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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5615_Библиотеки_им_академика_М_И_Перельмана.pdf
1 PEGylated Pharmaceutical Nanocarriers
17
molecules with various solubilities (Khodabakhsh etal. 2022). Cholesterol addition causes an ordered liquid phase, giving the bilayer stiffness and causing less
leaky niosomes. Diacetyl phosphate is well recognized for expanding vesicles and
giving them a charge, boosting entrapment effectiveness. Stearyl amine and diacylglycerol are additional charge- inducers that aid in the electrostatic stabilization
of the vesicles. Over liposomes, niosomes have particular advantages (Shahbazi
etal. 2023). Even in their emulsied state, niosomes are remarkably stable structures. Cholesterol improves the hydrodynamic diameter and trapping effectiveness of niosomes. They are chemically stable and require no specic storage or
protection conditions, like an inert atmosphere or low temperature. Because the
cost of the raw materials is relatively inexpensive, it can be manufactured industrially. Niosomes have been created using various substances, including sucrose
ester surfactants and polyoxymethylene alkyl ether surfactants. Like liposomes,
niosomes can entrap solutes (Huang et al. 2008). By delaying clearance from
circulation, increasing accessibility to a specic region, simply shielding the drug
from its biological environment, and delivering the drug under controlled conditions to a specic location, niosomes can enhance the performance of drug molecules (Davarpanah etal. 2018).
1.3.3.3 Ethosomes
A cutting-edge method of delivering medication, ethosomes predominantly penetrate biological membranes through the skin. Ethosomes are lipid vesicles utilized
primarily for transdermal medication administration, including phospholipids, alcohol (ethanol and isopropyl alcohol) in relatively high concentrations, and water
(Pandey etal. 2021). Since ethosomes penetrate the skin more quickly than liposomes, they can often be utilized instead of liposomes. However, the precise method
by which ethosomes can better penetrate deeper epidermal layers is still unclear
(Singhvi etal. 2020). The various PEGylated nanocarriers are shown in (Fig.1.2)
and PEGylated nanocarriers marketed formulations are listed in (Table1.2).
Fig. 1.2 Representation of various PEGylated nanocarriers
18
Table 1.2 PEGylated nanocarriers marketed formulations
Company
Hofmann-La Roche PEGASYS Hepatitis B and hepatitis C
Nektar pharma Cimzia Rheumatoid arthritis
Pzer Macugen Neovascular age-related macular
Amgen Neulasta Chemotherapy-induced neutropenia
Ortho Biotech Doxil Cancer
Pzer Somavert Acromegaly
Brand name
Indication
degeneration
P. Pingale et al.
1.4 Application ofPEGylated Nanocarriers
inVarious Diseases
1.4.1 Cancer
Existing chemotherapeutic drugs along with immune-regulatory and anti-tumor
active chemicals, increase the likelihood of curing cancer. Although it is a targeted
therapy, the fundamental drawback of the methods employed to treat this widespread
disease is that they cannot distinguish between cancer and healthy cells. As a result,
much study has been done on cancer treatment. By employing PEG as a carrier for
active compounds like doxorubicin, camptothecin, and paclitaxel, targeted therapy
for malignant cells can be obtained (Sanchez Armengol etal. 2022). Interleukin (IL)
2 has been altered to create aldesleukin, a recombinant protein. Some of the cell
types it stimulates in terms of proliferation and differentiation are B-cells, T-helper
cells, and natural killer cells. As an immunotherapy, it is applied to treating metastatic kidney cancer. However, if the dose of this active ingredient is increased due to
adverse effects, the number of individuals eligible for this therapy declines. This
results in a higher level of T-helper cell activation in the polymer- drug combination
NKTR-214, a prodrug of this molecule that maintains the amino acid sequence of
aldesleukin. Additionally, because PEG is utilized as a carrier, the medicine is
released more gradually, preserving a continuous dose (Akkın etal. 2021).
The existence of functional groups on the exterior of PEGylated dendritic structures that permit particular interactions with cancer cells is a different hypothesis. It
is inuenced by the number of functional groups present on the surface of the dendrimer and the length of the PEG chain. The capacity of cancer cells to circulate is
growing in cases with advanced malignancy. Since recovery under these circumstances is very challenging, focused therapy is a viable tactic. Polyamidoamine dendrimers (PAMAM dendrimers), in particular, have intriguing features. These
ethylenediamine-based dendrimers exhibit a pH-dependent surface afnity. Despite
this, PAMAM dendrimers exhibit hemolytic and poisonous characteristics. The
PAMAM dendrimer’s cationic surface most likely causes this. Research based on
this emphasizes both boosting biocompatibility and, on the one hand, optimizing
surface structure to lessen cationic characteristics (Li etal. 2022).
