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The targeted delivery of multicomponent cargos to cancer cells by nanoporous particle-supported lipid bilayers

A Corrigendum to this article was published on 23 May 2011

This article has been updated

Abstract

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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Figure 1: Schematic illustration of the nanoporous particle-supported lipid bilayer, depicting the disparate types of therapeutic and diagnostic agent that can be loaded within the nanoporous silica core, as well as the ligands that can be displayed on the surface of the SLB.
Figure 2: Physical and biophysical characteristics of protocells.
Figure 3: Schematic diagram depicting the successive steps of multivalent binding and internalization of targeted protocells, followed by endosomal escape and nuclear localization of protocell-encapsulated cargo.
Figure 4: Selective binding and internalization characteristics of SP94-targeted protocells.
Figure 5: Targeted delivery of multicomponent cargos to the cytosol and nuclei of HCC cells.
Figure 6: Cargo capacity, time-dependent release profiles and concentration-dependent cytotoxicity of SP94-targeted protocells and liposomes that encapsulate chemotherapeutic drugs.

Change history

  • 10 May 2011

    In the version of this Letter originally published, in Fig. 1 a double bond in the maleimide cycle of the crosslinker molecular structure was missing; the definition of the SP94 peptide in the text should have read H2N-SFSIIHTPILPLGGC-COOH; and in Fig. 6a the lowest value of the right-hand y axis should have read 106. These errors have now been corrected in the HTML and PDF versions.

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Acknowledgements

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.

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C.E.A. engineered protocells for targeted delivery, carried out most experiments, analysed data and wrote the manuscript; E.C.C. assisted with experiment coordination, data analysis and manuscript preparation; G.K.P. carried out confocal fluorescence microscopy imaging; D.P. synthesized and characterized multimodal particles; P.A.B. carried out FRAP experiments; T.N.H. assisted with DOX capacity and release studies; J.L. contributed to the development of the original protocell construct; N.J.C. developed the emulsion processing necessary to synthesize multimodal particles; B.P. and M.B.C. carried out flow cytometry experiments; X.J. synthesized unimodal particles; D.R.D. carried out small-angle neutron scattering experiments and analysed nitrogen sorption data; D.N.P. supervised development of the multimodal particles; D.G.E. supervised FRAP experiments; A.N.P. suggested the FRAP experiment and aided in its interpretation; P.N.D., C.L.W., B.C., W.W. and D.S.P. provided intellectual oversight for delivery experiments involving drugs, siRNA and protein toxins; C.J.B. conceived of the protocell construct, provided overall intellectual guidance, carried out final edits of the manuscript and is principal investigator of the main supporting grants.

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Correspondence to Carlee E. Ashley or C. Jeffrey Brinker.

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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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