TY - JOUR
T1 - Microenvironment-sensing, nanocarrier-mediated delivery of combination chemotherapy for pancreatic cancer
AU - Ray, Priyanka
AU - Nair, Gauthami
AU - Ghosh, Arnab
AU - Banerjee, Snigdha
AU - Golovko, Mikhail Y.
AU - Banerjee, Sushanta K.
AU - Reindl, Katie M.
AU - Mallik, Sanku
AU - Quadir, Mohiuddin
N1 - Funding Information:
This research was supported by NIH grant number 1P20 GM109024 from the National Institute of General Medical Sciences (NIGMS). TEM material is based upon work supported by the NSF under Grant No. 0923354. Funding for the Core Biology Facility used in this publication was made possible by NIH Grant Number 2P20 RR015566 from the National Center for Research Resources. MS analysis was supported through NIH funded COBRE Mass Spec Core Facility Grant 5P30GM103329-05. SM acknowledges the support through the NIH grant 1R01 GM 114080 (NIGMS). Partial support for this work was received from NSF Grant No. IIA-1355466 from the ‘North Dakota Established Program to Stimulate Competitive Research (EPSCoR)’ through the Center for Sustainable Materials Science. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Any opinions, findings, and conclusions or recommendations expressed are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. The work is partially supported by Merit review grant from Department of Veterans Affairs (Sushanta K. Banerjee, 5I01BX001989-04 and Snigdha Banerjee, I01BX001002-05), KUMC Lied Basic Science Grant Program (SKB), and Grace Hortense Greenley Trust, directed by The Research Foundation in memory of Eva Lee Caldwell (SKB). We thank S. Golovko for her excellent assistance with MS analysis.
Funding Information:
This research was supported by NIH grant number 1P20 GM109024 from the National Institute of General Medical Sciences (NIGMS). TEM material is based upon work supported by the NSF under Grant No. 0923354. Funding for the Core Biology Facility used in this publication was made possible by NIH Grant Number 2P20 RR015566 from the National Center for Research Resources. MS analysis was supported through NIH funded COBRE Mass Spec Core Facility Grant 5P30GM103329-05. SM acknowledges the support through the NIH grant 1R01 GM 114080 (NIGMS). Partial support for this work was received from NSF Grant No. IIA-1355466 from the ?North Dakota Established Program to Stimulate Competitive Research (EPSCoR)? through the Center for Sustainable Materials Science. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. Any opinions, findings, and conclusions or recommendations expressed are those of the author(s) and do not necessarily reflect the views of the National Science Foundation. The work is partially supported by Merit review grant from Department of Veterans Affairs (Sushanta K. Banerjee, 5I01BX001989-04 and Snigdha Banerjee, I01BX001002-05), KUMC Lied Basic Science Grant Program (SKB), and Grace Hortense Greenley Trust, directed by The Research Foundation in memory of Eva Lee Caldwell (SKB). We thank S. Golovko for her excellent assistance with MS analysis.
Publisher Copyright:
© 2019, The International CCN Society.
PY - 2019/9/1
Y1 - 2019/9/1
N2 - Limited effectiveness of Raf and MEK inhibitors has impelled the interest to use the inhibitors of Extra-cellular Receptor Kinase (ERK) pathway in combination with Gemcitabine (GEM) in pancreatic cancer. However, off-target abundance of ERK receptors, challenging physico-chemical properties, and dose-limiting toxicity of the inhibitor has presented critical challenges towards fabricating this combination amenable for clinical translation. Herein we report a pharmaceutical nanoformulation of GEM and an ERK inhibitor (SCH 772984) co-stabilized within a pH-sensing nanocarrier (NC, with a hydrodynamic diameter of 161 ± 5.0 nm). The NCs were modularly derived from a triblock, self-assembling copolymer, and were chemically conjugated with GEM and encapsulated with SCH772984 at a loading content of 20.2% and 18.3%, respectively. Through pH-mediated unfolding of the individual blocks of the copolymer, the NCs were able to control the release of encapsulated drugs, traffic through cellular membranes, engage target receptors, suppress proliferation of pancreatic cancer cells, and accumulate at disease sites. Collectively our studies showed the feasibility of co-delivery of a combination chemotherapy consisting of GEM and an ERK inhibitor from a NC platform, which can sense and respond to tumor microenvironment of pancreatic cancer setting.
AB - Limited effectiveness of Raf and MEK inhibitors has impelled the interest to use the inhibitors of Extra-cellular Receptor Kinase (ERK) pathway in combination with Gemcitabine (GEM) in pancreatic cancer. However, off-target abundance of ERK receptors, challenging physico-chemical properties, and dose-limiting toxicity of the inhibitor has presented critical challenges towards fabricating this combination amenable for clinical translation. Herein we report a pharmaceutical nanoformulation of GEM and an ERK inhibitor (SCH 772984) co-stabilized within a pH-sensing nanocarrier (NC, with a hydrodynamic diameter of 161 ± 5.0 nm). The NCs were modularly derived from a triblock, self-assembling copolymer, and were chemically conjugated with GEM and encapsulated with SCH772984 at a loading content of 20.2% and 18.3%, respectively. Through pH-mediated unfolding of the individual blocks of the copolymer, the NCs were able to control the release of encapsulated drugs, traffic through cellular membranes, engage target receptors, suppress proliferation of pancreatic cancer cells, and accumulate at disease sites. Collectively our studies showed the feasibility of co-delivery of a combination chemotherapy consisting of GEM and an ERK inhibitor from a NC platform, which can sense and respond to tumor microenvironment of pancreatic cancer setting.
KW - Drug delivery
KW - Extracellular Receptor Kinase (ERK)
KW - Nanocarrier
KW - Pancreatic cancer
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U2 - 10.1007/s12079-019-00514-w
DO - 10.1007/s12079-019-00514-w
M3 - Article
C2 - 30915617
AN - SCOPUS:85072921395
VL - 13
SP - 407
EP - 420
JO - Journal of Cell Communication and Signaling
JF - Journal of Cell Communication and Signaling
SN - 1873-9601
IS - 3
ER -