According to Daniels et al., the hypervascularity of solid tumors encourages
PEG-protein conjugates’ permeability. But human erythroleukemia (K562), human
1 PEGylated Pharmaceutical Nanocarriers
19
epidermoid carcinoma (KB), normal human hepatocyte LO2 cells, murine sarcoma
180 (S-180), and human erythroleukemia 180 (S-180) all responded more favorably
to transferrin (Tf)-conjugated systems. When Tf-PEG-protein conjugates were
compared to PEG-protein conjugates alone, the half-life was extended by 9.83h.
Additionally, Tf conjugates’ selectivity improved active site targeting and delayed
blood clearance (Sanchez Armengol etal. 2022).
1.4.2 Gene Delivery
The inability of nanoparticles to target specic sick areas after delivery is another
obstacle to clinical gene therapy. The most crucial idea is that a ligand receptormediated active targeting approach is needed to improve cellular uptake of nanoparticles by interacting with the receptors of targeted cells, such as antibodies, proteins,
peptides, and aptamers. Strong specic interactions between ligand and receptor pairs
and overexpression of the target receptors on target cells as compared to normal cells
are necessary for effective nanoparticle distribution. Passive targeting is used, particularly for tumors with weak vascular architecture and insufcient lymphatic drainage,
because these characteristics permit nanoparticles to extravasate into tumor tissues and
promote their retention in the interstitial space. PEGylation of nanoparticles is a method
to reduce serum aggregation by extending circulation periods and reducing potential
serum aggregation. After being exposed to sick tissues or outside stimuli like pH, temperature, light, or magnetic elds, stimulus- responsive nanoparticles may undergo
physical or chemical alterations. Response to internal or external stimuli allows one to
precisely customize the timing and location of gene therapy, considerably increasing
the likelihood that these nanoparticles will be used in clinical settings (Mollé etal. 2022).
By improving the expression of the cytokine interleukin-12, polyethylene glycol
polyethyleneimine-cholesterol (PEG-PEI-cholesterol) has been formulated as gene
delivery for ovarian cancer. The vast majority of clinical tests involving the transfer
of genes via nanoparticles focus on the lipidation of nucleic acids. Alnylam
Pharmaceuticals’ ALN-VSP uses systemic therapy to target vascular endothelial
growth factor (VEGF siRNAs) and reduce liver metastases, potentially sensitizing
cancer cells to chemotherapy. Patients with TTR amyloidosis received ALN-TTR02,
a lipid-based siRNA formulation, intravenously. The safety, tolerability, pharmacokinetics, and pharmacodynamics of multiple dosages of ALN-TTR02 were assessed
(Nguyen etal. 2020).
1.4.3 Diagnostics Imaging
The new discipline of nanomedical imaging and therapy relies heavily on nanoparticles. PEG often shields these compounds from the immune system when used
invivo. Signicant developments in PEG size, shape, density, loading level, molecular weight, charge, and purication have been established using a wide range of
nanoparticle coating and characterization techniques. Superparamagnetic iron oxide
(SPIO), one of the rst NP applications in imaging, was rst described in
20
publications from the 1960s and was widely used by the 1990s. SPIO and ultrasmall
SPIO (USPIO) can have their t12 extended by up to 200min and have their dextran
or PEG coating applied. Targeted SPIO makes it possible to perform molecular
imaging using MRI without the need for exogenous contrast chemicals. In the
1970s, gold nanoparticles (gold NPs) were rst utilized as immunogold to contrast
transmission electron microscopy, but they are now used to contrast computed
tomography and radiographs. Since then, numerous uses for PEGylated gold NPs
and nanorods have been documented (Chen etal. 2021).
P. Pingale et al.
1.4.4 Vaccines
The polymer utilized in these vaccinations to encapsulate the SLNPs, polyethylene
glycol (PEG), has been identied as the main trigger of these allergic responses.
Meals, cosmetics, and prescription medication formulas are among the additional
products that contain PEG.It is essential to keep nanoparticles colloidally stable in
biological uids and prevent their absorption by lter organs, increasing their
effectiveness and safety after vaccination (Garvey and Nasser 2021). Pre-incubating
Doxil, a PEGylated liposome used for cancer therapy, activates the complement of
anti-PEG antibodies linked to nanoparticles, according to an invitro investigation
using mouse plasma. This was accomplished by increasing the level of C3a.
Nevertheless, the study’s use of commercial monoclonal antibodies did not fairly
reect the invivo setting, where the average level of anti-PEG antibodies in participants who tested positive was 52ng/mL.The scientists found pre-existing anti-PEG
antibodies in plasma samples; however, the same investigation found no correlation
between this nding and the complement activation during Doxil incubation. This
was accurate when human volunteer plasma was directly evaluated. Doxil, from
Pzer/BioNTech and Moderna vaccines, has a PEGylated surface that can interact
with circulating antibodies and serum components, resulting in anaphylactic episodes in females (Bavli etal. 2020).
