TY - JOUR
T1 - Therapeutic Strategies to Overcome Fibrotic Barriers to Nanomedicine in the Pancreatic Tumor Microenvironment
AU - Tanaka, Hiroyoshi Y.
AU - Nakazawa, Takuya
AU - Enomoto, Atsushi
AU - Masamune, Atsushi
AU - Kano, Mitsunobu R.
N1 - Funding Information:
This study was funded by the Grant-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (JSPS) (grants 20K16989 to H.Y.T., 22H03051 to A.M., and 26293119 to M.R.K.), the Japan Agency for Medical Research and Development (AMED) (grants 22gm1210009s0104 and 22ck0106779h0001 to A.E.), Okayama University (H.Y.T. and M.R.K.), the Inamori Foundation (H.Y.T.), the Hokuto Foundation for Bioscience (H.Y.T.), the Research Foundation for Pharmaceutical Sciences (H.Y.T.), the Sanyo Broadcasting Foundation (H.Y.T.), the Pancreas Research Foundation of Japan (H.Y.T. and M.R.K.), the Ryobi Teien Memory Foundation (H.Y.T.), and the KAWASAKI Foundation for Medical Science and Medical Welfare (H.Y.T.). T.N. was supported by the Leave a Nest grant incu-be award.
Publisher Copyright:
© 2023 by the authors.
PY - 2023/2
Y1 - 2023/2
N2 - Pancreatic cancer is notorious for its dismal prognosis. The enhanced permeability and retention (EPR) effect theory posits that nanomedicines (therapeutics in the size range of approximately 10–200 nm) selectively accumulate in tumors. Nanomedicine has thus been suggested to be the “magic bullet”—both effective and safe—to treat pancreatic cancer. However, the densely fibrotic tumor microenvironment of pancreatic cancer impedes nanomedicine delivery. The EPR effect is thus insufficient to achieve a significant therapeutic effect. Intratumoral fibrosis is chiefly driven by aberrantly activated fibroblasts and the extracellular matrix (ECM) components secreted. Fibroblast and ECM abnormalities offer various potential targets for therapeutic intervention. In this review, we detail the diverse strategies being tested to overcome the fibrotic barriers to nanomedicine in pancreatic cancer. Strategies that target the fibrotic tissue/process are discussed first, which are followed by strategies to optimize nanomedicine design. We provide an overview of how a deeper understanding, increasingly at single-cell resolution, of fibroblast biology is revealing the complex role of the fibrotic stroma in pancreatic cancer pathogenesis and consider the therapeutic implications. Finally, we discuss critical gaps in our understanding and how we might better formulate strategies to successfully overcome the fibrotic barriers in pancreatic cancer.
AB - Pancreatic cancer is notorious for its dismal prognosis. The enhanced permeability and retention (EPR) effect theory posits that nanomedicines (therapeutics in the size range of approximately 10–200 nm) selectively accumulate in tumors. Nanomedicine has thus been suggested to be the “magic bullet”—both effective and safe—to treat pancreatic cancer. However, the densely fibrotic tumor microenvironment of pancreatic cancer impedes nanomedicine delivery. The EPR effect is thus insufficient to achieve a significant therapeutic effect. Intratumoral fibrosis is chiefly driven by aberrantly activated fibroblasts and the extracellular matrix (ECM) components secreted. Fibroblast and ECM abnormalities offer various potential targets for therapeutic intervention. In this review, we detail the diverse strategies being tested to overcome the fibrotic barriers to nanomedicine in pancreatic cancer. Strategies that target the fibrotic tissue/process are discussed first, which are followed by strategies to optimize nanomedicine design. We provide an overview of how a deeper understanding, increasingly at single-cell resolution, of fibroblast biology is revealing the complex role of the fibrotic stroma in pancreatic cancer pathogenesis and consider the therapeutic implications. Finally, we discuss critical gaps in our understanding and how we might better formulate strategies to successfully overcome the fibrotic barriers in pancreatic cancer.
KW - extracellular matrix
KW - fibroblast
KW - fibrosis
KW - nanomedicine
KW - pancreatic cancer
KW - tumor microenvironment
UR - http://www.scopus.com/inward/record.url?scp=85147861740&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85147861740&partnerID=8YFLogxK
U2 - 10.3390/cancers15030724
DO - 10.3390/cancers15030724
M3 - Review article
AN - SCOPUS:85147861740
SN - 2072-6694
VL - 15
JO - Cancers
JF - Cancers
IS - 3
M1 - 724
ER -
