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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5373_Библиотеки_им_академика_М_И_Перельмана.pdf
5 PEGylated Nanocarriers forSolubilization
147
Fig. 5.6 Solubility of noncovalently uorescein-PEG functionalized C nanotubes at different pH
values [(Nakayama-Ratchford etal. 2007), with permission]
nanoparticles functionalized with a hydrophobic zinc phthalocyanine (Camerin
etal. 2016). Also, water-soluble gold nanoparticles functionalized with a thiolated
PEG were synthesized (Penon etal. 2015) in addition to water-soluble, PEGylated
multifunctional antibody–porphyrin gold nanoparticles for targeted photodynamic
therapy (Penon et al. 2017). Furthermore, water-soluble gold nanoparticles
entrapped within PEG-modied polyethyleneimine were prepared and have potential use for blood pool and tumor computed tomography (CT) imaging (Zhou etal.
2014). In all of these cases, PEGylation achieved an increase in the water solubility
of the nanoparticles.
On the other hand, a study has described the development of a novel PEG-bPAMA, poly(ethylene glycol)-block-poly((2-N,N-dimethylamino)ethyl methacrylate) water-soluble polymer that was used to modify the surface of gold nanoparticle
rendering them completely dispersible under physiological conditions with high
dispersion stability (Miyamoto etal. 2008).
Metal oxide nanoparticles, such as alumina, silica, iron oxide, gadolinium oxide,
and cerium oxide, can function as controlled drug-delivery systems and magnetic
148
R. S. H. Mansour et al.
contrast agents, in addition to therapeutic and diagnostic materials in cancer. The
use of iron oxide nanoparticles, also known as magnetite nanoparticles such as
Fe3O4 and substituted iron oxides (MFe2O4 where M=Co, Mn, Zn or Mg) for biomedical applications, has been studied extensively (Laurent etal. 2008). For example, iron oxide nanoparticles have demonstrated a potential for various
nano-biomedical applications, including the hyperthermia treatment of tumor cells,
magnetic drug targeting, and magnetic contrast age (Pankhurst etal. 2003; Lu etal.
2007; Salunkhe etal. 2014; Kallumadil etal. 2009; Banerjee and Chen 2007).
In several cases, magnetic nanoparticles were successfully PEGylated to enhance
their aqueous solubility. Excellent stability and solubility were obtained in aqueous
dispersions and physiological media (Umut 2013). In one of the reported cases,
magnetic iron oxide nanoparticles were PEGylated, and their solubility was noticed
to increase as a function of the molecular weight of PEG from 550 to 5000.
Unfortunately, the increase in solubility was associated with an increase in particle
size in addition to a loss of the magnetic properties of the nanoparticles. Another
study showed that the solubilization kinetics of PEGylated supramagnetic iron
oxide nanoparticles was dependent on the conformation of the used PEG, even
though the extent of solubility was comparable. Dendritic PEGs resulted in a signicantly higher rate of solubilization than linear PEGs. The former nanoparticles
were suspended in water within seconds, whereas the latter nanoparticles required
hours. Additionally, some of the nanoparticles functionalized with linear PEG
exhibited substantially reduced aqueous solubility after freeze-drying. The different
solubility behavior between linear and dendritically stabilized nanoparticles was
attributed to the differences in the conformation of the dry shell of the nanoparticles.
Upon drying, the linear polymer chains of neighboring particles are likely to interdigitate, resulting in smaller interparticle separations and consequently increasing
van der Waals interactions, hence, the reduced dispersion rate. Contrastingly, the
dendritic conformation forms a more compact shell (Gillich etal. 2013).
5.4.4 Water-Soluble PEGylated Dendrimers
Dendrimers are nanostructures composed of hyper-branched polymers of homogeneous composition with an overall compact globular structure formed by layers
emanating from the center to the surface (Aranda-Lara etal. 2021).
