TY - JOUR
T1 - Trap and kill strategy for non-BRCA mutant pancreatic cancer by co-delivery of olaparib and JQ1 with plectin-1 targeting peptide nanoparticles
AU - Wang, Yazhou
AU - Du, Chong
AU - Zhao, Ying
AU - Nie, Guangjun
AU - Yang, Yinmo
N1 - Funding Information:
This work was supported by the Excellent Young Scientists Fund ( 31722021 ), the National Key R&D Program of China ( 2018YFA0208900 ), the National Natural Science Foundation of China ( 21877023 , 51673051 , 51861145302 , 81871954 , 81672353 , 81901886 ), Beijing Nova Program ( Z171100001117010 ), the Beijing Nova Programme Interdisciplinary Cooperation Project ( Z191100001119007 ), Youth Innovation Promotion Association CAS ( 2017056 ), the Innovation Research Group of the National Natural Science Foundation ( 11621505 ), the Key Research Project of Frontier science of the Chinese Academy of Sciences ( QYZDJ-SSW-SLH022 ) and the Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety, CAS ( NSKF201808 ).
Funding Information:
This work was supported by the Excellent Young Scientists Fund (31722021), the National Key R&D Program of China (2018YFA0208900), the National Natural Science Foundation of China (21877023, 51673051, 51861145302, 81871954, 81672353, 81901886), Beijing Nova Program (Z171100001117010), the Beijing Nova Programme Interdisciplinary Cooperation Project (Z191100001119007), Youth Innovation Promotion Association CAS (2017056), the Innovation Research Group of the National Natural Science Foundation (11621505), the Key Research Project of Frontier science of the Chinese Academy of Sciences (QYZDJ-SSW-SLH022) and the Key Laboratory of Biomedical Effects of Nanomaterials and Nanosafety, CAS (NSKF201808).
Publisher Copyright:
© 2020 Elsevier Ltd
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/8
Y1 - 2020/8
N2 - The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (Ola), which inhibits the repair of DNA single-strand breaks, has been approved recently by the Food and Drug Administration (FDA) of U.S. for treatment of advanced pancreatic cancer patients with BRCA (Breast Cancer) mutations. However, the response of the pancreatic cancer patients with non-BRCA mutant to Ola treatment remains suboptimal. There is an urgent need to develop effective therapeutic solutions for the majority pancreatic patients. Recently, the drug combination of Ola and the homologous recombination inhibitor JQ1 to treat non-BRCA mutant pancreatic cancers has showed promising outcomes. Herein, we took the advantage of peptide nanoparticle platform, which possesses high drug loading capacity, desirable pharmacokinetic profiles and integration of peptide targeting motif, and developed a tailor-designed plectin-1 targeting peptide nanoparticles (PTNPs) for co-delivery of Ola and JQ1 to treat non-BRCA mutant pancreatic cancers. We confirmed that the majority pancreatic tumor cells are plectin-1 positive. The PTNPs efficiently targeted plectin-1 positive pancreatic tumor cells in vitro and significantly accumulated in tumor site in vivo. The targeted co-delivery of Ola and JQ1 induced much more pancreatic tumor cell apoptosis and significantly enhanced the synergistic effect of combination treatment of Ola and JQ1 in both orthotopic and patient-derived xenograft (PDX) models. Furthermore, this precise delivery of highly coordinated drugs to tumor cells distinctly reduced adverse effects caused by combination of Ola and JQ1.
AB - The poly (ADP-ribose) polymerase (PARP) inhibitor olaparib (Ola), which inhibits the repair of DNA single-strand breaks, has been approved recently by the Food and Drug Administration (FDA) of U.S. for treatment of advanced pancreatic cancer patients with BRCA (Breast Cancer) mutations. However, the response of the pancreatic cancer patients with non-BRCA mutant to Ola treatment remains suboptimal. There is an urgent need to develop effective therapeutic solutions for the majority pancreatic patients. Recently, the drug combination of Ola and the homologous recombination inhibitor JQ1 to treat non-BRCA mutant pancreatic cancers has showed promising outcomes. Herein, we took the advantage of peptide nanoparticle platform, which possesses high drug loading capacity, desirable pharmacokinetic profiles and integration of peptide targeting motif, and developed a tailor-designed plectin-1 targeting peptide nanoparticles (PTNPs) for co-delivery of Ola and JQ1 to treat non-BRCA mutant pancreatic cancers. We confirmed that the majority pancreatic tumor cells are plectin-1 positive. The PTNPs efficiently targeted plectin-1 positive pancreatic tumor cells in vitro and significantly accumulated in tumor site in vivo. The targeted co-delivery of Ola and JQ1 induced much more pancreatic tumor cell apoptosis and significantly enhanced the synergistic effect of combination treatment of Ola and JQ1 in both orthotopic and patient-derived xenograft (PDX) models. Furthermore, this precise delivery of highly coordinated drugs to tumor cells distinctly reduced adverse effects caused by combination of Ola and JQ1.
KW - drug delivery
KW - non-BRCA mutation
KW - pancreatic cancer
KW - plectin-1 targeting peptide nanoparticles
KW - trap and kill strategy
UR - http://www.scopus.com/inward/record.url?scp=85084445084&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85084445084&partnerID=8YFLogxK
U2 - 10.1016/j.nantod.2020.100877
DO - 10.1016/j.nantod.2020.100877
M3 - Article
AN - SCOPUS:85084445084
VL - 33
JO - Nano Today
JF - Nano Today
SN - 1748-0132
M1 - 100877
ER -