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12 PEGylated Nanocarriers forDiagnostic Applications
357
macrophage recognition and clearance and extending their duration in circulation.
Regardless of the method of delivery, in vivo investigations have shown that
PEGylated NPs have minimal adverse impact on various cell lines. PEGylation has
been recognized as a particularly efcient and biocompatible way for decreasing
renal clearance (Huang etal. 2014) (Fig.12.4).
PEG-AuNPs have a negative charge, various biomolecules, including pharmaceuticals, genes, and targeting ligands, that can easily functionalize them. Surface
plasmon resonance (SPR) bands are present in PEG-AuNPs, which also have an
ultra-small size, a macroscopic quantum tunnelling effect, and a distinct surface
effect. PEG-AuNPs conrm the most promising material for a variety of biomedical
applications, such as biosensing, molecular imaging, drug carriers, and so on (Kong
etal. 2017).
Synthesized PEG-AuNPs have highly unique plasmonic features that enable the
detection of various compounds using SER spectroscopy, which can be done on
solid spots or in liquid droplets. The SER spectra obtained using this new class of
nanoparticles on various molecules of interest (methylene blue, rhodamine 6G,
doxorubicin, and 5-uorouracil) are highly reproducible due to their distinctive
plasmonic properties, making them excellent candidates for further use as SERS
substrates (Nițică etal. 2018).
Due to the unique properties of AuNPs, they have long been thought of as a possible tool for cancer diagnostics and delivery of drug applications. Among these
characteristics are a high surface area-to-volume ratio, stable nature, surface plasmon resonance, surface chemistry, and ease of synthesis. Additionally, the nontoxic and non-immunogenic properties of AuNPs as well as their EPR effect offer
additional benets by making it simple for drugs to penetrate and accumulate at
tumor sites. AuNPs are used mainly in ultrasensitive detection and imaging-based
therapeutic approaches necessary for treating fatal diseases like cancer because of
their optical qualities. Numerous varieties of AuNPs, including gold nanorods,
nanocages, nanostars, nanocubes, and nanospheres, have been developed for human
cancer and cell biology.
Fig. 12.4 Gold nanoparticles targeting tumor cells
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N. Gupta et al.
AuNPs’ optical characteristics depend on SPR.The SPR is a mechanism that
involves the resonance of gold electrons in response to an incoming radiation, which
causes them to simultaneously absorb and scatter light. Photoimaging can help
identify tumors in their early stages and direct them towards precise surgical intervention. Having a clear understanding of where the tumor ends and the healthy tissue begins is one of the main issues facing surgeons today. Throughout a surgical
procedure, the surgeons must decide how much of the tumor must be removed; if
they are too conservative, they risk leaving some tumor cells behind, and if they are
too liberal, they risk removing healthy tissues that may be crucial. The majority of
tumors come back over time because most treatments are highly conservative.
The tumors are only recognized when they reach a particular threshold since
MRI and Computed Tomography (CT) scans have limitations and can only detect
tumors above a size of several millimeters or roughly ten million cells. Gold
nanoparticles are targetedly injected into the tumor, where they precisely bond to
the cancer cells and scatter (shine), making it simpler for the surgeons to distinguish
between the tumor and healthy cells. This revolutionary method of cancer treatment
is called photoimaging. Due to their bioinertness and capacity to boost spatial and
temporal resolution for imaging, gold nanoparticles (nanorods, nanocages, and
nanoshells) are regarded as the best photo-imaging nanoparticles for cancer therapies currently on the market (Singh etal. 2018).
12.2.5 PEGylated PLGA Nanocarriers inDiagnostic Applications
Poly(D, L-lactic-co-glycolic acid) (PLGA) has been extensively used among the
range of organic or inorganic nanomaterials available for the development of drug
delivery systems for cancer therapy and detection because of its biocompatibility
and biodegradability.
Since lactic acid and glycolic acid, which are organic, non-toxic substances that
can eventually be broken down into water and carbon dioxide, may be produced
when PLGA and PLA are broken down, they have been utilized more frequently
than other materials in the production of nanocarriers. PLGA additionally gained
FDA approval for usage in medical applications.
The different targeting moieties can be added to the surface of PLGA-based drug
delivery systems to enable them to target tumors. Additionally, PEGylation of the
outer surface of the PLGA-based drug delivery systems may increase their blood
circulation time. The imaging properties for tumor diagnostics can also be acquired
by integrating the imaging agents into PLGA-based drug delivery systems. Potential
candidates for cancer therapies and diagnostics, called “cancer theranostics” can be
developed by co-loading therapeutic drugs and imaging agents into PLGA-based
drug delivery systems.
