Development of synthetic peptide-modified liposomes with LDL receptor targeting capacity and improved anticancer activity.
In this study, we report an active targeting liposomal formulation directed by a novel peptide (AA13) that specifically binds to the low density lipoprotein receptor (LDLR) overexpressed on acute myeloid leukemia (AML) cells. The objectives of this study were to evaluate the in vitro and in vivo tumor drug targeting delivery of AA13-anchored liposomes on AML cells. AA13 conjugated to the distal end of DSPE-PEG2000-maleimide was incorporated into the liposomes via a postinsertion method. To study the effect of the peptide decoration and density on tumor cell targeting and internalization by AML cells (THP-1 and NB4), stealth liposomes bearing 3% (peptide/S100PC, molar ratio, LL) and 7% (peptide/S100PC, molar ratio, HL) AA13 were prepared, respectively. Higher uptake of LL (1.9- and 2.6-fold) and HL (2.3- and 3.6-fold) targeted liposomes occurred in THP-1 and NB4 cells, respectively, compared to untargeted liposomes. An LDLR inhibitor was used to confirm inhibition of the receptor-mediated cellular association of AA13 modified liposome in both cells. Daunorubicin (DNR) demonstrated a 2.2- and 3.5-fold higher cytotoxicity with the HL formulation and a 1.2- and 2.0-fold higher cytotoxicity with the LL formulation compared to the unmodified liposomal formulation in THP-1 and NB4 cells, respectively. Tumor drug accumulation of DNR-loaded HL was greater than that of the untargeted liposome in the biodistribution assay. The in vivo efficacy study in BALB/c nude mice bearing NB4 xenografts treated with DNR loaded HL also showed more tumor volume inhibition and a longer survival time compared to the untargeted formulation. In conclusion, the AA13-anchored liposomes demonstrated desirable potential as a promising vector for enhanced AML tumor drug targeting.
Key Laboratory of Drug Targeting and Drug Delivery System, Ministry of Education & West China School of Pharmacy, Sichuan University , No.17, Section 3, Southern Renmin Road, Chengdu 610041, P. R. China.
Mei
M
Liu
Wei
W
Li
Caroline A
CA
Larregieu
Meng
M
Cheng
Bihan
B
Yan
Ting
T
Chu
Hui
H
Li
Sheng-jun
SJ
Mao
D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003630:Daunorubicin / Q000737:chemistry / Q000494:pharmacology; D016503:Drug Delivery Systems / Q000379:methods; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy; D008081:Liposomes / Q000737:chemistry* / Q000494:pharmacology*; D008301:Maleimides / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D010714:Phosphatidylethanolamines / Q000737:chemistry; D011092:Polyethylene Glycols / Q000737:chemistry; D011973:Receptors, LDL / Q000378:metabolism*; D014018:Tissue Distribution
C519184:1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-methoxy-poly(ethylene glycol 2000); D000970:Antineoplastic Agents; D008081:Liposomes; D008301:Maleimides; D010455:Peptides; D010714:Phosphatidylethanolamines; D011973:Receptors, LDL; C043592:maleimide; D011092:Polyethylene Glycols; D003630:Daunorubicin