Current
Pharmaceutical Design
ISSN: 1381-6128
Current Pharmaceutical Design
Volume 12, Number 36, 2006
Contents
Nanomedicine and Drug Delivery
Executive Editors: A.V. Kabanov and K. Levon
Editorial Pp. 4665-4666
Polymeric Micelles for Drug Delivery Pp.
4669-4684
S.R. Croy and G.S. Kwon
[Abstract]
Formulation of Drugs in Block Copolymer Micelles:
Drug Loading and Release Pp. 4685-4701
J. Liu, H. Lee and C. Allen
[Abstract]
Colloidal Microgels in Drug Delivery Applications
Pp. 4703-4712
S.V. Vinogradov
[Abstract]
Liposome-Nanogel Structures for Future Pharmaceutical
Applications Pp. 4713-4728
S. Kazakov and K. Levon
[Abstract]
Nanocarriers for Nuclear Imaging and Radiotherapy
of Cancer Pp. 4729-4749
A. Mitra, A. Nan, B.R. Line and H. Ghandehari
[Abstract]
The Role of Electrospinning in the Emerging Field
of Nanomedicine Pp. 4751-4770
S.Y. Chew, Y. Wen, Y. Dzenis and K.W. Leong
[Abstract]
General Articles
Statins and Solid Organ Transplantation Pp.
4771-4783
I.F. Gazi, E.N. Liberopoulos, V.G. Athyros, M. Elisaf
and D.P. Mikhailidis
[Abstract]
Exploiting EPR in Polymer Drug Conjugate Delivery
for Tumor Targeting Pp. 4785-4796
S. Modi, J.P. Jain, A.J. Domb and N. Kumar
[Abstract]
Abstracts
[Back
to top]
Editorial: Nanomedicine and Drug Delivery
A new interdisciplinary field of nanomedicine that
promises breakthrough advances to human health has emerged
over last years. This field develops innovative nanomaterials,
tools and devices operating at the nanoscale to diagnose,
treat, prevent and monitor diseases and traumatic injury,
relieve pain, and, overall, preserve and improve the human
health [1]. This field joins physical and engineering sciences
with pharmaceutics and medicine to translate newest discoveries
in nanoscience into clinical practice. The “next generation”
therapies must be able to deliver drugs, radionuclides, therapeutic
proteins and recombinant DNA to focal areas of disease or
to tumors to maximize clinical benefit while limiting untoward
side effects. It is not surprising therefore that the drug
delivery field has attracted great attention of the biomedical
community. The development of multifunctional, spatially ordered,
architecturally varied nanosystems for targeted drug delivery
is also seen as a priority in nanomedicine [1]. The knowledge
and experience in interactions of nanosized drug delivery
systems is invaluable for the nanomedicine researchers. Several
nanosized drug delivery systems have already been approved
for clinical use and more nanomaterials are being evaluated
in clinics [2]. Thus nanomedicine is not only “futuristic”
but also “realistic” field with a near-term prospective
to improve human health.
A symposium series focusing on the problems of nanomedicine
and drug delivery has started several years ago - the Fourth
International Nanomedicine Symposium is planned for October
8th-10th, 2006 (www.nanodds.org). By
gathering basic and clinical scientists with the common interest
of using nanotechnology in the delivery of therapeutic and
diagnostic agents this symposium series aims at narrowing
the gap between research communities in academia, government
and industry. This issue presents a collection of selected
review articles by the speakers and attendees of the Second
Nanomedicine and Drug Delivery Symposium held in Brooklyn,
NY in August 2004.
One promising class of nanomaterials for drug delivery are
polymer micelles. They were first proposed in 80’-ies
as nanocontainers for biological agents by H. Ringsdorf, A.
Kabanov and K. Kataoka [3-5], and have now attracted great
attention in the literature. Polymer micelles can incorporate
drugs into the hydrophobic polymer core protected by a hydrophilic
polymer corona. The corona enables long circulation times
of the micelles in the body and prevents the affect of the
drugs entrapped in the core on the non-target cells. By modifying
the surface of the micelles with antibodies, the site specific
delivery and release of the payload at the disease site has
been achieved. Several polymer micelle systems are now evaluated
in clinical trials. The article by S.R. Croy and G.S. Kwon
[6] opens the current issue with a comprehensive overview
of this rapidly developing field.
