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5 PEGylated Nanocarriers forSolubilization
157
Fig. 5.11 Solubilization of 5-uorouracil in PEGelated dendrimers [(Bhadra etal. 2003), with
permission]
Fig. 5.12 Solubilization of pyrene in PEGelated dendrimers [(Sideratou et al. 2001), with
permission]
158
Fig. 5.13 Drug
solubilization in PEGelated
dendrimers by the
formation of
multimolecular micelles
[(Wang etal. 2022),
reproduced with
permission]
R. S. H. Mansour et al.
Kazunori etal. 1993; Otsuka etal. 2003). These micellar systems can increase the
solubilization of hydrophobic drugs (Otsuka etal. 2003).
5.6.3 Added Advantages ofDrug Solubility Enhancement by
Nanocarriers PEGylation
An added advantage of dendrimer PEGylation in solubility enhancement is the
improved drug loading. The encapsulation of the drug in the dendrimers will
increase since the PEG chains will aid in loading additional drug molecules within
PEG chains. For example, the enhanced encapsulation of 5-uorouracil using
PEGylated PAMAM dendrimers was reported (Bhadra etal. 2003).
5.6.4 Factors Affecting Drug Solubilization Propensity
ofPEGylated Dendritic Nanocarriers
5.6.4.1 PEG Chain Length/Molecular Weight
In general, longer PEG chains, i.e., chains with higher molecular weight, are
expected to exert a better solubility enhancement effect. Attachment of shorter PEG
arms provides little improvement of drug solubility in comparison to the parent
dendrimers.
In generation three PEGyated PAMAM dendrimers, the PEG arm length was
found to signicantly affect pyrene water solubility (Fig.5.14). The short PEG arms
(PEG 750) did not substantially change solubility compared to the parent dendrimers.
It was hypothesized that these short chains produce a relatively open cavity due to
weak interaction. Increasing the PEG arm length to 2000 Da led to a noticeable
increase in pyrene solubility. This effect was attributed to forming a network of a thick
5 PEGylated Nanocarriers forSolubilization
Fig. 5.14 Effect of PEG chain length and dendrimer concentration on pyrene solubility [(Yang
etal. 2004), reproduced with permission]
159
PEG layer at the surface of the dendrimer, within which pyrene can bind. These longer
PEG chains gave each unimolecular micelle an isolated space to encapsulate the drug.
However, PEG 5000 showed a lower capability for solubility enhancement compared
to that of PEG 2000, and this could be a result of the higher tendency of the formed
unimolecular micelles to aggregate, thus shielding some of the potential sites available for drug binding because of PEG chains entanglement (Yang etal. 2004).
Partially PEGylated generation four PAMAM dendrimers were used to enhance
the water solubility of silybin. The longer PEG chain (PEG 2000) resulted in a
higher increase in silybin solubility compared to the shorter chain (PEG 550) (Diaz
etal. 2018). Similarly, PAMAM dendrimers PEGylated with PEG 2000 were found
to encapsulate higher number of molecules of adriamycin and methotrexate compared to those PEGylated with PEG 550. This effect was justied by the inability of
the shorter PEG chain to cover and stabilize the drug in addition to the ability of the
longer chains to modify the conformation of the dendrimer chain, making the inner
space of the dendrimer larger (Kojima etal. 2000).
5.6.4.2 Extent/Density/Substitution Percentage ofPEGylation
Increasing the PEGylation extent is supposed to provide better drug solubility
enhancement. Nevertheless, the number of PEG chains attached to the surface of the
dendrimer should be carefully controlled in order to preserve the exibility of the
nanosystem, which is an essential characteristic of using dendrimers in drug delivery. Moreover, crowded PEG arms may result in steric hindrance that reduces further coupling with other small molecules of interest to the dendrimer surface. To
illustrate the effect of PEGylation extent, diamino butane-64-poly(propylene imine)
dendrimers were PEGylated at two different levels. The densely PEGylated dendrimers showed a better ability to solubilize pyrene, betamethasone valerate, and
betamethasone dipropionate (Sideratou etal. 2001). Paclitaxel solubility was also
increased with increasing the generation of polyglycerol dendrimers, generations 3,
4, and 5 (Ooya etal. 2003).
160
R. S. H. Mansour et al.
5.6.4.3 Generation andConcentration oftheDendrimer
Similar to non-PEGylated dendrimers, the ability of the PEGylated derivatives to
enhance hydrophobic drug solubility increases with increasing dendrimer generation and concentration.
As shown in Fig. 5.10, PEGylated 4,4-bis(4-hydroxy phenyl) pentanol dendrimers of generation three were found superior to generation two in solubilizing
pyrene. The latter was also better at solubilizing pyrene than generation one.
Similarly, the effect of increasing the corresponding dendrimer concentration on the
enhanced drug solubility is evident (Liu etal. 2000). PEGylated lysine dendrimers
of generation 5 solubilized 0.411±0.11g of artemether/g of dendrimers compared
to 0.35±0.08g/g of generation 4 dendrimers (Bhadra etal. 2005). The solubility of
pyrene increases with increasing concentration of generation 3 PEGyated PAMAM
dendrimers, as shown in Fig.5.14 (Yang etal. 2004).
It is worth mentioning that even though higher generations of the dendrimers are
associated with higher drug solubilization of higher generation as they have a higher
tendency to entrap more hydrophobic drug molecules, PEGylation of the lower generation dendrimers may cause an enhanced drug solubility compared to the parent dendrimers. PEGylation will induce stretching out of the surface sites of the dendrimers as
a result of the PEG arms. Consequently, the dendritic inner space will expand to the
maximum in the aqueous phase providing a space for drug binding (Yang etal. 2004).
5.7 Conclusion andFuture Perspective
The wide range of promising potential pharmaceutical and biomedical applications
of PEGylated nanocarriers provides many advantageous criteria. The advantageous
enhanced solubility of these systems and the drugs they carry necessitate further
efforts to specically approach solubility issues of different types of nanocarriers.
Pharmaceutical solubilization of nanocarriers by PEGylation compromises a rich
area of research. Within the same context, protein PEGylation as a means to solubilize enzymes and proteins for facilitated nanoparticle production has also emerged.
This chapter discussed the amount of knowledge available in the literature pertaining to different aspects of solubility and solubility-related issues of PEGylated
nanocarriers. In most of the illustrated research, general approaches were employed
with no focus on detailed aspects. Specic focus on the factors affecting the solubilization, in addition to the relation between the PEGylated nanocarriers’ solubility
and the other advantages offered by them, is worthy of investigation.
Disclosures There is no conict of interest and disclosures associated with the
manuscript.
5 PEGylated Nanocarriers forSolubilization
161
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