Dendrimers have favorable applications in biomedical and pharmaceutical areas,
such as bioimaging and tissue engineering, in addition to drug and gene delivery
(D’Emanuele and Attwood 2005; Kimura etal. 2000). Nevertheless, several limitations, including hydrophobicity, restrict their use. In general, PEGylation of the
terminal groups of dendrimers can overcome these limitations, including their solubility. It can modify the solubility prole of dendrimers, making them a more soluble system (Sideratou etal. 2001; Gajbhiye etal. 2007; Quintana etal. 2002; Lee
etal. 2005; Luo etal. 2002). PEG chains that are coupled to dendrimers are proposed to form unimolecular micelles (Yang etal. 2004), thus aiding in the solubilization of the dendrimers.
5 PEGylated Nanocarriers forSolubilization
149
Fig. 5.7 Water-soluble PEGylated 4,4-bis(4-hydroxy phenyl)pentanol dendrimer in the form of
unimolecular micelle [(Liu etal. 2000), with permission]
Covalently PEG-functionalized Poly-amidoamine (PAMAM) dendrimers were
found to possess desirable characteristics such as nonimmunogenicity, nonantigenicity, noncytotoxicity, biocompatibility, and high water solubility (Barraza etal.
2016; Jiang etal. 2010; Luong etal. 2016; Ryan etal. 2008; Thakur etal. 2015).
Similarly, the hydrophobic dendritic hypercores made from 4,4-bis(4-hydroxy phenyl) pentanol were coupled with PEG as a hydrophilic shell, thus forming watersoluble dendritic unimolecular micelles (Liu et al. 2000) (Fig. 5.7). Moreover,
diamino butane poly(propylene imine) dendrimers were PEGylated to enhance their
hydrophilicity and modify their encapsulating properties and stabilizing ability
(Sideratou etal. 2001).
5.4.5 Water-Soluble PEGylated Polymeric Micelles
Polymeric micelles are spherical nanoparticles that are thermodynamically formed
from copolymers. The hydrophobic ends of the copolymers intertwine and form a
nucleus, whereas the hydrophilic ends are exposed on the surface. Polymeric
micelles have potential pharmaceutical and biomedical applications that are similar
to those of dendrimers (Aranda-Lara etal. 2021).
150
Fig. 5.8 Formation of PEGylated polymeric micelles [(Liu et al. 2014), reproduced with
permission]
R. S. H. Mansour et al.
Block copolymers containing PEG have been widely used and considered highly
soluble in water. Coupling of PEG with polycationic polymers such as poly(-lysine),
polyspermine, and polyethylenimine has been done to improve their solubility, consequently forming PEG-coupled copolymers that are reported to be capable of forming
self-assembling highly soluble complexes (Bhadra etal. 2002; Rackstraw etal. 2002)
in the form of polymeric micelles. PEG-poly(lactic-co- glycolic acid) (PEG-PLGA)
block copolymer forms an amphiphilic polymeric micelle in which PEG exists as a
hydrophilic corona while PLGA serves as a hydrophobic core (Mozar and Chowdhury
2018). PEG and arginine-grafted reducible poly(disulde amine) self-assembling
micelles were also prepared (Nam etal. 2012). These polymeric micelles were suitable candidate nanocarriers for the delivery of the hydrophobic drug paclitaxel.
PEGylated poly(β-benzyl -aspartate) polymeric micelles were also prepared and
showed a completely transparent aqueous solution (La etal. 1996).
In the other direction, a novel PEGylated polymer micelle formed from an amphiphilic block copolymer, PEG-b-poly(4-vinylbenzylphosphonate), spontaneously selfassemble in aqueous solutions into nanoparticles and was designed for bioimaging
applications (Kamimura et al. 2011). Other novel PEGylated polymeric micelles
(Fig.5.8) composed of an amphiphilic copolymer and PEG-grafted- polyethyleneimine/
amide were described for anticancer drug delivery (Liu etal. 2014).
5.5 Hydrated or Hydrophilic PEGylated Drug Nanocarriers
5.5.1 Hydrated PEGylated Lipid Nanocarriers
The degree of hydration on the membrane surface of liposomes plays a crucial role in
their aggregation. The liposome shell membrane should be satisfactorily hydrated to
reduce liposome aggregation and phagocytic cell uptake. The early attempts to increase
liposomal membrane hydration were performed in the 1980s. This was accomplished
by coating the membrane surface with hydrophilic polymers (Kraft etal. 2014). In 1995,
the US Food and Drug Administration (FDA) approved the rst liposome drug-delivery
system for human use. It was marketed under the name of Doxil and constituted of
PEGylated liposome-encapsulated doxorubicin (James 1995, p.201).
