Abstract
Protein affinity reagents (PARs), frequently antibodies, are essential tools for basic research, diagnostics, separations and for clinical applications. However, there is growing concern about the reproducibility, quality and cost of recombinant and animal-derived antibodies. This has prompted the development of alternatives that could offer economic, and time-saving advantages without the use of living organisms. Synthetic copolymer nanoparticles (NPs), engineered with affinity for specific protein targets, are potential alternatives to PARs. Although there are now a number of examples of abiotic protein affinity reagents (APARs), most have been evaluated in vitro limiting a realistic assessment of their potential for more demanding, practical in vivo applications. We demonstrate for the first time that an abiotic copolymer hydrogel nanoparticle (NP1) engineered to bind a key signaling protein, vascular endothelial growth factor (VEGF 165 ), functions in vivo to suppress tumor growth by regulating angiogenesis. Lightly cross-linked N-isopropylacrylamide based NPs that incorporate both sulfated N-acetylglucosamine and hydrophobic monomers were optimized by dynamic chemical evolution for VEGF 165 affinity. NP1 efficacy in vivo was evaluated by systemic administration to tumor-bearing mice. The study found that NP1 suppresses tumor growth and reduces tumor vasculature density. Combination therapy with doxorubicin resulted in increased doxorubicin concentration in the tumor and dramatic inhibition of tumor growth. NP1 treatment did not show off target anti-coagulant activity. In addition, >97% of injected NPs are rapidly excreted from the body following IV injection. These results establish the use of APARs as inhibitors of protein-protein interactions in vivo and may point the way to their broader use as abiotic, cost effective protein affinity reagents for the treatment of certain cancers and more broadly for regulating signal transduction.
| Original language | English |
|---|---|
| Pages (from-to) | 13-20 |
| Number of pages | 8 |
| Journal | Journal of Controlled Release |
| Volume | 295 |
| DOIs | |
| Publication status | Published - Feb 10 2019 |
Fingerprint
All Science Journal Classification (ASJC) codes
- Pharmaceutical Science
Cite this
Sequestering and inhibiting a vascular endothelial growth factor in vivo by systemic administration of a synthetic polymer nanoparticle. / Koide, Hiroyuki; Yoshimatsu, Keiichi; Hoshino, Yu; Ariizumi, Saki; Okishima, Anna; Ide, Takafumi; Egami, Hiromichi; Hamashima, Yoshitaka; Nishimura, Yuri; Kanazawa, Hiroaki; Miura, Yoshiko; Asai, Tomohiro; Oku, Naoto; Shea, Kenneth J.
In: Journal of Controlled Release, Vol. 295, 10.02.2019, p. 13-20.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Sequestering and inhibiting a vascular endothelial growth factor in vivo by systemic administration of a synthetic polymer nanoparticle
AU - Koide, Hiroyuki
AU - Yoshimatsu, Keiichi
AU - Hoshino, Yu
AU - Ariizumi, Saki
AU - Okishima, Anna
AU - Ide, Takafumi
AU - Egami, Hiromichi
AU - Hamashima, Yoshitaka
AU - Nishimura, Yuri
AU - Kanazawa, Hiroaki
AU - Miura, Yoshiko
AU - Asai, Tomohiro
AU - Oku, Naoto
AU - Shea, Kenneth J.
PY - 2019/2/10
Y1 - 2019/2/10
N2 - Protein affinity reagents (PARs), frequently antibodies, are essential tools for basic research, diagnostics, separations and for clinical applications. However, there is growing concern about the reproducibility, quality and cost of recombinant and animal-derived antibodies. This has prompted the development of alternatives that could offer economic, and time-saving advantages without the use of living organisms. Synthetic copolymer nanoparticles (NPs), engineered with affinity for specific protein targets, are potential alternatives to PARs. Although there are now a number of examples of abiotic protein affinity reagents (APARs), most have been evaluated in vitro limiting a realistic assessment of their potential for more demanding, practical in vivo applications. We demonstrate for the first time that an abiotic copolymer hydrogel nanoparticle (NP1) engineered to bind a key signaling protein, vascular endothelial growth factor (VEGF 165 ), functions in vivo to suppress tumor growth by regulating angiogenesis. Lightly cross-linked N-isopropylacrylamide based NPs that incorporate both sulfated N-acetylglucosamine and hydrophobic monomers were optimized by dynamic chemical evolution for VEGF 165 affinity. NP1 efficacy in vivo was evaluated by systemic administration to tumor-bearing mice. The study found that NP1 suppresses tumor growth and reduces tumor vasculature density. Combination therapy with doxorubicin resulted in increased doxorubicin concentration in the tumor and dramatic inhibition of tumor growth. NP1 treatment did not show off target anti-coagulant activity. In addition, >97% of injected NPs are rapidly excreted from the body following IV injection. These results establish the use of APARs as inhibitors of protein-protein interactions in vivo and may point the way to their broader use as abiotic, cost effective protein affinity reagents for the treatment of certain cancers and more broadly for regulating signal transduction.
AB - Protein affinity reagents (PARs), frequently antibodies, are essential tools for basic research, diagnostics, separations and for clinical applications. However, there is growing concern about the reproducibility, quality and cost of recombinant and animal-derived antibodies. This has prompted the development of alternatives that could offer economic, and time-saving advantages without the use of living organisms. Synthetic copolymer nanoparticles (NPs), engineered with affinity for specific protein targets, are potential alternatives to PARs. Although there are now a number of examples of abiotic protein affinity reagents (APARs), most have been evaluated in vitro limiting a realistic assessment of their potential for more demanding, practical in vivo applications. We demonstrate for the first time that an abiotic copolymer hydrogel nanoparticle (NP1) engineered to bind a key signaling protein, vascular endothelial growth factor (VEGF 165 ), functions in vivo to suppress tumor growth by regulating angiogenesis. Lightly cross-linked N-isopropylacrylamide based NPs that incorporate both sulfated N-acetylglucosamine and hydrophobic monomers were optimized by dynamic chemical evolution for VEGF 165 affinity. NP1 efficacy in vivo was evaluated by systemic administration to tumor-bearing mice. The study found that NP1 suppresses tumor growth and reduces tumor vasculature density. Combination therapy with doxorubicin resulted in increased doxorubicin concentration in the tumor and dramatic inhibition of tumor growth. NP1 treatment did not show off target anti-coagulant activity. In addition, >97% of injected NPs are rapidly excreted from the body following IV injection. These results establish the use of APARs as inhibitors of protein-protein interactions in vivo and may point the way to their broader use as abiotic, cost effective protein affinity reagents for the treatment of certain cancers and more broadly for regulating signal transduction.
UR - http://www.scopus.com/inward/record.url?scp=85058809301&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85058809301&partnerID=8YFLogxK
U2 - 10.1016/j.jconrel.2018.12.033
DO - 10.1016/j.jconrel.2018.12.033
M3 - Article
C2 - 30578808
AN - SCOPUS:85058809301
VL - 295
SP - 13
EP - 20
JO - Journal of Controlled Release
JF - Journal of Controlled Release
SN - 0168-3659
ER -