Key Takeaways
- •Cell-penetrating peptides, known as CPPs, come in various types.
- •According to physical and chemical traits, CPPs split into three groups: cationic, amphiphilic, and hydrophobic.
- •Cationic CPPs consist of short sequences high in arginine, lysine, and histidine.
Classes and Applications of Cell-Penetrating Peptides
Cell-penetrating peptides, known as CPPs, come in various types. Experts classify them by physicochemical properties, sources, intake mechanisms, and biomedical uses. No single standard exists for this grouping.
According to physical and chemical traits, CPPs split into three groups: cationic, amphiphilic, and hydrophobic. Cationic and amphiphilic forms lead, representing about 85% of cases. Hydrophobic types account for just 15%.
Cationic Cell-Penetrating Peptides
Cationic CPPs consist of short sequences high in arginine, lysine, and histidine. Known examples are TAT, Penetratin, Polyarginine, P22N, DPV3, and DPV6.
Arginine features a guanidine group that forms hydrogen bonds with negatively charged phosphate groups on cell membranes. This interaction aids entry at physiological pH. Research on oligo-arginine chains from 3 R to 12 R found that penetration ability rises when arginine reaches at least 8 units. Capacity grows further as arginine count increases.
Lysine shares cationic nature with arginine but lacks guanidine. On its own, lysine shows lower transmembrane efficiency.
Amphiphilic and Hydrophobic Cell-Penetrating Peptides
Amphiphilic CPPs contain both hydrophilic and hydrophobic regions. Subgroups include primary amphiphilic, secondary α-helix amphiphilic, β-folded amphiphilic, and proline-enriched amphiphilic forms.
Hydrophobic CPPs rely solely on non-polar amino acid residues. Their net charge stays below 20% of the total amino acid sequence charge. Some include hydrophobic motifs or chemical groups key to membrane penetration.
These hydrophobic CPPs receive less attention but do occur. Instances are fibroblast growth factor (K-FGF) and fibroblast growth factor 12 (F-GF12), both from Kaposi's sarcoma.
Tumor Treatment with Cell-Penetrating Peptides
CPPs deliver chemotherapeutic drugs or biologic agents into cells using their penetration power. They release payloads in the cytoplasm or at target sites to boost effects against tumor cells.
Dubikovskaya et al. attached the R8 peptide to paclitaxel (PTX), a common chemotherapy agent, via a biolysable disulfide linker. Inside cells, high glutathione levels break this bond. Tests in cell cultures and animal models showed CPP-paclitaxel outperforms paclitaxel alone. It works even in paclitaxel-resistant cells.
Delivery of Oligonucleotides and siRNA
Peptide, protein, and gene-based large molecules hold promise for disease treatment. Their size and poor lipid solubility block easy cell membrane crossing, limiting medical use.
Standard delivery options cover liposome methods, viral vectors, electroporation, and microinjection. Drawbacks include low efficiency, high cell toxicity, safety issues, and weak targeting.
Cell-penetrating peptides address these gaps with safer transport. Oligonucleotides and siRNA control protein activation and gene expression after transcription. They enable targeted gene therapy. siRNA acts via post-transcriptional gene silencing.
Li et al. developed sTOLP, a system with siRNAOA-R8 and TF-modified lipid nanoparticles (LNP). This uses cell-penetrating peptidyl-octadecarginine (OA-R8) and transferrin (Tf) for multifunctional delivery. In mice with HepG2 tumors, sTOLP-encapsulated siRNA cut tumor growth by 61.7%. It targeted hepatocytes and tumor cells without sparking immunogenicity or liver and kidney toxicity.
Inflammation-Targeted Therapy
Nuclear transcription factor kappaB (NF-κB) regulates genes in cells. In its resting state, the P50-P65 dimer binds an inhibitory protein.
Activation of NF-κB links to many inflammatory processes. Combining CPP (8K, octa-Lysine) with the NF-κB essential regulator binding domain (NBD) targets this pathway. Dave e