By applying external stimuli such as photo, ultrasound, magnetic eld, and
radiofrequency to the targeted areas, remotely triggered cancer therapy can enable
the selective and accurate removal of tumors and controlled release of chemotherapeutics. Additionally, remotely triggered cancer therapy can control when and how
12 PEGylated Nanocarriers forDiagnostic Applications
359
long the treatment lasts, allowing precise treatment and reducing systemic toxicity.
In addition to hydrophilic therapeutic drugs and imaging agents, therapeutic hydrophobic medicines and imaging agents can also be encapsulated into PLGA NPs by
using the water-in-oil-in-water (W/O/W) double emulsion method. This may
enhance the targeting and bioavailability of hydrophobic drugs and imaging agents
and ultimately lead to the accomplishment of cancer theranostics. A promising anticancer strategy that can selectively and accurately eliminate solid tumors and
remotely control the drug release is using outside factors to initiate cancer therapy
(Shen etal. 2020).
PLGA NPs delivered intravenously are rapidly eliminated by the RES and are
easily opsonized. A new class of amphiphilic block co-polymer nanoplatform,
PEG-PLGA NPs, has been developed through conjugating PEG with PLGA to
enhance the characteristics of PLGA nanoparticles and achieve long-term therapeutic benets. PLGA-based contrast agent composite nanomaterials’ biocompatibility
is substantially improved by PEGylation. Through the EPR effect, PEG-PLGA NPs
modied with ligands can target specic receptors on the tumor surface, facilitating
tumor targeting. However, more study is needed to determine the biocompatibility,
toxicity, and safety of these nanocarriers to ensure their clinical applicability.
Studies must continue searching for ways to customize NPs to recognize tumors as
new cancer-specic target molecules are constantly being found. This strategy could
potentially open new avenues for effective cancer treatment and diagnostic imaging
(Zhang etal. 2022).
12.3 Role ofPEGylated Nanocarriers inDiagnosis ofDiseases
Coating the surface of NPs with PEG, or “PEGylation,” is a commonly used
approach for improving the diagnostic and imaging application employed for various critical diseases.
12.3.1 PEGylated Nanocarriers inCancer Tissue Diagnosis
In the United States, cancer is the second greatest cause of morbidity and mortality,
and it is predicted that rates will rise for at least few years to come. Successfully
delivering innovative therapeutic medicines to the target site while preventing
adverse side effects from systemic treatment is a signicant challenge. The EPR
effect has become widely recognized due to the particular physiology of tumors,
which includes fenestrated vasculature and inadequate lymphatic drainage. By this
process, the tumor–neovasculature’s wide gaps between adjacent endothelial cells
enable passive targeting of the tumor site. At the same time, inadequate lymphatic
outow increases the retention of macromolecular therapies within the tumor mass.
The ability of the therapies to reach their designated cellular and intracellular
target locations while minimizing accumulation and action at nonspecic areas is
crucial for the success of anticancer therapies. PEG surface modication of
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N. Gupta et al.
nanoparticulate carriers has emerged as a strategy to improve hydrophobic drug
solubility, extend circulation time, reduce nonspecic uptake, and enable specic
tumor- targeting through the EPR effect.
Additionally, PEG modication has become a platform for incorporating active
targeting ligands, offering the drug and gene carriers unique tumor-targeting abilities through a exible tether. Longer circulation improves the possibility that the
nanocarriers will reach the tumor interstitium, where it may be possible to accumulate a more considerable portion of the given dose than the tumor would experience
when medications are administered parenterally without a carrier (Van Vlerken
etal. 2007). Due to PEG’s ability to allow for prolonged bloodstream circulation of
the NPs followed by passive accumulation in the tumor tissue, it has been widely
researched for the production of tumor-targetable NPs The PEG surface, in particular, makes it possible for NPs to bypass the RES and minimizing their clearance
from the liver site. Future brain tumor treatment is likely to be signicantly impacted
by nanotechnology. Especially, NPs could revolutionize brain research, tumor imaging, surgery, and adjuvant therapies. MRI is one of the most advanced nanotechnology applications for diagnosing brain tumors.
