapeutic
or diagnostic substances can be
stored5,11,14.
   
    
other molecules to connect to its
structure14. Dendrimers can be desig-
ned to have a hydrophilic surface and
still carry hydrophobic molecules in
their hydrophobic nuclei11.
Figure 1: Micelle nanoparticle.
Figure 2: Liposome drug delivery system.

Page 3 of 6
Review
Compeng interests: none declared. Conict of interests: none declared.
All authors contributed to the concepon, design, and preparaon of the manuscript, as well as read and approved the nal manuscript.
All authors abide by the Associaon for Medical Ethics (AME) ethical rules of disclosure.
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: Cordon CS, Piva MBR, Melo CM, Pinhal MAS, Suarez ER. Nanoparticles as platforms of molecular
delivery in diagnosis and therapy. OA Cancer 2013 Dec 01;1(2):15.
There are three key factors for
-
erations, composition and charge of
the surface14. For example, cationic
dendrimers are more toxic than
anionic or neutral dendrimers because
they can induce apoptosis through
pore formation on cell and organelle
membranes, including the mitochon-
dria15,16.
  -
tion also affects their distribution,
since dendrimers lacking hydrophilic
groups concentrate on the liver,
while negative or neutral dendrimers
stay longer in the circulation11.
Dendrimers are an excellent DDS
because of their mouldable structure
that enables control of size and rami-

At the beginning, the approach to

designs, the PPI and PAMAM, used
the divergent strategy (from core to

group is deprotected to create a new
reactive surface functionality and
then coupling with a new monomer.
This process should be repeated sev-
eral times depending on the number
of generations desired. In contrast,
the convergent method constructs
a dendrimer from the surface to the
centre17.
Superparamagnetic iron oxides
Iron oxide nanoparticles are formed
by a crystalline core of iron oxide
(iron oxide I, II or III) and a coating
layer (Figure 4A)5. The size of these
particles varies from 3 to 100 nm
and these particles can be synthe-
sised either by sonochemical reac-
tion of iron pentacarbonyl that uses
sound/ultrasound radiation or by
thermal treatment and oxidation11.
Superparamagnetic iron oxides
(SPIONs) present two important
advantages: magnetic property and
easy biodegradation, since they are
incorporated into the iron metabo-
lism pathway5.
Starch, PEG, silica and dextran are
commonly used as the outer layer.
It is important to point out that
dextran, compared with other materi-
als, presents higher biocompatibility
and lower molecular weight, and can
remain in the circulation without
triggering immune responses or
impairing liver function for long peri-
ods of time. However, dextran can suf-
fer opsonisation by plasma proteins.
The addition of polyethylene glycol
in the coating layer decreases the
opsonisation process and coating with
silica seems to have low toxicity5,11,18.
Nowadays, SPIONs have already
been approved as a contrast agent
for magnetic resonance diagnosis
and cancer treatment11. In addition,
a study has already been developed
in mice using SPION aerosol to
deliver drugs to the lungs with a
target-direct magnetic gradient19.
Mesoporous silica nanoparticles
Mesoporous silica nanoparticles
     
with pores that form channels of
nanometric dimensions (2–50 nm)20.
Such channels can store therapeutic
or diagnostic substances (Figure 5).
MSNs are synthesised using a
process called supramolecular self-
assembly, which consists of hydro-
lysis and condensation of a silica
precursor in the presence of surfac-
tant micelle templates, followed by
removal of the surfactant templates
to recover mesoporous silica parti-
cles. The production method of silica
nanoparticles provides different
size, morphology, pore size, number
of pores, crystallinity and surface
topography of the particles, which
can cause a large range of bio-

Figure 3: Structure of dendrimer.
Figure 4: Iron oxide and gold nanoparticles.