5 PEGylated Nanocarriers forSolubilization
151
Surface modication of lipid nanoparticles such as liposomes by PEGylation is
performed in a similar manner to PEGylation of proteins (Beauchamp etal. 1984).
PEGylated liposomes, also referred to as sterically stabilized or stealth liposomes,
were rst described by Allen and Chonn (1987). PEG is estimated to occupy an
additional hydration thickness of 5nm on the surface of the liposomes, which also
depends on the length and density of the PEG polymer (Woodle etal. 1992) without
signicantly modifying the overall charge property of liposome membranes (Kraft
etal. 2014).
5.5.2 Hydrophilic PEG-Coated Zein Nanocarriers
Zein is the main protein from corn and possesses a hydrophobic character. It is
insoluble in water and classied as a GRAS substance (Irache and GonzálezNavarro 2017; Penalva etal. 2015). Zein nanoparticles have the potential to be used
for oral drug delivery. Nevertheless, the surface of zein nanoparticles is considered
hydrophobic, thus denying them mucus-permeating properties. In an attempt to
PEGylate the surface of these nanoparticles with PEG 35000, their surface hydrophobicity was signicantly reduced, and the enhancement in hydrophilicity was
associated with increased mobility in pig intestinal mucus. The hydrophobicity of
the surface of the nanoparticles was inversely proportional to the PEG:zein ratio, as
shown in Fig.5.9. For example, the hydrophobicity of the nanoparticles prepared at
a PEG:zein ratio of 5% and those prepared at + a ratio of 75% were 60% and 25%
of that of the bare nanoparticles, respectively (Reboredo etal. 2021).
Fig. 5.9 Surface hydrophobicity of PEGylated zein nanoparticles, normalized relative to that of
the bare nanoparticles, as a function of the PEG:Zein ratio [(Reboredo etal. 2021), with permission]
152
R. S. H. Mansour et al.
5.6 Drug Solubilization Propensity
ofPEGylated Nanocarriers
As mentioned earlier, good water solubility is a prerequisite for the therapeutic utility of bioactive. Poor aqueous solubility limits the application or delivery of hydrophobic drugs as the release of the drug will be inadequate, consequently decreasing
its bioavailability and therapeutic effect (Yiyun and Tongwen 2005; Shadrack etal.
2015; Prajapati etal. 2009; Sacchetti and Nejati 2012). It is estimated that 40% of
the new chemical entities have low water solubility, which limits their clinical utility
(Savjani etal. 2012; Sareen etal. 2012). There are various approaches to increase
the solubility and bioavailability of drugs, such as comminution (particle size reduction), salt formation, complexation, co-crystallization, metastable forms, surfactants, and co-solvents. PEGylation of drugs and drug nanocarriers has emerged and
is employed to enhance drug solubility (Fig.5.3). Concerning this topic, most of the
discussion hereby is dedicated to dendrimers as the literature mainly focuses on the
PEGylation of this type of nanocarriers for modifying the solubility of hydrophobic drugs.
5.6.1 Survey ofNanocarriers Utilized inHydrophobic Drug
Solubility Enhancement
Complexation of drugs with dendrimers has been performed to enhance their solubility (Shadrack etal. 2018). In the late 1970s and early 1980s, the discovery of
dendrimers (Vögtle 2003; Tomalia et al. 2012) provided the basis for utilizing
PAMAM dendrimers in biomedical applications as solubility enhancers of poorly
soluble actives (Shadrack etal. 2015; Prajapati etal. 2009). PEGylation of dendrimers can additionally increase the solubility of hydrophobic drugs carried on the
dendrimers, among other improved properties (Gajbhiye etal. 2007; Luong etal.
2016; Yuan et al. 2010; Barraza et al. 2016; Jiang etal. 2010; Ryan et al. 2008;
Thakur etal. 2015; Diaz etal. 2018).
Generally, dendrimer’s ability to enhance drug solubility arises from their spherical shape, very low polydispersity, and accessible terminal groups (Gajbhiye etal.
