Fluorescent RGD-based pro-apoptotic peptide conjugates as mitochondria-targeting probes for enhanced anticancer activities - 30/05/20
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Graphical abstract |
(849 × 1200) 300 DPI.
Highlights |
• | Blood vessels are supporting tool for angiogenesis. |
• | Anticancer agents cut off nutrient oxygen, causes inhibition of angiogenesis. |
• | Cationic antimicrobial peptide depolarizes the mitochondrial membrane and induces cell apoptosis. |
• | Two-domain peptides serve as a new emerging tool for cancer theranostic. |
• | Cyclic short peptide motifs possess enhanced bioavailability and reduced proteolysis. |
Abstract |
We have designed 2-domain anticancer peptides with RGD-based KLAK bi-functional short motifs (linear and cyclic analogues). RGD tripeptide acts as tumor blood vessel ‘homing’ motif while KLAK tetrapeptide internalized in mitochondria and causes cell apoptosis. All three peptides (RGDKLAK; HM, cyclic-RGDKLAK; HMC-1, and RGD-cyclic-KLAK; HMC-2) were conjugated with fluorescein isothiocyanate isomer-I (5-FITC; F) for in-vivo and in-vitro optical imaging studies. These fluorescent-peptide (FL-peptide) analogues were analyzed to possess αvβ3-integrin targeting affinity, high uptake in in-vitro cell binding assays followed by in-vivo tumor xenograft mice studies. Pharmacological profile reveals that F-HMC-1 analogue exhibited selectively and specifically higher affinity for αvβ3-integrin than other analogues in U87MG cells in comparison with HeLa cells. The subcutaneous U87MG tumor xenograft mice models clearly visualized the uptake of F-HMC-1 in tumor tissue in contrast with normal tissues with tumor-to-normal tissue ratio (T/NT = 15.9 ± 1.1) at 2 h post-injection. These results suggested that F-HMC-1 peptide has potential diagnostic applications for targeting αvβ3-integrin assessed by optical imaging study in U87MG tumor xenograft mice models.
Le texte complet de cet article est disponible en PDF.Abbreviations : RGD, KLA, F-HM, F-HMC-1, F-HMC-2, FL, NGR, CAPs, CPPs, MG, ACPs, RGDfK, ECM, 5-FITC, ICG, MB, Cy, SPPS, EC, FDA, UHPLC, LC-MS2, RP-HPLC, NMR, DMF, DMSO, TEA, TFA, DIPEA, HATU, DMEM, IMDM, FBS, PBS
Keywords : RGD-based KLAK peptide, αvβ3-integrin, Mitochondria, U87MG tumor xenografts, Tumor-to-normal tissue ratio, Optical imaging
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Vol 127
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