Tumor and Neovascularization Targeting Peptides ANG, SP94, NGR, RGD, APRPG

Tumor-Targeting Peptides: Revolutionizing Cancer Treatment

The field of cancer therapy is in a critical period of transformation from traditional broad-spectrum killing to precision targeting strategies. In this change, tumor-targeting peptides have become a promising therapeutic and diagnostic tool by virtue of their unique advantages such as small molecular weight, strong tissue penetration, low immunogenicity, easy chemical modification and large-scale production. These molecules are able to act like "biological guidance systems", specifically recognizing and binding to specific receptors overexpressed on tumor cells or tumor neovasculature, thus opening up a new pathway for precision medicine. representative peptides, such as ANG, SP94, NGR, RGD, APRPG, etc., are leading the development of targeted therapies.

What Are Tumor Targeting Peptides?

Tumor-targeting peptides are a class of short-chain amino acid sequences obtained by rational design or high-throughput screening techniques (e.g. phage display libraries). Their core value lies in their ability to interact with tumor tissue-specific biomarkers with high affinity and selectivity, which include specific receptors, transporter proteins or neovascularization-related molecules. This specific recognition ability stems from the significant differences in molecular expression profiles between tumor cells and normal cells. Tumor cells, in order to support their rapid proliferation, invasion and metastasis, and to evade immune surveillance, express certain molecular targets at abnormally high levels on their surface or in the tumor microenvironment (especially on neovascular endothelial cells). Tumor-targeting peptides cleverly take advantage of these biological "loopholes" to achieve precise homing, laying the foundation for the subsequent delivery of therapeutic payloads (e.g., chemotherapeutic drugs, gene therapy vectors, radionuclides) or imaging agents.

Targeting Tumor Neovasculature: The Role of NGR and RGD Peptides

Sustained tumor growth and distant metastasis are highly dependent on the formation of new blood vessels (angiogenesis), which makes targeting tumor vascular endothelial cells an effective strategy to curb cancer progression. In this field, NGR peptides (characterized by the sequence Asn-Gly-Arg) and RGD peptides (characterized by the sequence Arg-Gly-Asp) play key roles.NGR peptides specifically recognize CD13 (aminopeptidase N), which is highly expressed on tumor vascular endothelial cells.RGD peptides, on the other hand, are the classical ligand modulators for the family of integrins (in particular, αvβ3 and αvβ5 integrins), which integrins are significantly upregulated on the surface of activated tumor vascular endothelial cells and a variety of invasive tumor cells. By binding to these receptors, NGR and RGD peptides not only serve as efficient targeting vectors for precise delivery of therapeutic agents to the tumor vascular site, but also interfere with the receptor-mediated downstream pro-angiogenic signaling pathway by themselves, resulting in direct anti-angiogenic effects.

Detailed Analysis of Key Tumor-Targeting Peptides

In-depth analysis of the unique properties and mechanism of action of representative targeted peptides is central to advancing them toward clinical application.

Angiopep-2 (ANG): Crossing the Blood-Brain Barrier for Glioma Targeting

Angiopep-2 (ANG) is a star peptide specifically designed to penetrate the blood-brain barrier (BBB) and target brain tumors. Its mechanism of action relies on the specific binding to LDL receptor-associated protein-1 (LRP-1), an important receptor responsible for macromolecular transcytosis on the BBB, which is highly expressed on endothelial cells and glioma cells of the BBB. ANG peptide mimics natural ligands and efficiently hijacks LRP-1-mediated transport pathways to efficiently transport drugs (e.g., chemotherapeutic, nucleic acid or nanoparticle) coupled to it from the blood circulation. (e.g., chemotherapeutic agents, nucleic acids, or nanoparticles) coupled to it from the blood circulation to the brain parenchyma with high efficiency. This property makes ANG peptide show great potential in the treatment of malignant gliomas and other central nervous system tumors, and provides an innovative solution to the key bottleneck of traditional drugs that are difficult to enter the brain.

SP94 Peptide and Its Liver Cancer Targeting Potential

SP94 peptide (sequence SFSIIHTPILPL) is a peptide with significant selectivity for hepatocellular carcinoma (HCC) selected from a phage display library. It has been shown that SP94 specifically binds to a specific receptor highly expressed on the surface of hepatocellular carcinoma cells (although the exact receptor is still under intensive characterization and may be related to certain heat shock proteins). This binding confers excellent hepatocellular carcinoma tissue targeting, resulting in significantly higher accumulation in tumor tissue than in normal liver tissue. Therefore, SP94 peptide is widely used as a targeting head to construct nanodelivery systems loaded with chemotherapeutic agents (e.g., adriamycin, sorafenib) or imaging probes, aiming to improve the precision and efficacy of hepatocellular carcinoma treatments while decreasing the systemic toxicity, which represents an important research direction for targeted therapies in hepatocellular carcinoma.

APRPG and Its Mechanism in Tumor Angiogenesis Inhibition

The APRPG peptide (sequence Ala-Pro-Arg-Pro-Gly) was inspired by part of the structure of vascular endothelial growth factor (VEGF), enabling it to target and antagonize the VEGF receptor (VEGFR).The VEGF/VEGFR signaling pathway is the central engine driving tumor angiogenesis.The APRPG peptide effectively inhibits the activation of the downstream pro-angiogenic signaling pathway mediated by VEGF by competitively binding to VEGFR ( mainly VEGFR-1), effectively blocking the interaction between VEGF and its receptor, thereby inhibiting the VEGFR-mediated activation of the downstream pro-angiogenic signaling pathway. This direct receptor antagonism mechanism enables APRPG peptide or its couplings to effectively inhibit the neovascularization of tumors, cut off the supply of nutrients and oxygen to tumors, and then curb the growth and metastasis of tumors.