2007). Their solubility enhancement effect depends on several factors, including
their core (Hawker etal. 1993), branching units (Ooya et al. 2003), terminal end
groups (Beezer etal. 2003), generation (Devarakonda etal. 2004), concentration,
and pH (Asthana etal. 2005). At the molecular interaction level, the hydrophobic
drug solubilization results from hydrophilic–hydrophobic interaction, ionic interaction, and drug encapsulation within the dendritic architecture (Sideratou etal. 2001).
On the other hand, dendrimers with a hydrophobic core and hydrophilic terminal
groups, such as PEGylated ones, demonstrate micellar behavior, which further aids
in solubilization (Sideratou etal. 2001; Newkome et al. 1985; Stevelmans etal.
1996). Additionally, the drug can also be attached to PEG (Gajbhiye etal. 2007).
PEGylation of dendrimers to enhance solubilization is considered superior to other
surface modication polymers and approaches since it imparts a list of desirable
5 PEGylated Nanocarriers forSolubilization
153
properties (Fig.5.3). Accordingly, the majority of the researchers utilized PEGylated
dendrimers to achieve higher solubility associated with other enhanced properties
such as biocompatibility (Liu etal. 1999; Nam etal. 2009; El-Sayed etal. 2002;
Wolinsky and Grinstaff 2008; Wei etal. 2006) and controlled release ability (Tekade
etal. 2009).
Many researchers have investigated the utility of PEGylated dendrimers in solubility enhancement and delivery of hydrophobic drugs. Water-soluble PEGylated
4,4-bis(4-hydroxy phenyl) pentanol dendrimers were found to solubilize drugs by
forming dendritic unimolecular micelles. This effect, shown in Fig.5.10, was demonstrated by pyrene solubilization in aqueous solution. The solubility of pyrene in
water is very low (8.0×10−7 M), and a dramatic increase to 2.85×10−4 M (356fold) in an aqueous solution of 1.00×10−4 M of generation 3 of the formed dendritic
micelle was observed (Liu etal. 2000). Pyrene, as a probe, in addition to betamethasone valerate and betamethasone dipropionate, as active drug ingredients, was solubilized in PEGylated diamino butane-64-poly(propylene imine) dendrimers
(Sideratou etal. 2001). The PEGylated dendrimers showed superior drug solubility
to that of the bare dendrimers. Besides, PEGylated PAMAM dendrimers resulted in
solubility enhancement of simvastatin of 33 folds in comparison to a 23 and 17.5
fold increase in solubility brought about by amine and hydroxyl functionalized dendrimers (Kulhari etal. 2011).
Table 5.2 shows the observed effects on the solubility of these drugs, along with
other examples.
Fig. 5.10 Pyrene solubilization by PEGylated 4,4-bis(4-hydroxy phenyl) pentanol dendrimer as
a function of dendrimer generation and concentration [(Liu etal. 2000), with permission]
154
Liu etal. (2000)
ReferencesAlone
Karthikeyan and
Vijayarajkumar (2015)
R. S. H. Mansour et al.
Sideratou etal. (2001)
Yang etal. (2004)
Diaz etal. (2018)
Kulhari etal. (2011)
Khandare etal. (2006)
Qi etal. (2015)
Bhadra etal. (2003)
M
−4
In PEGylated
dendrimer
2.85×10
In parent
dendrimer
–
M
−7
Solubility of drug/probe
8.0×10
−5
−6
solubility of the drug (no solubility data was mentioned)
M
M
−4
M 5.40×10
M 3.85×10
−5
2.15×10
2.95×10
–
M
−4
−6
M 2.56×10
−5
−7
1.84×10
−7
–
−1
M
6300μmolL
1093.25μM/L
−1
M 1.52×10
3380μmolL
–
−1
M 6.8×10
6.44×10
1280μmolL
33.4μM/L
−1
a
≈6.5ngmL
b
– 3.2mg/mL
–
−1
0.3μg/mL
5ngmL
efciency
Improved encapsulation ability Kojima etal. (2000)
Silybin
Simvastatin
Paclitaxel
Probucol
Pyrene
Imatinib The fth generation PEGylated dendrimer increased the aqueous
Pyrene –
Betamethasone
valerate
Betamethasone
dipropionate
Poly(propylene imine)
dendrimers
Diaminobutane-64-
poly(propylene imine)
Dendrimer Drug/probe
4,4-bis(4-hydroxy phenyl)
Table 5.2 PEGylated dendrimer mediated solubility enhancement of drugs
pentanol dendrimers
dendrimers
PAMAM dendrimers Pyrene
5-Fluorouracil Enhanced solubilization was evident by 12 folds improved entrapment
Methotrexate
Adriamycin
Lysine dendrimers Artemether Improved entrapment efciency Bhadra etal. (2005)
5 PEGylated Nanocarriers forSolubilization
(2005)
−1
mL
⋅
155
Improved entrapment efciency Namazi and Adeli
acid
Pyridine
Citric acid dendrimers 5-Amino salicylic
Mefenamic acid
diclofenac
–functionalized dendrimers was around 2.8ng
2
Polyglycerol dendrimers Paclitaxel 0.0003mg/mL – 2.305mg/mL Ooya etal. (2003)
