Tuned Density of Anti-Tissue Factor Antibody Fragment onto siRNA-Loaded Polyion Complex Micelles for Optimizing Targetability into Pancreatic Cancer Cells

Hyun Su Min; Hyun Jin Kim; Jooyeon Ahn; Mitsuru Naito; Kotaro Hayashi; Kazuko Toh; Beob Soo Kim; Yasuhiro Matsumura; Ick Chan Kwon; Kanjiro Miyata; Kazunori Kataoka

doi:10.1021/acs.biomac.8b00507

Tuned Density of Anti-Tissue Factor Antibody Fragment onto siRNA-Loaded Polyion Complex Micelles for Optimizing Targetability into Pancreatic Cancer Cells

Hyun Su Min, Hyun Jin Kim, Jooyeon Ahn, Mitsuru Naito, Kotaro Hayashi, Kazuko Toh, Beob Soo Kim, Yasuhiro Matsumura, Ick Chan Kwon, Kanjiro Miyata, Kazunori Kataoka

Research output: Contribution to journal › Article › peer-review

41 Citations (Scopus)

Abstract

Antibody fragment (Fab′)-installed polyion complex (PIC) micelles were constructed to improve targetability of small interfering RNA (siRNA) delivery to pancreatic cancer cells. To this end, we synthesized a block copolymer of azide-functionalized poly(ethylene glycol) and poly(l-lysine) and prepared PIC micelles with siRNA. Then, a dibenzylcyclooctyne (DBCO)-modified antihuman tissue factor (TF) Fab′ was conjugated to azido groups on the micellar surface. A fluorescence correlation spectroscopic analysis revealed that 1, 2, or 3 molecule(s) of Fab′(s) were installed onto one micellar nanoparticle according to the feeding ratio of Fab′ (or DBCO) to micelle (or azide). The resulting micelles exhibited ∼40 nm in hydrodynamic diameter, similar to that of the parent micelles before Fab′ conjugation. Flow cytometric analysis showed that three molecules of Fab′-installed PIC micelles (3(Fab′)-micelles) had the highest binding affinity to cultured pancreatic cancer BxPC3 cells, which are known to overexpress TF on their surface. The 3(Fab′)-micelles also exhibited the most efficient gene silencing activity against polo-like kinase 1 mRNA in the cultured cancer cells. Furthermore, the 3(Fab′)-micelles exhibited high penetrability and the highest cellular internalization amounts in BxPC3 spheroids compared with one or two molecule(s) of Fab′-installed PIC micelles. These results demonstrate the potential of anti-TF Fab′-installed PIC micelles for active targeting of stroma-rich pancreatic tumors.

Original language	English
Pages (from-to)	2320-2329
Number of pages	10
Journal	Biomacromolecules
Volume	19
Issue number	6
DOIs	https://doi.org/10.1021/acs.biomac.8b00507
Publication status	Published - 2018 Jun 11

Bibliographical note

Funding Information:
This work was financially supported by Center of Innovation (COI) program from Japan Science and Technology Agency (JST) and Grants-in-Aid for Scientific Research (KAKENHI Grant Numbers 25000006 for KK and 17H02098 for KM) from Ministry of Education Culture, Sports, Science and Technology (MEXT). This work was also partially supported by the Project for Cancer Research and Therapeutics Evolution (P-CREATE) and Basic Science and Platform Technology Program for Innovative Biological Medicine from Japan Agency for Medical Research and Development (AMED) and the Mochida Memorial Foundation for Medical and Pharmaceutical Research. H.S.M. was supported by Global Innovative Research Center (GiRC) project (2012K1A1A2A01055811) of National Research Foundation of Korea and Overseas Researcher under Postdoctoral Fellowship of Japan Society for the Promotion of Science (JSPS).

Publisher Copyright:
© 2018 American Chemical Society.

