Release date:2020/4/9 11:05:29
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 targeted nano-preparation.
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 nano-preparations
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.
4. Conclusion

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.
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