Solubility of probucol in NH
Solubility of paclitaxel–bis (PEG) conjugate was 2.5mg/mL
a
b
156
R. S. H. Mansour et al.
PEG 4000-modied liposomes were designed to increase the aqueous solubility
of quercetin, which is an anticancer drug that also possesses antioxidant, antithrombotic, antihypertensive, angio-protective, and anti-inammatory effects. Quercetin
has a low water solubility of 1.53± 0.27 μg/mL, and the PEGylated liposomes
increased this value by 2.2 folds (Demirbolat et al. 2022). In another attempt,
PEGylated liposomes were prepared to enhance the solubility of paclitaxel, but the
PEGylated formulation showed similar solubility to that of the parent liposomes
(Yang etal. 2007b).
5.6.2 Proposed Mechanisms ofEnhanced Drug Solubilization
Mediated By PEGylation ofNanocarriers
The fundamental mechanisms of the solubility enhancement effect of PEG were
mentioned earlier (refer to Sect. 5.1.3). Regarding enhanced solubility of drugs carried on nanoparticles, several mechanisms are recognized. The occurrence of these
mechanisms depends on the designed PEGylated nanosystem.
Generally, in non-PEGylated dendrimers, the drug could be entrapped inside the
core of the dendritic structure. Noncovalent bonding, such as hydrogen bonds,
hydrophobic interactions, and electrostatic interactions, is involved in the entrapment process. Interaction of the drug with the periphery of the dendrimer could also
occur via covalent bond formation (Choudhary etal. 2017; Menjoge et al. 2010;
Milhem etal. 2000; Bhadra etal. 2005). The former effect may further induce the
formation of unimolecular micelle or the so-called “dendritic box” (Menjoge etal.
2010). The overall result of these effects will be an enhancement of the solubility of
the loaded drug.
It has been proposed that PEGylation of the dendrimers will add to the abovementioned effects by providing a PEG coat in which the drug can also be solubilized
(Sideratou etal. 2001; Yang etal. 2004) by interaction with the surface arms of PEG
(Diaz et al. 2018; Kojima et al. 2000). This effect is possibly mediated by the
enhanced complexation between the drug and the dendrimer by steric and electronic
effects provided by the additional functional groups of PEG (Bhadra etal. 2003).
On the other hand, PEG results in the formation of unimolecular micelles capable
of increasing the solubilization of the hydrophobic drug (Yang etal. 2004; Gajbhiye
etal. 2007; Bhadra etal. 2003; Liu etal. 2000). Illustrative examples of enhanced
drug solubilization by dual effects of the formation of unimolecular micelles and
enhanced complexation with the PEG coat in PEGylated dendrimers are shown in
Figs. 5.11 and 5.12. The formation of multimolecular micelles from PEGylated
dendrimers was also suggested to play a role in drug solubility enhancement (Wang
etal. 2022) as shown in Fig.5.13.
PEGylated polymeric micelles work similarly to PEGylated dendrimers.
Solubilization by the formation of polymeric or copolymeric PEG micelles occurs
when macromolecular PEG polymers or copolymers are added above their corresponding CAC, as they readily self-assemble to form micellar-like, nanosized, thermodynamically stable systems with core–shell structures (Hagan et al. 1995;