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8 PEGylated Nanocarriers forGene Therapy
Fig. 8.2 De-PEGylation technology in liposomes. PEG molecules on the liposome’s surface are
cleaved once the liposome binds to the suitable target cell through specic identication of the
receptor by the ligand. Gene delivery is made more effective by the release of PEG, which speeds
up membrane fusion of the liposome and liposome breakdown
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with them. In general, steric barrier stability and circulation time are higher in liposomes that have a brush-like covering. PEGylated liposomes, on the other hand,
exhibit noticeably decreased cellular uptake or endosomal escape, which lessens the
overall effect of gene silencing (de Souza Guimaraes etal. 2022).
Recurrent PEG-liposome injection is thought to cause fast blood clearance,
which dramatically reduces the drug’s therapeutic impact. Activated B-cells generate IgM antibodies following the initial injection. The subsequent delivery results in
drug-IgM binding, complement system activation, and macrophage liposome capture (Koudelka etal. 2016). This phenomenon is an incredibly quick immunological
response that happens 10 min after the initial intravenous administration.
Additionally, it appears that spleen is the primary generator of anti-PEG IgM. It
should be noted that, the rate of immune response activation is higher when nucleic
acids are used to stimulate the immune response and that the release of IgM antibodies is dosage dependent. However, because of MPS cell saturation, the third and
subsequent injections of PEG-liposomes do not have such a dramatic effect (Wang
etal. 2023).
Shroff etal. created PEGylated liposomes with the bronectin-mimetic peptideamphiphile PR_b integrated into their bilayer, which may target a variety of cancer
cells which can overexpress, including the MDA-MB-231 breast cancer cells utilized in this investigation. To maximize the therapeutic potential of doxorubicin
through PEGylation and active targeting to cancer cells, we have encapsulated it
inside liposomes (Shroff and Kokkoli 2012). The ndings demonstrate that PR_b- functionalized stealth liposomes could bind to MDA-MB-231 cells with high specicity, and the binding would be modulated by peptide concentration. When the
intracellular trafcking of the doxorubicin liposomes was investigated, it was shown
that most of them were likely in the early endosomes minutes after administration,
while after a longer length of time, they have been collected in the late endosomes
and lysosomes. Particularly at higher doxorubicin concentrations, it was discovered
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L. Mishra et al.
that the functionalized liposomes delivered more cytotoxicity than that of nontargeted and GRGDSP-functionalized stealth liposomes and were just as lethal as free
doxorubicin (Demirgoz etal. 2008).
In order to efciently and specically transport their therapeutic payload to the
breast cancer cells, the PR_b-functionalized PEGylated nanoparticles investigated
in this study present a viable approach.
8.3.2 PEGylated Micelles
Anticancer drug-containing polymeric micelles were rst created independently by
Kataoka and Kabanov. Anti-cancer medications are integrated into micelles with the
help of chemical conjugation or physical entrapment. Clinical experiments are
being conducted on several micelles, and the polymer-micelle system is developing.
Micelles are also utilized in the system for delivering genes. A PIC can self- assemble
from a cationic polymer and DNA.In order to establish a complex with DNA, a
block or graft copolymer made of hydrophilic-cationic polymers, including PEGpoly(-lysine) and PEG-poly[N-(2-aminoethyl)-2-aminoethyl] aspartamide (PEGPAsp(DET)), is typically utilized. Numerous invitro and invivo tests have been
conducted to show the impact of PEG shielding. PEG shielding, for instance, considerably reduces the accessibility and utilization of biomacromolecules, such as
serum proteins, and attenuates the charged state of the polyplex, which inhibits the
aggregation.
The Kataoka group has conducted substantial research on the creation of micelles
utilized for gene delivery systems and has created a number of block copolymers,
including PEG-PLL and PEG-PAsp(DET) (Torchilin 2007). Because its cationic
component has been discovered to decay more quickly than PEG-PLL under various physiological settings, PEG-PAsp(DET) is the one that is largely studied as a
potential carrier of genes. Due to the increase in cytotoxicity of the cationic polymeric with molecular weight, biodegradability of the cationic polymer is crucial in
minimizing toxicity. By reducing electrostatic contact, the breakdown of cationic
polymers enables the release of plasmid DNA.PEG-PAsp(DET)’s effectiveness as
a gene carrier has been assessed invivo (Cagel etal. 2017).
