Synthesis and therapeutic evaluation of an aptide-docetaxel conjugate targeting tumor-associated fibronectin.
Targeted delivery of anticancer drugs to tumors has attracted considerable research interest because of its potential to reduce adverse toxicity while improving therapeutic efficacy. In this study, we synthesized and evaluated the therapeutic efficacy of a conjugate of a high-affinity peptide (aptide) and the anticancer drug docetaxel (DTX). A fibronectin extra domain B (EDB)-specific aptide (APTEDB) was used as a cancer-specific targeting ligand. An APTEDB-DTX conjugate was synthesized from an alkyne-modified aptide and azide-modified DTX via click chemistry. A microscopy study revealed selective binding of dye-labeled APTEDB to EDB-overexpressing cancer cells. The cytotoxicity of the conjugate toward EDB-overexpressing murine lung carcinoma (LLC) and human glioblastoma (U87MG) was similar to that of free DTX. In a pharmacokinetic study, APTEDB-DTX formulated with PEG400/ethanol(5%) exhibited a circulation half-life similar to that of a Tween-80/ethanol formulation of parent DTX. Finally, an evaluation of intravenously injected APTEDB-DTX in mice bearing EDB-positive tumors showed that APTEDB-DTX inhibited the growth of both LLC allograft and U87MG xenograft tumors with an efficacy better than the parent-DTX formulation but with much lower toxicity, as evidenced by reduced body weight loss. Taken together, these results indicate that the aptide-drug conjugate system described here may hold potential as a targeted therapy regimen.
School of Life Sciences, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Gwangju 500-712, Republic of Korea.
Hyungjun
H
Kim
KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon 305-701, Republic of Korea.
Yonghyun
Y
Lee
KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon 305-701, Republic of Korea.
In-Hyun
IH
Lee
KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon 305-701, Republic of Korea.
Sunghyun
S
Kim
KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon 305-701, Republic of Korea.
Daejin
D
Kim
KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon 305-701, Republic of Korea.
Phei Er
PE
Saw
School of Life Sciences, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Gwangju 500-712, Republic of Korea.
Jinju
J
Lee
KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon 305-701, Republic of Korea.
Minsuk
M
Choi
School of Life Sciences, Gwangju Institute of Science and Technology, 123 Cheomdangwagi-ro, Gwangju 500-712, Republic of Korea.
Yong-Chul
YC
Kim
KAIST Institute for the BioCentury, Department of Biological Sciences, Korea Advanced Institute of Science and Technology, 291 Daehak-ro, Daejeon 305-701, Republic of Korea. Electronic address: syjon@kaist.ac.kr.
Sangyong
S
Jon
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D045744:Cell Line, Tumor; D000077143:Docetaxel; D005260:Female; D005353:Fibronectins / Q000737:chemistry*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010455:Peptides / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D017434:Protein Structure, Tertiary; D043823:Taxoids / Q000008:administration & dosage* / Q000737:chemistry / Q000493:pharmacokinetics; D047368:Tumor Burden / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
C000601127:APT(EDB) peptide; D000970:Antineoplastic Agents; D005353:Fibronectins; D010455:Peptides; D043823:Taxoids; D000077143:Docetaxel
Aptides; Conjugates; Docetaxel; Drug delivery; Extra domain B; Targeted therapy