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

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10 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 languageEnglish
Pages (from-to)2320-2329
Number of pages10
JournalBiomacromolecules
Volume19
Issue number6
DOIs
Publication statusPublished - 2018 Jun 11
Externally publishedYes

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ASJC Scopus subject areas

  • Bioengineering
  • Biomaterials
  • Polymers and Plastics
  • Materials Chemistry

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