A variety of polyion complex (PIC) micelles were created by Gao etal., and
PEGylated in a range of ratios (PEG2k and PEG550). To clarify the effect of
PEGylation patterns on the biodistribution of micelles, comprehensive research
was conducted on the murine macrophage absorption, plasma protein adsorption,
and invivo biodistribution using iodine-125 as the tracer. They showed that the
reticuloendothelial system (RES) cleared PEGylated micelles with shorter hydrophilic PEG chains mixed quickly on the surface, and that single PEG2k PEGylated
micelles would effectively extend blood circulation time and increase their deposition over tumor sites (Shiraishi and Yokoyama 2019; Gao etal. 2013). The goal
of the current work is to increase the comprehension of the PEGylation technique
and create the best nanocarriers for medication administration and imaging
applications.
8 PEGylated Nanocarriers forGene Therapy
249
Camptothecin (CPT), a weakly soluble anticancer medication andby Mu etal.,
prepared itsmicelles made from the blend of poly (ethylene glycol)-phosphatidyl
ethanolamine conjugate (PEG-PE) and -tocopherol poly ethylene glycol 1000 succinate (TPGS) (Mu etal. 2005). When compared to previously described PEG-PEonly micelles, the solubilization of CPT by the mixture of micelles ware found more
effective. The developed formulationi.e.CPT-loaded mixed micelles, remain stable
throughout storage as well as ondilutionalso, the cytotoxicity of the mixed micelles
containing CPT was noticeably greater when compared to the free drug against the
number of cancer cells. For poorly soluble medicines and imaging applications,
PEG-PE/TPGS mixed micelles may be used as therapeutic nanocarriers with
increased solubilization capability (Mu etal. 2005; Gao etal. 2008).
8.3.3 PEGylated Nanogels
Nanoparticles made of a polymers network and cross-linked chemically or physically are referred to as nanogels. In PEGylated nanogel particles with a polyamine
core that has undergone chemical cross-linking and a PEG surface 94. The
PEGylated nanogels exhibit greater durability against very diluted and high salt
environments than those of self-assembled nanocarriers like liposomes and micelles
due to their covalently cross-linked polyamine gel core (Tamura etal. 2011). In
vitro,studies suggested that it was possible to stabilize nucleic acids and effectively
deliver them inside the cells with success; but when nanogel was injected intravenously inside the bloodstream, it tended to mix with anionic serum proteins in order
to produce substantial aggregates. Although, the non-fouling characteristics of the
nanogel surface needs to be enhanced in order to use nanogels as a gene delivery
mechanism for systemic applicability (Chen etal. 2018).
Nanogels may to some extent expose amino groups, that connect to serum proteins and cells that are outside the particle due to their loosely cross-linked gel
structure. Moreover, the PEGylated nanogels that had a cross-linked density of 5%
demonstrated the lowest toxicity (LD50>200 mg/kg), that is quite sufcient for
invivo utilities. In reality, the nanogel caused severe hemolysis when the crosslinking density is of 1%. It was necessary to further raise the PEG corona density in
order to further enhance the bioinert nature of nanogels. This stable nanoparticle is
useful for researching how PEGylation alters the physicochemical parameters of the
nanoparticle surface and affects in vivo pharmacokinetics characteristics (Gupta
et al. 2015). High PEG-density nanogels can be created using the new postPEGylation procedure, that refers to a quaternized reaction involving the amine in
the nanogel core as well as the bromobenzyl-terminated PEG, in order to create
long-circulation nanogels (Fig. 8.2). In comparison to nanogels without postPEGylation, those that had it considerably increased the blood circulation time.
This work unequivocally shows how PEGylation of nanoparticles affects their biodistribution (Vijayan etal. 2017).
