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Editorial
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Nanogels in the race for drug delivery
“Even a moderate increase in the efficacy of present drug delivery systems has
proven to be a real challenge.”
We are currently witnessing a rapid growth of
interest in nanotech applications for medicine,
most of them focused on radical improvements
of current therapies and diagnostic modalities. After a real boom in the development of
novel micro- and nano-sized particulate drug
delivery systems (DDS) in academic laboratories and pharmaceutical companies all over
the world; however, we have now reached the
point when the first ‘reality check’ can be made
and the many limits and shortcomings of existing DDS can be evaluated. The major effect
of drug administration in loaded DDS can
be determined as a principal change in drug
pharmacokinetics and bioavailability. Many
current DDS have been developed with the aim
of reducing biodegradation or in vivo toxicity
of drugs. Others have focused on increasing
bioavailability, cell-selective accumulation, or
activity of encapsulated drugs after administration. Initial generations of DDS were optimized in cell cultures by modifications of the
chemical structure or physicochemical properties in order to effectively modulate cellular
drug accumulation, release kinetics and overall
therapeutic effect.
the effect, from kidney ‘drainage’ or retention
of DDS in bypassing organs to accumulation
of nanocarriers in fatty and muscular tissues.
An extremely effective ‘deactivation’ factor for Serguei V Vinogradov
administered nanoformulations was the capture Department of Pharmaceutical
of nanocarriers by macrophages of the endothe- Sciencess, College of Pharmacy
lial reticulum, by alveolar macrophages in lungs, and Center for Drug Delivery
and by macrophage populations in the liver and and Nanomedicine, University
spleen. An important role in recognition by of Nebraska Medical Center,
macrophages was attributed to serum proteins Omaha, NE, USA
(opsonins) that had adsorbed on the surface of Tel.: +1 402 559 9362
nanocarriers and made them ‘visible’ to macro- Fax: +1 402 559 9345
phages. Particle size, shape, surface charge and [email protected]
polymer brush density of nanocarriers have been determined to be among the main characteristics
responsible for premature clearance. All in all,
the doses of administered nanocarrier-loaded
drugs that reached tumors or targeted organs
(except liver, kidney and spleen) rarely exceeded
5–10% of the injected dose. This means an
extremely low observed efficacy of nanodelivery. Even a moderate increase in the efficacy of
present DDS has proven to be a real challenge.
The most promising DDS have been selected
for in vivo evaluation. Here, the principal difficulties started to appear. Despite some success
stories, a huge gap between the in vitro properties of DDS and the behavior of nanocarriers following injections into a living body was observed
in practically every laboratory. The major cause
of these differences was the interaction of the
surface of DDS with serum components and
fast clearance of ‘covered’ nanocarriers from
blood circulation. Special conditions added to
Per aspera ad astra: fighting
deficiencies & limitations of DDS
Our initial optimism about rational nanoengineering of DDS and ‘smart’ design is fading fast
after multiple failures of drug nanoformulations
in clinical trials. The recent history of nonviral
gene delivery gives us stunning examples of the
slow shift from the initial simplistic designs of
nanocarriers to the ‘real-life’ complex structures
with virus-like properties that would be able to
cross multiple biological barriers on their way
to efficient nuclear expression in target cells. It
is now evident that the size or shape of virus
particles, surface properties, pattern of cellbinding proteins and the ability to hide from
the immune system determine the invasive
power of infection and virus persistence in the
organism. Therefore, a promising approach to
improve the properties of human constructs may
10.2217/NNM.09.103 © 2010 Future Medicine Ltd
Nanomedicine (2010) 5(2), 165–168
“...a promising approach to improve the
properties of human constructs may
include applying real viral properties or
bionics, mimicking nature.”
ISSN 1743-5889
165
Editorial
Vinogradov
include applying real viral properties or bionics, mimicking nature. In that regard, studies of
bloodborne pathogens and infections may shed
some light upon the requirements for long-term
circulation of nanoparticles in the 10–200 nm
range in the blood.
