Peptide-drug conjugate linked via a disulfide bond for kidney targeted drug delivery.
Chronic kidney disease (CKD) is a worldwide public health problem, and unfortunately, the therapeutic index of clinically available drugs is limited. Thus, there is a great need to exploit effective treatment strategies, and the carrier-drug approach is an attractive method to improve the kidney specificity of the therapeutic agents. The aim of this present study is to develop a peptide-drug conjugate for the kidney targeted delivery of angiotensin-converting enzyme (ACE) inhibitor captopril (CAP), since G3-C12 peptide (ANTPCGPYTHDCPVKR) could specifically accumulate in the kidney after intravenous injection. Therefore, FITC labeled G3-C12 peptide (G3-C12-FITC) and peptide-drug conjugate (G3-C12-CAP) with a disulfide bond which can be cleaved by reduced glutathione in the kidney were prepared by solid-phase peptide synthesis. The fluorescence imaging of G3-C12-FITC revealed that the labeled peptide specifically accumulated in the kidney soon after i.v. injection to mice, and the accumulation is due largely to the reabsorption of the peptide by the proximal renal tubule cells. Furthermore, in comparison with the corresponding nonconjugated form, a 2.7-fold increase in renal area under concentration-time curve produced by the conjugate was observed in mice. Interestingly, the CAP entirely released in the kidney even at 0.05 h postinjection through disulfide reduction. As a consequence, the in vivo renal ACE inhibition was significantly increased. In conclusion, these findings suggest the potential of G3-C12 peptide serving as a suitable candidate carrier for kidney-targeted drug delivery.
Key Laboratory of Drug Targeting and Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University , Southern Renmin Road, No. 17, Section 3, Chengdu 610041, P. R. China.
Qian
Q
Geng
Xun
X
Sun
Tao
T
Gong
Zhi-Rong
ZR
Zhang
D000595:Amino Acid Sequence; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D002216:Captopril / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D004220:Disulfides / Q000737:chemistry* / Q000378:metabolism; D004337:Drug Carriers / Q000737:chemistry / Q000378:metabolism; D016503:Drug Delivery Systems; D007668:Kidney / Q000378:metabolism*; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry* / Q000378:metabolism; D060327:Solid-Phase Synthesis Techniques
D000806:Angiotensin-Converting Enzyme Inhibitors; D004220:Disulfides; D004337:Drug Carriers; D010455:Peptides; D002216:Captopril