The second article by C. Allen and colleagues focuses on the
problems of drug loading within the micelles and drug release
from the micelles [7]. The interactions between the drug and
the micelle core are discussed in terms of their influence
on the drug loading and release properties of the micelles.
The balance between drug loading and micelle stability is
highlighted as a critical factor in the optimization of micelle-drug
formulations. The methods employed to prepare drug-loaded
micelles and the drug release assays are reviewed. The in
vivo performance of micelles as delivery systems is evaluated
by comparing the pharmacokinetics of free drug and drug administered
in micelle-based formulations.
A different approach to drug loading and release was realized
in a relatively new class of nanosized drug carriers called
“nanogels”. First proposed in the end of the 90’-ies
the nanogels represent cross-linked networks of water soluble
polymers of nanoscale size. These networks are swollen and
do not have a hydrophobic core in aqueous dispersions in the
absence of the drug. However, the added drug can spontaneously
bind to the polymer chains of the nanogels, for example, due
to electrostatic interactions, and become entrapped in nanogel
particles. This method allows for very high degrees of loading
of drugs in nanogels. Nanogels are “soft” materials
that change shape and volume as the chemical composition of
the environment changes or upon interaction with the cell
membranes. These properties can be used facilitate the release
of the loaded drugs within the target cells. The work on nanogels
and other colloidal microgels has been overviewed by S. Vinogradov
[8].
The theme of colloidal gels is continued by Kazakov and Levon
in the fourth article of this issue [9]. This article focuses
on a new type of nanoparticles – lipobeads – a
liposome-hydrogel assembly. These materials have a bi-compartmental
structure containing inner nanogel core and external lipid
bilayer surrounding the core. It is proposed that such materials
display high biocompatibility and stability and can deliver
a broad range of bioactive molecules to a target cell. The
responsive lipobeads can release their payload within the
cells triggered due to the changes in the chemical composition
of the environment. Reversibly and irreversibly aggregated
lipobeads are proposed as novel, so-called combined, drug
delivery systems.
Several nanomaterials used in drug delivery, such as nanoparticles,
liposomes, water-soluble polymers, micelles and dendrimers,
can incorporate diagnostic and therapeutic radionuclides.
By targeting these species to the cancer cells more accurate
detection, staging and therapy of cancer can be achieved.
New nuclear imaging techniques such as dual modality imaging
with positron emission tomography/computed tomography (PET/CT)
provide high sensitivity and spatial resolution and are available
for the noninvasive detection of the nanocarriers in the body.
The paper by Mitra et al. [10] presents a brief but
comprehensive overview of the various nuclear imaging techniques
and the use of nanocarriers to deliver radionuclides for the
diagnosis and therapy of cancer.
The final article by Chew et al. [11] focuses on
the use of novel materials – electrospun nanofibers
in nanomedicine. Electrospinning is a simple and versatile
technique that can produce a macroporous scaffold comprising
randomly oriented or aligned nanofibers. These materials can
be used to mimic the in vivo the extracellular matrix
which often includes topography at the nanoscale and therefore
can be used to design entirely new generation of cell substrate
defined at the submicron scale. The nanofibers can also incorporate
various biologically active agents enabling a drug delivery
function into the fibrous scaffold. This paper is contributed
by pioneers in biomedical use of nanofibers and covers electrospinning
process, and describes the electrospun fibers fabricated for
biomedical applications such as drug delivery and tissue engineering.
In conclusion, taken together, the outstanding articles in
this issue provide a current summary to several major approaches
developed in nanomedicine and drug delivery field. Therefore,
we believe that the present issue will be of considerable
interest to academic, government and industrial scientists
and graduate students willing to lean about this fascinating
field that is continuously in growth.
References
[1] Nanomedicine. An ESF – European Medical Research
Councils (EMRC) Forward Look report, European Science Foundation,
2005.
[2] Duncan R. The dawning era of polymer therapeutics. Nat
Rev Drug Discov 2003; 2(5): 347-360.
