The application of
tumor targeting
ligands to the treatment of
cancer holds promise for improving efficacy and reducing toxicity. LT7 (L(HAIYPRH))
peptide, a phage display-selected
peptide, exhibited high binding affinity to
transferrin receptor (TfR) overexpressed on
tumor cells. However, its in vivo
tumor targeting efficiency was impaired due to enzymatic degradation in blood circulation. To improve the stability and targeting ability, a retro-inverso analogue of LT7
peptide, named DT7
peptide (D(HRPYIAH)), was designed for targeted
therapy of
hepatocellular carcinoma. The result of computer simulation predicted that DT7 bound to TfR
protein more efficiently than LT7, and this prediction was confirmed experimentally by surface plasmon resonance (SPR). Ex vivo stability experiment demonstrated that DT7 possessed stronger ability against proteolysis than LT7 in fresh mouse serum. We further prepared DT7-, LT7-, and
transferrin (Tf)-modified
liposomes (DT7-LIP, LT7-LIP, and Tf-LIP, respectively). DT7-LIP showed a significantly stronger in vitro targeting ability than LT7-LIP and Tf-LIP under normal condition and simulated biological condition. In addition, the in vitro antitumor effect of DTX-loaded DT7-LIP was markedly enhanced in comparison to DTX-loaded LT7-LIP and DTX-loaded Tf-LIP. In vivo imaging indicated that DT7-LIP had better
tumor accumulation than LT7-LIP and Tf-LIP. For in vivo antitumor studies, the
tumor growth rate of mice treated with DTX-loaded DT7-LIP was significantly inhibited compared to that in mice treated with DTX-loaded LT7-LIP and DTX-loaded Tf-LIP. Overall, this study verified the potential of the stable DT7
peptide in improving the efficacy of
docetaxel in the treatment of
hepatocellular carcinoma. STATEMENT OF SIGNIFICANCE: A phage display library-selected LT7 (L(HAIYPRH))
peptide exhibited high affinity to
transferrin receptor (TfR). However, its bioactivity was impaired in vivo as L-
peptides are susceptible to degradation by
proteolytic enzymes. Here, we designed a retro-inverso
peptide DT7(D(HRPYIAH)) and demonstrated its increased serum stability and higher binding affinity to TfR. A stabilized targeted drug delivery system was further constructed by modified DT7
peptide on the surface of
liposomes. The data indicated that DT7
peptide-modified
liposomes exhibited higher targeting ability in vitro and in vivo. More importantly, DT7-modified
liposomes demonstrated positive preclinical significance in enhancing the
therapeutic effects against
hepatocellular carcinoma.