CREKA peptide is a selective non-covalent binding agent targeting fibrin, type IV collagen, and fibronectin, often used as a targeting ligand to modify delivery carriers. CREKA peptide specifically recognizes fibrin, fibronectin, and type IV collagen that are excessively deposited in the tumor microenvironment or fibrotic tissue, mediating the targeted accumulation of the carrier at the lesion site and promoting drug internalization into target cells (such as cancer cells and activated hepatic stellate cells). CREKA peptide can enhance targeted delivery efficiency, increase drug concentration at the lesion site, and reduce systemic side effects [1] [2] [3].
In Vivo, In a CCl4-induced hepatic fibrosis model in male C57BL/6 J mice, CREKA peptide (200 μg DiD/kg; i.v.; single dose) selectively accumulates in fibrotic liver tissue, accumulating significantly in activated hepatic stellate cells; its fluorescence intensity is significantly higher than that of unmodified liposomes, and the degree of accumulation gradually increased with the progression of hepatic fibrosis (4 weeks, 8 weeks, 12 weeks)[2]; CREKA peptide (combined with 1 mg/kg Sorafenib, loaded onto CREKA-modified liposomes; i.v.; twice weekly; 4 weeks) significantly reduces hepatic fibrosis, decreases collagen deposition, inhibits hepatic inflammatory infiltration and angiogenesis, and reduced the expression of fibrosis-related genes and proteins such as α-SMA, Col1a1, and TIMP-1 in the CCl4-induced hepatic fibrosis model in C57BL/6 J mice, while also inhibiting the phosphorylation of p-PDGFR-β, p-Akt, and p-Erk[2].
In Vitro, CREKA peptide (0.5 mM, 1 mM; 1 hour) covalently bound to PEG particles showed significantly higher binding affinity to fibrin than free CREKA (approximately 70%) and peptide-free particles (45%), with a binding rate of 94% at 0.5 mM[1][3]. CREKA peptide (modified on PEG particles, particle concentration 0.1 mg/mL; 24 hours, 72 hours) showed no significant toxicity to HeLa cervical cancer cells and human BJ skin fibroblasts, with cell viability above 80%[1][3]. CREKA peptide (modified on PEG particles, loaded with DOX, particle concentration 0.1 mg/mL; 1 hour) significantly increased the uptake efficiency of DOX by HeLa cells, with an uptake rate of 111%, higher than PEG particles (50%), PEG-IKVAV particles (34%), and dual-peptide modified particles (34%)[1][3]. CREKA peptide (modified on liposomes, DiD concentration 200 ng/mL; 2-4 hours) promoted cellular uptake by human hepatic stellate cells LX2, with significantly higher fluorescence intensity than unmodified liposomes. Uptake was dependent on clathrin- and caveolin-mediated endocytosis and inhibited by free CREKA and fibronectin antibodies[2]. CREKA peptide (modified on liposomes, loaded with 1 μM sorafenib; 48 hours) significantly inhibited the mRNA expression of α-SMA, Col1a1, Col5a1, and TIMP-2 in LX2 cells, reduced α-SMA and Col1a1 protein levels, and inhibited collagen synthesis[2].
References:
[1]. Okur AC, et al. Targeting cancer cells via tumor-homing peptide CREKA functional PEG nanoparticles. Colloids Surf B Biointerfaces. 2016 Nov 1;147:191-200.
[2]. Li R, et al. CREKA-modified liposomes target activated hepatic stellate cells to alleviate liver fibrosis by inhibiting collagen synthesis and angiogenesis. Acta Biomater. 2023 Sep 15;168:484-496.
In Vivo, In a CCl4-induced hepatic fibrosis model in male C57BL/6 J mice, CREKA peptide (200 μg DiD/kg; i.v.; single dose) selectively accumulates in fibrotic liver tissue, accumulating significantly in activated hepatic stellate cells; its fluorescence intensity is significantly higher than that of unmodified liposomes, and the degree of accumulation gradually increased with the progression of hepatic fibrosis (4 weeks, 8 weeks, 12 weeks)[2]; CREKA peptide (combined with 1 mg/kg Sorafenib, loaded onto CREKA-modified liposomes; i.v.; twice weekly; 4 weeks) significantly reduces hepatic fibrosis, decreases collagen deposition, inhibits hepatic inflammatory infiltration and angiogenesis, and reduced the expression of fibrosis-related genes and proteins such as α-SMA, Col1a1, and TIMP-1 in the CCl4-induced hepatic fibrosis model in C57BL/6 J mice, while also inhibiting the phosphorylation of p-PDGFR-β, p-Akt, and p-Erk[2].
In Vitro, CREKA peptide (0.5 mM, 1 mM; 1 hour) covalently bound to PEG particles showed significantly higher binding affinity to fibrin than free CREKA (approximately 70%) and peptide-free particles (45%), with a binding rate of 94% at 0.5 mM[1][3]. CREKA peptide (modified on PEG particles, particle concentration 0.1 mg/mL; 24 hours, 72 hours) showed no significant toxicity to HeLa cervical cancer cells and human BJ skin fibroblasts, with cell viability above 80%[1][3]. CREKA peptide (modified on PEG particles, loaded with DOX, particle concentration 0.1 mg/mL; 1 hour) significantly increased the uptake efficiency of DOX by HeLa cells, with an uptake rate of 111%, higher than PEG particles (50%), PEG-IKVAV particles (34%), and dual-peptide modified particles (34%)[1][3]. CREKA peptide (modified on liposomes, DiD concentration 200 ng/mL; 2-4 hours) promoted cellular uptake by human hepatic stellate cells LX2, with significantly higher fluorescence intensity than unmodified liposomes. Uptake was dependent on clathrin- and caveolin-mediated endocytosis and inhibited by free CREKA and fibronectin antibodies[2]. CREKA peptide (modified on liposomes, loaded with 1 μM sorafenib; 48 hours) significantly inhibited the mRNA expression of α-SMA, Col1a1, Col5a1, and TIMP-2 in LX2 cells, reduced α-SMA and Col1a1 protein levels, and inhibited collagen synthesis[2].
References:
[1]. Okur AC, et al. Targeting cancer cells via tumor-homing peptide CREKA functional PEG nanoparticles. Colloids Surf B Biointerfaces. 2016 Nov 1;147:191-200.
[2]. Li R, et al. CREKA-modified liposomes target activated hepatic stellate cells to alleviate liver fibrosis by inhibiting collagen synthesis and angiogenesis. Acta Biomater. 2023 Sep 15;168:484-496.