Current Medicinal Chemistry, 2012, 19, ????-???? 1
0929-8673/12 $58.00+.00 © 2012 Bentham Science Publishers
Image-Guided Nanosystems for Targeted Delivery in Cancer Therapy
A.K. Iyer1, J. He2,3 and M.M. Amiji*,1
1Department of Pharmaceutical Sciences, School of Pharmacy, Northeastern University, Boston, MA 02115, USA; 2Center for
Molecular and Functional Imaging, Department of Radiology and Biomedical Imaging, University of California at San Francisco,
San Francisco, CA 94143, USA; 3UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, CA 94143, USA
Abstract: Current challenges in early detection, limitations of conventional treatment options, and the constant evolution of cancer cells
with metastatic and multi-drug resistant phenotypes require novel strategies to effectively combat this deadly disease. Nanomedical
technologies are evolving at a rapid pace and are poised to play a vital role in diagnostic and therapeutic interventions - the so-called
“theranostics” – with potential to advance personalized medicine. In this regard, nanoparticulate delivery systems can be designed with
tumor seeking characteristics by utilizing the inherent abnormalities and leaky vasculature of solid tumors or custom engineered with
targeting ligands for more specific tumor drug targeting. In this review we discuss some of the recent advances made in the development
of multifunctional polymeric nanosystems with an emphasis on image-guided drug and gene delivery. Multifunctional nanosystems
incorporate variety of payloads (anticancer drugs and genes), imaging agents (optical probes, radio-ligands, and contrast agents), and
targeting ligands (antibodies and peptides) for multi-pronged cancer intervention with potential to report therapeutic outcomes. Through
advances in combinatorial polymer synthesis and high-throughput testing methods, rapid progress in novel optical/radiolabeling
strategies, and the technological breakthroughs in instrumentation, such as hybrid molecular and functional imaging systems, there is
tremendous future potential in clinical utility of theranostic nanosystems.
Keywords: Drug delivery, image-guided delivery, liposomes, multifunctional nanosystems, personalized medicine, polymeric nanoparticles,
theranostics, tumor targeting.
1.1. Cancer Challenges
The diagnosis and treatment of many cancers stills remains
elusive and a major barrier to effective clinical outcomes. A recent
review by Hanahan and Weinberg  elucidates the “hallmark”
characteristics of cancers and the deregulation and signaling
pathways that are involved in the development and progression of
tumors. Cancer cells are known to possess unique characteristics of
dividing and proliferating rapidly, resisting cell death or apoptosis,
and having devastating invasive potentials. Also, tumor cells have
the ability to infiltrate surrounding normal tissues or penetrate into
lymphatics and/or blood vessels enabling them to circulate (called
circulating tumor cells) and migrate to multiple distant sites or
organs, forming secondary tumors [1, 2]. This process called
“tumor metastasis” often occurs at an advanced stage of the disease
and is generally beyond the scope of surgical resection or other
forms of treatment, largely responsible due to the failure in early
detection and management of the disease. Even in the case where
surgical resection is a viable option, there is always a high risk of
relapse of the disease due to existence of microscopic
subpopulations of recalcitrant tumor cells that are speculated to
possess “stem cell like” characteristics , that play a key role in
self-renewal and formation of new types of tumors . Apart from
these inherent destructive qualities, tumor cells have the capability
to reprogram themselves to suite various demanding and testing
conditions of the tumor microenvironment, such as the ability to
survive (and often thrive) in highly acidic pH [5, 6] and very low
oxygen or hypoxic conditions [7-10]. Moreover, most tumors cells
acquire resistance or become insensitive to a broad spectrum of
structurally and functionally different (and otherwise effective)
anticancer agents on prolonged exposure; a process known as
acquired tumor multi-drug resistance (MDR) [11-13]. The micro-
environmental selection pressures that leads to the acquired MDR
phenotype is well known to be a major reason for drug treatment
failure in cancer patients . Also, the genomic instability in
cancers gives rise to accumulation of mutations and this instability
leads to intratumoral (i.t.) heterogeneity in successive generations
*Address correspondence to this author at the Department of Pharmaceutical Sciences,
School of Pharmacy, Northeastern University, Boston, MA 02115, USA; Tel: (617)
373-3137; Fax: (617) 373-8886; E-mail: email@example.com
of tumors . These ever-changing and unpredictable genetic
mutations in cancers  make them a tricky target to pursue, and a
major hurdle in the successful management of this malignant
1.2. Systemic Delivery Challenges
Most of the conventional treatments for the management of
cancers involve chemotherapy using low molecular weight
anticancer agents that are systemically administered by the
intravenous (i.v.) route. This intervention inherently lacks the
ability to target tumors selectively. The drug indiscriminately
diffuses across blood vessels into normal tissues and tumors alike,
not only causing acute and often dose limiting side effects to cancer
patients [17, 18] but also effecting in dilution of the drug, wherein
the percent-injected dose that usually reaches the tumor is often
very low, leading to suboptimal drug utilization and efficacy .
Low molecular weight anticancer compounds also suffer from short
plasma circulation half-lives due to their rapid clearance through
renal excretion. Also naked proteins, peptides, DNA, small
interfering RNA (siRNA), and therapeutic molecules that are
administered via the blood stream are generally labile and prone to
degradation in the presence of serum or plasma components [20,
21]. These shortfalls make systemic delivery of drugs and genes a
1.3. Role of Molecular Imaging in Cancer
Many cancers can be prevented, better managed, or even cured
if the pathological tissue is detected early and the progression of the
disease can be effectively monitored through physiological rather
than anatomical changes [22, 23]. In this regard, molecular imaging
using targeted contrast agents, such as nuclear and optical probes,
can play a leading role in screening, detection, and management of
cancers [24, 25]. Imaging the molecular features or signatures of
cancer cells/tissues can also serve an important clinical function
[26-28]. For instance, molecular imaging using radiolabeled
ligands, antibodies, or peptides that can target/bind to molecular
markers, receptors or over-expressed targets on specific tumor cell
surfaces can not only help locate such tumors (Fig. 1) , but also
be used to study the biological effects of such molecules in the
progression of the disease . Also, imaging the downstream
markers or effector molecules that signal cell death or apoptosis can
provide indicators of treatment response much earlier than physical
2 Current Medicinal Chemistry, 2012 Vol. 19, No. 1 Iyer et al.
changes start to appear, such as tumor shrinkage . Thus,
molecular imaging of cancers can afford a gamut of meaningful
information that can be applied for mechanistic understanding of
the disease  as wells as early detection , and for studying
multiple events, such as non-invasive
accumulation/localization of the nanoparticles in vivo, its biological
fate, visualizing the progression/regression of the disease , and
quantifying the effect of drug treatment in individual patients that
usually vary on a case-by-case basis. Molecular imaging technology
as applied to a cancer therapy is thus heralded to play a major role
in the era of personalized medicine .
2. MOLECULAR IMAGING SYSTEMS IN CANCER
As discussed in the above section, the role of imaging in
characterization of cancers at the molecular level would have major
clinical implications, especially, for early detection of the disease,
predicting the risk of tumor formation from precancerous lesions
and ways to manage and treat the disease, including development of
new molecular target based therapeutics . In this regard,
imaging systems has already been an integral part in screening,
diagnosis, and staging of many cancers . Among them,
magnetic resonance imaging (MRI) has been a popular tool in
tumor detection because of its high depth penetration, spatial
resolution and high soft tissue contrast . More importantly,
MRI-based imaging circumvents the use of harmful ionizing
radiation . A significant amount of research in the field of MRI
has been focused on the development of contrast agents to improve
image signal intensity, and among them Gd3+-based MRI agents
have been most successful [38, 39].
X-ray computed tomography (CT) has also been used
extensively for screening, detection, and measuring the progression
of cancer in clinics . In the conventional setting iodinated
contrast agents are generally used to enhance the contrast for CT
imaging. One such example is the intraarterial (i.a.) administration
of the first commercially available polymer conjugated anticancer
agent, SMANCS that is given to patients using iodinated lipid
contrast agent (Lipiodol®). SMANCS-Lipiodol® serves both as a
diagnostic tool and a drug for therapeutic use; the contrast agent
helps detect the accumulation of SMANCS in solid tumors and also
facilitates imaging/monitoring the regression of tumors based on X-
ray CT . It has been reported that the radiation exposure to
patients while undergoing CT scans in the past may itself serve as a
source of cancers , however with the advancement in novel
imaging technologies such as low-dose CT, the mortality from
cancers could not only be reduced but the screening also resulted in
detection of many tumors at early stages .
Among the nuclear modality imaging, positron emission
tomography (PET) and single photon emission computed
tomography (SPECT) having high detection sensitivity has been the
most sought, for staging and follow up of solid tumors in patients in
the clinics [44, 45]. Also, the vast choice of radionuclides and
versatility of conjugation chemistries available for radiolabeling are
yet another key advantage with nuclear modality imaging [46, 47].
Another prominent feature of nuclear imaging is its ability to image
biological processes and metabolic activity in tissues and organs,
e.g., PET using the analog of glucose 2-[18F]-fluoro-2-deoxy-D-
glucose (18F-FDG) containing the 18F isotope with a moderate half-
life ≈ 110 min and high-energy positron emission (0.6335 MeV)
, is routinely used to detect tumors . Solid tumors usually
have higher uptake of 18F-FDG due to relative higher levels of
glucose transporters and the action the enzyme hexokinase .
The average FDG PET sensitivity and specificity across all
oncology applications is estimated at 84 % . However, the
production of positron emitting PET nuclides generally requires a
dedicated and costly cyclotron in close proximity to the imaging
facility due to the short half-lives of radionuclides. It is for this
reason that radiolabeling drugs/molecular markers with PET-
radiotracers are difficult to produce and image within the time
frame of their decay . 68Ga is a valuable alternative to 18F for
PET imaging because it does not need an on-site cyclotron and also
because of its high positron emission of 1.899 MeV [52, 53].
Another alternative to PET, is the use of SPECT imaging.