Surface decoration of nanosized DDS with
targeting ligands recognizing specific cellular receptors in the attempt to mimic endogenous immunoglobulins then became a major
approach to systemic delivery of encapsulated
drugs. However, in DDS design, factors such as
the hydrodynamic shape of nanocarriers were
seldom taken in account. The critical cell-binding efficacy of many circulating nanocarriers and
their retention in tumors, the blood–brain barrier, and so on, will inversely relate to their size
or, more precisely, to the cross-sectional area facing the shearing forces of blood flow. The importance of attaching multiple ligands to the surface
of DDS for binding cellular receptors in concert
was only recently recognized as an important
requirement for efficient systemic targeting; no
such restriction was identified for antibody–drug
conjugates with a hydrodynamic radius (rh) not
exceeding 2 nm. However, the shearing forces of
blood flow could ‘tear off’ already-bound larger
nanoparticles with an efficacy in direct proportion to their rh 2. Evidently, soft nanocarriers,
which are capable of flattening themselves on
the vascular surface and simultaneously anchoring in multiple points, have a better chance of
specific retention in the targeted site of disease.
Ex pluribus unum: nanogels
& other nanocarriers
Nanogels have been included only recently in the
long list of known physical nanocarriers, which
have found applications as DDS, from supramolecular dendrimers with a rh of less than 10 nm
to biodegradable nanoparticles with a rh of up to
1 µm. The term ‘nanogels’ defines small hydrogel particles formed by physically or chemically
crosslinked polymer networks. Dispersed in
aqueous media, swollen nanogel networks are
soft and can encapsulate a considerable volume
of water. Biological agents and drugs can be
loaded into nanogels via a spontaneous process
including interactions between the agent and the
polymer matrix, forming hydrophilic particles
with high dispersion stability. Nanogels were able
to physically protect biological molecules from
degradation in vivo and have been preclinically
investigated for many types of active molecules,
ranging from small drugs to biomacromolecules.
Following the first decade of their development,
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Nanomedicine (2010) 5(2)
nanogels demonstrated excellent potential for
systemic drug delivery, design of multifunctional
nanocarriers (e.g., theranostics) and triggered
drug-release applications [1–5] . Key features of
nanogels will be discussed below in comparison
with the currently most advanced DDS.
Solid nanoparticles (SNPs) composed from
biodegradable polymers have found applications in various fields of nanomedicine, including drug delivery. Biodegradable solid polymer
nanoparticles demonstrated great promise as
drug delivery carriers and have high biocompatibility. The drug is usually released from a SNP
because of matrix erosion that can be controlled by the polymer content of the nanocarrier.
The storage ability of nanoparticles in lyophilized form has generally been good. In theory,
biodegradable SNPs can sustainably release the
drug, optimizing its pharmaceutical profile over
time and, thus, increasing drug efficacy. Alas,
currently, predictions of drug pharmacokinetics are difficult because of the poor understanding of in vivo biodistribution and behavior of
nanocarriers. Moreover, some properties of SNPs
are not easily compatible with design of nextgeneration smart nanocarriers. Introduction of
outlying stabilizing polymer molecules, targeted
moieties and imaging capabilities were found to
be notoriously difficult for biodegradable SNPs.
By contrast, nanogels sharing many useful properties of SNPs, such as lyophilizing ability and
biocompatibility, are devoid of these problems
and can be easily modified with various ligands
on their surface and in the internal volume of
their network.
Liposomes have been around for 30 years
and extensively studied, so that many liposomal
drugs have already been moved into the clinic.
Despite the evident advantages of liposomes,
these pharmaceutical formulations are far from
ideal, with a short shelf-life, significant drug
leakage, high accumulation in the liver and so
on. Since the introduction of polyethylene glycol
(PEG)ylated ‘stealth’ liposomes, these carriers
have advanced immeasurably. However, as was
observed repeatedly in clinical trials, intravenously injected PEGylated stealth liposomes
may induce acute pseudoallergic reactions associated with complement activation. PEG chains
associated with an anionic phosphate moiety
of phospholipids were found to trigger several
pathways of the human complement system.
