Encapsulation of drugs within nanocarriers that selectively target malignant cells promises to mitigate side effects of conventional chemotherapy and to enable delivery of the unique drug combinations needed for personalized medicine. To realize this potential, however, targeted nanocarriers must simultaneously overcome multiple challenges, including specificity, stability and a high capacity for disparate cargos. Here we report porous nanoparticle-supported lipid bilayers (protocells) that synergistically combine properties of liposomes and nanoporous particles. Protocells modified with a targeting peptide that binds to human hepatocellular carcinoma exhibit a 10,000-fold greater affinity for human hepatocellular carcinoma than for hepatocytes, endothelial cells or immune cells. Furthermore, protocells can be loaded with combinations of therapeutic (drugs, small interfering RNA and toxins) and diagnostic (quantum dots) agents and modified to promote endosomal escape and nuclear accumulation of selected cargos. The enormous capacity of the high-surface-area nanoporous core combined with the enhanced targeting efficacy enabled by the fluid supported lipid bilayer enable a single protocell loaded with a drug cocktail to kill a drug-resistant human hepatocellular carcinoma cell, representing a 106-fold improvement over comparable liposomes.
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This work was supported by the NIH/Roadmap for Medical Research under grant PHS 2 PN2 EY016570B; NCI Cancer Nanotechnology Platform Partnership grant 1U01CA151792-01; the Air Force Office of Scientific Research grant FA 9550-07-1-0054/9550-10-1-0054; the US Department of Energy, Office of Basic Energy Sciences, Division of Materials Sciences and Engineering; the Sandia National Laboratories’ Laboratory Directed Research and Development (LDRD) programme; the President Harry S. Truman Fellowship in National Security Science and Engineering at Sandia National Laboratories (C.E.A.); the UCLA Center for Nanobiology and Predictive Toxicology (NIEHS grant 1U19ES019528-01) and the NSF ERC Center for Environmental Implications of Nanotechnology at UCLA (NSF:EF-0820117). C.E.A. was supported by IGERT Fellowship Grant NSF DGE-0504276, and E.C.C. and N.J.C. were supported by NSF IGERT grant DGE- 0549500. T.N.H. was supported by NSF Nanoscience and Microsystems REU program (grant DMR-0649132) at the University of New Mexico Center for Micro-Engineered Materials. N.J.C and D.N.P. were supported by NSF PREM/DMR 0611616. R. Lee provided guidance for imaging protocols and FRAP experiments, M. Aragon created schematic diagrams, R. Sewell carried out nitrogen sorption experiments and Y-B. Jiang carried out TEM imaging. Cryogenic TEM was carried out at Baylor College of Medicine (Houston, TX) by C. Jia-Yin Fu, H. Khant and W. Chiu. Some images in this paper were generated in the University of New Mexico Cancer Center Fluorescence Microscopy Facility, supported by NCRR, NSF and NCI as detailed at http://hsc.unm.edu/crtc/microscopy/Facility.html. Data were generated in the Flow Cytometry Shared Resource Center supported by the University of New Mexico Health Sciences Center and the University of New Mexico Cancer Center. Sandia is a multiprogramme laboratory operated by Sandia Corporation, a wholly owned subsidiary of Lockheed Martin Company, for the US Department of Energy’s National Nuclear Security Administration under contract DE-AC04-94AL85000.
The authors declare no competing financial interests.
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Ashley, C., Carnes, E., Phillips, G. et al. The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers. Nature Mater 10, 389–397 (2011). https://doi.org/10.1038/nmat2992
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