TY - JOUR
T1 - Codelivery of doxorubicin and JIP1 siRNA with novel EphA2-targeted pegylated cationic nanoliposomes to overcome osteosarcoma multidrug resistance
AU - Haghiralsadat, F.
AU - Amoabediny, G.
AU - Naderinezhad, S.
AU - Zandieh-Doulabi, B.
AU - Forouzanfar, T.
AU - Helder, M.N.
PY - 2018/7/3
Y1 - 2018/7/3
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
UR - http://www.scopus.com/inward/record.url?scp=85049607070&partnerID=8YFLogxK
UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85049607070&origin=inward
UR - https://www.ncbi.nlm.nih.gov/pubmed/30013340
U2 - https://doi.org/10.2147/IJN.S150017
DO - https://doi.org/10.2147/IJN.S150017
M3 - Article
C2 - 30013340
SN - 1176-9114
VL - 13
SP - 3853
EP - 3866
JO - International journal of nanomedicine
JF - International journal of nanomedicine
ER -