Although SPECT generally has lower radionuclide detection
Fig. (1). Novel radiolabeled scFv antibodies for targeted imaging of tumors. The figure shows in vivo tumor targeting and imaging of 99mTc-labeled M40 single
chain fragment antibody (scFv) in mouse bearing both sarcomatoid (VAMT-1) and epithelioid (M28) mesothelioma. (A) Single photon emission computed
tomography/X-ray computed tomography (SPECT/CT) fused coronal image of 99mTc-M40 imaged 3 hours after injection. (B) 3D fused SPECT/CT coronal
image. (C) blocking control study (the target-mediated uptake is confirmed by ≈ 70 % reduction in tumor activity following administration of 10-fold excess
of unlabeled scFv). (D) Positron emission tomography/X-ray computed tomography (PET/CT) fused coronal image of 2-[18F]-fluoro-2-deoxy-D-glucose (18F-
FDG) imaged 1 hour after injection (for comparison). The figure shows the ability of the novel M40 scFv to target both sarcomatoid (VAMT-1) and
epithelioid (M-28) mesothelioma tumors effectively in mouse models demonstrating the utility of such agents in imaging/detection of all subtypes of
mesotheliomas. Adapted with permission from Ref. . Copyright AACR (2011).
Image-Guided Nanosystems for Cancer Therapy Current Medicinal Chemistry, 2012 Vol. 19, No. 1 3
efficiency over PET, recent advancements in multi-aperture pinhole
SPECT technology significantly reduces the difference in detection
efficiencies between both modalities . 99mTc is a versatile
radioisotope for SPECT imaging that emits readily detectable 140
KeV γ-rays with a half-life ≈ 6 h . The time frame of its decay
is ideally suited for labeling for in vivo setting because it is long
enough for scanning with SPECT instrument but at the same time
keeps the radiation exposure low and helps reduce radiation burden
to patients . 99mTc is thus currently the most commonly used
isotope for disease diagnosis, especially for cancers. Gamma
emitting SPECT nuclides such as 111In, having longer half-lives,
could be advantageous in imaging pharmacokinetics and tissue
biodistribution of radiolabeled drugs in small animal models, using
In the past few decades, along with the increased interest in
novel nanoprobe development, there has been a burgeoning growth
in the development of cross-functional imaging technologies that
are revolutionalizing the field of biomedical imaging and
nanotechnology. For instance, CT or MRI that can provide
structural information are being combined with radionuclide
imaging techniques such as PET/SPECT or optical imaging that
lacks these features . Some such examples include the clinical
hybrid/fused PET-CT and SPECT-CT , and preclinical small
animal micro-PET/SPECT-CT imaging systems, which has the
ability to co-register both functional and anatomical features
previously lacking in SPECT or PET alone . In this regard, it is
important to note that the breakthrough in preclinical small animal
imaging systems have helped to carry forward the advances made
in translational research into clinical practice [61, 62]. Other
combinations of functional and structural imaging modalities such
as PET/MRI and optical/MRI are also under development for both
preclinical and clinical imaging .
Among the non-radioactive imaging tools, optical imaging
using fluorescently labeled drugs/molecular markers is becoming
very attractive and promising for in vitro screening as well for in
vivo preclinical/clinical assessments [64-66]. Nevertheless, the
application of fluorescence imaging for detecting cancers was
demonstrated as early as 1948 by Moore et al. using sodium
fluorescein as the fluorophore . In recent times, the two most
commonly utilized optical imaging techniques are based on 2D-
fluorescence reflectance imaging (FRI) and 3D-fluorescence
molecular tomography (FMT) imaging. The 3D tomographic
imaging using FMT is in a way similar to CT scans but without the
use of ionizing radiations .
In the current scenario of molecular marker-based cancer
screening/identification and detection, fluorescence imaging is
proving to be an indispensable tool for rapid assessment.
Furthermore, the commercial availability of wide range of near-
infrared (NIR) optical probes, the relative ease of photo-labeling
and development of reliable chemical conjugation chemistries,
coupled with low cost and relative easy access to optical imaging
stations makes them a preferred choice for molecular imaging .
However, fluorescence imaging also have their own problems and
pitfalls such as low sensitivity due to low penetration of fluorescent
light in tissues, rapid bleaching or quenching of the fluorophore,
and auto fluorescence (or false positive background signal) from
soft tissues. Irrespective of these limitations, optical imaging based
(nano)-probe development is moving in the right direction with
many product pipelines in preclinical development .
3. MULTIFUNCTIONAL NANOPARTICLE DELIVERY
SYSTEMS FOR CANCER
3.1. Polymeric and Liposomal Nanoparticulate Formulations
Drugs/genes encapsulated in nanoparticles offers several
advantages over conventional treatment regimens in the
management of cancers [70, 71]. As discussed earlier,
chemotherapy involving systemic administration of a free drug
(often a low molecular weight anticancer compound), suffers from
many drawbacks, such as short plasma half-lives (necessitating high
dose and frequent drug administration) and severe systemic toxicity
due to distribution in non-target sites. Apart from these limitations,
most of the anticancer drugs are hydrophobic in nature and,
therefore, insoluble or poorly soluble in water, which makes it
challenging to administer an adequate therapeutic dose.
Encapsulation of such molecules in nanoparticulate formulations
using biodegradable and biocompatible polymers or liposomal
delivery systems can increase the drug payload, protect the
encapsulated drugs from degradation in the bloodstream and also
prolong their half-lives several folds [72-74]. Thus nanoparticulate
drug formulations necessitate less frequent dose administration to
cancer patients, thereby greatly improving the patient’s quality of
Additionally, in the conventional therapeutic approach, the only
way to achieve desired clinical outcome is by waiting for tumor
regression after treatment. It is impossible to know if the drug has
actually reached the tumor mass or remains available for sufficient
duration to induce the tumoricidal effect. In this regard, image-
guided therapeutic delivery using nanoparticles offers great
potential in determination of drug availability at the target site as
well as monitoring the therapeutic effect of the encapsulated
payload in real-time with specific information on individual
patients rather relying on the averages for clinical decision making
3.2. Passive and Active Targeting to Cancers
It is well known that tumor cells posses devastating invasive
potentials and divide and multiply at phenomenal rates. In order to
cater to the ever-increasing oxygen and nutritional demands of the
growing tumors, cancer cells start “neovasculatization” or the
formation of new blood vessels. This phenomenon of
“angiogenesis” then starts to feed the rapidly growing tumor mass
. The tumor microenvironment and angiogenic characteristics
of solid tumors are thus found to be very different from normal
tissues. For instance, the tumor blood vessels are often aberrant or
“leaky” . The endothelial cells are disorganized or poorly
aligned with large fenestrations and the perivascular cells and
basement membrane are frequently abnormal or totally absent in the
vascular wall. Furthermore, tumor tissues have a wide lumen and
often lack the lymphatic clearance system [78-80]. It was found that
the anatomical defectiveness and the functional abnormalities of the
tumor blood vessels could be used to deliver macromolecular
anticancer drugs selectively to solid tumor tissues - a phenomenon
called the “enhanced permeability and retention” (EPR) effect of
macromolecular drugs (Fig. 2), discovered by Matsumura and
Maeda more than two and a half decades ago .
Most solid tumors have elevated levels of vascular permeability
mediators such as vascular endothelial growth factor (VEGF),
matrix metalloproteinases (MMPs),
bradykinin (BK), nitric oxide (NO), and peroxynitrite [81-84]. The
overproduction of the vascular permeability mediators and the
defective vascular architecture leads to extensive leakage of blood
plasma components, lipid particles, and macromolecules into the
tumors interstitium . Furthermore, the slow venous return in the
tumor tissues and the poor lymphatic drainage system helps retain
the macromolecules for extended times periods while the
extravasations into the tumor tissues continues . It is thus
possible to achieve very high local concentration of the
macromolecular drugs in the tumor tissues. Drugs and genes
encapsulated in macromolecular delivery systems such as
liposomes, polymeric nanoparticles, and micelles are thus able to
take advantage of this unique phenomenon to passively target tumor
4 Current Medicinal Chemistry, 2012 Vol. 19, No. 1 Iyer et al.
tissues [87, 88]. The EPR effect is now considered as a guiding
principle for passive tumor targeting using polymer drug conjugates
and nanoparticles [86, 89].
In general, macromolecules above the renal excretion threshold
(typically above 40 kDa) are able to circulate for long periods of
time in the blood and accumulate in solid tumors . Also,
liposomes, polymeric micelles and nanoparticles in the size range
of 20-200 nm have been shown to extravasate and accumulate
effectively in the tumor tissues . This is because the vascular
pore size in the solid tumors can range from 200 to 600 nm .
The EPR effect will be optimal if the nanosystems can evade the
reticuloendothelial system (RES) and show prolonged circulation
half-life in the blood. In this regard, grafting a poly(ethylene glycol)
(PEG) chain to the nanosystems can provide stealth characteristics
and allow RES escape thereby rendering long plasma circulation
half-life. For example, in the clinical setting doxorubicin loaded in
PEG-grafted liposomes demonstrated enhanced tumor accumulation
of doxorubicin and reduced toxicities compared with the free form
of the drug .
Passive targeting can be a gateway to deliver drugs and imaging
agents to many of the vascularized solid tumors, however, the
delivery to avascular, hypovasclar, or necrotic regions of tumors
still remains a challenge . In this regard, active targeting using
antibodies/ligands that can recognize and selectively bind to
antigens or receptors overexpressed on tumor cells can be more
promising (Fig. 2). Also, the specificity and delivery efficiency of
passively targeted nanosystems can be remarkably improved when
tumor targeting ligands are also made part of the delivery systems
. One such nanoparticulate delivery system developed in our
group is based on epidermal growth factor receptors (EGFR)
peptide-grafted nanoparticles for active targeting to MDR ovarian
cancer cells overexpressing EGFR [95, 96]. Werner et al. have used
folate-based active targeting to deliver nanoparticles to ovarian
cancer that overexpress folate receptors. Such particles are
internalized by active transport via receptor-mediated endocytosis
. In another example of active targeting, the arginine-glycine-
aspartic acid (RGD) tripeptide was coupled to nanoparticles to
target α5β5 or α5β3 integrin receptors that are overexpressed on
vascular endothelial cells of angiogenic blood vessels of the
proliferating tumor cells . Nucleic acid construct such as
aptamers that can selectively bind to prostate-specific membrane
antigen (PSMA) on prostate cancer cells are also being pursued as
active targeting agents to target prostate tumors.