Gold nanoparticles (GNPs) prepared by Nakamura et al. in poly-[2-(N,N-
diethylamino) ethyl methacrylate] (PEAMA) gel core, the PEGylated nanogel
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L. Mishra et al.
including GNPs synthesized at pH6and 60°Ctemperature, (PEGylated GNG) was
shown the maximum GNP-loading capacity (Nakamura et al. 2010). PEGylated
GNG showed an outstanding photothermal efcacy (ΔT=7.7°C) when exposed to
an Ar ion (Ar+) laser at a uence of 39Wcm−2 for 6min (14kJcm−2). It should be
noted that PEGylated GNG demonstrated non-cytotoxicity within the total absence
of irradiation with Ar+ laser (480mgmL−1: >90% cell viability), while pronounced
cytotoxicity (IC50=110μgmL−1) were noticed for PEGylated GNG according to
irradiation supplied with Ar+ laser at a uence of 26 W cm−2 for at least 5 min
(7.8kJcm−2), considering heat-generation from GNPs in the cells, and these resulted
in selective and non-invasive cancer Photodynamic therapy (PTT). Consequently, a
potential nanomedicine for cancer PTT would be PEGylated GNG, that has a high
GNP-loading capacity (Miyamoto etal. 2008).
8.3.4 PEGylated Inorganic Nanoparticles
The topic of medicinal delivery has also sparked interest in inorganic nanoparticles.
These inorganic nanoparticles, including silicon oxide, calcium phosphate, iron
oxide, and gold are simple to manufacture with adjustable sizes and are simple to
functionalize. Because of their low toxicity, gold nanoparticles have been extensively exploited in gene delivery systems; nonetheless, inorganic nanoparticles are
often unstable and may prove hazardous in biological systems. Therefore, it is anticipated that surface modication will increase biological stability and compatibility
(Karakoti etal. 2011). Inorganic nanoparticles can be made more stable and toxicfree by using PEG to modify their surfaces. Thiol groups, for instance, make good
anchors for gold nanoparticles.
For the purpose of gene delivery invivo, Kawano etal. coupled electroporation
with PEG-modied cationic gold nanoparticles. By reducing chloroauric acid
(HAuCl4) with sodium borohydride (NaBH4) in the presence of 2-aminoethanol and
PEG-SH, they created cationic gold nanoparticles. Plasmid DNA can be attached to
resulting PEG-modied cationic gold nanoparticle. Mice were intravenously
injected with DNA complexes including PEG-modied nanoparticles, and electroporation was used to conrm gene expression (Chopra 2004). One issue is that
under physiological settings, de-PEGylation of inorganic nanoparticles caused by
mono-end-functionalized PEG frequently leads to particle aggregation. This issue
might be solved by alternative methods of stabilizing gold nanoparticles, such as
numerous anchoring among gold nanoparticle as well as functionalized PEG like
penta-ethylene hexamine-ended PEG (N6-PEG). Other than gold nanoparticles,
multiple anchoring technique can also be used to stabilize the inorganic nanoparticles.
For mesoporous silicon (PSi), a particular dual PEGylation (DPEG) technique
was created by Nissinen etal., and put through in vitro as well as invivo testing
(Nissinen etal. 2016). The half-life of the nanoparticles was increased from 1 to
241 min by the DPEG coating, which drastically altered their in vivo behavior.
Additionally, uncoated nanoparticles would quickly deposit in the liver, whereas the
spleen was where the coated particles accumulated. The particle’s protein coronas
8 PEGylated Nanocarriers forGene Therapy
251
varied greatly from one another. While the coated nanoparticles had proteins that
could inhibit cellular uptake, the uncoated particles have signicantly more amount
of proteins adsorbed, particularly liver and immune active proteins (Nakki et al.