ASJC Scopus subject areas

Bioengineering
Biomaterials
Polymers and Plastics
Materials Chemistry

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1021/acs.biomac.8b00507

Cite this

Min, H. S., Kim, H. J., Ahn, J., Naito, M., Hayashi, K., Toh, K., Kim, B. S., Matsumura, Y., Kwon, I. C., Miyata, K., & Kataoka, K. (2018). Tuned Density of Anti-Tissue Factor Antibody Fragment onto siRNA-Loaded Polyion Complex Micelles for Optimizing Targetability into Pancreatic Cancer Cells. Biomacromolecules, 19(6), 2320-2329. https://doi.org/10.1021/acs.biomac.8b00507

@article{8452c46d9f2b484b8d3816c7514b8318,

title = "Tuned Density of Anti-Tissue Factor Antibody Fragment onto siRNA-Loaded Polyion Complex Micelles for Optimizing Targetability into Pancreatic Cancer Cells",

abstract = "Antibody fragment (Fab′)-installed polyion complex (PIC) micelles were constructed to improve targetability of small interfering RNA (siRNA) delivery to pancreatic cancer cells. To this end, we synthesized a block copolymer of azide-functionalized poly(ethylene glycol) and poly(l-lysine) and prepared PIC micelles with siRNA. Then, a dibenzylcyclooctyne (DBCO)-modified antihuman tissue factor (TF) Fab′ was conjugated to azido groups on the micellar surface. A fluorescence correlation spectroscopic analysis revealed that 1, 2, or 3 molecule(s) of Fab′(s) were installed onto one micellar nanoparticle according to the feeding ratio of Fab′ (or DBCO) to micelle (or azide). The resulting micelles exhibited ∼40 nm in hydrodynamic diameter, similar to that of the parent micelles before Fab′ conjugation. Flow cytometric analysis showed that three molecules of Fab′-installed PIC micelles (3(Fab′)-micelles) had the highest binding affinity to cultured pancreatic cancer BxPC3 cells, which are known to overexpress TF on their surface. The 3(Fab′)-micelles also exhibited the most efficient gene silencing activity against polo-like kinase 1 mRNA in the cultured cancer cells. Furthermore, the 3(Fab′)-micelles exhibited high penetrability and the highest cellular internalization amounts in BxPC3 spheroids compared with one or two molecule(s) of Fab′-installed PIC micelles. These results demonstrate the potential of anti-TF Fab′-installed PIC micelles for active targeting of stroma-rich pancreatic tumors.",

author = "Min, {Hyun Su} and Kim, {Hyun Jin} and Jooyeon Ahn and Mitsuru Naito and Kotaro Hayashi and Kazuko Toh and Kim, {Beob Soo} and Yasuhiro Matsumura and Kwon, {Ick Chan} and Kanjiro Miyata and Kazunori Kataoka",

note = "Funding Information: This work was financially supported by Center of Innovation (COI) program from Japan Science and Technology Agency (JST) and Grants-in-Aid for Scientific Research (KAKENHI Grant Numbers 25000006 for KK and 17H02098 for KM) from Ministry of Education Culture, Sports, Science and Technology (MEXT). This work was also partially supported by the Project for Cancer Research and Therapeutics Evolution (P-CREATE) and Basic Science and Platform Technology Program for Innovative Biological Medicine from Japan Agency for Medical Research and Development (AMED) and the Mochida Memorial Foundation for Medical and Pharmaceutical Research. H.S.M. was supported by Global Innovative Research Center (GiRC) project (2012K1A1A2A01055811) of National Research Foundation of Korea and Overseas Researcher under Postdoctoral Fellowship of Japan Society for the Promotion of Science (JSPS). Publisher Copyright: {\textcopyright} 2018 American Chemical Society.",

year = "2018",

month = jun,

day = "11",

doi = "10.1021/acs.biomac.8b00507",

language = "English",

volume = "19",

pages = "2320--2329",

journal = "Biomacromolecules",

issn = "1525-7797",

publisher = "American Chemical Society",

number = "6",

}

TY - JOUR

T1 - Tuned Density of Anti-Tissue Factor Antibody Fragment onto siRNA-Loaded Polyion Complex Micelles for Optimizing Targetability into Pancreatic Cancer Cells

AU - Min, Hyun Su

AU - Kim, Hyun Jin

AU - Ahn, Jooyeon

AU - Naito, Mitsuru

AU - Hayashi, Kotaro

AU - Toh, Kazuko

AU - Kim, Beob Soo

AU - Matsumura, Yasuhiro

AU - Kwon, Ick Chan

AU - Miyata, Kanjiro

AU - Kataoka, Kazunori

N1 - Funding Information: This work was financially supported by Center of Innovation (COI) program from Japan Science and Technology Agency (JST) and Grants-in-Aid for Scientific Research (KAKENHI Grant Numbers 25000006 for KK and 17H02098 for KM) from Ministry of Education Culture, Sports, Science and Technology (MEXT). This work was also partially supported by the Project for Cancer Research and Therapeutics Evolution (P-CREATE) and Basic Science and Platform Technology Program for Innovative Biological Medicine from Japan Agency for Medical Research and Development (AMED) and the Mochida Memorial Foundation for Medical and Pharmaceutical Research. H.S.M. was supported by Global Innovative Research Center (GiRC) project (2012K1A1A2A01055811) of National Research Foundation of Korea and Overseas Researcher under Postdoctoral Fellowship of Japan Society for the Promotion of Science (JSPS). Publisher Copyright: © 2018 American Chemical Society.