In effect, active targeting using ligands or antigens coupled to
nanoparticles serve as secondary targeting mechanism for
binding/intracellular trafficking of the drug payload  after the
primary (passive) targeting based on the EPR effect (Fig. 2). Such
multimodal smart delivery systems are currently intensely pursued
and have the potential to revolutionalize cancer theranostics .
3.3. Multifunctional Polymeric Nanoparticulate Delivery
The aim of developing a multi-functional nanoparticulate
delivery system is to achieve several inter-related goals using a
single “nanoplatform”. For instance, a nanosystem can be designed
with low, moderate, or high level of complexity depending on the
requirements of the delivery system and the disease target in the
body such as: i) protection of the payload from degradation on
systemic delivery and elimination of the side effects associated with
Fig. (2). Passive and active tumor drug targeting. The scheme shows the passive and active targeting mechanisms of multifunctional image guided
nanoparticles and the difference in the vasculature of normal and tumor tissues. Drugs and small molecules diffuse freely in and out of the normal and tumor
blood vessels due to their small size and thus the effective drug concentration in the tumor drops rapidly with time. On the opposite, macromolecular drugs and
nanoparticles can passively target tumors due to the leaky vasculature, but they cannot diffuse back into blood stream due to their large size (EPR effect).
Targeting molecules such as antibodies or peptides present on the nanoparticles can selectively bind to cell surface receptors/antigens overexpressed by tumor
cells and can be taken up by receptor-mediated endocytosys (active targeting). The image guiding molecules and contrast agents conjugated/encapsulated in
the nanoparticles can be useful for targeted imaging and (non-invasive) visualization of nanoparticle accumulation/localization, as well as for mechanistic
understanding of events and efficacy of drug treatment simultaneously.
Image-Guided Nanosystems for Cancer Therapy Current Medicinal Chemistry, 2012 Vol. 19, No. 1 5
free drug ; ii) evasion of the immune system and reduction in
RES clearance by surface functionalization of nanoparticles with
stealth molecules, such as PEG, thereby enabling long circulation
half-life in vivo ; iii) to take advantage of the nano-size and
passively target tumor tissues based on the EPR effect ; iv) to
load with single (and often large doses of) or multiple therapeutic
payloads that works synergistically to have a compounded effect on
tumor therapy [106, 107]. In this regard, biodegradable polymeric
nanoparticles based delivery also offers the flexibility to devise the
system to have spatial and temporal control (or controlled erosion
characteristics) [108-110]. For example, the delivery vehicle can be
engineered to release one agent concomitantly with another or if
desired, after a time delay, or in a controlled fashion based on the
therapeutic requirement of the payloads ; v) surface decoration
with targeting molecules such as antibodies or peptides that can
help locate, bind, and/or internalize the nanoparticles into the tumor
cells, or with agents that can trigger the release of the payload
(drugs/genes) in specific location or organelles within the tumor
cells [89, 111-114]; and, vi) targeted and non-targeted nanoparticles
can be designed to facilitate intracellular distribution of the payload
that can be critical for many drugs and genes whose sites of action
are generally located in the cytoplasm or the nucleus . For
example, plasmid DNA, oligonucleotides, micro RNA, siRNA,
peptides, and proteins have their targets in the cytoplasm or
nucleus. Thus, there is a need for these molecules to be transported
inside the cell . More importantly, intracellular trafficking of
drugs and genes is more challenging for morbid and recalcitrant
tumor cells equipped with drug efflux pumps such as P-
glycoprotein (P-gp) and MDR proteins, which are responsible for
MDR . In such cases, nanoparticle-based delivery systems
have shown to evade the drug efflux pathway, thus increasing the
intracellular drug delivery efficiency [117, 118].
4. IMAGE-GUIDED DELIVERY SYSTEMS FOR CANCERS
4.1. Rationale for Image-Guided Delivery
The concept of image guidance as an integral component of
drug delivery system has major advantages over conventional
methodologies of drug treatment. For instance, in the conventional
scenario an anticancer drug or a therapeutic agent is systemically
administered to cancer patients. This type of delivery often lacks
targeting of drugs/genes to specific organs/tissues or sites of interest
(tumors), and there is neither any means of (in situ) tracking or
imaging the in vivo fate nor the ability to measure the delivery
efficiency of drugs/genes. Also, the bioavailability, therapeutic
efficacy, and dose response of drug/gene treatment has to be
estimated based on separate sets of experiments. For example,
imaging the regression of tumors in patients after drug treatment by
imaging modalities such as X-ray CT or radiographic examination
will in itself be a separate intervention. In this regard, co-
administering the image guiding molecules as part of the delivery
system can help to achieve multiple goals in a single dosing, such
as real-time and concurrent assessment of drug delivery
efficiency/targeting, in vivo fate of drug and sites of
localization/accumulation, modes of excretion, as well as imaging
and monitoring the progress of drug treatment.
4.2. Role of Imaging in Nanotechnology
As discussed above, molecular imaging using conventional
molecules such as contrast agents and optical/radiolabeled probes
based on molecular markers have played a key role in disease
identification, monitoring, and staging of cancers. Nanotechnology
is another important area of science that is growing rapidly, which
involves development of novel materials at the nanometer length
dimensions, with unique physico-chemical properties that neither
resemble the bulk nor the native molecular forms of the individual
components . Apart from catering to the broad interest in the
area of biomedical research, nanotechnology is poised to play a
leading role in biomedical imaging especially for medical
conditions such as cancer . In this regard, the merging of
nanotechnology with molecular imaging provides a versatile
platform for novel (nano-) probe design that can augment the
capabilities of conventional imaging agents such as enhanced
sensitivity, specificity and signal amplification and also provide a
modular platform for devising systems with multifunctional
features. For instance, nanoparticles can be designed with
Fig. (3). Radiolabeled immunoliposomes for targeted imaging of tumors. SPECT/CT fused images (coronal view, and transverse view) of 111In- labeled
targeted immunoliposomes taken after 24 h after injection in mouse bearing both sarcomatoid (VAMT-1) and epithelioid (M28) mesothelioma. The uptake of
the radiolabeled immunoliposome in both epithelioid (M28) and sarcomatoid (VAMT-1) subtypes of mesothelioma tumors at 24 h is clearly seen. Adapted
with permission from Ref. . Copyright Elsevier (2011).
6 Current Medicinal Chemistry, 2012 Vol. 19, No. 1 Iyer et al.
fluorescent dyes, radioactive probes, contrast agents, and
therapeutic molecules (anticancer drugs and oligonucleotides), all
in a single construct that can facilitate multimodal and
multipronged strategies for simultaneous detection, prognosis, and
treatment of cancers. [59, 107, 121-124].
Many of the biocompatible polymers are suited to encapsulate
drugs and therapeutic molecules in high concentrations/loading
. Furthermore, many polymeric systems have versatile (and
often abundant) functional groups that can: i) facilitate synthesis of
novel block copolymers that can assist in self assembly [125, 126];
or, ii) be used for conjugation of multiple types of imaging
probes/drugs ; as well as, iii) targeting ligands for multimodal
(targeted-) imaging . Such multifunctional polymeric systems
can form stable self-assembled nanostructures capable of drug/gene
encapsulation, with built-in image guidance . Nanoparticles
are also of great value in evaluating the stability and in vivo fate of
the delivery systems itself for developing robust nanosystems for
future clinical applications. Examples of these nanosystems include
dendrimers, liposomes (Fig. 3), polymeric micelles and
nanoparticles [117, 130-137].
For the development of such diverse multifunctional image-
guided delivery systems, traditional “one polymer-at-a-time”
approaches are laborious and time consuming and require large
amount of resources for optimization and arriving at the right
formulation for the intended therapeutic application. In this respect,
combinatorial approaches and high throughput polymer synthesis
and screening are needed [138-140]. Also, high-throughput
methods can be used for better understanding of structure-property
relationship between the components forming the nanosystems such
as carrier polymer and the drug/genes encapsulated within them. In
our laboratory, we are developing a novel “mix and match” type
combinatorial polymer library screening  and depending on
the type of biodegradable/biocompatible carrier polymers, their
molecular weight, surface
hydrophilic/hydrophobic character they can be matched with the
drug or gene of interest . In this regard, targeting the
polymeric nanosystems with ligands (biomarkers, antibodies,
charge, functionality, and
peptides), and imaging (MRI, optical, radioactive) probes can
provide a quick and reliable assessment on the right ratios of the
building blocks for efficient and stable encapsulation of drugs and
genes into the nanoparticles . This type of approach will,
therefore, expedite the rational design and development of
multifunctional nanosystems in cancer therapy. Another important
criterion in selection of materials is the inherent toxicity/non-
compatibility of some of the components used in building the multi-
component delivery systems. The combinatorial “mix and match”
type screening can thus be useful in developing and identifying
nanosystems that can be designed, for instance to be biocompatible
or devoid of immunogenicity/toxicity or complement activation in
vivo, by the right choice/selection of materials such as incorporation
of counter ion containing moieties to reduce surface charge or by
including PEG-modified blocks to prevent immune recognition
. The schematic representation of formation or self-assembly
of multifunctional nanoparticles from the corresponding building
blocks is shown in Fig. (4).
5. ILLUSTRATIVE EXAMPLES OF IMAGE-GUIDED DRUG
DELIVERY SYSTEMS FOR CANCER
The approach of using imaging and contrast agents for
monitoring drug delivery has already been a part of clinical
intervention. For example the first prototype polymer conjugated
drug SMANCS dissolved in a iodinated lipid contrast medium
(Lipiodol®) is used clinically for simultaneous drug delivery, tumor
detection, and measuring the delivery efficiency in patients using
X-ray CT .