[3] Bader H, Ringsdorf H and Schmidt B. Water-soluble polymers
in medicine. Angew. Makromol. Chem. 1984; 123/124:
457-485.
[4] Kabanov AV, Chekhonin VP, Alakhov VYu, Batrakova EV, Lebedev
AS, Melik-Nubarov NS, Arzhakov SA, Levashov AV, Morozov GV,
Severin ES, Kabanov VA. The neuroleptic activity of haloperidol
increases after its solubilization in surfactant micelles.
Micelles as microcontainers for drug targeting. FEBS Lett
1989; 258 (2): 343-345.
[5] Yokoyama M, Okano T, Sakurai Y, Ekimoto H, Shibazaki C,
Kataoka K. Toxicity and antitumor activity against solid tumors
of micelle-forming polymeric anticancer drug and its extremely
long circulation in blood. Cancer Res. 1991; 51(12): 3229-3236.
[6] Croy SR, Kwon GS. Polymeric micelles for drug delivery.
Curr Pharm Design 2006; 12(36): 4669-4684.
[7] Liu J, Lee H, C. Allen C. Formulation of drugs in block
copolymer micelles: drug loading and release. Curr Pharm Design
2006; 12(36): 4685-4701.
[8] Vinogradov SV. Colloidal microgels in drug delivery applications.
Curr Pharm Design 2006; 12(36): 4703-4712.
[9] Kazakov S, Levon K. Liposome-nanogel structures for future
pharmaceutical applications. Curr Pharm Design 2006; 12(36):
4713-4728.
[10] Mitra A, Nan A, Line BR, Ghandehari H. Nanocarriers for
nuclear imaging and radiotherapy of cancer. Curr Pharm Design
2006; 12(36): 4729-4749.
[11] Chew SY, Wen Y, Dzenis Y, Leong KW. The role of electrospinning
in the emerging field of nanomedicine. Curr Pharm Design 2006;
12(36): 4751-4770.
Alexander V. Kabanov, Ph.D., Dr.Sc.
Parke-Davis Professor of Pharmaceutical Sciences and Director,
Center for Drug Delivery and Nanomedicine,
University of Nebraska Medical Center
5830 Nebraska Medical Center
Omaha, Nebraska 68198-5830
USA
E-mail: akabanov@unmc.edu
Kalle Levon, Ph.D.
Professor and Director,
Herman F. Mark Polymer Research Institute,
Polytechnic University,
Six MetroTech Center,
Brooklyn, New York 11201
USA
E-mail: klevon@poly.edu
[Back to top]
Polymeric Micelles for Drug Delivery
S.R. Croy and G.S. Kwon
Polymeric micelles are nanoscopic core/shell structures
formed by amphiphilic block copolymers. Both the inherent
and modifiable properties of polymeric micelles make them
particularly well suited for drug delivery purposes. An emphasis
of this review has been placed on both the description and
characterization techniques of the physical properties of
polymeric micelles. Relevant properties discussed include
micellar association, morphology, size and stability. These
properties and characterization techniques are included to
provide context for the known advantages and applications
of polymeric micelles for drug delivery. The advantages and
applications discussed include solubilization of poorly soluble
molecules, sustained release and size advantages, and protection
of encapsulated substances from degradation and metabolism.
The three most widely studied block copolymer classes are
characterized by their hydrophobic blocks, and are poly(propylene
oxide), poly(L-amino acid)s and poly(ester)s. These three
classes of block copolymers are reviewed with multiple examples
of current research in which formulation techniques with polymeric
micelles have been applied to some of the most challenging
molecules in the pharmaceutical industry. The polymeric micelles
used for drug delivery in these examples have shown the abilities
to attenuate toxicities, enhance delivery to desired biological
sites and improve the therapeutic efficacy of active pharmaceutical
ingredients.
[Back to top]
Formulation of Drugs in Block Copolymer Micelles:
Drug Loading and Release
J. Liu, H. Lee and C. Allen
Block copolymer micelles have become accepted as a viable
strategy for drug formulation and delivery. Block copolymer
micelles may serve as solubilizers and/or true drug carriers
depending on their drug retention properties in vivo.