Similar effects were also observed with the injection of other PEGylated DDS, such as carbon
nanotubes. The major advantage of liposomes
is their homology with cellular membranes and
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Nanogels in the race for drug delivery
the ability to fuse with them, releasing the cargo
inside the cells. Some cationic and amphiphilic
nanogels have also demonstrated prominent
membranotropic properties and were able to fuse
with cellular membranes, coming very close to
liposomes in this capability [6] .
Polymeric micelles represent the third major
class of DDS, although, in a general sense, they
may be considered as excipients, surfactant-­
stabilizers of poorly soluble drugs. When the size
of nanocarriers is concerned, micelles will probably lead the group, because they usually have
the smallest diameter and are produced from
one amphiphilic polymer component. Major
minuses of micelles are low storage stability
and problems with lyophilization; a relatively
low drug encapsulation is another drawback.
Recently, a novel advanced approach, so-called
‘wet milling’ of solid low-soluble drugs, was
developed for preparing heavily drug-loaded
micelles stabilized by an amphiphilic polymer.
Sometimes, the boundary between micelles and
nanogels is vague; crosslinked micelles are frequently called nanogels. They have all of the
attributes of nanogels, including pore size and
environmentally dependent volume change (collapse). The principal advantage of both types of
nanocarriers is a high water content, assuring
their excellent dispersion stability. Low soluble
drugs can be efficiently encapsulated in micelles,
while hydrophilic compounds and bioactive
macromolecules are the most frequent drug
candidates for encapsulation in nanogels.
Nanogel-specific properties can be utilized
for the design of smart nanocarriers for various types of delivered molecules. The following
examples will help to illustrate the extensive
potential of nanogel networks for drug delivery.
In application to hybrid nanocarriers, formation of hydrogel nanolayers is now considered
as one of the best methods for the preparation
of stabilized nanocarriers with functionally
active metal or mineral cores for imaging or
phototherapeutic purposes. Hybrid nanogels
containing smaller gold, ferromagnetic, or fluorescent (quantum dot) SNPs can be a useful
platform for the development of smart DDS,
but the indestructibility of these components
gives rise to some potential issues associated
with chronic toxicity. Tissue staining is one of
the known visible results of metal SNP accumulation. A hydrogel outlayer makes the solid
core biocompatible; in view of future ‘nano(ro)
bot’ development this type of supramolecular
architecture seems most versatile. Nanogels
encapsulating gold SNPs or quantum dots may
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Editorial
Nanogel concept
Drug molecule
Figure 1. Nanogel concept.
Figure created as a result of an idea from Alexander Kabanov, University of
Nebraska Medical Center, USA. Parts adapted from [9] .
serve as recent examples of multifunctional
theranostics in the initial stage of preclinical
development [6] .
In the second example, an easy and efficient
encapsulation of therapeutic proteins into a
cholesteryl–pullulan nanogel network was
achieved by Akiyoshi et al. in Japan [7] . A protein
of interest mixed with a cholesteryl–pullulan
molecule formed small nanogel particles with
the protein in the core protected by hydrophilic
polymer chains. Various proteins were shown to
become more stable, or active, or be delivered
into targeted cells more efficiently.
A strong focus of recent research has been the
engineering of particles with definite shapes, a
pharmaceutical parameter having received little
attention in the past. As recently became evident, spherical particles are subjected to stronger
phagocytosis than ellipsoid or disc-shaped ones.
Therefore, rational shape design may provide an
additional advantage in drug delivery, avoiding
capture by macrophages. In the third example,
uniform nanogels have been fabricated by lithographic PRINT process using master-mold process in various shapes and sizes. This innovative
PRINT technology that allowed preparation of
drug-loaded, shape- and size-optimized uniform
nanocarriers was developed by DeSimone et al.
in the USA and recently distinguished by NIH
and MIT awards [8] .