Recently, more sophisticated and complex designs for image
guided drug delivery are being assessed in the in vitro and
preclinical settings by utilizing nanotechnology. Along these lines,
Yu et al, have developed PSMA aptamer-conjugated to
superparamagnetic iron oxide
doxorubicin that could be used for prostate cancer-specific
nanotheranostics . These agents are capable of not only
detecting prostate tumors in vivo (by MRI) but also can selectively
deliver doxorubicin to the tumor tissues .
nanoparticles loaded with
Fig. (4). Multifunctional nanosytems for theranostics. Schematic representation of the formation of: (A) multifunctional self-assembled targeted nanoparticle,
and (B) multifunctional targeted radio-immunoliposome from the corresponding building blocks. The multifunctional nanoparticles and liposomes can be
engineered by self-assembly of polymers/lipids containing various functionalities such as amphiphilic block copolymers, to facilitate formation of stable
nanoparticles loaded with drugs, genes, and imaging agents; antibody and radiolabeled polymer blocks for targeting and imaging; as well as, PEG chains for
enabling long circulation half-life in vivo.
Image-Guided Nanosystems for Cancer Therapy Current Medicinal Chemistry, 2012 Vol. 19, No. 1 7
In another study, Santra et al. have used multimodal optical and
MRI agents containing biocompatible nanoparticles that could
demonstrate targeted optical/MR imaging and cell killing towards
folate receptors expressing cancer cells . A modified solvent
diffusion method was also developed for co-encapsulation of both
an anticancer drug (docetaxel) and NIR dyes into nanoparticles,
which are new additions to the arsenal of nano-delivery systems for
detection, diagnosis, and treatment of cancers .
Ross’s group has been actively pursuing light-activable
theranostic nanoparticles for the imaging and photodynamic therapy
of brain tumors . In this construct, both iron oxide
nanoparticles and photofrin (a potent photosensitizer) was
incorporated within PEG-modified polyacrylamide nanoparticles
. Further, the particles were tagged with a vascular homing
(F3) peptide that binds selectively to nucleolin on angiogenic
endothelial cells and tumor cell surfaces. These particles
demonstrated selective targeting and pronounced antitumor effect in
rat brain animal tumor models .
In another approach, quantum dot (QD)-aptamer conjugates
were used for concurrent cancer imaging and therapy of
doxorubicin delivery based on the bi-fluorescence resonance energy
transfer (Bi-FRET) technique . The surface of quantum dots
was functionalized with a RNA aptamer that could recognize the
extracellular domains of PSMA. The anticancer drug, doxorubicin
was intelligently loaded onto the nanosystem by intercalation of
drug in the double-stranded stem of aptamer forming the QD-
aptamer (doxorubicin) conjugate with reversible self-quenching
properties based on a Bi-FRET mechanism . This smart
multifunctional nanoparticulate system was able to deliver
doxorubicin to the targeted prostate cancer cells as well as sense
and image the drug delivery to the cancer cells by activating the
fluorescence of QDs . Such advanced delivery systems
demonstrate the versatility of nanoparticles for highly specific,
sensitive and therapeutically effective strategies for simultaneous
disease detection and therapy.
Koo et al. have used pH responsive polymeric micelles for
simultaneous non-invasive in vivo imaging and photodynamic
therapy of tumors in mice models . A Michael type addition
reaction was utilized to conjugate a pH-sensitive polymer, poly(b-
amino ester) with methoxiPEG. The block copolymer could self
assemble with hydrophobic radiosensitizer protoporphyrin IX
(PpIX), forming stable nanosized micelles. These micelles showed
marked pH-responsive demicellization and release of the
photosensitizer in the tumors due to the acidic pH conditions.
Furthermore, the micelles showed clear tumor accumulation as
assessed by fluorescence imaging and complete tumor ablation
when irradiated with laser light in tumor bearing mice models,
thereby demonstrating their
potentials for photodynamic
6. ILLUSTRATIVE EXAMPLES OF IMAGE-GUIDED
NUCLEIC ACID DELIVERY FOR CANCER
Gene therapy based on RNA interference (RNAi) mechanism
has been well established and has currently become a major area of
research that hold great promise for the management of diseases
such as cancers. Although RNAi agents have high efficiency and
specificity, the major hurdle still remains its delivery to target
tumor/tissues and intracellular trafficking after localization in the
sites of interest . In this regard, the ability to image/detect and
deliver siRNA has become increasingly important. Researchers in
Moore’s group have developed a dual-purpose probe for in vivo
delivery and simultaneous imaging of siRNA accumulation in
tumors by using high-resolution MRI and NIR in vivo optical
imaging techniques . The siRNA was covalently conjugated to
nanoparticles consisting of NIR dye conjugated magnetic
nanoparticles. Furthermore, the nanoparticles were decorated with a
specific membrane translocation peptide that enables their
intracellular delivery and cytosolic availability . Taken
together, their study demonstrates the feasibility of in vivo tracking
of siRNA, in vivo dual modality imaging of tumor uptake of
nanoparticles, as well as silencing ability of the siRNA-conjugated
In another study, Kumar et al. used superparamagnetic iron
oxide nanoparticles as a construct for combined optical/MR
imaging and delivery of siRNA to solid tumors . The
nanoconstruct, apart from performing its function as a dual
modality imaging agent and a vehicle for the delivery of siRNA
also served as a tool to study basic tumor biology and therapy
. The nanoconstruct consisted of magnetic nanoparticles (for
MRI), a Cy3 fluorophore (for optical imaging), a targeting peptide
(EPPT) that could home to a specific antigen (uMUC-1)
overexpressed by the majority of human breast cancer cells, and a
synthetic siRNA that downregulates the BIRC5 antiapoptotic gene
in breast cancer cells . The nanoconstruct demonstrated
specific tumor uptake and significant downregulation of BIRC5
gene, in animal tumor models. More importantly, the tumor uptake
could be visualized both by MRI and NIR optical imaging .
Researchers from Park’s group developed a polyelectrolyte
complex micelle-based VEGF siRNA delivery system for anti-
angiogenic gene therapy . The complexation of the PEG-
conjugated VEGF siRNA was achieved by charge interaction with
poly(ethyleneimine) (PEI). This complex formed a stable core-shell
nanostructure with the PEI/siRNA forming the central core and
PEG chains forming the corona. The i.v. and i.t. injection of the
micelles in mice demonstrated significant inhibition of VEGF
expression in the tumor tissue and suppressed tumor growth without
detectable toxicities . Furthermore, to confirm the feasibility
of siRNA-based gene therapy and imaging in vivo, optical imaging
was undertaken using a Cy5.5 labeled siRNA. The Cy5.5 labeled
siRNA containing polyelectrolyte complex micelles predominantly
accumulated in the tumor, affirming the feasibility of this approach
In order to overcome the dose-limiting side effects of
conventional chemotherapeutic agents and the therapeutic failure
due to MDR, we designed and evaluated a novel biocompatible
lipid-modified dextran-based self-assembled polymeric nanosystem
that could encapsulate MDR-1 siRNA as well as doxorubicin [71,
151]. Further, in order to image the transfection efficacy of siRNA-
loaded nanoparticles on cell lines we utilized the green fluorescence
protein (GFP) expressing BHK-21 cells, and performed confocal
fluorescence microscopy to visualize the downregulation of GFP. It
was observed the GFP siRNA was efficiently incorporated into
cells and effectively inhibited the expression of GFP in a dose
dependent manner. Similarly, the MDR1 siRNA-loaded dextran
nanoparticles efficiently suppress P-gp expression in a drug
resistant osteosarcoma cell lines. A combination therapy of the
MDR1 siRNA-loaded nanocarriers with doxorubicin revealed
pronounced increase in drug uptake in the nucleus (assessed by
confocal fluorescence microscopy imaging) of MDR cells. These
results demonstrate that our approach may be useful in reversing
MDR by increasing the amount of drug accumulation in MDR cells.
Thus, the delivery using non-toxic and biocompatible dextran-based
nanosystems offers a versatile platform for the incorporation of
multiple payloads for simultaneous imaging and delivery of
therapeutic molecules that can be translatable for human clinical
In another study, Huh et al. designed a siRNA delivery system
containing the biodegradable and biocompatible polymer glycol
chitosan (GC) and PEI (Fig. 5) . The polymers were
conjugated with 5β-cholanic acid (CA) to stabilize the nanoparticles
and endow them with tumor-homing ability. The nanoparticles were
formed by mixing GC-CA and PEI-CA to form self-assembled GC–
8 Current Medicinal Chemistry, 2012 Vol. 19, No. 1 Iyer et al.
PEI nanostructures, due to the strong hydrophobic interactions of
5β-cholanic acids in the polymers. The cationic charge on the GC–
PEI nanoparticles was used to complex with the negatively charged
red fluorescence protein (RFP) gene silencing siRNA designed to
inhibit RFP expression. In vitro studies with RFP expressing
B16F10 tumor cells incubated with siRNA–GC–PEI nanoparticles
revealed time-dependent cellular uptake of the nanoparticles, and
lead to a significant inhibition of RFP gene expression in
RFP/B16F10-bearing mice models, thus demonstrating their
potentials as a promising vector for siRNA delivery (Fig. 5) .
Multifunctional nanoparticles utilizing the active and passive
tumor targeting principles has played a leading role in addressing
some of the critical issues related to cancer drug delivery, such as
overcoming the inherent limitations of drug/genes (with regard to
stability, non-specificity, and short half-life), and the anatomical
and patho-physiological barriers in delivering them specifically to
tumor tissues. In this respect, the role of image guidance is of
paramount importance in drug delivery and many of the
nanosystems currently employ image guiding molecules or
drugs/genes labeled with imaging probes for several reasons, i.e.,
measuring delivery efficiency, selectivity, sites of localization of
drugs/genes, and concurrent measurement of the drug treatment
response (such as reduction in tumor volume). Also, in situ imaging
of the molecular events while the drug is being delivered using
nanoparticles can provide startling insights about the molecular
mechanism of tumor progression (such as its invasion and
metastatic behavior) that can assist a great deal in the future design
and development of novel molecular nanoprobes-based delivery
systems. More importantly, the development of such image-guided
delivery systems can aid in the early detection of cancers, which
can be regarded as one of the most powerful tools in deciphering
possible cures for this deadly disease. These types of advanced
multifunctional precision image-guided nanosystems are thus
envisaged to play a major role in the era of personalized cancer
CONFLICT OF INTEREST
Authors would like to acknowledge the support from the
National Cancer Institute’s Cancer Nanotechnology Platform
Partnership (CNPP) grant U01- CA151452 to Mansoor Amiji, and
NIH R01 CA135358 and the American Cancer Society grant IRG-
97-150-10 to Jiang He.