2015). These factors, coupled with the agglomeration seen in blood circulation,
were determined to be the root causes of the variations in behavior invivo. By
inserting superparamagnetic oxide of iron nanocrystals inside the pores of the particles, which made dynamic imaging possible, the bio-fate of the particles was monitored by magnetic resonance imaging. The current study’s ndings open the door
to further developmental strategies of the porous inorganic system for delivery in
the sense of active targeting because the carriers are easily modiable chemically,
enabling magnetically targeted distribution and diagnostics (Sarparanta etal. 2012).
8.3.5 PEGylated Polymeric Nanoparticles
Polymer nanoparticles (PNPs) are tiny polymeric nanospheres (NS) and nanocapsules. Matrix particles, or those whose entire mass is solid, include nanospheres.
The surface of the sphere or the particle matrix may have molecules adsorbed on it.
Polymer nanoparticles have increasingly been expanding and they play important
roles in a broad range of areas, such as photonics, electronics, conducting materials,
sensors, healthcare, biotechnology, environmental control, and environmental technology. Biodegradable nanoparticles are extensively employed in biotechnology
and medicine to enhance the therapeutic efcacy of various medications. The solubility, bioavailability, retention duration, effectiveness, specicity, tolerability, and
drug therapeutic index values of medicines that have been nano encapsulated in
PNPs are all increased. PNPs can be functionalized to accomplish the so-called
“intelligent targeting,” i.e., targeted distribution to certain cells, tissues, or organs
(Lukasiewicz etal. 2021).
Several biodegradable polymers including polylactic acid (PLA), polycaprolactone (PCL), polyglycolic acid (PGA), and polylactide-co-glycoside (PLGA) are
being studied for efcient use in drug delivery systems. Numerous medications
have been effectively encapsulated in PNPs to increase their bioactivity, bioavailability, and regulate delivery. Diseases include cancer, AIDS, insulin resistance,
malaria, prion infections, and tuberculosis are the principal areas of application.
When creating new drug delivery systems, PNP characteristics including toxicity,
biocompatibility, biodistribution, and immunogenicity are critical. It is widely
known that the criteria that affect these properties are the size, particles charges, and
surface changes. The effects of possible nanocarriers that on cells of the immune
system, which act as the body’s rst line of defense against dangers from the outside, are particularly crucial to study (Xin etal. 2011).
It is essential to develop carriers that, to phagocytic cells like macrophages, are
undetectable (“the stealth property”). Immune system cells called macrophages
play a role in inammation. When activated, macrophages phagocyte harmful substances like scavengers. When macrophages are exposed to pathogenic particulates,
which may also be nanoparticles, this process of activation takes place. Because
252
nanoparticles are perceived as foreign and adequately ingested and digested by
phagocytic cells, macrophages represent the rst obstacle in the route of pharmaceutical nanocarriers to their destinations. Therefore, one of the primary objectives
in developing novel methods for drug delivery is to reduce the absorption of PNPs
by macrophages (Gajbhiye etal. 2020).
Paclitaxel (PTX)-loaded PEG-poly (trim ethylene carbonate) (MPEG-PTMC)
NPs were investigated for their potential anticancer properties against glioblastoma
multiforme by Xin etal. in 2010. Twelve hours after the intravenous injection, there
was a considerably greater concentration of PEGylated NPs in the tissues of brain
tumors. Additionally, PTX-loaded PEGylated NPs showed much greater in vivo
anticancer effects than saline or Taxol, which resulted in a longer than the mean
duration of survival for mice treated with them (27days) (Xin etal. 2010). Angiopepanchored PEG-PCL NPs (ANG-PEG-PCL NPs) were created by a similar team of
researchers to take advantage of the overexpressed low-density lipoprotein receptorrelated protein 1 (LRP1) seen over the BBB as well as glioma cells. On U87 MG
glioma cells, PTX-loaded ANG-PEG-PCL NPs showed better inhibitory effects.
The research also showed that the intracranial U87 MG glioma tumor-bearing
invivo model accumulated more targeted NPs (Xin etal. 2011).