PY - 2018/6/11

Y1 - 2018/6/11

N2 - Antibody fragment (Fab′)-installed polyion complex (PIC) micelles were constructed to improve targetability of small interfering RNA (siRNA) delivery to pancreatic cancer cells. To this end, we synthesized a block copolymer of azide-functionalized poly(ethylene glycol) and poly(l-lysine) and prepared PIC micelles with siRNA. Then, a dibenzylcyclooctyne (DBCO)-modified antihuman tissue factor (TF) Fab′ was conjugated to azido groups on the micellar surface. A fluorescence correlation spectroscopic analysis revealed that 1, 2, or 3 molecule(s) of Fab′(s) were installed onto one micellar nanoparticle according to the feeding ratio of Fab′ (or DBCO) to micelle (or azide). The resulting micelles exhibited ∼40 nm in hydrodynamic diameter, similar to that of the parent micelles before Fab′ conjugation. Flow cytometric analysis showed that three molecules of Fab′-installed PIC micelles (3(Fab′)-micelles) had the highest binding affinity to cultured pancreatic cancer BxPC3 cells, which are known to overexpress TF on their surface. The 3(Fab′)-micelles also exhibited the most efficient gene silencing activity against polo-like kinase 1 mRNA in the cultured cancer cells. Furthermore, the 3(Fab′)-micelles exhibited high penetrability and the highest cellular internalization amounts in BxPC3 spheroids compared with one or two molecule(s) of Fab′-installed PIC micelles. These results demonstrate the potential of anti-TF Fab′-installed PIC micelles for active targeting of stroma-rich pancreatic tumors.

AB - Antibody fragment (Fab′)-installed polyion complex (PIC) micelles were constructed to improve targetability of small interfering RNA (siRNA) delivery to pancreatic cancer cells. To this end, we synthesized a block copolymer of azide-functionalized poly(ethylene glycol) and poly(l-lysine) and prepared PIC micelles with siRNA. Then, a dibenzylcyclooctyne (DBCO)-modified antihuman tissue factor (TF) Fab′ was conjugated to azido groups on the micellar surface. A fluorescence correlation spectroscopic analysis revealed that 1, 2, or 3 molecule(s) of Fab′(s) were installed onto one micellar nanoparticle according to the feeding ratio of Fab′ (or DBCO) to micelle (or azide). The resulting micelles exhibited ∼40 nm in hydrodynamic diameter, similar to that of the parent micelles before Fab′ conjugation. Flow cytometric analysis showed that three molecules of Fab′-installed PIC micelles (3(Fab′)-micelles) had the highest binding affinity to cultured pancreatic cancer BxPC3 cells, which are known to overexpress TF on their surface. The 3(Fab′)-micelles also exhibited the most efficient gene silencing activity against polo-like kinase 1 mRNA in the cultured cancer cells. Furthermore, the 3(Fab′)-micelles exhibited high penetrability and the highest cellular internalization amounts in BxPC3 spheroids compared with one or two molecule(s) of Fab′-installed PIC micelles. These results demonstrate the potential of anti-TF Fab′-installed PIC micelles for active targeting of stroma-rich pancreatic tumors.

UR - http://www.scopus.com/inward/record.url?scp=85047431863&partnerID=8YFLogxK

U2 - 10.1021/acs.biomac.8b00507

DO - 10.1021/acs.biomac.8b00507

M3 - Article

C2 - 29767505

AN - SCOPUS:85047431863

SN - 1525-7797

VL - 19

SP - 2320

EP - 2329

JO - Biomacromolecules

JF - Biomacromolecules

IS - 6

ER -

Tuned Density of Anti-Tissue Factor Antibody Fragment onto siRNA-Loaded Polyion Complex Micelles for Optimizing Targetability into Pancreatic Cancer Cells

Abstract

Bibliographical note

ASJC Scopus subject areas

UN SDGs

Access to Document

Other files and links

Fingerprint

Cite this