As MRI contrast agents, several NPs have been developed. Iron oxide (IO) crystals have produced NP-based contrast agents with an organic shell-like PEG.The
primary advantage of NPs-based materials is that they can give more accurate information regarding the size of a tumor. Both gadolinium-based contrast agents and
NPs-based contrast agents increase tumors by traveling through regions with damaged blood-brain barrier (BBB), where they change the magnitude of the MRI signal. IO-based NPs can be used to nd improved MRI.Additionally, IO-based NPs
have a propensity to persist longer inside the tumor and more precisely delineate
tumor margins than freely diffusing gadolinium chelates. NPs also have the ability
to target molecular tumors very specically. Developing NPs with specic cellular
imaging capabilities, such as stem cells or endothelial cells, is feasible. As tumorspecic contrast agents, several IO NPs now under research appear promising. NPsbased MRI contrast agents have the potential to make tumor areas visible that would
not have been seen with conventional MRI, particularly at the tumor–brain interface. Furthermore, NPs may eventually enhance the accuracy of brain tumor resection (Orringer etal. 2009).
12.3.2 PEGylated Nanocarriers inDiagnosis ofGlioma–
Brain Tumor
The most prevalent and deadly malignant brain tumor is glioma. Due to a lack of
effective treatment, glioblastoma (GBM) patients often only survive for
12–15months after diagnosis. The most successful treatment for glioma patients is
surgical resection, and maximizing safe resection is essential in improving the
prognosis of patients with low or high-grade gliomas. However, the inltrative
nature of the tumors makes it challenging to strike a balance between maximum
cytoreduction and preservation of normal brain tissue. It is believed that small
12 PEGylated Nanocarriers forDiagnostic Applications
361
glioma cells that inltrate the region around the primary tumor are the cause of
over 90% of recurrent tumors, which manifest within a margin of 2–3cm from the
primary site. It has been established that one of the most signicant predictors of
overall survival and progression-free survival and neurological prognosis is the
degree of resection.
Thus, maximum safe resection becomes tremendously essential. Therefore, a
technique that can delineate the boundary of tumors to realize maximum safe resection and protect the normal brain tissues is urgently needed. It has been proved that
intraoperative uorescein is used to guide the surgical resection and can improve the
overall survival and progression-free survival of patients. Although research suggests that uorescence, such as sodium uorescein, 5-aminolevulinate acid, and
others, can be used to guide the removal of gliomas, their clinical utility is constrained by problems such as low quantum uorescence yield and poor
photostability.
To deliver chemotherapy medications to the brain, various NP compositions have
been studied. Most of these formulations made use of polymers that complied with
the strict standards necessary to be approved for use in biological applications.
Nanoparticle technology has improved with the optimization of drug loading,
encapsulation effectiveness, and release prole during the past few years. Brain
cancer imaging has been made easier by using NPs with ligands attached to their
surfaces. To shield NPs from RES and blood protein interactions, PEGylation of
NPs has been frequently used in medication delivery.
PEGylated QDs are uorescent nanocarriers with many notable benets in the
eld of bio-imaging for therapeutic and diagnostic purposes. Compared to the standard uorescent materials, maximum safe resection becomes extremely important
since it is essential for improving the prognosis of patients with low- or high-grade
gliomas by surgical resection. However, both grade gliomas tend to penetrate deeply
into the parenchyma around them, so resecting them is challenging. Therefore, it is
crucial to develop a method that makes it possible to see the tumor’s border to carry
out the safest possible resection and safeguard the healthy brain tissues. First, we
have to search for a biomarker that is only expressed in tumors and not in
healthy organs.
In contrast to normal tissues, epidermal growth factor receptor (EGFRvIII) had
only been found in gliomas, lung cancer, breast cancer, squamous cell carcinoma of
the head and neck, and colorectal cancer. EGFRvIII is a tumor-specic antigen or
one that is exclusively expressed in tumors and not in normal tissues. EGFRvIII is,
therefore, the perfect target for the treatment of gliomas. Second, the antibody
EGFRvIII, like many drugs, is too large to pass across the BBB.Thus, a small
chemical that can cross the BBB and specically bind to EGFRvIII is required.
PEGylated QDs can be used to mark the EGFRvIII (Tang etal. 2017).
Another study suggests that the oncogene BMI-1, a central protein in the polycomb group, could be an entirely novel therapeutic target for GBM.PTC209, a
BMI-1 inhibitor, has been incorporated into a PLGA-PEG NP coupled with CD133
antibody (Nano-PTC209) to increase effectiveness and decrease toxicity. NPs signicantly increased apoptosis and signicantly reduced cell viability in a
362
N. Gupta et al.
dose- dependent manner. Additionally, they markedly reduced cells’ capacity for
migration and increased the production of reactive oxygen species (Poonaki
etal. 2021).