Bi-FRET = bi-fluorescence resonance energy transfer
BK = bradykinin
CA = 5β-cholanic acid
CT = X-ray computed tomography
EGFR = epidermal growth factor receptors
EPR = enhanced permeability and retention
18F-FDG = 2-[18F]-fluoro-2-deoxy-D-glucose
FMT = 3D-fluorescence molecular tomography
FRI = 2D-fluorescence reflectance imaging
GC = glycol chitosan
GFP = green fluorescence protein
i.a. = intraarterial
i.t. = intratumoral
i.v. = intravenous
MDR = multi-drug resistance
MMPs = matrix metalloproteinases
MRI = magnetic resonance imaging
NIR = near-infrared
NO = nitric oxide
PEG = poly(ethylene glycol)
PEI = poly(ethyleneimine)
PET = positron emission tomography
P-gp = P-glycoprotein
PGs = prostaglandins
PpIX = protoporphyrin IX
PSMA = prostate-specific membrane antigen
QD = quantum dot
RES = reticuloendothelial system
RFP = red fluorescence protein
RGD = arginine-glycine-aspartic acid
RNAi = RNA interference
Fig. (5). Image-guided gene silencing using polymeric nanoparticles. (A) Schematic representation of siRNA-loaded in hydrophobically-modified GC and PEI
nanoparticle (siRNA-GC-PEI NP). (B) In vivo NIR fluorescence imaging of SCC7 tumor-bearing mice 1 h post-injection of Cy5.5-siRNA-GC-PEI NP. (C) In
vivo knockdown of targeted proteins by siRNA (left image) and siRNA-GC-PEI NP (right image) after i.v. injection in B16F10-RFP tumor-bearing mice. The
mice were observed by dual modality imaging using light microscopy and by NIR fluorescence imaging system. Adapted with permission from Ref. .
Copyright Elsevier (2010).
Image-Guided Nanosystems for Cancer Therapy Current Medicinal Chemistry, 2012 Vol. 19, No. 1 9
= small interfering RNA
= single photon emission computed tomography
= vascular endothelial growth factor.
 Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: the next generation. Cell,
2011, 144(5), 646-674.
Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell, 2000, 100(1),
Gupta, P.B.; Chaffer, C.L.; Weinberg, R.A. Cancer stem cells: mirage or
reality? Nat. Med., 2009, 15(9), 1010-1012.
Al-Hajj, M.; Clarke, M.F. Self-renewal and solid tumor stem cells.
Oncogene, 2004, 23(43), 7274-7282.
Martinez-Zaguilan, R.; Seftor, E.A.; Seftor, R.E.; Chu, Y.W.; Gillies, R.J.;
Hendrix, M.J. Acidic pH enhances the invasive behavior of human
melanoma cells. Clin. Exp. Metastasis, 1996, 14(2), 176-186.
Gatenby, R.A.; Gawlinski, E.T. The glycolytic phenotype in carcinogenesis
and tumor invasion: insights through mathematical models. Cancer Res.,
2003, 63(14), 3847-3854.
Asosingh, K.; De Raeve, H.; de Ridder, M.; Storme, G.A.; Willems, A.; Van
Riet, I.; Van Camp, B.; Vanderkerken, K. Role of the hypoxic bone marrow
microenvironment in 5T2MM murine myeloma tumor progression.
Haematologica, 2005, 90(6), 810-817.
Dang, C.V.; Lewis, B.C.; Dolde, C.; Dang, G.; Shim, H. Oncogenes in tumor
metabolism, tumorigenesis, and apoptosis. J. Bioenerg. Biomembr., 1997,
Vaupel, P.; Mayer, A. Hypoxia in cancer: significance and impact on clinical
outcome. Cancer Metastasis Rev., 2007, 26(2), 225-239.
Milane, L.; Duan, Z.; Amiji, M. Role of hypoxia and glycolysis in the
development of multi-drug resistance in human tumor cells and the
establishment of an orthotopic multi-drug resistant tumor model in nude mice
using hypoxic pre-conditioning. Cancer Cell. Int., 2011, 11, 3.
Dutour, A.; Leclers, D.; Monteil, J.; Paraf, F.; Charissoux, J.L.; Rousseau,
R.; Rigaud, M. Non-invasive imaging correlates with histological and
molecular characteristics of an osteosarcoma model: application for early
detection and follow-up of MDR phenotype. Anticancer Res., 2007, 27(6B),
Biedler, J.L. Genetic aspects of multidrug resistance. Cancer, 1992, 70(6
Jabr-Milane, L.S.; van Vlerken, L.E.; Yadav, S.; Amiji, M.M. Multi-
functional nanocarriers to overcome tumor drug resistance. Cancer Treat.
Rev., 2008, 34(7), 592-602.
Donnenberg, V.S.; Donnenberg, A.D. Multiple drug resistance in cancer
revisited: the cancer stem cell hypothesis. J. Clin. Pharmacol., 2005, 45(8),
Cahill, D.P.; Kinzler, K.W.; Vogelstein, B.; Lengauer, C. Genetic instability
and darwinian selection in tumours. Trends Cell Biol., 1999, 9(12), M57-60.
Loeb, L.A.; Loeb, K.R.; Anderson, J.P. Multiple mutations and cancer. Proc.
Natl. Acad. Sci. U. S. A., 2003, 100(3), 776-781.
Rowinsky, E.K.; Chaudhry, V.; Forastiere, A.A.; Sartorius, S.E.; Ettinger,
D.S.; Grochow, L.B.; Lubejko, B.G.; Cornblath, D.R.; Donehower, R.C.
Phase I and pharmacologic study of paclitaxel and cisplatin with granulocyte
colony-stimulating factor: neuromuscular toxicity is dose-limiting. J. Clin.
Oncol., 1993, 11(10), 2010-2020.
Steinherz, L.J.; Steinherz, P.G.; Tan, C.T.; Heller, G.; Murphy, M.L. Cardiac
toxicity 4 to 20 years after completing anthracycline therapy. JAMA, 1991,
Allen, T.M.; Cullis, P.R. Drug delivery systems: entering the mainstream.
Science, 2004, 303(5665), 1818-1822.
Tseng, Y.C.; Mozumdar, S.; Huang, L. Lipid-based systemic delivery of
siRNA. Adv. Drug Deliv. Rev., 2009, 61(9), 721-731.
Whitehead, K.A.; Langer, R.; Anderson, D.G. Knocking down barriers:
advances in siRNA delivery. Nat. Rev. Drug Discov., 2009, 8(2), 129-138.
Wulfkuhle, J.D.; Liotta, L.A.; Petricoin, E.F. Proteomic applications for the
early detection of cancer. Nat. Rev. Cancer, 2003, 3(4), 267-275.
Ott, J.J.; Ullrich, A.; Miller, A.B. The importance of early symptom
recognition in the context of early detection and cancer survival. Eur. J.
Cancer, 2009, 45(16), 2743-2748.
Weissleder, R. Molecular imaging in cancer. Science, 2006, 312(5777),
Massoud, T.F.; Gambhir, S.S. Molecular imaging in living subjects: seeing
fundamental biological processes in a new light. Genes Dev., 2003, 17(5),
Ntziachristos, V.; Chance, B. Probing physiology and molecular function
using optical imaging: applications to breast cancer. Breast Cancer Res.,
2001, 3(1), 41-46.
Tolmachev, V.; Orlova, A.; Nilsson, F.Y.; Feldwisch, J.; Wennborg, A.;
Abrahmsen, L. Affibody molecules: potential for in vivo imaging of
molecular targets for cancer therapy. Expert Opin. Biol. Ther., 2007, 7(4),
Jaffer, F.A.; Weissleder, R. Molecular imaging in the clinical arena. JAMA,
2005, 293(7), 855-862.
Iyer, A.K.; Lan, X.; Zhu, X.; Su, Y.; Feng, J.; Zhang, X.; Gao, D.; Seo, Y.;
Vanbrocklin, H.F.; Broaddus, V.C.; Liu, B.; He, J. Novel human single chain
antibody fragments that are rapidly internalizing effectively target epithelioid
and sarcomatoid mesotheliomas. Cancer Res., 2011, 71(7), 2428-2432.
Yang, D.J.; Azhdarinia, A.; Wu, P.; Yu, D.F.; Tansey, W.; Kalimi, S.K.;
Kim, E.E.; Podoloff, D.A. In vivo and in vitro measurement of apoptosis in
breast cancer cells using 99mTc-EC-annexin V. Cancer Biother.
Radiopharm., 2001, 16(1), 73-83.
Sumer, B.; Gao, J. Theranostic nanomedicine for cancer. Nanomedicine
(Lond.), 2008, 3(2), 137-140.
Gross, S.; Piwnica-Worms, D. Spying on cancer: molecular imaging in vivo
with genetically encoded reporters. Cancer Cell, 2005, 7(1), 5-15.
Weissleder, R. Molecular imaging: exploring the next frontier. Radiology,
1999, 212(3), 609-614.
Corsten, M.F.; Hofstra, L.; Narula, J.; Reutelingsperger, C.P. Counting heads
in the war against cancer: defining the role of annexin A5 imaging in cancer
treatment and surveillance. Cancer Res., 2006, 66(3), 1255-1260.
Mankoff, D.A.; O'Sullivan, F.; Barlow, W.E.; Krohn, K.A. Molecular
imaging research in the outcomes era: measuring outcomes for
individualized cancer therapy. Acad. Radiol., 2007, 14(4), 398-405.
Weissleder, R.; Pittet, M.J. Imaging in the era of molecular oncology.
Nature, 2008, 452(7187), 580-589.
Semelka, R.C.; Armao, D.M.; Elias, J., Jr.; Huda, W. Imaging strategies to
reduce the risk of radiation in CT studies, including selective substitution
with MRI. J. Magn. Reson. Imaging, 2007, 25(5), 900-909.
