PEGylated RGD Peptides: A Promising Tool for Targeted Drug Delivery

RGD is a sequence peptide composed of three amino acids: Arg-Gly-Asp. It is widely present in proteins of the extracellular matrix (ECM) (such as laminin, glassnectin, fibrinogen, osteopontin, etc.). It is an integrin receptor antagonist peptide that can specifically bind to 11 types of integrins. RGD peptide-modified biomaterials have a wide range of applications. For example, RGD-functionalized polyethylene glycol particles can be used for tumor targeting and intracellular uptake; RGD-modified hyaluronic acid hydrogels can be used to improve the cell activity of hMSCs; and the supramolecular nanofibers of RGD peptide can promote the repair of kidneys by extracellular vesicles.

Fig. 1. RGD peptide-based lipids for targeted mRNA delivery (RSC Adv. 2022,12: 25397-25404).

RGD Peptide Sequence

RGD peptide can be divided into linear peptides and cyclic peptides. They are the smallest recognized short peptide sequences for many extracellular matrix proteins (such as VN, FN, FGN, collagen, etc.). RGD can effectively cause cell adhesion, localize to a specific cell line and produce specific cellular responses. Studies have found that RGD sequence peptides have a wide range of biological activities and can be used to treat cardiovascular diseases, osteoporosis, inflammation and other diseases. They can also prevent and treat tumors caused by abnormal cell adhesion, especially the metastasis of developmental tumors. On the other hand, RGD sequence peptides can be used as stimulants to promote the regeneration of damaged organs and tissues, wound healing, etc. In addition, RGD serves as a receptor for certain integrins, and its selectivity partially depends on the conformation of RGD and the amino acid residues surrounding RGD. For this reason, in recent years, many scientific and technological workers have synthesized a series of RGD tripeptides, tetrapeptides, pentapeptides, etc., as well as RGD cyclic peptides, double-line peptides, RGD mimetic peptides, etc.

RGD Peptide Integrin

Integrins are cell membrane adhesion receptors that constitute the ECM. They are heterodimeric transmembrane glycoproteins composed of α subunits and β subunits. Integrins control various cellular functions necessary for the occurrence, development, and metastasis of solid tumors by activating signal transduction pathways. αvβ3 in the integrin family is highly expressed on the surface of various solid cancer tumor cells, and it can recognize the RGD peptide sequence. RGD peptide can prevent tumor cells from adhering to the extracellular matrix by competitively binding to integrin receptors, or directly induce tumor cell apoptosis, ultimately achieving the purpose of inhibiting tumor cell proliferation, invasion and metastasis. Therefore, it can be used to develop biological targets for anti-angiogenic drugs and molecular imaging probes for early tumor diagnosis.

Fig. 2. Generalized information on the structure of an integrin receptor (Int J Mol Sci. 2022, 23(22): 13735).

Cyclic RGD Peptide

RGD linear peptide has low stability, poor clinical performance, and poor selectivity for specific integrin receptors. Compared with RGD linear peptide, RGD cyclic peptide has a more stable structure and stronger binding affinity and selectivity for integrin receptors. Currently, researchers are conducting various transformations and modifications on RGD cyclic peptides:

• Number of amino acids: The conventional RGD peptide has 5 amino acids, which is called a 5-membered ring. It can also have 6 or 7 amino acids, etc.
• Types of amino acids: Some amino acids can be replaced with similar amino acids, such as Tyr and Phe, Gly and Ala, and some amino acids can also be N-methylated.
• Modification of functional groups: Functional groups such as thiol, azide, alkynyl, alkenyl, and maleimide can be added to the RGD cyclic peptide to facilitate combination with other molecules or materials.
• Label modification: PEG, Biotin, FITC, FAM, TAMRA, DOTA, HYNIC, etc. can be modified on the RGD cyclic peptide as needed.
• Ring formation method: At present, most RGD cyclic peptides form amide bond rings and disulfide bond rings. They can also be transformed into interester ring formation, thioester ring formation, etc.

RGD Peptide Cancer Targeting

Conjugation with Drug Molecules

Hydrophobic drug molecules containing thiol groups are coupled with the cysteine thiol groups in the hydrophilic cRGD and iRGD peptide sequences through disulfide bonds to enhance their tumor targeting and penetration. Conjugating RGD peptides to drug molecules can help target specific cells that overexpress integrin receptors. In addition, RGD peptides can promote the uptake of drug molecules into cells by interacting with integrin receptors on the cell surface, thereby improving drug delivery and bioavailability.

Conjugation with Lipid Materials

Preparing iRGD and lipid materials into liposomes enables the liposomes to have the ability of tumor targeting and deep penetration, and increases the breast cancer therapeutic effect of the drug. This approach may increase the accumulation of the drug at the tumor site while minimizing its contact with healthy tissue, thereby increasing its efficacy and reducing potential side effects.

Other Conjugation Materials

Through electrostatic interaction, iRGD-NH2 is adsorbed to the surface of the DNA carrier to form new nanoparticles. Its anti-tumor model showed that the treatment group added with iRGD showed superior anti-tumor and anti-angiogenesis efficiency, and had good safety.

PEGylated RGD Peptide

When RGD peptides are PEGylated, the resulting products retain the ability to bind to integrin receptors while also benefiting from the enhanced pharmacokinetic properties conferred by PEGylation. Therefore, PEGylated RGD peptides show great potential in improving drug delivery to target sites while minimizing off-target effects.

Fig. 3. RGD-functionalized PEG particles for tumor targeting and intracellular uptake (Biomacromolecules. 2019, 20(9): 3592-3600).

The combination of RGD peptides and PEGylation opens up new possibilities for targeted drug delivery in various medical applications. One of the most promising areas of research is the treatment of cancer. By conjugating anticancer drugs to pegylated RGD peptides, researchers are able to deliver these drugs specifically to tumor cells, thereby increasing their efficacy and reducing their systemic toxicity. This targeted approach holds great promise for improving the outcomes of cancer treatment and reducing the side effects associated with traditional chemotherapy. In addition to cancer treatment, PEGylated RGD peptides have shown potential in treating other diseases, such as cardiovascular and inflammatory diseases. By targeting integrin receptors on specific cell types involved in these diseases, pegylated RGD peptides could provide a more effective and safer alternative to traditional treatments.

BOC Sciences is committed to providing various functional group-modified PEGylated RGD peptide products, including cRGD-PEG-COOH, cRGD-PEG-DSPE, cRGD-PEG-MAL, mPEG-cRGD, RGD-PEG-NH2, RGD-PEG- NHS etc. We can modify RGD peptides with PEGs of various molecular weights and structures based on our customers' specific needs. In addition, custom PEGylation services for peptides are also quickly available at BOC Sciences.

References

1. Mitchell, M.J. et al. RGD peptide-based lipids for targeted mRNA delivery and gene editing applications. RSC Adv. 2022,12: 25397-25404.
2. Nikitin, M.P. et al. Delivery of Theranostic Nanoparticles to Various Cancers by Means of Integrin-Binding Peptides. Int J Mol Sci. 2022, 23(22): 13735.
3. Caruso, F. et al. Ligand-Functionalized Poly(ethylene glycol) Particles for Tumor Targeting and Intracellular Uptake. Biomacromolecules. 2019, 20(9): 3592-3600.