Peptide-mediated Trans-BBB Delivery Service

Creative Peptides provides peptide modification services to enhance brain-specific drug delivery by employing blood-brain barrier penetration techniques including receptor-mediated transport (such as Angiopep-2) and cell-penetrating peptide conjugation (such as RVG).

Introduce to Peptide-Mediated Brain Drug Delivery

Blood-brain barrier (BBB) functions as a major obstacle for brain-targeted drugs because it prevents most medications and large molecules from entering brain tissue. This barrier is formed by endothelial cells that connect densely and block the passage of lipophilic drugs along with large molecules which reduces the therapeutic potential of many drugs. The development of effective treatments for neurological diseases remains difficult because the BBB prevents adequate drug concentrations from reaching the brain.

Researchers use drug modifications with peptides that bind to specific brain cell receptors to bypass the blood-brain barrier. Through these peptide modifications drugs can exploit receptor-mediated transcytosis which helps therapeutic agents pass through the BBB more effectively. The attachment of peptide sequences that bind selectively to receptors abundant on brain endothelial cells enables these drugs to traverse the BBB and reach specific brain regions.

This peptide-mediated targeting mechanism significantly improves the efficiency of drug distribution in the brain, ensuring that higher concentrations of the drug reach the desired site of action. Additionally, this approach enhances the therapeutic effects while minimizing side effects, as the drug is directed specifically to the target tissue. As a result, peptide-modified drug delivery systems hold great promise in enhancing the treatment of neurological disorders by overcoming the limitations imposed by the BBB.

Advanced Platforms for Trans-BBB Delivery Service

Diversified Peptide Synthesis and Modification Solutions

Creative Peptides offers a wide range of blood-brain barrier penetrating peptide conjugations, including Angiopep-2 and T7 Peptide, designed to enhance drug or cargo delivery across the BBB. We specialize in custom peptide synthesis with precise control over sequence, length, and post-synthetic modifications, including PEGylation, phosphorylation, and glycosylation. These modifications improve pharmacokinetic properties such as stability, solubility, and bioavailability, expanding the range of applications for peptide-based therapeutics.
Our platform supports the conjugation of peptides with small molecule drugs, antibodies, or nanoparticles to optimize brain-targeted delivery. Using automated solid-phase peptide synthesizers, we ensure high-throughput, scalable production, providing tailored solutions for BBB penetration and other therapeutic needs. Creative Peptides combines advanced peptide synthesis with comprehensive modification options to meet diverse drug delivery requirements.

Analytical and Characterization Tools

To ensure the quality and functionality of our peptide-based drug candidates, Creative Peptides uses advanced analytical techniques. High-Performance Liquid Chromatography (HPLC) is employed for peptide purification, while Mass Spectrometry (MS) allows for detailed structural analysis, molecular weight determination, and conjugation efficiency. NMR spectroscopy is used for three-dimensional structural characterization, providing insights into peptide-receptor interactions and optimizing designs for improved BBB penetration.

In Vitro and In Vivo BBB Testing Models

Creative Peptides provides robust in vitro and in vivo testing platforms to evaluate BBB penetration potential. Our in vitro models, using human-derived endothelial cell monolayers cultured on Transwell systems, replicate the blood-brain barrier's selective permeability and allow real-time transport assessment of peptides. For in vivo testing, animal models (such as mice and rats) are used to track the pharmacokinetics and biodistribution of peptides, providing critical data on brain penetration efficiency via imaging techniques like MRI and fluorescence.

Comprehensive Peptide-mediated Trans-BBB Delivery Service

Receptor-Mediated Peptide Permeabilization

Receptor-mediated peptide permeabilization is an active targeting strategy based on specific receptors on the surface of BBB endothelial cells. Peptides (e.g., Angiopep-2, T7 peptide, RVG29) that bind to receptors (e.g., LRP1, TfR, nAChR) with high affinity are designed to trigger endocytosis and deliver drugs to the brain. This mechanism has high specificity and high penetration, which can significantly increase the concentration of drugs in the brain, and is suitable for targeted therapy of central nervous system diseases such as glioma and Alzheimer's disease.

Angiopep-2 Modification

Angiopep-2 is a 19-amino acid peptide derived from the Kunitz-type serine protease inhibitor family, known for its high affinity binding to the low-density lipoprotein receptor-related protein 1 (LRP1). LRP1 is highly expressed in the blood-brain barrier and brain tumor cells, making Angiopep-2 a widely used ligand in brain-targeted drug delivery systems. Compared to other ligands such as transferrin (Tf) and lactoferrin (Lf), Angiopep-2 exhibits superior BBB penetration capability through receptor-mediated endocytosis.

