Key Takeaways
- •Peptides show lower affinity and shorter half-life in the body than antibodies.
- •Peptide-drug conjugates link tumor-homing peptides to small molecules or chemotherapeutic agents through linkers.
- •Peptides face challenges like lower affinity, rapid body clearance, short half-life, and breakdown by proteases compared to antibodies.
Peptides Outperform Antibodies in Key Areas
Peptides show lower affinity and shorter half-life in the body than antibodies. However, they surpass antibodies in tissue penetration and cellular internalization. These traits make peptides ideal for guiding carriers like nanoparticles, extracellular vesicles, and cells, along with payloads such as cytotoxic peptides and radioisotopes, directly to tumors.
Peptide-drug conjugates link tumor-homing peptides to small molecules or chemotherapeutic agents through linkers. Peptides also bind selectively to cell surface receptors and proteins, including immune checkpoints, receptor kinases, and hormone receptors, to block their activity or act as hormone analogs. Inside cells, peptides disrupt protein-protein interactions, positioning them as multifunctional agents in cancer treatment.
Drawbacks and Benefits Relative to Antibodies
Peptides face challenges like lower affinity, rapid body clearance, short half-life, and breakdown by proteases compared to antibodies. On the positive side, they offer superior deep tissue penetration, efficient cell entry, reduced immunogenicity, minimal toxicity to bone marrow and liver, and straightforward chemical modifications. For insights into peptide stability, check the Half-Life Calculator.
Over 80 peptide therapeutics exist on the market, such as glucagon-like peptide-1 liraglutide for type 2 diabetes treatment and leuprolide, a somatostatin analog for prostate cancer. Peptides also help identify peptide-mimetic epitopes, develop vaccines, and map protein-protein interaction sites. Their main uses in targeted therapy involve delivering carriers like nanoparticles, extracellular vesicles, and cells, plus payloads like cytotoxic peptides, radioisotopes, and small molecules; inhibiting cell surface receptors and proteins; and blocking intracellular protein-protein interactions.
Tumor-Homing Peptides Enhance Nanoparticle Delivery
Tumor-homing peptides direct nanoparticles to cancer cells via interactions with cell surface receptors or partners. These peptides target tumor cells specifically to boost nanoparticle uptake. Multivalent peptide display on nanoparticles strengthens binding affinity, and nanoparticle attachment shields peptides from protease degradation.
RGD peptides stand out as prominent tumor-homing examples, including RGD4C (ACDCRGDCFCG) and Cilengitide (RGDfV). They target αvβ3 integrins, which appear at high levels on angiogenesis endothelial cells in tumor blood vessels, and block blood vessel growth. Studies have examined RGD peptide binding to drug or drug-loaded nanoparticles for cancer therapy.
Advanced RGD Variants and Other Targeting Peptides
iRGD (CRGDR/KGPDC), a modified RGD peptide, binds αV integrin and boosts drug tissue permeability. Its binding to αV integrins on tumor endothelial cells triggers protease cleavage into CRGDR/K and GPDC. The CRGDR/K fragment, with its C-terminal CendR motif (R/KXXR/K), then binds neuropilin-1 to activate endocytosis, enhancing drug penetration whether linked or co-administered.
The mitochondrial protein p32, or gC1qR, overexpresses in tumors and appears abnormally on tumor cell surfaces, in tumor lymphatics, and on myeloid cells like tumor-associated macrophages (TAMs). LyP-1 peptide (CGQKRTRGC) binding to p32 directs nanoparticle albumin-bound paclitaxel to accumulate in tumor tissue, curbing growth better than non-targeted versions.
Vascular endothelial growth factor receptor 2 (VEGFR-2) resides mainly on tumor endothelial cells. K237 peptide (HTMYYHHYQHHL), which binds VEGFR-2, attaches to paclitaxel nanoparticles to halt angiogenesis, trigger tumor endothelial apoptosis, and cause tumor necrosis.
Targeting Receptors on Tumors and Macrophages
Type II interleukin 4 receptor (IL4R), made of IL4Rα and IL13Rα1, rises in tumors like breast, lung, head and neck, and glioblastoma versus normal tissues. IL4RPep-1 peptide (CRKRLDRNC) binds IL4R to improve nanoparticle delivery to these tumors. IL4R also marks M2-polarized pro-tumor TAMs more than M1 anti-tumor ones, serving as a TAM drug delivery target.
Mannose receptor CD206 identifies M2 macrophages. mUNO peptide (CSPGAK), a CD206 binder, labels nanoparticles for selective delivery to M2 TAMs, shifting them from M2 to M1 phenotypes. Explore peptide terms in the Peptide Glossary.
Peptide-Modified Extracellular Vesicles for Delivery
Extracellular vesicles (EVs), or exosomes, act as natural nanoparticles secreted by cells into circulation. They transport DNA, RNA, proteins, and lipids between cells. Tumor-homing peptides on therapeutic-loaded exosomes cut side effects in cancer therapy.
Exosome surface changes use genetic or non-genetic methods. Genetic engineering fuses exosomal protein Lamp2 to neuron-specific RVG peptide (YTIWMPENPRPGTPCDIFTNSRGKRASNG) in dendritic cells (DCs). These exosomes target γ-aminobutyric acid (GABA) receptors to deliver short interfering RNAs to brain neurons, microglia, and oligodendrocytes, knocking out genes with minimal off-target uptake.
Mouse immature DCs engineered to secrete Lamp2-iRGD (CRGDR/KGPDC) exosomes deliver drugs efficiently to αv integrin-positive breast cancer cells, slowing tumor growth. Tumor cell-derived exosomes with platelet-derived growth factor receptor transmembrane domain fused to GE11 peptide (YHWYGYTPQNVI), an EGFR binder, target let-7a microRNA to breast cancer tissues. pH-sensitive GALA peptide (WEAALAEALAEALAEHLAEALALEALAA) in engineered tumor exosomes delivers antigens to DC cytoplasm, aiding presentation via major histocompatibility complex class I and DC maturation.
Non-Genetic Exosome Modifications
Non-genetic tweaks employ lipid anchors, electrostatic bonds, and ligand-receptor ties. M1 macrophage exosomes loaded with NF-κBp50 siRNA and miR-511-3p promote M1 polarization, then modified with IL4RPep-1 via phospholipid anchors to target IL4R-high M2 TAMs, halting tumor advance by shifting them to M1-like states.
Blood exosomes gain tumor accumulation through transferrin receptor interactions with transferrin-coupled superparamagnetic nanoparticles, electrostatic L17E endosomolytic peptide, and cholesterol-anchored miR-21 inhibitors on lipid membranes for endosomal escape and drug delivery. Surface-labeled exosomes with chi
Peptides hold strong promise in cancer therapy through targeted delivery and biological interference. Their advantages in penetration and modification support ongoing research applications. Tools like the Free peptide tools page offer resources for peptide studies.
