Advances in PEGylated Targeted Nano preparation .pdf
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Advances in PEGylated Targeted
Polyethylene glycol has good hydrophilicity and flexibility, can improve the
pharmacokinetics and pharmacodynamics of drugs, and modifying it to the
surface of targeted nano- preparation can increase the residence time and
concentration of drugs in vivo. Now, PEG-modified targeted nano-preparations
have become a hot research topic in the field of pharmaceutics. This article
summarizes the physical and chemical methods of PEGylation in targeted
nano-preparations, which includes physically inserting PEG-lipids derivatives
in targeted nano-preparation or modifying PEG with targeted nano-preparation.
In addition, the influence of PEG parameters (molecular mass, modified
density and spatial conformation) on properties of targeted nano-preparation
was also discussed, which is important to preferable structure PEGylated
Keywords: polyethylene glycol modification; targeted nano preparations;
physical insertion; covalent binding; parameter optimization; PEGylation
Nanoparticle-based drugs have the following characteristics:
① Increase the solubility of hydrophobic drugs;
② Prolong the residence time of the drug in the body;
③ Slow and controlled release of drugs in the body;
④ Actively or passively target the drug to the site of drug action to reduce
adverse reactions to normal tissues.
After decades of development, polyethylene glycol (PEG) modification
technology has been widely used in different medical fields. Modification of
PEG to targeted nano-preparations can be achieved in different ways, such as
physically inserting PEG-lipid derivatives (such as PEG-DSPE,
PEG-cholesterol, PEG-fatty acids, etc.) into the nano-preparation; The
modified PEG is chemically attached to the nanoformulation. In order to
construct the optimal PEG-modified targeted nano-preparation, while exploring
the PEG modification method, people began to pay attention to the influence of
PEG parameters (relative molecular mass, modification density, spatial
conformation, etc.) on the properties of the targeted nano-preparation.
1. PEG-Physical Modification Targeting Nano-Preparation
In 1990, Blume et al. And Klibanov et al. Successfully used PEG-lipid
derivatives to increase the stability of their modified liposomes in vitro and in
vivo. The results of this study allow researchers to use more PEG-lipid
physical insertion nano-preparation with relatively low price, variety, simple
synthesis, high safety, good biocompatibility and better modification effects.
1.1 PEG-DSPE modified targeted nano-preparations
The research team used DSPE-PEG anisamide modified rHDL / (DCA-PEI /
p53) complex to prepare dual-targeted nanoparticles, which was
simultaneously mediated by Sigma and SR-BI receptors, and simultaneously
delivered chemical drugs Dichloroacetate (DCA) and the therapeutic gene p53
enter tumor cells. The nanoparticles have a uniform particle size, a neutral
charge on the surface, and low toxicity to normal cells. The synergistic effect of
DCA and p53 can effectively prevent tumor cell growth and reduce the tumor
volume of mice to (443.23 ± 78.13) mm3.
1.2 PEG-cholesterol modification targeted nano-preparations
The researchers separately made cholesterol succinic acid monoester and
mPEG-cholesterol derivative or mPEG-DSPE into vesicles or liposomes,
wrapped calcein, and then conducted pharmacokinetic investigations
respectively. The experimental results show that the calcein removal rate of
liposomes modified with mPEG-DSPE is significantly improved, and the
phenomenon of accelerated blood removal is obvious. The plasma clearance
rate of liposomes modified with mPEG-cholesterol derivatives is almost
unchanged, which proves that liposomes modified with mPEG-cholesterol
derivatives can effectively slow or eliminate accelerated blood clearance.
1.3 PEG-fatty acid modified targeted nano preparations
The researchers made PEG-fatty acid ester and decyl grafted cyclodextrin
derivative (CD-C10) into nanoparticles with PEG surface modification by
nano-coprecipitation method. The drug release time in vitro was 96h, and the
half lethal rate was 13nmol / L, far superior to nanoparticles without PEG
modification on the surface.
2. PEG chemical modification targeting nano preparation
PEG only contains -OH, but it can be chemically reacted with different reactive
groups to modify the surface of the nanoparticles.