Page 4 of 6
Review
Compeng interests: none declared. Conict of interests: none declared.
All authors contributed to the concepon, design, and preparaon of the manuscript, as well as read and approved the nal manuscript.
All authors abide by the Associaon for Medical Ethics (AME) ethical rules of disclosure.
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: Cordon CS, Piva MBR, Melo CM, Pinhal MAS, Suarez ER. Nanoparticles as platforms of molecular
delivery in diagnosis and therapy. OA Cancer 2013 Dec 01;1(2):15.
This array of features can be achieved
by changing the parameters of
synthesis, such as silica precursor
or co-surfactants, size of the surfac-
tant template or concentration of
surfactants21.
Silica nanoparticles are absorbed
by endocytosis usually facilitated
by clathrin protein, which forms a
polymeric net around the endocytosis
vesicle21. It has been shown that
adding polyethyleneimine (positively
charged) to MSN reduces toxicity and
increases absorption and the speed
to reach the site of action5. Moreover,
    -
gated with SPIONs that generate a
magnetic nucleus to orientate the
particle to the site of action or for
image diagnosis22.
Silica nanoparticles seem very
promising due to easy synthesis,
capacity of storage and controlled
release of large amounts of substances
     
is a lack of information about their
bioelimination, kinetics and toxicity.
Thus, many studies are still required
to make safe use of these particles21.
Gold nanoparticles
Gold nanoparticles are solid particles
of size 50 nm or less (Figure 4B). This
type of nanomaterial can be func-
tionalised with DNA, RNA and anti-
bodies. Gold nanoparticles can be
synthesised by reduction with citrate
in water. Additionally, gold nanoparti-
cles present unique optical-electronic
property: electromagnetic frequency
induces a resonant coherent oscil-
lation of free electrons, called sur-
face plasmon resonance. Thus, gold
nanoparticles can absorb radiation
and emit a rich red light5,11,14,23.
This type of nanomaterial has been
researched for many applications
such as organic photovoltaic that
converts electromagnetic energy
into electric energy; sensory probes;
therapeutic agents; drug delivery in
biological and medical applications
as autoimmune diseases, allergy and
cancer; electronic conductors and
catalysis.
A study in humans has already
been performed using gold nanopar-
ticles to diagnose lung cancer. A gold

healthy individuals from patients
with lung cancer by their breath. The
sensor detects organic volatile sub-
stances which are elevated in lung
cancer patients24.
Graphene
Graphene is composed of a carbon
sheet. Carbon atoms are attached
with each other by an sp2 bond, form-
ing a hexagonal structure (Figure 6).
This material presents a high mechan-
ical strength, absorbs in the infrared
region and conducts electricity and
heat5,25.
     -
liated mechanically from graphite.
Later, the graphitisation of hexagonal
silicon carbide crystals during anneal-
ing at vacuum and high temperatures
was reported. Under such annealing
conditions, the top layers of silicon
carbide crystals undergo thermal
decomposition; the carbon atoms
remain on the surface and form gra-
phene layers. Many different methods
of synthesis are being researched.
Nowadays, the most common tech-
niques of synthesis are as follows:
– arc discharge—electrons with high
pressure, produced by arc discharge,
collide on the surface of graphite25
– laser ablation—laser beam hits on
the graphite, and this reaction uses
a transition metal as catalyst and
chemical vapour deposition25.
Polyethylene glycol can be associ-
ated with graphene oxide to decrease
toxicity and to allow targeting of
ligands5,25.
Carbon nanotubes
Carbon nanotube is the graphene in
a cylindrical form. This type of nano-
material presents a unidimensional
cavity of size 50–200 nm; it can be
formed by a single wall or multiple
walls (Figure 7)5,14.
Since 2004, carbon nanotubes
have been studied with the aim to
transport chemotherapeutic agents
into cancer cells. In addition, carbon
nanotubes can be applied to the
photothermal ablation of tumours.
Both these uses seem to be effective
in the treatment of cancer5,26.
Until now, there is little information
about the toxicity of carbon nano-
tubes, because of which it cannot be
used in vivo. Dermal reactions, altera-
tion of immune system and increase
in oxidative stress have already been
Figure 5: Silica particle.