Aime, S.; Cabella, C.; Colombatto, S.; Geninatti Crich, S.; Gianolio, E.;
Maggioni, F. Insights into the use of paramagnetic Gd(III) complexes in MR-
molecular imaging investigations. J. Magn. Reson. Imaging, 2002, 16(4),
Caravan, P.; Ellison, J.J.; McMurry, T.J.; Lauffer, R.B. Gadolinium(III)
chelates as MRI contrast agents: structure, dynamics, and applications.
Chem. Rev., 1999, 99(9), 2293-2352.
Kaneko, M.; Eguchi, K.; Ohmatsu, H.; Kakinuma, R.; Naruke, T.; Suemasu,
K.; Moriyama, N. Peripheral lung cancer: screening and detection with low-
dose spiral CT versus radiography. Radiology, 1996, 201(3), 798-802.
Maeda, H. SMANCS and polymer-conjugated macromolecular drugs:
advantages in cancer chemotherapy. Adv. Drug Deliv. Rev., 2001, 46(1-3),
Brenner, D.J.; Hall, E.J. Computed tomography--an increasing source of
radiation exposure. N. Engl. J. Med., 2007, 357(22), 2277-2284.
Aberle, D.R.; Adams, A.M.; Berg, C.D.; Black, W.C.; Clapp, J.D.;
Fagerstrom, R.M.; Gareen, I.F.; Gatsonis, C.; Marcus, P.M.; Sicks, J.D.
Reduced lung-cancer mortality with low-dose computed tomographic
screening. N. Engl. J. Med., 2011, 365(5), 395-409.
Bangerter, M.; Kotzerke, J.; Griesshammer, M.; Elsner, K.; Reske, S.N.;
Bergmann, L. Positron emission tomography with 18-fluorodeoxyglucose in
the staging and follow-up of lymphoma in the chest. Acta. Oncol., 1999,
Keidar, Z.; Israel, O.; Krausz, Y. SPECT/CT in tumor imaging: technical
aspects and clinical applications. Semin. Nucl. Med., 2003, 33(3), 205-218.
Berger, F.; Gambhir, S. Recent advances in imaging endogenous or
transferred gene expression utilizing radionuclide technologies in living
subjects: applications to breast cancer. Breast Cancer Res., 2001, 3(1), 28-
Phelps, M. PET: the merging of biology and imaging into molecular
imaging. J. Nucl. Med., 2000, 41(4), 661-681.
Pan, D.; Gambhir, S.; Toyokuni, T.; Iyer, M.; Acharya, N.; Phelps, M.;
Barrio, J. Rapid synthesis of a 5 -fluorinated oligodeoxy-nucleotide: a model
antisense probe for use in imaging with positron emission tomography
(PET). Bioorg. Med. Chem. Lett., 1998, 8(11), 1317-1320.
Wahl, R.L.; Quint, L.E.; Greenough, R.L.; Meyer, C.R.; White, R.I.;
Orringer, M.B. Staging of mediastinal non-small cell lung cancer with FDG
PET, CT, and fusion images: preliminary prospective evaluation. Radiology,
1994, 191(2), 371-377.
Nabi, H.A.; Zubeldia, J.M. Clinical applications of (18)F-FDG in oncology.
J. Nucl. Med. Technol., 2002, 30(1), 3-9; quiz 10-11.
Gambhir, S.S.; Czernin, J.; Schwimmer, J.; Silverman, D.H.; Coleman, R.E.;
Phelps, M.E. A tabulated summary of the FDG PET literature. J. Nucl. Med.,
2001, 42(5 Suppl.), 1S-93S.
Mitterhauser, M.; Toegel, S.; Wadsak, W.; Lanzenberger, R.; Mien, L.;
Kuntner, C.; Wanek, T.; Eidherr, H.; Ettlinger, D.; Viernstein, H. Pre vivo,
ex vivo and in vivo evaluations of [68Ga]-EDTMP. Nucl. Med. Biol., 2007,
Maecke, H.; Hofmann, M.; Haberkorn, U. 68Ga-labeled peptides in tumor
imaging. J. Nucl. Med., 2005, 46(1 suppl), 172S-178S.
Funk, T.; Despres, P.; Barber, W.C.; Shah, K.S.; Hasegawa, B.H. A
multipinhole small animal SPECT system with submillimeter spatial
resolution. Med. Phys., 2006, 33(5), 1259-1268.
Banerjee, S.; Pillai, A.; Raghavan, M.; Ramamoorthy, N. Evolution of Tc-
99m in diagnostic radiopharmaceuticals. Semin. Nucl. Med., 2001, 31, 260-
Hamoudeh, M.; Kamleh, M.A.; Diab, R.; Fessi, H. Radionuclides delivery
systems for nuclear imaging and radiotherapy of cancer. Adv. Drug Deliv.
Rev., 2008, 60(12), 1329-1346.
10 Current Medicinal Chemistry, 2012 Vol. 19, No. 1 Iyer et al.
 Chow, T.H.; Lin, Y.Y.; Hwang, J.J.; Wang, H.E.; Tseng, Y.L.; Pang, V.F.;
Liu, R.S.; Lin, W.J.; Yang, C.S.; Ting, G. Therapeutic efficacy evaluation of
111In-labeled PEGylated liposomal vinorelbine in murine colon carcinoma
with multimodalities of molecular imaging. J. Nucl. Med., 2009, 50(12),
Ting, G.; Chang, C.H.; Wang,
radiopharmaceuticals for tumor imaging and therapy. Anticancer Res., 2009,
Jones, E.F.; He, J.; VanBrocklin, H.F.; Franc, B.L.; Seo, Y. Nanoprobes for
medical diagnosis: current status of nanotechnology in molecular imaging.
Curr. Nanosci., 2008, 4(1), 17-29.
Mariani, G.; Bruselli, L.; Kuwert, T.; Kim, E.E.; Flotats, A.; Israel, O.;
Dondi, M.; Watanabe, N. A review on the clinical uses of SPECT/CT. Eur. J.
Nucl. Med. Mol. Imaging, 2010, 37(10), 1959-1985.
Chatziioannou, A. Instrumentation for molecular imaging in preclinical
research: Micro-PET and Micro-SPECT. Proc. Am. Thorac. Soc., 2005, 2,
Cherry, S. Multimodality imaging: beyond PET/CT and SPECT/CT. Semin.
Nucl. Med., 2009, 39, 348-353.
Judenhofer, M.S.; Wehrl, H.F.; Newport, D.F.; Catana, C.; Siegel, S.B.;
Becker, M.; Thielscher, A.; Kneilling, M.; Lichy, M.P.; Eichner, M.; Klingel,
K.; Reischl, G.; Widmaier, S.; Rocken, M.; Nutt, R.E.; Machulla, H.J.;
Uludag, K.; Cherry, S.R.; Claussen, C.D.; Pichler, B.J. Simultaneous PET-
MRI: a new approach for functional and morphological imaging. Nat. Med.,
2008, 14(4), 459-465.
Kaijzel, E.L.; van der Pluijm, G.; Lowik, C.W. Whole-body optical imaging
in animal models to assess cancer development and progression. Clin.
Cancer Res., 2007, 13(12), 3490-3497.
Choy, G.; Choyke, P.; Libutti, S.K. Current advances in molecular imaging:
noninvasive in vivo bioluminescent and fluorescent optical imaging in cancer
research. Mol. Imaging, 2003, 2(4), 303-312.
Sokolov, K.; Follen, M.; Aaron, J.; Pavlova, I.; Malpica, A.; Lotan, R.;
Richards-Kortum, R. Real-time vital optical imaging of precancer using anti-
epidermal growth factor receptor antibodies conjugated to gold
nanoparticles. Cancer Res., 2003, 63(9), 1999-2004.
Moore, R.L. Treatment of an infant with paroxysmal auricular tachycardia.
Pediatrics, 1948, 2(3), 266-271.
Graves, E.E.; Weissleder, R.; Ntziachristos, V. Fluorescence molecular
imaging of small animal tumor models. Curr. Mol. Med., 2004, 4(4), 419-
Hilderbrand, S.A.; Weissleder, R. Near-infrared fluorescence: application to
in vivo molecular imaging. Curr. Opin. Chem. Biol., 2010, 14(1), 71-79.
Potineni, A.; Lynn, D.M.; Langer, R.; Amiji, M.M. Poly(ethylene oxide)-
modified poly(beta-amino ester)
biodegradable system for paclitaxel delivery. J. Control. Release, 2003,
Susa, M.; Iyer, A.K.; Ryu, K.; Choy, E.; Hornicek, F.J.; Mankin, H.; Milane,
L.; Amiji, M.M.; Duan, Z. Inhibition of ABCB1 (MDR1) expression by an
siRNA nanoparticulate delivery system to overcome drug resistance in
osteosarcoma. PLoS One, 2010, 5(5), e10764.
van Vlerken, L.E.; Vyas, T.K.; Amiji, M.M. Poly(ethylene glycol)-modified
nanocarriers for tumor-targeted and intracellular delivery. Pharm. Res., 2007,
Harris, J.M.; Martin, N.E.; Modi, M. Pegylation: a novel process for
modifying pharmacokinetics. Clin. Pharmacokinet., 2001, 40(7), 539-551.
Tiwari, S.B.; Amiji, M.M. Improved oral delivery of paclitaxel following
administration in nanoemulsion formulations. J. Nanosci. Nanotechnol.,
2006, 6(9-10), 3215-3221.
Kim, K.; Kim, J.H.; Park, H.; Kim, Y.S.; Park, K.; Nam, H.; Lee, S.; Park,
J.H.; Park, R.W.; Kim, I.S.; Choi, K.; Kim, S.Y.; Kwon, I.C. Tumor-homing
multifunctional nanoparticles for cancer theragnosis: Simultaneous
diagnosis, drug delivery, and therapeutic monitoring. J. Control. Release,
2010, 146(2), 219-227.
Folkman, J. Angiogenesis in cancer, vascular, rheumatoid and other disease.
Nat. Med., 1995, 1(1), 27-31.
Ghosh, K.; Thodeti, C.K.; Dudley, A.C.; Mammoto, A.; Klagsbrun, M.;
Ingber, D.E. Tumor-derived endothelial cells exhibit aberrant Rho-mediated
mechanosensing and abnormal angiogenesis in vitro. Proc. Natl. Acad. Sci.
