Codelivery of doxorubicin and JIP1 siRNA with novel EphA2-targeted pegylated cationic nanoliposomes to overcome osteosarcoma multidrug resistance

Fateme Haghiralsadat, Ghasem Amoabediny, Samira Naderinezhad, Behrouz Zandieh-Doulabi, Tymour Forouzanfar, Marco N. Helder

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Purpose: Osteosarcoma (OS) mostly affects children and young adults, and has only a 20%–30% 5-year survival rate when metastasized. We aimed to create dual-targeted (extracellular against EphA2 and intracellular against JNK-interacting protein 1 [JIP1]), doxorubicin (DOX)-loaded liposomes to treat OS metastatic disease. Materials and methods: Cationic liposomes contained N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate (DOTAP), cholesterol, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and distearoyl-phosphatidylethanolamine–methyl-poly(ethylene glycol) (DSPE–mPEG) conjugate. EphA2 targeting was accomplished by conjugating YSA peptide to DSPE–mPEG. Vesicles were subsequently loaded with DOX and JIP1 siRNA. Results: Characteristics assessment showed that 1) size of the bilayered particles was 109 nm; 2) DOX loading efficiency was 87%; 3) siRNA could be successfully loaded at a liposome:siRNA ratio of >24:1; and 4) the zeta potential was 18.47 mV. Tumor-mimicking pH conditions exhibited 80% siRNA and 50.7% DOX sustained release from the particles. Stability studies ensured the protection of siRNA against degradation in serum. OS cell lines showed increased and more pericellular/nuclear localizations when using targeted vesicles. Nontargeted and targeted codelivery caused 70.5% and 78.6% cytotoxicity in OS cells, respectively (free DOX: 50%). Targeted codelivery resulted in 42% reduction in the siRNA target, JIP1 mRNA, and 46% decrease in JIP1 levels. Conclusion: Our dual-targeted, DOX-loaded liposomes enhance toxicity toward OS cells and may be effective for the treatment of metastatic OS.
Original languageEnglish
Pages (from-to)3853-3866
Number of pages14
JournalInternational Journal of Nanomedicine
Volume13
DOIs
Publication statusPublished - 2018

Cite this

@article{16e8195e169844f8bd8041e375a2dcc2,
title = "Codelivery of doxorubicin and JIP1 siRNA with novel EphA2-targeted pegylated cationic nanoliposomes to overcome osteosarcoma multidrug resistance",
abstract = "Purpose: Osteosarcoma (OS) mostly affects children and young adults, and has only a 20{\%}–30{\%} 5-year survival rate when metastasized. We aimed to create dual-targeted (extracellular against EphA2 and intracellular against JNK-interacting protein 1 [JIP1]), doxorubicin (DOX)-loaded liposomes to treat OS metastatic disease. Materials and methods: Cationic liposomes contained N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate (DOTAP), cholesterol, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and distearoyl-phosphatidylethanolamine–methyl-poly(ethylene glycol) (DSPE–mPEG) conjugate. EphA2 targeting was accomplished by conjugating YSA peptide to DSPE–mPEG. Vesicles were subsequently loaded with DOX and JIP1 siRNA. Results: Characteristics assessment showed that 1) size of the bilayered particles was 109 nm; 2) DOX loading efficiency was 87{\%}; 3) siRNA could be successfully loaded at a liposome:siRNA ratio of >24:1; and 4) the zeta potential was 18.47 mV. Tumor-mimicking pH conditions exhibited 80{\%} siRNA and 50.7{\%} DOX sustained release from the particles. Stability studies ensured the protection of siRNA against degradation in serum. OS cell lines showed increased and more pericellular/nuclear localizations when using targeted vesicles. Nontargeted and targeted codelivery caused 70.5{\%} and 78.6{\%} cytotoxicity in OS cells, respectively (free DOX: 50{\%}). Targeted codelivery resulted in 42{\%} reduction in the siRNA target, JIP1 mRNA, and 46{\%} decrease in JIP1 levels. Conclusion: Our dual-targeted, DOX-loaded liposomes enhance toxicity toward OS cells and may be effective for the treatment of metastatic OS.",
keywords = "Cationic liposome, Extracellular targeting, Functionalization, Intracellular targeting, MAP kinase 8 interacting protein 1, MAPK8IP1",
author = "Fateme Haghiralsadat and Ghasem Amoabediny and Samira Naderinezhad and Behrouz Zandieh-Doulabi and Tymour Forouzanfar and Helder, {Marco N.}",
year = "2018",
doi = "10.2147/IJN.S150017",
language = "English",
volume = "13",
pages = "3853--3866",
journal = "International Journal of Nanomedicine",
issn = "1176-9114",
publisher = "Dove Medical Press Ltd.",

}

Codelivery of doxorubicin and JIP1 siRNA with novel EphA2-targeted pegylated cationic nanoliposomes to overcome osteosarcoma multidrug resistance. / Haghiralsadat, Fateme; Amoabediny, Ghasem; Naderinezhad, Samira; Zandieh-Doulabi, Behrouz; Forouzanfar, Tymour; Helder, Marco N.