12.3.3 PEGylated Nanocarriers inDiagnosis ofGastrointestinal
Tract Imaging
Molecular imaging techniques have a profound impact on the diagnosis and prognosis of disorders, including those affecting the gastrointestinal tract. Colorectal
cancer is the second biggest leading cause of death, closely followed by stomach
cancer for mortality. The keys to effective treatments for gastrointestinal cancer are
early detection and fast intervention. Gastrointestinal endoscopy is an invasive procedure; gas-barium double-contrast imaging is resistant to gastrointestinal cancer in
its early stages, which increases the likelihood of mistaken diagnoses. The noninvasive methods used to diagnose a variety of disorders with the advancement of
medical examination technology include MRI, CT, single-photon emission computed tomography (SPECT), ultrasonography (US), positron emission tomography
(PET), as well as optical imaging techniques.
Designing and synthesizing contrast agents with strong imaging properties that
are appropriate for gastrointestinal imaging is therefore crucial. Additionally, it is
more realistic to diagnose and predict GI disease by doping other materials to do
various imaging modes. PEGylated NPs performed better on CT scans and absorbed
more X-ray than iodinated contrast material at the same concentrations. The NPs
might also be applied to MRI in the presence of Gd. PEGylated nanomaterials had
shown excellent biocompatibility and low systemic toxicity in both invitro and
invivo toxicity tests. PEGylated NPs are excellent techniques as CT/MRI dualmodal contrast agents for in vivo imaging of the GI tract. These NPs showed
improvement in CT imaging compared to the commercially available iodine contrast agents (Cui etal. 2020).
The two varieties of MRI contrast agents now in use are T1 and T2 contrast agents.
Gadolinium and Mn are primarily used in T1 contrast agents. Fe3O4 NPs with a
superparamagnetic eld are T2 agents. Targetable contrast agents are a crucial component of molecular imaging, which could signicantly improve the precision and
accuracy of monitoring. Various Mn3O4-based contrast agents have been reported
for tumor imaging, including MRI with a mix of uorescence. A Mn-based contrast
agent surface coated with PEG exhibits good results for MRI of stomach cancer
monitoring. The MRI effects were instantly markedly amplied by these PEGylated
NPs, which could effectively concentrate in stomach cancer tissues and cells.
Additionally they have the potential to serve as a novel MRI contrast agent for the
postoperative monitoring of gastric cancer (Li etal. 2020).
An efcient oral MRI contrast agent for gastrointestinal tract imaging is NPs of
gadolinium-incorporated Prussian blue with PEG coating. It exhibits high r1 relaxivity (i.e., high sensitivity) and excellent temporal stability, with contrast enhancement characteristics remaining nearly unchanged when passing throughout the GI
12 PEGylated Nanocarriers forDiagnostic Applications
363
tract. Other commonly employed oral contrast agents lack the ability to pass through
cell membranes to serve as cellular MRI probes, have modest relaxivity values, and
exhibit poor temporal stability when administered to the GI tract. Based on its applicability as MRI contrast agent, it is tempting to hypothesize that gadoliniumincorporated Prussian blue presents the potential for developing a sensitive cellular
MRI probe for early cancer detection in the GI tract. These PEGylated NPs have
very high r1 relaxivity and can rapidly penetrate the cell (Perera etal. 2016).
12.4 Conclusion andFuture Resolutions
PEGylated components are typically used to prevent opsonization and protein binding in serum for therapeutic proteins and NPs to show extended circulation periods.
It has been shown to be a practical scaffold for incorporating active targeting ligands
and inuencing intracellular target localization. PEG has signicantly developed
drug delivery systems, particularly for detecting, diagnosing, and treating tumors.
PEG’s adaptability will make it possible to investigate new applications and make
ongoing advancements to anticancer therapies and diagnosis. Preclinical and clinical trials for more PEGylated proteins and short peptides are anticipated to begin
soon. There are also numerous PEGylated nanoparticle medicinal and diagnostic
compounds in active development. Accelerating the clinical translation of innovative PEGylated agents, including carbon nanotubes, nanodiamonds, microbubbles,
dendrimers, and other nanoparticles, will require using existing technology and creating new techniques in the diagnostic application.
A number of key requirements, such as non-toxicity, non-immunogenicity, target
selectivity, and biodegradability, need to be fullled by nanomedicines in order for
them to be commercially successful for the diagnostic application. The production
of multifunctional PEG molecules that can be grafted with anti-biofouling compounds, uorescent agents, and other functional polymers is critical in developing
PEGylated NPs. PEGylated nanocarriers have a promising future in biomedical
research and diagnostics, particularly in the elds of disease diagnosis, early detection, cellular and deep tissue imaging, drug/gene delivery, and multifunctional therapies. These efforts would essentially simplify, accelerate, and minimize the
invasiveness of the diagnosing processes. PEGylated nanocarriers would be an
appealing material for diagnostic and imaging applications in the following years
and could alter the normal business practices of pharmaceutical companies. .
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