U. S. A., 2008, 105(32), 11305-11310.
Greish, K.; Fang, J.; Inutsuka, T.; Nagamitsu, A.; Maeda, H. Macromolecular
therapeutics: advantages and prospects with special emphasis on solid
tumour targeting. Clin. Pharmacokinet., 2003, 42(13), 1089-1105.
Padera, T.P.; Kadambi, A.; di Tomaso, E.; Carreira, C.M.; Brown, E.B.;
Boucher, Y.; Choi, N.C.; Mathisen, D.; Wain, J.; Mark, E.J.; Munn, L.L.;
Jain, R.K. Lymphatic metastasis in the absence of functional intratumor
lymphatics. Science, 2002, 296(5574), 1883-1886.
Matsumura, Y.; Maeda, H. A new concept for macromolecular therapeutics
in cancer chemotherapy: mechanism of tumoritropic accumulation of
proteins and the antitumor agent smancs. Cancer Res., 1986, 46, 6387-6392.
Maeda, H.; Wu, J.; Sawa, T.; Matsumura, Y.; Hori, K. Tumor vascular
permeability and the EPR effect in macromolecular therapeutics: a review. J.
Control. Release, 2000, 65(1-2), 271-284.
Senger, D.R.; Galli, S.J.; Dvorak, A.M.; Perruzzi, C.A.; Harvey, V.S.;
Dvorak, H.F. Tumor cells secrete a vascular permeability factor that
promotes accumulation of ascites fluid. Science, 1983, 219(4587), 983-985.
 H.E. Cancer nanotargeted
nanoparticles as a pH-sensitive
 Dvorak, H.F.; Nagy, J.A.; Feng, D.; Brown, L.F.; Dvorak, A.M. Vascular
permeability factor/vascular endothelial growth factor and the significance of
microvascular hyperpermeability in angiogenesis. Curr. Top. Microbiol.
Immunol., 1999, 237, 97-132.
Senger, D.R.; Galli, S.J.; Dvorak, A.M.; Perruzzi, C.A.; Harvey, V.S.;
Dvorak, H.F. Tumor cells secrete a vascular permeability factor that
promotes accumulation of ascites fluid. Science, 1983, 219(4587), 983-985.
Maeda, H. The enhanced permeability and retention (EPR) effect in tumor
vasculature: the key role of tumor-selective macromolecular drug targeting.
Adv. Enzyme Regul., 2001, 41, 189-207.
Iyer, A.; Khaled, G.; Fang, J.; Maeda, H. Exploiting the enhanced
permeability and retention effect for tumor targeting. Drug Discov. Today,
2006, 11(17-18), 812-818.
Maeda, H.; Bharate, G.Y.; Daruwalla, J. Polymeric drugs for efficient tumor-
targeted drug delivery based on EPR-effect. Eur. J. Pharm. Biopharm., 2009,
Duncan, R.; Ringsdorf, H.; Satchi-Fainaro, R. Polymer therapeutics--
polymers as drugs, drug and protein conjugates and gene delivery systems:
past, present and future opportunities. J. Drug Target., 2006, 14(6), 337-341.
Ganta, S.; Devalapally, H.; Shahiwala, A.; Amiji, M. A review of stimuli-
responsive nanocarriers for drug and gene delivery. J. Control. Release,
2008, 126(3), 187-204.
Danhier, F.; Feron, O.; Préat, V. To exploit the tumor microenvironment:
passive and active tumor targeting of nanocarriers for anti-cancer drug
delivery. J. Control. Release, 2010, 148(2), 135-146.
Yuan, F.; Dellian, M.; Fukumura, D.; Leunig, M.; Berk, D.A.; Torchilin,
V.P.; Jain, R.K. Vascular permeability in a human tumor xenograft:
molecular size dependence and cutoff size. Cancer Res., 1995, 55(17), 3752-
Davis, S.S. Biomedical applications of nanotechnology--implications for
drug targeting and gene therapy. Trends Biotechnol., 1997, 15(6), 217-224.
Kuszyk, B.S.; Corl, F.M.; Franano, F.N.; Bluemke, D.A.; Hofmann, L.V.;
Fortman, B.J.; Fishman, E.K. Tumor transport physiology: implications for
imaging and imaging-guided therapy. Am. J. Roentgenol., 2001, 177(4), 747-
Marcucci, F.; Lefoulon, F. Active targeting with particulate drug carriers in
tumor therapy: fundamentals and recent progress. Drug Discov. Today, 2004,
Milane, L.; Duan, Z.F.; Amiji, M. Pharmacokinetics and biodistribution of
lonidamine/paclitaxel loaded, EGFR-targeted nanoparticles in an orthotopic
animal model of multi-drug resistant breast cancer. Nanomedicine, 2011,
Milane, L.; Duan, Z.; Amiji, M. Development of EGFR-targeted polymer
blend nanocarriers for combination paclitaxel/lonidamine delivery to treat
multi-drug resistance in human breast and ovarian tumor cells. Mol. Pharm.,
2011, 8(1), 185-203.
Werner, M.E.; Karve, S.; Sukumar, R.; Cummings, N.D.; Copp, J.A.; Chen,
R.C.; Zhang, T.; Wang, A.Z. Folate-targeted nanoparticle delivery of chemo-
and radiotherapeutics for the treatment of ovarian cancer peritoneal
metastasis. Biomaterials, 2011, 32(33), 8548-8554.
Rihova, B. Receptor-mediated targeted drug or toxin delivery. Adv. Drug
Deliv. Rev., 1998, 29(3), 273-289.
Lue, N.; Ganta, S.; Hammer, D.X.; Mujat, M.; Stevens, A.E.; Harrison, L.;
Ferguson, R.D.; Rosen, D.; Amiji, M.; Iftimia, N. Preliminary evaluation of a
nanotechnology-based approach for the more effective diagnosis of colon
cancers. Nanomedicine (Lond.), 2010, 5(9), 1467-1479.
Farokhzad, O.C.; Karp, J.M.; Langer, R. Nanoparticle-aptamer bioconjugates
for cancer targeting. Expert Opin. Drug Deliv., 2006, 3(3), 311-324.
Iyer, A.K.; Su, Y.; Feng, J.; Lan, X.; Zhu, X.; Liu, Y.; Gao, D.; Seo, Y.;
Vanbrocklin, H.F.; Courtney Broaddus, V.; Liu, B.; He, J. The effect of
internalizing human single chain antibody fragment on liposome targeting to
epithelioid and sarcomatoid mesothelioma. Biomaterials, 2011, 32(10),
Benyettou, F.; Lalatonne, Y.; Chebbi, I.; Di Benedetto, M.; Serfaty, J.M.;
Lecouvey, M.; Motte, L. A multimodal magnetic resonance imaging
nanoplatform for cancer theranostics. Phys. Chem. Chem. Phys., 2011,
O'Brien, M.E.; Wigler, N.; Inbar, M.; Rosso, R.; Grischke, E.; Santoro, A.;
Catane, R.; Kieback, D.G.; Tomczak, P.; Ackland, S.P.; Orlandi, F.; Mellars,
L.; Alland, L.; Tendler, C. Reduced cardiotoxicity and comparable efficacy
in a phase III trial of pegylated liposomal doxorubicin HCl (CAELYX/Doxil)
versus conventional doxorubicin for first-line treatment of metastatic breast
cancer. Ann. Oncol., 2004, 15(3), 440-449.
Otsuka, H.; Nagasaki, Y.; Kataoka, K. PEGylated nanoparticles for
biological and pharmaceutical applications. Adv. Drug Deliv. Rev., 2003,
Maeda, H.; Matsumura, Y. EPR effect based drug design and clinical outlook
for enhanced cancer chemotherapy. Adv. Drug. Deliv. Rev., 2011, 63(3), 129-
van Vlerken, L.E.; Duan, Z.; Little, S.R.; Seiden, M.V.; Amiji, M.M.
Biodistribution and pharmacokinetic analysis of Paclitaxel and ceramide
administered in multifunctional polymer-blend nanoparticles in drug resistant
breast cancer model. Mol. Pharm., 2008, 5(4), 516-526.
Cao, N.; Cheng, D.; Zou, S.; Ai, H.; Gao, J.; Shuai, X. The synergistic effect
of hierarchical assemblies of siRNA and chemotherapeutic drugs co-
Image-Guided Nanosystems for Cancer Therapy Current Medicinal Chemistry, 2012 Vol. 19, No. 1 11 Download full-text
delivered into hepatic cancer cells. Biomaterials, 2011, 32(8), 2222-2232.
Bhavsar, M.D.; Amiji, M.M. Gastrointestinal distribution and in vivo gene
transfection studies with nanoparticles-in-microsphere oral system (NiMOS).
J. Control. Release, 2007, 119(3), 339-348.
Uhrich, K.E.; Cannizzaro, S.M.; Langer, R.S.; Shakesheff, K.M. Polymeric
systems for controlled drug release. Chem. Rev., 1999, 99(11), 3181-3198.
Dillen, K.; Vandervoort, J.; Van den Mooter, G.; Ludwig, A. Evaluation of
ciprofloxacin-loaded Eudragit RS100 or RL100/PLGA nanoparticles. Int. J.
Pharm., 2006, 314(1), 72-82.
Ghotbi, Z.; Haddadi, A.; Hamdy, S.; Hung, R.W.; Samuel, J.; Lavasanifar, A.
Active targeting of dendritic cells with mannan-decorated PLGA
nanoparticles. J. Drug Target., 2011, 19(4), 281-292.
Choi, C.H.; Alabi, C.A.; Webster, P.; Davis, M.E. Mechanism of active
targeting in solid tumors with transferrin-containing gold nanoparticles.
Proc. Natl. Acad. Sci. U. S. A., 2010, 107(3), 1235-1240.
Choi, K.Y.; Chung, H.; Min, K.H.; Yoon, H.Y.; Kim, K.; Park, J.H.; Kwon,
I.C.; Jeong, S.Y. Self-assembled hyaluronic acid nanoparticles for active
tumor targeting. Biomaterials, 2010, 31(1), 106-114.
Pecot, C.V.; Calin, G.A.; Coleman, R.L.; Lopez-Berestein, G.; Sood, A.K.