2.1 PEG-NH2 modification targeting nano preparation
By chemically modifying the PEG end group to -NH2, the PEG can be
chemically linked to the nanoparticle through dehydration condensation with
-COOH. The researchers used long-chain oleoyl fatty acid to react with
mPEG-NH2, and self-assembled to form micelles, and finally prepared
PEG-coated superparamagnetic iron oxide nanoparticles. The PEG layer on
the surface of the nanoparticles prevents the nanoparticles from settling,
making the nanoparticles highly stable in pH 3-10 aqueous solution or 0.3mol /
L Nacl salt solution.
2.2 PEG-COOH modified targeted nano preparations
The researchers connected mPEG-COOH and branched PEI through amide
bonds, and then synthesized PEG-modified PEI to synthesize nanoparticles
(Au PENPs). Due to low cytotoxicity and hemolytic reaction, Au PENPs can be
used for CT imaging. PEG modification greatly improves the biocompatibility of
AuNPs, the half-life is extended from 11.2h to 31.76h, reducing the absorption
of macrophages, and can be more widely used in tumor CT imaging.
2.3 PEG-CHO modified targeted nano preparations
The PEG-modified drug delivery system can prolong its circulation time in the
body, but it needs to be quickly released after reaching the target site to
achieve the therapeutic effect. The researchers oxidized PEG-OH to
CHO-PEG-CHO and chemically modified it onto polydopamine-coated Fe3O4
nanoparticles (PDA-coated Fe3O4NPs). The PEG chain extends into the
solution and forms a brush-like structure under specific conditions, improving
the hydrophobicity and rigidity of the magnetic nanoparticles. PEG acts as a
link between the enzyme and the support, making PDA magnetic materials
better for enzyme immobilization.
2.4 PEG-SH modified targeted nano preparations
The researchers replaced PEG-SH and dithiothreitol (DTTC) with CTAB
coated with gold nanoparticles to form PEG and dye-coated gold nanorods
(PEG-DTTC-GNRs). Since it is not toxic to tissues, organs and nerves, the cell
survival rate at a maximum dose of 8 μg / mL is still as high as 86%, and it can
be used for in vivo sentinel lymph node (SLN) imaging and tumor targeting and
diagnosis. And it has opened a new way for the realization of high-efficiency,
non-toxic optical imaging methods.
2.5 PEG-NHS modified targeted nano preparations
Kaminskas et al. Connected PEG-NHS to dendrimers containing symmetrical
analogues of L-lysine or lysine in the outer layer to make PEG-modified
polylysine dendrimers. Encapsulated with doxorubicin, the preparation has the
characteristics of pH-sensitive doxorubicin release, long blood circulation time
and tumor targeting.
2.6 PEG-OH modified targeted nano preparations
The researchers used the hydroxyl group of PEG to connect PLA through the
ester bond at both ends to synthesize HO-PLA-PEG-PLA-OH, and then
connected pyropheophor-ea (PPa) and F3 peptide. The prepared
nanoparticles co-deliver the photosensitizer PPa and the chemotherapy drug
paclitaxel, and finally the nanoparticle PPNP is prepared. In this nanoparticle,
the encapsulation rate of the two drugs is high [(71.07 ± 2.57%), (67 ± 3.05)%],
which actively targets the tumor and realizes the synergistic effect of
chemotherapy and photodynamic therapy.
3. Effect of PEG parameters on the properties of targeted
Because PEG is hydrophilic, uncharged, and easily modified to the surface of
nanoparticles, most studies have used PEG-modified nanoparticles as the
best choice for long-cycle nanoparticles. However, the ability of PEG to repel
proteins and macrophages depends on different PEG parameters, such as
relative molecular mass, density, spatial conformation, flexibility, etc.
PEG is a hydrophilic macromolecular polymer, and its modification to the nano
preparation can weaken or eliminate the conditioning effect of plasma protein,
reduce the phagocytosis of the nano preparation by RES, and thus prolong the
blood circulation time. Drugs or fluorescent dyes with a short half-life can be
wrapped in PEG-modified nano preparations, prolonging their action time and
improving their efficacy.
However, the current methods of modifying PEG to the surface of
nano-formulations are not diverse and the existing technology still has
shortcomings. Therefore, greater efforts need to be made to improve the PEG
modification technology, and the PEG modification method and the analysis
method are used to confirm the modification results. Table 1 summarizes the
physical and chemical methods of PEG modification mentioned in this article.
Biochempeg provides kinds of PEG-lipids that can be used in bioconjugation,
drug formulation and nanoparticle delivery.