Targeting glioblastoma cells expressing CD44 with liposomes encapsulating doxorubicin and displaying chlorotoxin-IgG Fc fusion protein

Hafizah Mahmud, Tomonari Kasai, Apriliana Cahya Khayrani, Mami Asakura, Aung Ko Ko Oo, Juan Du, Arun Vaidyanath, Samah El-Ghlban, Akifumi Mizutani, Akimasa Seno, Hiroshi Murakami, Junko Masuda, Masaharu Seno

Research output: Contribution to journalArticle

10 Citations (Scopus)

Abstract

We recently have established a successful xenograft model of human glioblastoma cells by enriching hyaluronic acid-dependent spheroid-forming populations termed U251MG-P1 cells from U251MG cells. Since U251MG-P1 cells have been confirmed to express CD44 along with principal stemness marker genes, OCT3/4, SOX2, KLF4 and Nanog, this CD44 expressing population appeared to majorly consist of undifferentiated cells. Evaluating the sensitivity to anti-cancer agents, we found U251MG-P1 cells were sensitive to doxorubicin with IC50 at 200 nM. Although doxorubicin has serious side-effects, establishment of an efficient therapy targeting undifferentiated glioblastoma cell population is necessary. We previously designed a chlorotoxin peptide fused to human IgG Fc region without hinge sequence (M-CTX-Fc), which exhibited a stronger growth inhibitory effect on the glioblastoma cell line A172 than an original chlorotoxin peptide. Combining these results together, we designed M-CTX-Fc conjugated liposomes encapsulating doxorubicin and used U251MG-P1 cells as the target model in this study. The liposome modified with M-CTX-Fc was designed with a diameter of approximately 100–150 nm and showed high encapsulation efficiency, adequate loading capacity of anticancer drug, enhanced antitumor effects demonstrating increasing uptake into the cells in vitro; M-CTX-Fc-L-Dox shows great promise in its ability to suppress tumor growth in vivo and it could serve as a template for targeted delivery of other therapeutics.

Original languageEnglish
Article number659
JournalInternational Journal of Molecular Sciences
Volume19
Issue number3
DOIs
Publication statusPublished - Mar 1 2018

Fingerprint

encapsulating
Liposomes
Glioblastoma
Doxorubicin
Peptides
Fusion reactions
Immunoglobulin G
fusion
Cells
proteins
Proteins
Hyaluronic acid
Hinges
cells
Encapsulation
Tumors
Genes
Hyaluronic Acid
Heterografts
peptides

Keywords

  • Doxorubicin
  • Glioblastoma cells
  • Liposome
  • M-CTX-Fc
  • MMP-2
  • Specific targeting

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry

Cite this

Targeting glioblastoma cells expressing CD44 with liposomes encapsulating doxorubicin and displaying chlorotoxin-IgG Fc fusion protein. / Mahmud, Hafizah; Kasai, Tomonari; Khayrani, Apriliana Cahya; Asakura, Mami; Oo, Aung Ko Ko; Du, Juan; Vaidyanath, Arun; El-Ghlban, Samah; Mizutani, Akifumi; Seno, Akimasa; Murakami, Hiroshi; Masuda, Junko; Seno, Masaharu.

In: International Journal of Molecular Sciences, Vol. 19, No. 3, 659, 01.03.2018.

Research output: Contribution to journalArticle

Mahmud, Hafizah ; Kasai, Tomonari ; Khayrani, Apriliana Cahya ; Asakura, Mami ; Oo, Aung Ko Ko ; Du, Juan ; Vaidyanath, Arun ; El-Ghlban, Samah ; Mizutani, Akifumi ; Seno, Akimasa ; Murakami, Hiroshi ; Masuda, Junko ; Seno, Masaharu. / Targeting glioblastoma cells expressing CD44 with liposomes encapsulating doxorubicin and displaying chlorotoxin-IgG Fc fusion protein. In: International Journal of Molecular Sciences. 2018 ; Vol. 19, No. 3.
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AU - Mahmud, Hafizah

AU - Kasai, Tomonari

AU - Khayrani, Apriliana Cahya

AU - Asakura, Mami

AU - Oo, Aung Ko Ko

AU - Du, Juan

AU - Vaidyanath, Arun

AU - El-Ghlban, Samah

AU - Mizutani, Akifumi

AU - Seno, Akimasa

AU - Murakami, Hiroshi

AU - Masuda, Junko

AU - Seno, Masaharu

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AB - We recently have established a successful xenograft model of human glioblastoma cells by enriching hyaluronic acid-dependent spheroid-forming populations termed U251MG-P1 cells from U251MG cells. Since U251MG-P1 cells have been confirmed to express CD44 along with principal stemness marker genes, OCT3/4, SOX2, KLF4 and Nanog, this CD44 expressing population appeared to majorly consist of undifferentiated cells. Evaluating the sensitivity to anti-cancer agents, we found U251MG-P1 cells were sensitive to doxorubicin with IC50 at 200 nM. Although doxorubicin has serious side-effects, establishment of an efficient therapy targeting undifferentiated glioblastoma cell population is necessary. We previously designed a chlorotoxin peptide fused to human IgG Fc region without hinge sequence (M-CTX-Fc), which exhibited a stronger growth inhibitory effect on the glioblastoma cell line A172 than an original chlorotoxin peptide. Combining these results together, we designed M-CTX-Fc conjugated liposomes encapsulating doxorubicin and used U251MG-P1 cells as the target model in this study. The liposome modified with M-CTX-Fc was designed with a diameter of approximately 100–150 nm and showed high encapsulation efficiency, adequate loading capacity of anticancer drug, enhanced antitumor effects demonstrating increasing uptake into the cells in vitro; M-CTX-Fc-L-Dox shows great promise in its ability to suppress tumor growth in vivo and it could serve as a template for targeted delivery of other therapeutics.

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