Page 5 of 6
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Compeng interests: none declared. Conict of interests: none declared.
All authors contributed to the concepon, design, and preparaon of the manuscript, as well as read and approved the nal manuscript.
All authors abide by the Associaon for Medical Ethics (AME) ethical rules of disclosure.
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: Cordon CS, Piva MBR, Melo CM, Pinhal MAS, Suarez ER. Nanoparticles as platforms of molecular
delivery in diagnosis and therapy. OA Cancer 2013 Dec 01;1(2):15.
reported during studies with carbon
nanotubes. Also, graphene seems to
be toxic to the lung26.

elimination of nanoparticles
The shape of nanoparticles is impor-
     -
cacy. Spherical particles have better
  
tend to migrate laterally in the cir-
culation (margination), decreasing
extravasation to tissue. However,
elongated particles are able to over-
come phagocytosis27.
Biodegradation and excretion are
important factors to determine the

adverse effects. A good biodistribu-
tion and half-life time are impor-
   
therapeutic agent carried out by the
particle4. PEG has been applied at
the surface of some nanoparticles in
order to increase the circulation time,
decreasing toxicity3. Nevertheless,
unnatural PEG is not biodegradable
and may suffer decomposition by
oxidation. Some adverse effects, such
as vacuolisation of the renal epithelia,
are common after chronic treatment
with PEGylated particles28. In order
to overcome PEG issues, a peptide
constituted by proline, alanine and
serine was developed showing low
cost of production, water absorption

accumulation, maintenance of bioacti-
vity of the compound and biodegrad-
ability presenting low toxic effects29.


-
cial to a good performance. The most
     
antibodies and peptides developed
against cell targets, but some poly-
mers can also be used27. Some mole-
cules may also be applied to evade the
5.
Conclusion
Nanoparticles present a very prom-
ising perspective to improve the diag-
-
    
the nanoparticle carries the thera-
peutic agent dissolved, encapsulated,
adsorbed or dispersed with the aim to
protect the drug, and increase its sol-
ubility or improve its biodistribution
-
imising adverse effects. Some systems
such as dendrimers and liposomes are
very versatile, allowing incorpora-
tion of hydrophobic and hydrophilic
-
vantages of low biodegradation and
leaking of the agents, respectively.
Micelles are suitable for hydro-
phobic molecules, but may use toxic
materials in their compositions. SPI-
     
resonance and easily biodegradable;
however, at high doses they pro-
mote intense oxidative stress. Gold
particles are very useful as sensors,
but they are immunogenic. Silica
particles are easy to synthesise and
functionalise; however, very less in-
formation about their biodegradation
is available. The graphene structures,
such as carbon nanotubes, are inter-
esting strategies due to the photo-
thermal, mechanical, electrical and
optical properties; however, they are
very toxic and accumulative. The exo-
cytosis of undissolved particles and
time-consuming synthesis are also
limitations of some nanoparticles.
The disadvantages of these nanopar-
ticles must be overcome in order to
    
systems. However, the importance of
nanoparticles has been growing now-
adays, presenting a very promising
perspective to improve the diagnosis

Abbreviations list
DDS, drug delivery systems; MSN,
mesoporous silica nanoparticle;
PAMAM, polyamidoamine; PEG, poly-
ethylene glycol; PLL, poly--lysine;
PPI, polypropylenimine; SPION,
superparamagnetic iron oxide.
References
      
     
potential oral delivery systems of proteins
Figure 6: Graphene structure.
Figure 7: Carbon nanotube.

Page 6 of 6
Review
Compeng interests: none declared. Conict of interests: none declared.
All authors contributed to the concepon, design, and preparaon of the manuscript, as well as read and approved the nal manuscript.
All authors abide by the Associaon for Medical Ethics (AME) ethical rules of disclosure.
Licensee OA Publishing London 2013. Creative Commons Attribution License (CC-BY)
For citation purposes: Cordon CS, Piva MBR, Melo CM, Pinhal MAS, Suarez ER. Nanoparticles as platforms of molecular
delivery in diagnosis and therapy. OA Cancer 2013 Dec 01;1(2):15.
and vaccines: a mechanistic approach. J
Control Release. 2006 Nov;116(1):1–27.
     
A pilot study of freeze drying of poly
(epsilon-caprolactone) nanocapsules
stabilized by poly(vinyl alcohol): for-
mulation and process optimization. Int
J Pharm. 2006 Feb 17;309(1–2):178–88.
     