Clinical Applications and Drug Delivery Platforms

Translating tumor-targeting peptides from laboratory concepts to clinical applications is of core value. However, limitations such as peptide molecules' inherent susceptibility to protease degradation, short in vivo circulation time, and susceptibility to rapid renal clearance pose significant challenges. Advanced drug delivery platforms, especially nanotechnology, offer key solutions to overcome these obstacles and maximize the therapeutic efficacy of targeted peptides.

Peptide-Conjugated Nanoparticles for Targeted Cancer Therapy

Modification of tumor-targeting peptides (e.g., ANG, SP94, NGR, RGD, APRPG) on the surface of a variety of nanoparticles (NPs) by covalent bonding or physical adsorption is currently the most dominant delivery strategy. These nanocarriers include liposomes, polymer micelles (e.g., PLGA, PLA-PEG), dendrimers, and inorganic nanoparticles (e.g., gold nanoparticles, mesoporous silica). Peptide-modified nanoparticles integrate multiple advantageous functions: surface-modified peptides guide the entire nanocarrier to efficiently enrich in tumor tissues or tumor vascular sites through active targeting mechanism, which significantly enhances passive targeting based on the EPR effect; the core of the nanocarrier effectively protects the loaded drugs (including chemotherapeutic agents, siRNAs, photosensitizers, etc.) from degradation in the biological environment, and can be used in tumor microenvironment specific stimuli (e.g., low pH, specific enzymes, high redox levels) to achieve controlled drug release; surface engineering (e.g., PEGylation) can significantly reduce the uptake of the reticuloendothelial system, prolonging the time of the nanoparticles in the somatic circulation, and increasing the chances of their reaching the tumor site; in addition, such systems can be loaded with therapeutic drugs and imaging probes (e.g., near-infrared fluorescent dyes, MRI contrast agents) simultaneously to Visualization and monitoring of the treatment process (i.e., diagnostic and therapeutic integration). Numerous preclinical studies have conclusively demonstrated that peptide-nanocouplings significantly improve anti-tumor efficacy in a variety of tumor models (including liver cancer, glioma, breast cancer, lung cancer, etc.), while dramatically reducing toxicity and side effects on normal tissues.

Challenges and Future Perspectives in Tumor Peptide Drug Development

Although tumor-targeting peptides show exciting promise, they still face a number of serious challenges on the road to clinical drug conversion. The first challenge lies in improving the in vivo stability of the peptide molecules and optimizing their pharmacokinetic profiles, which involves enhancing their resistance to proteolytic degradation and prolonging their half-life in the circulation, with strategies such as peptide chain cyclization, introduction of D-amino acid substitutions, or PEG modification. Secondly, the heterogeneity of tumors leads to significant spatial and temporal differences in target expression, while the high mesenchymal hydraulics, hypoxic regions, and dense extracellular matrix within solid tumors severely limit the homogeneous penetration and effective delivery of targeted peptides and their nanocarriers within tumor tissues. Scale-up production and cost control is another major bottleneck for industrialization. Complex peptide synthesis, high purity requirements, precise coupling process with nanocarriers, its GMP-compliant large-scale production process and cost-effective control still need to be broken through. In addition, the potential immunogenicity of certain peptides and the non-specific effects due to off-target binding need to be rigorously evaluated over time and the peptide design continuously optimized to improve its target specificity. Finally, there is still a gap between the effective transition from successful animal model studies to clinical patient treatment, and there is a need to develop more reliable and predictive preclinical models and design more efficient clinical trial protocols to accelerate the translation process.

Looking ahead, the field of tumor-targeting peptides is poised for dynamic and innovative opportunities. The development of novel smart peptides with dual or multiple targeting capabilities (e.g., targeting both tumor cell surface receptors and tumor vascular endothelial markers) is an important trend. Designing peptide-nanosystems that can generate smart responses to multiple stimulatory signals from the tumor microenvironment (e.g., pH changes, specific enzyme activities, reactive oxygen species ROS levels, and glutathione GSH concentrations) can lead to more precise drug release and potentiation. Utilizing artificial intelligence (AI) and machine learning technologies to accelerate the rational design and virtual screening of novel high-affinity and high-specificity targeting peptides will greatly enhance R&D efficiency. Exploring peptide-drug couplings (PDCs) as a more economical and penetrating alternative to antibody-drug couplings (ADCs) holds great promise. Deepening the potential of targeted peptides for tumor immunotherapy applications is also in the spotlight, such as their use for targeted delivery of immune checkpoint modulators, cytokines or as carriers for novel tumor vaccines. With the continuous deep integration and breakthroughs in biotechnology, material science and nanomedicine, tumor-targeting peptides and their advanced delivery systems will surely occupy a more and more important position in the grand blueprint of precision cancer treatment and diagnosis, bringing new hope for the ultimate conquest of cancer.

Targeting Peptides Services at Creative Peptides

Targeting Peptides Product Table