RNA interference in the clinic: challenges and future directions. Nat. Rev.
Cancer, 2011, 11(1), 59-67.
Torchilin, V.P. Recent approaches to intracellular delivery of drugs and
DNA and organelle targeting. Annu. Rev. Biomed. Eng., 2006, 8, 343-375.
Panyam, J.; Labhasetwar, V. Targeting intracellular targets. Curr. Drug.
Deliv., 2004, 1(3), 235-247.
Devalapally, H.; Duan, Z.; Seiden, M.V.; Amiji, M.M. Modulation of drug
resistance in ovarian adenocarcinoma by enhancing intracellular ceramide
using tamoxifen-loaded biodegradable polymeric nanoparticles. Clin.
Cancer. Res., 2008, 14(10), 3193-3203.
van Vlerken, L.E.; Duan, Z.; Seiden, M.V.; Amiji, M.M. Modulation of
intracellular ceramide using polymeric nanoparticles to overcome multidrug
resistance in cancer. Cancer Res., 2007, 67(10), 4843-4850.
Daniel, M.C.; Astruc, D. Gold nanoparticles: assembly, supramolecular
chemistry, quantum-size-related properties, and applications toward biology,
catalysis, and nanotechnology. Chem. Rev., 2004, 104(1), 293-346.
Sahoo, S.K.; Labhasetwar, V. Nanotech approaches to drug delivery and
imaging. Drug Discov. Today, 2003, 8(24), 1112-1120.
McCarthy, J.R.; Weissleder, R. Multifunctional magnetic nanoparticles for
targeted imaging and therapy. Adv. Drug Deliv. Rev., 2008, 60(11), 1241-
Gindy, M.E.; Prud'homme, R.K. Multifunctional nanoparticles for imaging,
delivery and targeting in cancer therapy. Expert Opin. Drug Deliv., 2009,
Koning, G.A.; Krijger, G.C. Targeted multifunctional lipid-based
nanocarriers for image-guided drug delivery. Anticancer Agents Med. Chem.,
2007, 7(4), 425-440.
Lammers, T.; Subr, V.; Peschke, P.; Kuhnlein, R.; Hennink, W.E.; Ulbrich,
K.; Kiessling, F.; Heilmann, M.; Debus, J.; Huber, P.E.; Storm, G. Image-
guided and passively tumour-targeted polymeric nanomedicines for
radiochemotherapy. Br. J. Cancer, 2008, 99(6), 900-910.
Iyer, A.K.; Greish, K.; Fang, J.; Murakami, R.; Maeda, H. High-loading
nanosized micelles of copoly(styrene-maleic acid)-zinc protoporphyrin for
targeted delivery of a potent heme oxygenase inhibitor. Biomaterials, 2007,
Wang, F.; Bronich, T.K.; Kabanov, A.V.; Rauh, R.D.; Roovers, J. Synthesis
and evaluation of a star amphiphilic block copolymer from poly(epsilon-
caprolactone) and poly(ethylene glycol) as a potential drug delivery carrier.
Bioconjug. Chem., 2005, 16(2), 397-405.
Gillies, E.R.; Frechet, J.M. Dendrimers and dendritic polymers in drug
delivery. Drug Discov. Today, 2005, 10(1), 35-43.
Peer, D.; Karp, J.M.; Hong, S.; Farokhzad, O.C.; Margalit, R.; Langer, R.
Nanocarriers as an emerging platform for cancer therapy. Nat. Nanotechnol.,
2007, 2(12), 751-760.
Kim, J.; Piao, Y.; Hyeon, T. Multifunctional nanostructured materials for
multimodal imaging, and simultaneous imaging and therapy. Chem. Soc.
Rev., 2009, 38(2), 372-390.
Wijagkanalan, W.; Kawakami, S.; Hashida, M. Designing dendrimers for
drug delivery and imaging: pharmacokinetic considerations. Pharm. Res.,
2011, 28(7), 1500-1519.
Liu, M.; Frechet, J.M. Designing dendrimers for drug delivery. Pharm. Sci.
Technol. Today, 1999, 2(10), 393-401.
Gabizon, A.; Chisin, R.; Amselem, S.; Druckmann, S.; Cohen, R.; Goren, D.;
Fromer, I.; Peretz, T.; Sulkes, A.; Barenholz, Y. Pharmacokinetic and
imaging studies in patients receiving a formulation of liposome-associated
adriamycin. Br. J. Cancer, 1991, 64(6), 1125-1132.
Mikhaylova, M.; Stasinopoulos, I.; Kato, Y.; Artemov, D.; Bhujwalla, Z.M.
Imaging of cationic multifunctional liposome-mediated delivery of COX-2
siRNA. Cancer Gene Ther., 2009, 16(3), 217-226.
Magin, R.L.; Wright, S.M.; Niesman, M.R.; Chan, H.C.; Swartz, H.M.
Liposome delivery of NMR contrast agents for improved tissue imaging.
Magn. Reson. Med., 1986, 3(3), 440-447.
Mackiewicz, N.; Gravel, E.; Garofalakis, A.; Ogier, J.; John, J.; Dupont,
D.M.; Gombert, K.; Tavitian, B.; Doris, E.; Duconge, F. Tumor-targeted
polydiacetylene micelles for in vivo imaging and drug delivery. Small, 2011,
Li, X.; Qian, Y.; Liu, T.; Hu, X.; Zhang, G.; You, Y.; Liu, S. Amphiphilic
multiarm star block copolymer-based multifunctional unimolecular micelles
for cancer targeted drug delivery and MR imaging. Biomaterials, 2011,
Feng, X.; Lv, F.; Liu, L.; Tang, H.; Xing, C.; Yang, Q.; Wang, S. Conjugated
polymer nanoparticles for drug delivery and imaging. ACS Appl. Mater.
Interfaces, 2010, 2(8), 2429-2435.
Goldberg, M.; Mahon, K.; Anderson, D. Combinatorial and rational
approaches to polymer synthesis for medicine. Adv. Drug Deliv. Rev., 2008,
Abeylath, S.C.; Ganta, S.; Iyer, A.K.; Amiji, M. Combinatorial-designed
multifunctional polymeric nanosystems for tumor-targeted therapeutic
delivery. Acc. Chem. Res., 2011, 44(10), 1009-1017.
Green, J.J.; Langer, R.; Anderson, D.G. A Combinatorial polymer library
approach yields insight into nonviral gene delivery. Acc. Chem. Res., 2008,
Kim, S.H.; Jeong, J.H.; Lee, S.H.; Kim, S.W.; Park, T.G. Local and systemic
delivery of VEGF siRNA using polyelectrolyte complex micelles for
effective treatment of cancer. J. Control. Release, 2008, 129(2), 107-116.
Maeda, H.; Sawa, T.; Konno, T. Mechanism of tumor-targeted delivery of
macromolecular drugs, including the EPR effect in solid tumor and clinical
overview of the prototype polymeric drug SMANCS. J. Control. Release,
2001, 74(1-3), 47-61.
Yu, M.K.; Kim, D.; Lee, I.H.; So, J.S.; Jeong, Y.Y.; Jon, S. Image-guided
prostate cancer therapy using aptamer-functionalized thermally cross-linked
superparamagnetic iron oxide nanoparticles. Small, 2011, 7(15), 2241-2249.
Santra, S.; Kaittanis, C.; Grimm, J.; Perez, J.M. Drug/dye-loaded,
multifunctional iron oxide nanoparticles for combined targeted cancer
therapy and dual optical/magnetic resonance imaging. Small, 2009, 5(16),
Reddy, G.R.; Bhojani, M.S.; McConville, P.; Moody, J.; Moffat, B.A.; Hall,
D.E.; Kim, G.; Koo, Y.E.; Woolliscroft, M.J.; Sugai, J.V.; Johnson, T.D.;
Philbert, M.A.; Kopelman, R.; Rehemtulla, A.; Ross, B.D. Vascular targeted
nanoparticles for imaging and treatment of brain tumors. Clin. Cancer Res.,
2006, 12(22), 6677-6686.
Bagalkot, V.; Zhang, L.; Levy-Nissenbaum, E.; Jon, S.; Kantoff, P.W.;
Langer, R.; Farokhzad, O.C. Quantum dot-aptamer conjugates for
synchronous cancer imaging, therapy, and sensing of drug delivery based on
bi-fluorescence resonance energy transfer. Nano Lett., 2007, 7(10), 3065-
Koo, H.; Lee, H.; Lee, S.; Min, K.H.; Kim, M.S.; Lee, D.S.; Choi, Y.; Kwon,
I.C.; Kim, K.; Jeong, S.Y. In vivo tumor diagnosis and photodynamic therapy
via tumoral pH-responsive polymeric micelles. Chem. Commun. (Camb.),
2010, 46(31), 5668-5670.
Shegokar, R.; Al Shaal, L.; Mishra, P.R. SiRNA delivery: challenges and
role of carrier systems. Pharmazie, 2011, 66(5), 313-318.
Medarova, Z.; Pham, W.; Farrar, C.; Petkova, V.; Moore, A. In vivo imaging
of siRNA delivery and silencing in tumors. Nat. Med., 2007, 13(3), 372-377.
Kumar, M.; Yigit, M.; Dai, G.; Moore, A.; Medarova, Z. Image-guided
breast tumor therapy using a small interfering RNA nanodrug. Cancer Res.,
2010, 70(19), 7553-7561.
Susa, M.; Iyer, A.K.; Ryu, K.; Hornicek, F.J.; Mankin, H.; Amiji, M.M.;
Duan, Z. Doxorubicin loaded polymeric nanoparticulate delivery system to
overcome drug resistance in osteosarcoma. BMC Cancer, 2009, 9, 399.
Huh, M.S.; Lee, S.Y.; Park, S.; Lee, S.; Chung, H.; Choi, Y.; Oh, Y.K.; Park,
J.H.; Jeong, S.Y.; Choi, K.; Kim, K.; Kwon, I.C. Tumor-homing glycol
chitosan/polyethylenimine nanoparticles for the systemic delivery of siRNA
in tumor-bearing mice. J. Control. Release, 2010, 144(2), 134-143.