L. Mishra et al.
8.4 Applications ofPEGylated Nanocarriers
forGene Delivery
8.4.1 Cancer
Cancer is one of the mysterious and terrifying disease which is the uncontrolled
proliferation. Multicellular organisms have been shown to be affected by cancer for
more than 200 million years, and the cancer evidence in the progenitors of contemporary humans dates back around million years. However, in contrast to various
infectious diseases, parasitic diseases, as well as many environmental diseases, this
disease is not likely brought on by an outside factor. In cancer, human cells being
having a sense of their uncontrolled growth, andwhich further changes into pathogenic organisms or the nuclei of tumors, often serves as its various agents of destruction (Yin etal. 2021; Dart 2022).
Cancers are legitimately known to be “genetic diseases” because genetic mutations play a signicant part in the disease. Mutations are mainly responsible for
causing and elevating the outcomes of the cancer, which canbe considered as a
major factorfor induction of cancer. This is because external agents carry the huge
potential to dismiss cellular functions and produce mutations, they also play greater
role in the genesis of cancer (Ma etal. 2022; Chakravarty and Solit 2021).
Cancer gene therapy is a novel area of research promised with several potential
treatments. The phrase “gene therapy” is known as a broad spectrum of medical
procedures that utilizes genetic material to alter cells (either invitro or invivo) to
treat a disease. Several preclinical and invitro animal models applicable to test a
wide variety of gene therapy drugs have been demonstrated for astounding success.
8 PEGylated Nanocarriers forGene Therapy
253
Gene therapy is utilized for development of cancer vaccines, induction of target
viruses to cancer cells for lysis and death, reducing the blood supply towards the
tumor, and induce genes into the cancer cells which further causes death or restoration of normal cellular phenotype, and showed to improve survival in various models of lung cancer (Giamas 2020; Giamas and Gagliano 2022).
Pegylated nanocarriers have demonstrated encouraging outcomes in the treatment of cancer. Figure8.3 represents multifunctional pegylated nanocarriers for
cancer therapy. These nanocarriers can encapsulate medications and deliver them
precisely to cancer cells with the least chances of harm to healthy cells. These nanocarriers have been “pegylated,” or have had polyethylene glycol (PEG) chains added
to their surface. Because of the complexity of cancer biology and off-site toxicity
with multidrug resistance, the conventional treatment regimen for use in cancer having a single chemotherapeutic agent falls far short of clinical expectations and is
also linked to low Quality of Life (Gajbhiye etal. 2020; Jain and Nahar 2010).
The PEGylation of nanocarriers would shield both compounds from the
harsh gastro-intestinal tract (GIT) GIT environment and subsequently encourage
intestinal absorption through the lymphatic route into the systemic circulation This
alteration can assist prevent their clearance and promote their accumulation in
tumors by increasing their stability, lengthening the time they spend in the bloodstream, and decreasing their detection by the immune system. Many anticancer
medications, including paclitaxel, doxorubicin, and cisplatin, have been delivered
via pegylated nanocarriers. For added cancer cell selectivity, they might be functionalized with targeted ligands like antibodies or peptides. Pegylated nanocarriers
Fig. 8.3 Multifunctional PEGylated nanocarriers for gene delivery in cancer cell
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L. Mishra et al.
have been shown in studies to improve the therapeutic index of anticancer medicines by lowering their toxicity and boosting their efcacy (Koide etal. 2009; Wang
etal. 2015a). They can also get around several drawbacks of conventional chemotherapy, which includes low solubility, non-specic distribution, and drug resistance. Pegylated nanocarriers have a lot of potential for the development of safer
and more effective cancer treatments.
Further study is required, though, to improve their layout, assess their long-term
security, and deal with potential difculties including immunogenicity and drug
resistance. Due to their capacity to safeguard and distribute therapeutic nucleic
acids to cancer cells, PEGylated nanocarriers are an effective tool for cancer gene
therapy. Mostly made of biodegradable polymers, these nanocarriers have a stable
nanoparticle structure. The nanocarrier in cancer gene therapy can transfer different
nucleic acids, like as plasmid DNA, small interfering RNA (siRNA), or microRNA
(miRNA), which can control the expression of genes in cancer cells. For instance,
miRNA can be used to restore the expression of tumor suppressor genes after
miRNA has been used to quiet the expression of oncogenes (Muralidharan etal.