Angiopep-2-modified nanocarriers have demonstrated significant advantages in glioma treatment by enhancing drug uptake in tumor tissues while minimizing toxicity to normal brain cells. For instance, Wang et al. developed Angiopep-2-modified PLGA nanoparticles co-delivering doxorubicin (DOX) and epidermal growth factor receptor siRNA (ANG-PLGA-DOX-siRNA), which effectively transported therapeutic agents into glioma cells (U87MG) and exhibited strong inhibitory effects.

Beyond glioma, Angiopep-2-modified nanocarriers have also been explored for treating neurodegenerative diseases such as Alzheimer's and Parkinson's, offering a promising strategy for enhancing brain drug delivery.

T7 Peptide Modification

T7 peptide is a transferrin receptor (TfR)-based peptide that is able to penetrate the blood-brain barrier through endocytosis. TfR is highly expressed in the brain, especially in brain tumor cells, so the T7 peptide is widely used in the design of brain-targeted drug delivery systems.

T7 peptide-modified nanocarriers can significantly increase the accumulation of drugs in the brain and reduce toxicity to normal brain tissue. For example, Liang et al. found that T7 peptide-modified vincristine (VCR) exhibited higher brain uptake in mice and effectively inhibited glioma growth. In addition, T7 peptide-modified nanocarriers have also been used in the treatment of other neurological diseases, such as Parkinson's disease and Alzheimer's disease.

RVG29 Peptide Conjugation

The nicotinic acetylcholine receptor (nAChR) is expressed on the surface of brain microvascular endothelial cells (BCEC). RVG29, a 29-amino-acid peptide derived from the rabies virus glycoprotein (RVG), specifically binds to nAChR. This binding allows RVG29 to transport nucleic acids, genes, or drugs into BCECs, crossing the blood-brain barrier and entering the brain.

RVG29-modified nanoparticles, such as paclitaxel-loaded polyethylene glycol-polylactic acid-hydroxyacetic acid copolymer nanoparticles (DTX-NPs), have shown excellent penetration capabilities and the ability to cross the BBB. In vitro uptake studies in C6 cells revealed that these nanoparticles were taken up through specific binding to nAChR on the cell surface.

By binding to nAChR, RVG29 enables highly targeted drug delivery, enhancing drug uptake in neuronal cells while minimizing toxicity to normal brain tissue. As a result, RVG29-modified nanocarriers have proven effective in treating neurological diseases such as Parkinson's disease and Alzheimer's disease.

Transporter-Mediated Peptide Permeabilization

Transporter-mediated peptide permeabilization modification harnesses the ability of transporter proteins on the BBB, such as glutathione transporters, to actively transport drugs. By modifying endogenous transporter substrates (e.g., glutathione tripeptide), drugs can be recognized by transporters and delivered across membranes. Its advantages lie in its low immunogenicity and physiological compatibility, and it is suitable for the delivery of small molecule drugs or anti-inflammatory agents, such as glutathione-modified liposomes, for the improvement of pathological symptoms in encephalomyelitis models.

Glutathione Transporter (GSH) Modification

Glutathione, an endogenous tripeptide with antioxidant properties, enters the brain by specifically binding to the glutathione transporter on the blood-brain barrier. Glutathione-modified methylprednisolone-loaded polyethylene glycol liposomes (GSH-PEG-LP) have been shown to significantly increase the drug's circulation time and brain uptake in healthy rats. In an acute autoimmune encephalomyelitis rat model, free methylprednisolone showed no effect, while GSH-PEG-LP notably improved pathological symptoms. The glutathione transporter, which is widely present on cell membranes, facilitates the transport of glutathione. By attaching glutathione to peptides, efficient brain-targeted drug delivery can be achieved. Glutathione-modified peptides enter cells through this GSH-transport-mediated mechanism, releasing drugs intracellularly. Studies have demonstrated that glutathione-modified peptides significantly enhance drug distribution efficiency in the brain while reducing toxicity to normal brain tissue.

Adsorption-Mediated Peptide Permeabilization

Adsorption mediates the electrostatic adsorption of the positive charge of the dependent peptide and the negative charge of the BBB film to penetrate the barrier. For example, arginine/lysine-rich TAT peptides penetrate cell membranes through non-specific adsorption, promoting drug internalization. Although the penetration efficiency is high, there is a risk of off-target, and it is necessary to optimize the selectivity in combination with the targeted molecule, which is suitable for the rapid delivery of nucleic acids, proteins, and other macromolecules.

