Doxorubicin/heparin composite nanoparticles for caspase-activated prodrug chemotherapy.
Caspase-activated prodrug chemotherapy is introduced and demonstrated using the composite nanoparticles (NPs), which deliver doxorubicin (DOX) and DEVD-S-DOX together to the tumor tissue. DEVD-S-DOX, DOX linked to a peptide moiety (DEVD), is a prodrug that is cleaved into free DOX by caspase-3 upon apoptosis. DEVD-S-DOX has no therapeutic efficacy, but it changes into free DOX with the expression of caspase-3. With the accumulation of the composite NPs in the tumor tissue by the enhanced permeation and retention (EPR) effect, a small exposure of DOX in the tumor cells initiated apoptosis in a localized area of the tumor tissue, which induced caspase-3 activation. Cleavage of DEVD-S-DOX into free DOX by caspase-3 continued with repetitive activation of caspase-3 and cleavage of DEVD-S-DOX at the tumor site. The composite NPs were characterized with transmittance electron microscopy (TEM) and particle size analyzer. We then evaluated the nanoparticle drug release, therapeutic efficacy, and in vivo biodistribution for tumor targeting using a non-invasive live animal imaging technology and the quantification of DOX with high performance liquid chromatography. DOX-induced apoptosis-targeted chemotherapy (DIATC) was verified by in vitro/in vivo DEVD-S-DOX response to free DOX and cellular uptake behavior of the composite NPs with flow cytometry analysis. Significant antitumor efficacy with minimal cardiotoxicity was also observed, which supported DIATC for improved chemotherapy.
College of Pharmacy, Korea University, 2511 Sejongro, Sejong, 30019, Republic of Korea.
Nisar Ul
NU
Khaliq
College of Pharmacy, Korea University, 2511 Sejongro, Sejong, 30019, Republic of Korea.
Febrina Carolina
FC
Sandra
College of Pharmacy, Korea University, 2511 Sejongro, Sejong, 30019, Republic of Korea.
Dal Yong
DY
Park
College of Pharmacy, Korea University, 2511 Sejongro, Sejong, 30019, Republic of Korea.
Jae Young
JY
Lee
College of Pharmacy, Korea University, 2511 Sejongro, Sejong, 30019, Republic of Korea.
Keun Sang
KS
Oh
Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu, 41061, Republic of Korea.
Dongkyu
D
Kim
Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergent Science and Technology, Seoul National University, Seoul, 151-742, Republic of Korea.
Youngro
Y
Byun
Center for Theragnosis, Korea Institute of Science and Technology, 39-1 Hawolgok-dong, Sungbuk-gu, Seoul, 136-791, Republic of Korea; KU-KIST School, Korea University, Seoul, 02841, Republic of Korea.
In-San
IS
Kim
Center for Theragnosis, Korea Institute of Science and Technology, 39-1 Hawolgok-dong, Sungbuk-gu, Seoul, 136-791, Republic of Korea; KU-KIST School, Korea University, Seoul, 02841, Republic of Korea.
Ick Chan
IC
Kwon
Department of Otolaryngology, Asan Medical Center, University of Ulsan, College of Medicine, 388-1 Pungnap-dong, Songpa-gu, Seoul, 138-736, Republic of Korea.
Sang Yoon
SY
Kim
College of Pharmacy, Korea University, 2511 Sejongro, Sejong, 30019, Republic of Korea; Biomedical Research Center, Korea University Guro Hospital, Guro-gu, Seoul, 08308, Republic of Korea. Electronic address: shyuk@korea.ac.kr.
Soon Hong
SH
Yuk
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D053148:Caspase 3 / Q000378:metabolism*; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006493:Heparin / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D008297:Male; D051379:Mice; D053758:Nanoparticles / Q000008:administration & dosage / Q000032:analysis / Q000378:metabolism / Q000627:therapeutic use*; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage / Q000378:metabolism / Q000493:pharmacokinetics / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D014018:Tissue Distribution
D000903:Antibiotics, Antineoplastic; D011355:Prodrugs; C052784:doxorubicin-heparin; D004317:Doxorubicin; D006493:Heparin; D053148:Caspase 3
Caspase-3; Doxorubicin; Doxorubicin prodrug; Doxorubicin-induced apoptosis-targeted chemotherapy; Heparin; The composite nanoparticles