Desimone JM. PRINT: a novel platform
 -
ticle theranostics. Acc Chem Res. 2011
Oct 18;44(10):990–8.
     
   
for drug delivery. ACS nano. 2010 Sep
28;4(9):4967–70.

-
ogy of engineered nanomaterials: focus
on biocompatibility, biodistribution and
biodegradation. Biochimica et Biophysi-
ca Acta. 2011 Mar;1810(3):361–73.
   
drug delivery. Nat Nanotech. 2008
Mar;3(3):131–2.
-
tives and potential applications of nano-
medicine in breast and prostate cancer.
Med Res Rev. 2013 Jan;33(1):3–32.
     
and challenges associated with the use
of drug delivery systems in cancer ther-
apy. Biochem Pharmacol. 2010 Sep 1;80
(5):762–70.
-
meric micelles for improved delivery of
anticancer agents: recent developments
in preclinical studies. Pharmaceutics.
2013;5(1):201–19.
 
Pinho SC. Solid lipid nanoparticles: clas-
sical methods of lab production. Química
Nova. 2011;34(10):1762–9.
     
cellular drug delivery. Bioorg Med Chem.
2009 Apr 15;17(8):2950–62.
   
Surface Forces. 3th ed. Amsterdam:
Academic Press; 2011.
    
MM, Thompson DH. Cytosolic drug
delivery using pH- and light-sensitive
liposomes. Adv Drug Delivery Rev. 1999
Aug 20;38(3):317–38.
      
Advances for central nervous system
delivery of therapeutics. ACS Chem
Neuros ci. 2014 Nov 26;5(1):2–13

      
       
cationic nanoparticles induce defects in
supported lipid bilayers. Nano Lett. 2008
Feb;8(2):420–4.
      
      
Nanosized poly amidoamine (PAMAM)
dendrimer-induced apoptosis mediated
by mitochondrial dysfunction. Toxicol
Lett. 2009 Oct 28;190(2):202–7.
    
PMH. Dendrimers: design, synthesis
and chemical properties. J Mat Chem.
2006;16:3785–98.
    
C, Feliu N, Ye F, Gabrielsson S, et al.
   
coated iron oxide nanoparticles of
different sizes by primary human
macrophages and dendritic cells.
Toxicol Appl Pharmacol. 2011 Jun
1;253(2):81–93.
     
       
Targeted delivery of magnetic aerosol
droplets to the lung. Nat Nanotechnol.
2007 Aug;2(8):495–9.
    
     
particles as controlled release drug
delivery and gene transfection carri-
ers. Adv Drug Deliv Rev. 2008 Aug 17;
60(11):1278–88.
    -
ity of mesoporous silica nanoparticles.
Chem Res Toxicol. 2012 Nov;25(11):
2265–84.
       
Hsu YH, Chang C, et al. Multifunc-
tional mesoporous silica nanopar-
ticles for intra cellular labeling and
animal magnetic resonance imaging
studies. Chembiochem. 2008 Jan 4;
9(1):53–7.
     
particles in nanomedicine: prepara-
tions, imaging, diagnostics, therapies
and toxicity. Chem Soc Rev. 2009;38
(6):1759–82. [Review]. 2009 Jun;38
(6):1759–82.
      
M, Shehada N, Broza YY, et al. Diagnos-
ing lung cancer in exhaled breath using
gold nanoparticles. Nat Nanotechnol.
2009;4:669–73.
   
Graphene: synthesis and applications.
Mat Today. 2012;15(3):86–97.
     
delivery & cancer therapy. Mat Today.
2011 Aug;14(7–8):316–23.
     
Ferrari M. Intravascular delivery of
par ticulate systems: does geometry
really matter? Pharm Res. 2009 Jan;
26(1):235–43.

G, Shopp G. Short communication: renal
tubular vacuolation in animals treated
 
proteins. Toxicol Sci. 1998 Apr;42(2):
152–7.
     
      
al. PASylation: a biological alternative to
PEGylation for extending the plasma
half-life of pharmaceutically act ive
proteins. Protein engineering, design
& selection: PEDS. 2013 Aug;26(8):
489–501.