1.4.5 Rheumatoid Arthritis
To create 1,2-distearoyl-sn-glycero-3-phospho-ethanolamine-poly (DSPE- PEG2000),
MMP-responsive PEGylated lipid nanoparticles, the ester bond of triglycerol monostearate (TGMS), and the PEG chain (PEG) are being used to create a new treatment
strategy for RA.After being administered intravenously to arthritic rats, it has been
demonstrated that this method reduces joint swelling and lowers the production of
TNF- and IL-1in joint tissues. The released dexamethasone (Dex) was found to be an
effective medication delivery strategy for the treatment of RA (He etal. 2020).
1.4.6 Hemophilia
PEGylation improves a protein, peptide, or small-molecule drug’s pharmacokinetic,
pharmacodynamic, and immunological properties by covalently adding PEG.Today, a
1 PEGylated Pharmaceutical Nanocarriers
21
proven technique known as PEGylation of proteins is used to address various therapeutic issues. To increase the factor VIII (FVIII) or factor IX circulation half- life, many
PEGylated coagulation proteins are created for hemophilia A and B.The hemophiliac
individuals’ quality of life and adherence to therapy can be signicantly enhanced by
the lengthening of the half-life, which leads to fewer injections. According to the currently available safety data for PEGylated proteins with high molecular weight PEG,
there are no known safety concerns with long-term (chronic) use in human or animal
models. The chronic use of PEGylated products that are now on the market has been
proven safe, opening the door for those with hemophilia to do so (Chowdary 2020).
1.4.7 Pain Therapy
Although there is a growing need for effective, safe pain medications, few active
components are now being studied in clinical trials. This provides potential for
future research and development. An opioid receptor antagonist with PEG compatibility is naloxegol. Despite being utilized as an antagonist to an agonist, research
has found that the mechanism also applies to a chemical with a comparable composition. According to a 2019 study by Ekladious etal., using PEG on oxycodone
considerably lowers the side effects. The two medications are polymer-drug conjugates. Opioid-based pain management is no longer the exclusive option; PEG coupling and research into nonsteroidal, anti-inammatory pharmaceuticals have been
made possible. A well-known anti-inammatory cytokine called interleukine-10
(IL-10) has demonstrated promising results in managing neuropathic pain.
Soderquist etal. modied IL-10 using two distinct PEGylation methods to assess
the feasibility of the process. The ndings indicated that PEGylation of IL-10 would
be an effective method for treating pain. To assess cellular proliferation in more
depth, invitro tests were carried out, and total ATP concentrations and EC50 values
were established. When compared to unmodied IL-10, the EC50 of PEG-5000-ILacylation, PEG-5000-IL-amination, and PEG-20000-IL-amination increased by
34.4, 3.09, and 3.15 times, respectively (Sánchez-Cid etal. 2022).
1.4.8 Diabetes
Diabetes (DA) is a metabolic disorder brought on by insulin resistance or insufciency
(types 1 and 2). DA symptoms can include polyuria, glucosuria, vision disturbances, or
issues with wound healing, among others. But type 2 diabetes is increasingly becoming
a problem for the general public. Polymer–protein conjugates have decreased glucose
levels through exogenous insulin delivery (Kumar etal. 2020) successfully.
Calceti etal. revealed their ndings in 2004 for the oral administration of insulin
utilizing a PEG-based nanocarrier. The outcomes demonstrated that PEGylated
insulin was progressively released from the polymeric carrier. In this region, PEGbased modied insulin does not show more permeability than unmodied, contrary
to past studies that claimed that the better paracellular transport that follows from
conjugating low molecular weight PEGs to pharmaceuticals could boost drug
22
permeability. All insulin types supplied had comparable biological and pharmacological activity, according to the ndings of invivo experiments conducted on diabetic mice. Insulin that has been changed using PEG does not have better
permeability in this area than unmodied insulin. All insulin types supplied had
comparable biological and pharmacological activity, according to the ndings of
invivo experiments conducted on diabetic mice (Sanchez Armengol etal. 2022).
PEX168, a different pharmaceutical substance, is currently in the third stage of
clinical trials and is most likely to be approved. It is thought to be used for type 2
diabetes and renal failure and is referred to as a long-acting GLP-1 receptor agonist.
Patients with mild or moderate renal impairment had AUC0 increases of 13 and
100.7% higher than expected and had longer half-lives (Javia etal. 2022).