2014; Xue etal. 2015). In Table8.1, different kinds of PEGylated nanocarriers and
their clinical status is described.
8.4.1.1 Breast Cancer
PEGylated nanocarriers are a promising approach for gene therapy in breast cancer.
Gene therapy involves the introduction of genes into cells to treat or prevent disease.
However, the induction of genes to specic cells inside the body can be challenging.
Nanocarriers are small particles which can encapsulate and induce therapeutic
genes to targeted cells in the body. PEGylation, which is the process of attaching
polyethylene glycol (PEG) onto the surface of the nanocarrier, increases their circulation time in the body and improves their stability (Braden et al. 2014; Liu
etal. 2022).
In breast cancer, gene therapy can be used to target specic genes which are
involved in the development and progression of the disease. For example, tumor
suppressor genes can be introduced to retard the growth and spread of cancer cells.
Nanocarriers can be designed to specically target breast cancer cells and deliver
the therapeutic genes directly to the tumor site (Dastjerd etal. 2022).
Several types of PEGylated nanocarriers have been generated for gene therapy in
breast cancer, including liposomes, polymeric nanoparticles, and dendrimers. These
nanocarriers could be modied to enhance their targeting ability, enhance their stability, and control the release of the therapeutic genes. Overall, PEGylated nanocarriers offer a promising approach for gene therapy in case of breast cancer. While
more research is needed to optimize their design and delivery, they have the huge
potential to improve the effectiveness and reduce down the side effects of current
breast cancer treatments. Several studies have demonstrated the potential of
PEGylated nanocarriers for gene therapy in breast cancer. For example, one study
used PEGylated liposomes to deliver a gene that inhibits tumor growth to breast
cancer cells in vitro, resulting in a signicant reduction in tumor cell viability.
Another study used PEGylated nanoparticles to deliver a gene that enhances the
8 PEGylated Nanocarriers forGene Therapy
255
immune response to breast cancer cells in a mouse model, resulting in a signicant
reduction in tumor growth (Dastjerd et al. 2022; Bottai et al. 2017; Sahu and
Pattanayak 2020).
Overall, the utilization of pegylated nanocarriers for gene therapy in breast cancer holds great promise as a targeted and effective treatment strategy. However,
future research is needed to optimize the design as well as delivery of these nanocarriers, and signicantly evaluate their safety and efcacy in clinical trials.
8.4.1.2 Lung Cancer
Lung cancer is still the emerging cause of cancer death all over the world. More
people will die from lung cancer than from breast, prostate, and colon cancers put
together. Before the fth decade of life, lung cancer is quite uncommon; subsequently, the risk rises with age. Women are less impacted than men. Remarkably,
only 15% of smokers acquire lung cancer despite smoking being the exposure most
closely linked to the disease (it is thought to be the cause of 80–90% of cases),
pointing to a hereditary vulnerability (Bade and Dela Cruz 2020; Nasim etal. 2019).
PEGylated nanocarriers have also been investigated as an efcient delivery system for gene therapy in lung cancer. Lung cancer is one of the leading causes of
cancer-related deaths around worldwide, and traditional treatment options including
chemotherapy and radiation therapy often have limited efcacy and can cause signicant side effects. Gene therapy using PEGylated nanocarriers offers a promising
strategy for targeted and effective management of lung cancer (Shahbazi etal. 2023).
One of the emerging challenges in the treatment of lung cancer is the ability of
cancer cells to develop resistance to chemotherapy and other treatments. Gene therapy using nanocarriers can be used to deliver genes that sensitize cancer cells to
chemotherapy or radiation therapy, making these treatments more effective.
PEGylation of the nanocarriers can improve their stability and circulation time,
allowing for targeted delivery of therapeutic genes into the cancer cells while minimizing toxicity to healthy tissues (Lara-Guerra and Roth 2016).