In: International Journal of Nanomedicine, Vol. 13, 2018, p. 3853-3866.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Codelivery of doxorubicin and JIP1 siRNA with novel EphA2-targeted pegylated cationic nanoliposomes to overcome osteosarcoma multidrug resistance

AU - Haghiralsadat, Fateme

AU - Amoabediny, Ghasem

AU - Naderinezhad, Samira

AU - Zandieh-Doulabi, Behrouz

AU - Forouzanfar, Tymour

AU - Helder, Marco N.

PY - 2018

Y1 - 2018

N2 - Purpose: Osteosarcoma (OS) mostly affects children and young adults, and has only a 20%–30% 5-year survival rate when metastasized. We aimed to create dual-targeted (extracellular against EphA2 and intracellular against JNK-interacting protein 1 [JIP1]), doxorubicin (DOX)-loaded liposomes to treat OS metastatic disease. Materials and methods: Cationic liposomes contained N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate (DOTAP), cholesterol, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and distearoyl-phosphatidylethanolamine–methyl-poly(ethylene glycol) (DSPE–mPEG) conjugate. EphA2 targeting was accomplished by conjugating YSA peptide to DSPE–mPEG. Vesicles were subsequently loaded with DOX and JIP1 siRNA. Results: Characteristics assessment showed that 1) size of the bilayered particles was 109 nm; 2) DOX loading efficiency was 87%; 3) siRNA could be successfully loaded at a liposome:siRNA ratio of >24:1; and 4) the zeta potential was 18.47 mV. Tumor-mimicking pH conditions exhibited 80% siRNA and 50.7% DOX sustained release from the particles. Stability studies ensured the protection of siRNA against degradation in serum. OS cell lines showed increased and more pericellular/nuclear localizations when using targeted vesicles. Nontargeted and targeted codelivery caused 70.5% and 78.6% cytotoxicity in OS cells, respectively (free DOX: 50%). Targeted codelivery resulted in 42% reduction in the siRNA target, JIP1 mRNA, and 46% decrease in JIP1 levels. Conclusion: Our dual-targeted, DOX-loaded liposomes enhance toxicity toward OS cells and may be effective for the treatment of metastatic OS.

AB - Purpose: Osteosarcoma (OS) mostly affects children and young adults, and has only a 20%–30% 5-year survival rate when metastasized. We aimed to create dual-targeted (extracellular against EphA2 and intracellular against JNK-interacting protein 1 [JIP1]), doxorubicin (DOX)-loaded liposomes to treat OS metastatic disease. Materials and methods: Cationic liposomes contained N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium methyl-sulfate (DOTAP), cholesterol, 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), and distearoyl-phosphatidylethanolamine–methyl-poly(ethylene glycol) (DSPE–mPEG) conjugate. EphA2 targeting was accomplished by conjugating YSA peptide to DSPE–mPEG. Vesicles were subsequently loaded with DOX and JIP1 siRNA. Results: Characteristics assessment showed that 1) size of the bilayered particles was 109 nm; 2) DOX loading efficiency was 87%; 3) siRNA could be successfully loaded at a liposome:siRNA ratio of >24:1; and 4) the zeta potential was 18.47 mV. Tumor-mimicking pH conditions exhibited 80% siRNA and 50.7% DOX sustained release from the particles. Stability studies ensured the protection of siRNA against degradation in serum. OS cell lines showed increased and more pericellular/nuclear localizations when using targeted vesicles. Nontargeted and targeted codelivery caused 70.5% and 78.6% cytotoxicity in OS cells, respectively (free DOX: 50%). Targeted codelivery resulted in 42% reduction in the siRNA target, JIP1 mRNA, and 46% decrease in JIP1 levels. Conclusion: Our dual-targeted, DOX-loaded liposomes enhance toxicity toward OS cells and may be effective for the treatment of metastatic OS.

KW - Cationic liposome

KW - Extracellular targeting

KW - Functionalization

KW - Intracellular targeting

KW - MAP kinase 8 interacting protein 1

KW - MAPK8IP1

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30013340

U2 - 10.2147/IJN.S150017

DO - 10.2147/IJN.S150017

M3 - Article

VL - 13

SP - 3853

EP - 3866

JO - International Journal of Nanomedicine

JF - International Journal of Nanomedicine

SN - 1176-9114

ER -