P. Pingale et al.
1.4.9 Others
PEGylation, the covalent attachment of a PEG derivative to molecules, enhances a
molecule’s water solubility and biocompatibility, particularly helpful for medication development. To achieve regulatory compliance for medical uses, PEGylated
compounds need to undergo rigorous characterization using sophisticated analytical
techniques. PEGylation of peptides, proteins, and small compounds, including
folate, mannose, prodrugs, oligonucleotides, cells, nanoparticles, virus particles,
and surfaces, commonly uses bifunctional PEG derivatives. Multi-arm PEG derivatives are primarily used to create hydrogels for controlled release of medicines,
medical devices, regenerative medicine, and various other applications, such as cell
culture, wound sealing, and wound healing (Ibrahim etal. 2022).
PEGs have been used in a wide range of applications for many years, according
to reports in the scientic literature. Their use is growing in various research and
development elds as regulatory authorities worldwide gain more expertise and
comfort using these materials in drug and medical device applications. PEGs are
employed in creating medical devices, drug research, and diagnostics in various
ways, including medication administration, wound healing, cell culture models, and
tissue regeneration (Janrao etal. 2022).
1.5 Limitations andChallenges Associated withPEGylation
ofNanocarriers
PEGylation negatively impacts the physicochemical properties of NPs, increasing
particle size—especially with high molar weight PEG, which could increase RES
absorption—and cause a fast release of the therapeutic contents from NPs within a
short period. For instance, it has been shown that doxorubicin-loaded PEGylated
liposomes release drugs more quickly than their non-PEGylated counterparts; 90%
of the loaded drug was released 3h after IV administration. Therefore, assuming
that the loaded drug cargo is released after entering the target cells was incorrect.
Compared to polylactic lactic acid (PLA) polymer particles, research has revealed
1 PEGylated Pharmaceutical Nanocarriers
23
that morphine escapes from poly (-lactide) or PLA-PEG block copolymer particles
much faster. Additionally, it has been demonstrated that the amount of PEG in the
copolymer affects the release rate. The initial burst release is more noticeable in
particles with a PEG concentration of 5% instead of 3%.
Instead of a burst release, 0–1% PEG-containing particles showed a continuous,
persistent release throughout time. The T80% of particles without PEG was around 15
and 30 times longer than that of particles with 3 and 5% PEG, respectively. T80%
denotes the moment when morphine’s cumulative release percentage surpassed 80%.
This shows that laden components may be freed from PEG-containing particles before
the polymer degrades. In other words, particles may become empty of their loaded
cargo while moving before they degrade. Furthermore, a comparable propensity was
shown by PLA and PEGylated poly (lactic-co-glycolic acid) (PLGA) NPs (Sebak 2018).
PEGylated nanocarriers have better physicochemical characteristics and pharmacokinetic proles than those that have not. However, they may not advantage
from the enhanced permeability and retention of the tumor’s leaky vasculature or be
unable to escape the reticulo endothelial system (RES) sequestration and clearance.
Additionally, PEGylation has the potential to produce undesirable particles and
post-in vivo administration restrictions on them, such as restricted RES uptake evasion, allergic reactions, reduced intracellular accumulation, and interference with
subcellular processing (Nunes etal. 2022). Figure 1.3 shows the major limitations
of PEGylation and PEGylated products in a clinical trial are listed in (Table1.3).
Fig. 1.3 Major limitations of PEGylation
24
Table 1.3 PEGylated products in a clinical trial
Products
ThermoDox Doxorubicin Hepatocellular
MM-302 Doxorubicin Breast cancer Merrimack Phase I/II
S-CKD602 Potent topoisomerase
2B3-102
(ENX-201)
SPI-077 Cisplatin Lung, head and neck
2B3-101
(2X-111)
Active agent Indication Company
Celsion Phase III
carcinoma and also
recurring chest wall
breast cancer
Cancer Alza
I inhibitor
Methylprednisolone Acute relapses of
multiple sclerosis
cancer
Doxorubicin Brain metastases and
recurrent malignant
glioma
Corporation
2-BBB
Therapeutic
Alza
Corporation
2-BBB
Therapeutic
P. Pingale et al.
Phase
(Terminated)
Phase I
Phase I
Phase II
Phase I/IIa
1.6 Conclusion
This chapter has discussed all the aspects related to PEGylation like PEGylation,
determination of PEGylation, PEGylation of nanocarriers, applications of
PEGylation, and challenges associated with PEGylation. It also explains the characteristics of PEG that play an important role in drug delivery. PEG serves as a useful
component as a solubility enhancer and for passive targeting. It is also highlighted
that PEGylated nanocarriers show prolong drug circulation, increase permeability,
enhancement in drug accumulation and retention, and avoid adverse effects.
Nanocarriers act as potential treatments for various diseases. Hence, PEGylated
nanocarriers have an excellent chance to be more efcient anti-cancer treatment in
upcoming era. They can be used in the management of diseases caused due to bacteria, fungi, and viruses. Moreover, the efciency of PEGylated nanocarriers in drug
delivery for specic targets should be studied systemically to attain the desired and
safe output.
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