Several studies have shown the potential of PEGylated nanocarriers for gene
therapy in lung cancer. For example, one study used PEGylated nanoparticles to
deliver a gene that sensitizes cancer cells to radiation therapy in a mouse model of
lung cancer, resulting in an efcient reduction in tumor growth. Another study used
PEGylated liposomes to deliver a gene that inhibits tumor growth in lung cancer
cells invitro. In addition to sensitizing cancer cells to traditional treatments, gene
therapy using nanocarriers can also be used to deliver genes that improves the
immune response against cancer cells. For example, a study using PEGylated
nanoparticles to deliver a gene that enhances the immune response in a mouse
model of lung cancer which resulted in a signicant reduction in tumor growth
(Nair etal. 2020).
Overall, the use of pegylated nanocarriers for gene therapy in lung cancer holds
great promise as a targeted and effective treatment approach. However, more
research is required to optimize the design and delivery of these nanocarriers, and to
evaluate their safety and efcacy in clinical trials.
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8.4.1.3 Colon Cancer
Together with breast, prostate, and lung cancers, colon cancer is also one of the most
common tumors worldwide and is regarded as a major cause of death. Being the second most leading cause of cancer-related death, colon cancer is a major global health
concern. There are drawbacks and certain side effects which are associated with conventional cancer treatments such as surgery, radiation, and chemotherapy. As a result,
existing cancer treatment methods must be updated, and new methods must take their
place. PEGylated nanocarriers for gene therapy present a potential approach for the
focused and efcient treatment of colon cancer. The stability as well as circulation
time of the nanocarriers can be increased through PEGylation, enabling the targeted
delivery of therapeutic genes to cancer cells with the least amount of harm to normal
tissues (Pawlik 2018; Otani etal. 2019; Zwacka and Dunlop 1998).
The capability of cancer cells to acquire resistance to chemotherapy and other
treatments is one of the difculties in treating colon cancer. Nanocarrier-based gene
therapy can be used to transfer genes that make cancer cells more susceptible to
chemotherapy or radiation therapy, increasing the efcacy of these therapies. For
instance, in a study utilizing PEGylated nanoparticles to carry a gene that makes
colon cancer cells more susceptible to chemotherapy, the tumor growth in a mouse
model of colon cancer was signicantly reduced.
Pishavar etal. (2020), in their study, they have studied about 5% and 3% of
PAMAM primary amine and performed its substitution fortransmitting of the plasmid encoding IL-12 gene. In colon cancer cells, the characteristics of modied
PAMAMs incorporating size, surface charge density, cytotoxicity, and transfection
efciency were examined. According to an invitro investigation, this modied carrier was able to double the amount of IL-12 production when compared to the
unmodied PAMAM.An effective and secure non-viral IL-12 gene for colon cancer immunogens therapy may be produced by enhancing the polymer hydrophobic
balance as well as by modulating the surface positive charge (Pishavar etal. 2020).
8.4.1.4 Brain Cancer
The most prevalent form of brain cancer, glioblastoma, is one of the most fatal and
severe neoplasms and is known to be very invasive. The majority of brain cancer
patients still have a poor prognosis, and the median survival time rarely surpasses
16months despite breakthroughs in surgery and medicine. The blood-brain barrier
(BBB), which protected the central nervous system by acting as a semi-permeable
membrane, greatly hinders drug transport to the brain (Tang etal. 2019).
PEGylated nanocarriers have been studied as a potential drug delivery system for
gene therapy in brain cancer. Brain cancer, including gliomas and other types of
brain tumors, are particularly challenging to treat due to the blood-brain barrier,
which can prevent therapeutic agents from reaching the brain (Mehrabian etal. 2022).
PEGylation of nanocarriers can help to overcome this barrier by improving the
stability and circulation time of the nanocarriers, allowing them to pass the bloodbrain barrier and deliver therapeutic genes directly to the brain tumor cells.
Additionally, PEGylation can reduce the clearance of the nanocarriers by the
immune system, allowing for more effective and sustained delivery of therapeutic genes.