Crosslinked hydrogel networks usually form
smooth and elastic outlayers that generate
extremely low friction with various surfaces,
including the endothelium of blood vessels.
This property may be useful for the design of
cell-associated DDS, so that the biological function of cells circulating in blood/lymphatics will
not be affected. Other specific features of nanogels, including stimuli-induced drug release via
temperature or pH-dependent volume collapse,
can also be very useful in designing smart,
stimuli-responsive DDS.
www.futuremedicine.com
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Editorial
Vinogradov
Tempus fugit: time is the best judge
The successful clinical translation of therapeutic
nanoformulations requires the optimization of
many distinct parameters of nanocarriers, including variation in carrier composition, drug loading
and surface properties (polymer or ligand density, hydrophobicity and charge). While various
high-throughput or combinatorial methods have
been suggested for optimization of biomaterials
and DDS, unfortunately, in real life, sometimes
those modifications intended to increase a specific
efficacy of nanodelivery can suppress other useful
properties of nanocarriers, and vice versa. Current
pharmacology mostly deals with single drugs and
tries to avoid drug interactions. The goal of creating computerized models of drug action, similar
to the existing ones in current ‘subnano’ pharmacology, is only twinkling as a distant star for drugencapsulated DDS. It is clearly evident that drug
nanoencapsulation will not just simplify drug
delivery or enhance drug efficacy, but, in its own
way will make drug choices and prediction of
drug pharmacokinetics more difficult and prone
to errors, and influence of many factors associated
with DDS.
The hype and hope of nanotechnology challenging many previously unimaginable goals are
especially high now and many believe in forthcoming breakthroughs in the areas of diagnostic
imaging, complementation of diagnostic tools
with therapeutic modalities (theranostics), or
nanoencapsulation of biotech proteins and novel
Bibliography
1
Kabanov AV, Vinogradov SV: Nanogels as
pharmaceutical carriers: finite networks of
infinite capabilities. Angew. Chem. Intern. Ed.
48, 5418–5429 (2009).
2
Raemdonck K, Demeester J, DeSmedt S:
Advanced nanogel engineering for drug
delivery. Soft Matter 5, 707–715 (2009).
3
Vinogradov SV: Hydrophilic colloidal
networks (micro- and nanogels) in drug
delivery and diagnostics. In: Structure and
Functional Properties of Colloidal Systems.
Hidalgo-Alvarez R (Ed.). CRC Press, Taylor
& Francis Group, Boca Raton–London–New
York, NY, USA 367–386 (2009).
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genetically active macromolecules for clinical
applications. However, we must be patient and
clear-headed to evaluate the pros and cons of existing DDS. Evidently, only a small fraction of the
invented DDS will be able to get over multiple
obstacles on their way to clinical studies and, eventually, to the pharmaceutical market of approved
drug formulations. The major part of these inventions will remain buried in the archives of the US
Patent Office. Our times may still be compared
with the period of the California Gold Rush when
new gold prospector sites were claimed and even
fought over, sometimes without clear idea about
their gold content or real outputs. Nanogel nanocarriers are now reaching the age of adolescence
and have already demonstrated the promise of
a ‘wunderkind’ child in comparison with other
already advanced DDS. Time will judge whether
these promises are going to become a reality.
Financial & competing interests disclosure
The author is very grateful for support in the development
of nanogels from NIH (R01 CA102791, R01 NS050660,
R01 CA136921 and R21 NS063879) and from
A Kabanov, the director of Center for Drug Delivery and
Nanomedicine, UNMC (Omaha, NE, USA). The author
has no other relevant affiliations or financial involvement
with any organization or entity with a financial interest in
or financial conflict with the subject matter or materials
discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of
this manuscript.
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