Indeed the formulation of hydrophobic drugs in these micelle
systems has been shown to provide up to a 30 000 fold increase
in the water solubility of some compounds. In addition, the
administration of drugs in copolymer micelles has been shown
to reduce their toxicity and improve their therapeutic efficacy.
The present review is focused on the drug loading and release
properties of block copolymer micelles. Specifically, the
properties of the drug, properties of the micelle core and
the presence of interactions between the drug and the coreforming
block are discussed in terms of their influence on the drug
loading and release properties of the micelles. The various
methods employed to prepare drug-loaded micelles are reviewed
and the in vitro release assays used to predict the
in vivo release characteristics of the formulations
are discussed. The balance between drug loading and micelle
stability is highlighted as a critical factor in the optimization
of micelle-based formulations. The in vivo performance
of micelles as delivery systems is evaluated by comparing
the pharmacokinetics of free drug and drug administered in
micelle-based formulations.
Overall, the composition-property and property-performance
relationships outlined in this review may aid in guiding the
rational design of block copolymer micelles for drug delivery.
In addition, suggestions for future research in this area
are provided as a means to assist in furthering block copolymer
micelles as one of the leading advanced drug delivery technologies
for the systemic administration of drugs.
[Back to top]
Colloidal Microgels in Drug Delivery Applications
S.V. Vinogradov
Colloidal microgels have recently received attention as environmentally
responsive systems and now are increasingly used in applications
as carriers for therapeutic drugs and diagnostic agents. Synthetic
microgels consist of a crosslinked polymer network that provides
a depot for loaded drugs, protection against environmental
hazards and template for post-synthetic modification or vectorization
of the drug carriers. The aim of this manuscript is to review
recent attempts to develop new microgel formulations for oral
drug delivery, to design metal-containing microgels for diagnostic
and therapeutic applications, and to advance approaches including
the systemic administration of microgels. Novel nanogel drug
delivery systems developed in the authors’ laboratory
are discussed in details including aspects of their synthesis,
vectorization and recent applications for encapsulation of
low molecular weight drugs or formulation of biological macromolecules.
The findings reviewed here are encouraging for further development
of the nanogels as intelligent drug carriers with such features
as targeted delivery and triggered drug release.
[Back to top]
Liposome-Nanogel Structures for Future Pharmaceutical
Applications
S. Kazakov and K. Levon
Nanoparticles have been extensively studied as drug delivery
systems. In this review, we focus on a relatively new type
of nanoparticles – lipobeads – a liposome-hydrogel
assembly as a novel drug delivery system. An appropriate assemblage
of spherical hydrogel particles and liposomes combines the
properties of both classes of materials and may find a variety
of biomedical applications. The bi-compartmental structure
of lipobeads is a natural configuration. Thus, the technology
of their preparation can be a key step of designing more stable
and effective vaccines. Biocompatibility and stability, ability
to deliver a broad range of bioactive molecules, environmental
responsiveness of both inner nanogel core and external lipid
bilayer, and individual specificity of both compartments make
the liposome-nanogel design a versatile drug delivery system
relevant for all known drug administration routes and suitable
for different diseases with possibility of efficient targeting
to different organs. New findings on reversible and irreversible
aggregation of lipobeads can lead to novel combined drug delivery
systems regarding lipobeads as multipurpose containers. The
research on hydrogel-liposome submicrometer structures has
just begun and fundamental studies on interactions between
hydrogels and liposomes are in demand.
[Back to top]
Nanocarriers for Nuclear Imaging and Radiotherapy
of Cancer
A. Mitra, A. Nan, B.R. Line and H. Ghandehari
Several nanoscale carriers (nanoparticles, liposomes, water-soluble
polymers, micelles and dendrimers) have been developed for
targeted delivery of cancer diagnostic and therapeutic agents.
These carriers can selectively target cancer sites and carry
large payloads, thereby improving cancer detection and therapy
effectiveness. Further, the combination of newer nuclear imaging
techniques providing high sensitivity and spatial resolution
such as dual modality imaging with positron emission tomography/computed
tomography (PET/CT) and use of nanoscale devices to carry
diagnostic and therapeutic radionuclides with high target
specificity can enable more accurate detection, staging and
therapy planning of cancer.
