TY - JOUR
T1 - Designing Liposomes to Suppress Extracellular Matrix Expression to Enhance Drug Penetration and Pancreatic Tumor Therapy
AU - Ji, Tianjiao
AU - Lang, Jiayan
AU - Wang, Jing
AU - Cai, Rong
AU - Zhang, Yinlong
AU - Qi, Feifei
AU - Zhang, Lijing
AU - Zhao, Xiao
AU - Wu, Wenjing
AU - Hao, Jihui
AU - Qin, Zhihai
AU - Zhao, Ying
AU - Nie, Guangjun
N1 - Funding Information:
We thank Prof. Saraswati Sukumar from Johns Hopkins University School of Medicine for critical reading of the manuscript. This work was supported by the grants from MOST 973 (2013CB932701), NSFC (grant nos. 81630068, 21373067, 51673051, 31325010, 11621505, and 31571021), Beijing Nova Program (grant no. Z171100001117010), Beijing Natural Science Foundation (grant no. 7172164), Beijing Municipal Science and Technology Commission no. Z161100000116035, the Frontier Research Program of Chinese Academy of Sciences (grant no. QYZDJ-SSW-SLH022), and Youth Innovation Promotion Association CAS (grant no. 2017056).
Publisher Copyright:
© 2017 American Chemical Society.
PY - 2017/9/26
Y1 - 2017/9/26
N2 - During pancreatic tumor development, pancreatic stellate cells (PSCs) proliferate exuberantly to secrete extracellular matrix (ECM) in the tumor stroma, which presents major barriers for drug delivery and penetration in tumor tissue. Thus, down-regulating ECM levels via regulation of the PSCs may allow enhanced penetration of therapeutic drugs and thereby enhancing their therapeutic efficacy. To regulate the PSCs, a matrix metalloproteinase-2 (MMP-2) responsive peptide-hybrid liposome (MRPL) was constructed via coassembly of a tailor-designed MMP-2 responsive amphiphilic peptide and phospholipids. By utilizing the MMP-2-rich pathological environment, the pirfenidone (PFD) loaded MRPL (MRPL-PFD) can specifically release PFD at the pancreatic tumor site and down-regulate the multiple components of ECM expressed by the PSCs. This resulted in a significant increase in the penetration of gemcitabine into the tumor tissue and enhanced the efficacy of gemcitabine for pancreatic tumor. Our design tailored for antifibrosis of pancreatic cancer may provide a practical approach to build functional liposomes through supramolecular assembly, and regulation of ECM may be a promising adjuvant therapeutic strategy for pancreatic and other ECM-rich tumors.
AB - During pancreatic tumor development, pancreatic stellate cells (PSCs) proliferate exuberantly to secrete extracellular matrix (ECM) in the tumor stroma, which presents major barriers for drug delivery and penetration in tumor tissue. Thus, down-regulating ECM levels via regulation of the PSCs may allow enhanced penetration of therapeutic drugs and thereby enhancing their therapeutic efficacy. To regulate the PSCs, a matrix metalloproteinase-2 (MMP-2) responsive peptide-hybrid liposome (MRPL) was constructed via coassembly of a tailor-designed MMP-2 responsive amphiphilic peptide and phospholipids. By utilizing the MMP-2-rich pathological environment, the pirfenidone (PFD) loaded MRPL (MRPL-PFD) can specifically release PFD at the pancreatic tumor site and down-regulate the multiple components of ECM expressed by the PSCs. This resulted in a significant increase in the penetration of gemcitabine into the tumor tissue and enhanced the efficacy of gemcitabine for pancreatic tumor. Our design tailored for antifibrosis of pancreatic cancer may provide a practical approach to build functional liposomes through supramolecular assembly, and regulation of ECM may be a promising adjuvant therapeutic strategy for pancreatic and other ECM-rich tumors.
KW - MMP-2 responsive
KW - down-regulation of ECM
KW - enhanced pancreatic tumor therapy
KW - pancreatic stellate cells
KW - peptide-hybrid liposome
UR - https://www.scopus.com/pages/publications/85029955064
UR - https://www.scopus.com/inward/citedby.url?scp=85029955064&partnerID=8YFLogxK
U2 - 10.1021/acsnano.7b01026
DO - 10.1021/acsnano.7b01026
M3 - Article
C2 - 28806504
AN - SCOPUS:85029955064
SN - 1936-0851
VL - 11
SP - 8668
EP - 8678
JO - ACS Nano
JF - ACS Nano
IS - 9
ER -