Journal
JOURNAL OF PHARMACEUTICAL SCIENCES
Volume 104, Issue 5, Pages 1815-1824Publisher
ELSEVIER SCIENCE INC
DOI: 10.1002/jps.24407
Keywords
liposome; cancer chemotherapy; nanoparticle; cancer; glass transition; pH responsive delivery system; lipid-drug interaction; membrane integrity
Funding
- Life Science Discovery Fund (LSDF) [3127535]
- Institute of Translational Health Sciences
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Artemisinin (ART), a well-known antimalaria drug, also exhibits anticancer activities. We previously reported a group of novel dimeric artemisinin piperazine conjugates (ADPs) possessing pH-dependent aqueous solubility and a proof-of-concept lipid nanoparticle formulation based on natural egg phosphatidylcholine (EPC). EPC may induce allergic reactions in individuals sensitive to egg products. Therefore, the goal of this report is to develop ADP-synthetic lipid particles suitable for in vivo evaluation. We found that ADP binds to 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC) with greater than 90% efficiency and forms drug-lipid particles (d approximate to 80 nm). Cryo-electron microscopy of the ADP drug-lipid particles revealed unilamellar vesicle-like structures. Detailed characterization studies show insertion of the ADP lead compound, ADP109, into the DPPC membrane and the presence of an aqueous core. Over 50% of the ADP109 was released in 48 hours at pH4 compared with less than 20% at neutral. ADP109-lipid particles exhibited high potency against human breast cancer, but was tolerated well by nontumorigenic cells. In MDA-MB-231 mouse xenograft model, lipid-bound ADP109 particles were more effective than paclitaxel in controlling tumor growth. Cellular uptake studies showed endocytosis of the nanoparticles and release of core-trapped marker throughout the cytosol at 37 degrees C. These results demonstrate, for the first time, the in vivo feasibility of lipid-bound ART dimer for cancer chemotherapy. (c) 2015 Wiley Periodicals, Inc. and the American Pharmacists Association J Pharm Sci 104:1815-1824, 2015
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