The successful clinical applications of radiolabeled monoclonal
antibodies for cancer detection and therapy bode well for
the future of nanoscale carrier systems in clinical oncology.
Several radiolabeled multifunctional nanocarriers have been
effective in detecting and treating cancer in animal models.
Nonetheless, further preclinical, clinical and long-term toxicity
studies will be required to translate this technology to the
care of patients with cancer. The objective of this review
is to present a brief but comprehensive overview of the various
nuclear imaging techniques and the use of nanocarriers to
deliver radionuclides for the diagnosis and therapy of cancer.
[Back to top]
The Role of Electrospinning in the Emerging Field
of Nanomedicine
S.Y. Chew, Y. Wen, Y. Dzenis and K.W. Leong
The fact that in vivo the extracellular matrix (ECM)
or substratum with which cells interact often includes topography
at the nanoscale underscores the importance of investigating
cell-substrate interactions and performing cell culture at
the submicron scale. An important and exciting direction of
research in nanomedicine would be to gain an understanding
and exploit the cellular response to nanostructures. Electrospinning
is a simple and versatile technique that can produce a macroporous
scaffold comprising randomly oriented or aligned nanofibers.
It can also accommodate the incorporation of drug delivery
function into the fibrous scaffold. Endowed with both topographical
and biochemical signals such electrospun nanofibrous scaffolds
may provide an optimal microenvironment for the seeded cells.
This review covers the analysis and control of the electrospinning
process, and describes the types of electrospun fibers fabricated
for biomedical applications such as drug delivery and tissue
engineering.
[Back to top]
Statins and Solid Organ Transplantation
I.F. Gazi, E.N. Liberopoulos, V.G. Athyros, M. Elisaf
and D.P. Mikhailidis
Dyslipidaemia is common in solid organ transplant recipients
and its presence is associated with chronic rejection and
accelerated atherosclerosis, leading to an increased prevalence
of cardiovascular disease (CVD). CVD is a major cause of morbidity
and mortality in transplant recipients. It is therefore of
interest and clinical value to introduce agents that effectively
and safely reduce the incidence of this outcome.
In the present review we consider the potential benefits of
statin administration in adults who have undergone solid organ
(mainly renal, heart and liver) transplantation, as well as
in paediatric transplant patients. We also briefly review
the effects of combination therapy with ezetimibe and statins
in this population. Overall, statins are efficient and safe
drugs for the management of dyslipidaemias in transplant populations,
and in most trials they had a beneficial effect on long-term
survival rates, CVD events and rejection rates. The transplanted
population is different from other patient groups, mostly
due to concomitant immunosuppressive therapy.
Statins, at an appropriate dosage, should be prescribed to
dyslipidaemic transplanted patients but they should be closely
monitored for adverse effects.
[Back to top]
Exploiting EPR in Polymer Drug Conjugate Delivery
for Tumor Targeting
S. Modi, J.P. Jain, A.J. Domb and N. Kumar
Treatment of tumor tissue without affecting normal cells has
always been formidable task for drug delivery scientists and
this task is effectively executed by polymer drug conjugate
(PDC) delivery. The novelty of this concept lies in the utilization
of a physical mechanism called enhanced permeability and retention
(EPR) for targeting tumors. EPR is a physiological phenomenon
that is customary for fast growing tumor and solves the problem
of targeting the miscreant tissue. PDCs offer added advantages
of reduced deleterious effects of anticancer drugs and augmentation
of its formulation capability (e.g. Solubility). There are
now at least eleven PDCs that have entered phase I/II/III
clinical trial as anticancer drugs. PDCs once entered into
the tumor tissue, taking advantage of EPR, are endocytosed
into the cell either by simple or receptor mediated endocytosis.
Various polymeric carriers have been used with hydrolyzable
linker arm for conjugation with bioactive moiety. The hydrolyzable
linkages of PDC are broken down by acid hydrolyses of lysosomes
and releases the drug. High concentrations of the chemotherapeutic
agent are maintained near the nucleus, the target site. Passive
targeting by PDCs is due to the physiological event of EPR,
which is becoming one of the major thrust areas for targeting
solid tumors.
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