TY - JOUR
T1 - Antibody-Assisted Delivery of a Peptide-Drug Conjugate for Targeted Cancer Therapy
AU - Kim, Hyungjun
AU - Hwang, Dobeen
AU - Choi, Minsuk
AU - Lee, Soyoung
AU - Kang, Sukmo
AU - Lee, Yonghyun
AU - Kim, Sunghyun
AU - Chung, Junho
AU - Jon, Sangyong
N1 - Funding Information:
This work was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT (Leading Researcher Program: NRF-2018R1A3B1052661).
Publisher Copyright:
Copyright © 2018 American Chemical Society.
PY - 2019/1/7
Y1 - 2019/1/7
N2 - A number of cancer-targeting peptide-drug conjugates (PDCs) have been explored as alternatives to antibody-drug conjugates (ADCs) for targeted cancer therapy. However, the much shorter circulation half-life of PDCs compared with ADCs in vivo has limited their therapeutic value and thus their translation into the clinic, highlighting the need to develop new approaches for extending the half-life of PDCs. Here, we report a new strategy for targeted cancer therapy of a PDC based on a molecular hybrid between an antihapten antibody and a hapten-labeled PDC. An anticotinine antibody (Ab cot ) was used as a model antihapten antibody. The anticancer drug SN38 was linked to a cotinine-labeled aptide specific to extra domain B of fibronectin (cot-APT EDB ), yielding the model PDC, cot-APT EDB -SN38. The cotinine-labeled PDC showed specific binding to and cytotoxicity toward an EDB-overexpressing human glioblastoma cell line (U87MG) and also formed a hybrid complex (HC) with Ab cot in situ, designated HC[cot-APT EDB -SN38/Ab cot ]. In glioblastoma-bearing mice, in situ HC[cot-APT EDB -SN38/Ab cot ] significantly extended the circulation half-life of cot-APT EDB -SN38 in blood, and it enhanced accumulation and penetration within the tumor and, ultimately, inhibition of tumor growth. These findings suggest that the present platform holds promise as a new, targeted delivery strategy for PDCs in anticancer therapy.
AB - A number of cancer-targeting peptide-drug conjugates (PDCs) have been explored as alternatives to antibody-drug conjugates (ADCs) for targeted cancer therapy. However, the much shorter circulation half-life of PDCs compared with ADCs in vivo has limited their therapeutic value and thus their translation into the clinic, highlighting the need to develop new approaches for extending the half-life of PDCs. Here, we report a new strategy for targeted cancer therapy of a PDC based on a molecular hybrid between an antihapten antibody and a hapten-labeled PDC. An anticotinine antibody (Ab cot ) was used as a model antihapten antibody. The anticancer drug SN38 was linked to a cotinine-labeled aptide specific to extra domain B of fibronectin (cot-APT EDB ), yielding the model PDC, cot-APT EDB -SN38. The cotinine-labeled PDC showed specific binding to and cytotoxicity toward an EDB-overexpressing human glioblastoma cell line (U87MG) and also formed a hybrid complex (HC) with Ab cot in situ, designated HC[cot-APT EDB -SN38/Ab cot ]. In glioblastoma-bearing mice, in situ HC[cot-APT EDB -SN38/Ab cot ] significantly extended the circulation half-life of cot-APT EDB -SN38 in blood, and it enhanced accumulation and penetration within the tumor and, ultimately, inhibition of tumor growth. These findings suggest that the present platform holds promise as a new, targeted delivery strategy for PDCs in anticancer therapy.
KW - SN38
KW - anticotinine antibody
KW - aptides
KW - cancer therapy
KW - extra domain B of fibronectin
KW - peptide-drug conjugates
UR - http://www.scopus.com/inward/record.url?scp=85059623957&partnerID=8YFLogxK
U2 - 10.1021/acs.molpharmaceut.8b00924
DO - 10.1021/acs.molpharmaceut.8b00924
M3 - Article
C2 - 30521347
AN - SCOPUS:85059623957
SN - 1543-8384
VL - 16
SP - 165
EP - 172
JO - Molecular Pharmaceutics
JF - Molecular Pharmaceutics
IS - 1
ER -