TAT Peptide Modification

TAT peptide is a peptide based on the TAT protein of human immunodeficiency virus (HIV), which has strong penetrating ability. TAT peptides are able to enter cells through direct penetration or endocytosis and release drugs within the cells.

TAT peptide-modified nanocarriers are able to enter cells through direct penetration or endocytosis and release drugs within cells. Studies have shown that TAT peptide-modified nanocarriers can significantly improve the efficiency of drug distribution in the brain and reduce toxicity to normal brain tissue.

Penetratin Modification

Penetratin is a peptide based on insect antimicrobial peptides with strong penetrating ability. Penetratin-modified nanocarriers are able to enter cells through direct penetration or endocytosis and release drugs within the cell.

Penetratin-modified nanocarriers are able to enter cells through direct penetration or endocytosis and release drugs within the cell. Studies have shown that Penetratin-modified nanocarriers can significantly improve the efficiency of drug distribution in the brain and reduce toxicity to normal brain tissue.

Transportan Modification

Transportan is a transporter-based peptide with strong penetrating ability. Transportan-modified nanocarriers are able to enter cells through direct penetration or endocytosis and release drugs within cells.

Transportan-modified nanocarriers are able to enter cells through direct penetration or endocytosis and release drugs within cells. Studies have shown that Transportan-modified nanocarriers can significantly improve the efficiency of drug distribution in the brain and reduce toxicity to normal brain tissue.

Two-Stage Targeted Peptide Permeabilization

Two-stage targeting achieves a synergistic effect of penetrating BBB+ lesion targeting by combining two functional molecules. For example, after Angiopep-2 binds to LRP1 to penetrate the BBB, TAT peptide enhances tumor cell uptake or in combination with a targeted antibody (e.g., CD133mAb) to precisely localize glioma stem cells. This strategy reduces peripheral accumulation and increases the window of treatment, making it ideal for complex brain diseases such as glioblastoma multiforme.

Receptor and Penetrating Peptide Co-modification

Two-stage targeting technology further improves the efficiency and targeting of drugs in the brain by combining two different targeting mechanisms. For example, Angiopep-2 co-modified with TAT peptide nanocarriers are able to penetrate the blood-brain barrier through LRP1-mediated endocytosis and directly penetrate the cell membrane in a TAT peptide-mediated manner.

Studies have shown that two-stage targeting technology can significantly improve the efficiency of drug distribution in the brain and reduce toxicity to normal brain tissue. In addition, the two-stage targeting technology can also enhance the targeting of drugs to specific lesion sites.

Receptor and Antibody Co-modification

Angiopep-2 co-modified nanocarriers with CD133 monoclonal antibody (mAb) can penetrate the blood-brain barrier through LRP1-mediated endocytosis and target glioblastoma multiforme in a CD133 antibody-mediated manner.

Studies have shown that Angiopep-2 co-modified nanocarriers with CD133mAb can significantly improve the targeting of glioblastoma multiforme and reduce toxicity to normal brain tissue.

Advantages of Our Peptide-mediated Trans-BBB Delivery Service

Application of Peptide-mediated Trans-BBB Delivery

Customized Service Process

FAQ

1. What is BBB-penetrating peptide modification?

2. Which peptides are commonly used for BBB penetration?

3. What applications does this modification support?

4. How does Creative Peptides ensure modification success?

5. Can you provide custom peptide modifications?

6. What is the typical turnaround time?

References

1. Huang, Na, et al., PLGA nanoparticles modified with a BBB-penetrating peptide co-delivering Aβ generation inhibitor and curcumin attenuate memory deficits and neuropathology in Alzheimer's disease mice. Oncotarget 8.46 (2017): 81001.
2. Wang, Lei, et al., Co-delivery of doxorubicin and siRNA for glioma therapy by a brain targeting system: angiopep-2-modified poly (lactic-co-glycolic acid) nanoparticles. Journal of drug targeting 23.9 (2015): 832-846.
3. Liang, Meng, et al., Enhanced blood–brain barrier penetration and glioma therapy mediated by T7 peptide-modified low-density lipoprotein particles. Drug delivery 25.1 (2018): 1652-1663.
4. Habib, Saffiya, and Moganavelli Singh., Angiopep-2-modified nanoparticles for brain-directed delivery of therapeutics: a review. Polymers 14.4 (2022): 712.