title: Integrated nanotechnology platform for tumor-targeted multimodal imaging and therapeutic cargo release.
abstract: A major challenge of targeted molecular imaging and drug delivery in cancer is establishing a functional combination of ligand-directed cargo with a triggered release system. Here we develop a hydrogel-based nanotechnology platform that integrates tumor targeting, photon-to-heat conversion, and triggered drug delivery within a single nanostructure to enable multimodal imaging and controlled release of therapeutic cargo. In proof-of-concept experiments, we show a broad range of ligand peptide-based applications with phage particles, heat-sensitive liposomes, or mesoporous silica nanoparticles that self-assemble into a hydrogel for tumor-targeted drug delivery. Because nanoparticles pack densely within the nanocarrier, their surface plasmon resonance shifts to near-infrared, thereby enabling a laser-mediated photothermal mechanism of cargo release. We demonstrate both noninvasive imaging and targeted drug delivery in preclinical mouse models of breast and prostate cancer. Finally, we applied mathematical modeling to predict and confirm tumor targeting and drug delivery. These results are meaningful steps toward the design and initial translation of an enabling nanotechnology platform with potential for broad clinical applications.
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8656, Japan; The University of Tokyo Hospital, Tokyo 113-8656, Japan;
authors.forename: Hitomi
authors.initials: H
authors.lastname: Hosoya
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
authors.forename: Andrey S
authors.initials: AS
authors.lastname: Dobroff
authors.affiliation: David H. Koch Center, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Wouter H P
authors.initials: WH
authors.lastname: Driessen
authors.affiliation: Department of NanoMedicine and BioMedical Engineering, School of Medicine, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77054; Department of Proteomics and Systems Biology, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, TX 77054; Department of Imaging Physics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77054;
authors.forename: Vittorio
authors.initials: V
authors.lastname: Cristini
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
authors.forename: Lina M
authors.initials: LM
authors.lastname: Brinker
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
authors.forename: Fernanda I
authors.initials: FI
authors.lastname: Staquicini
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
authors.forename: Marina
authors.initials: M
authors.lastname: Cardó-Vila
authors.affiliation: Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545;
authors.forename: Sara
authors.initials: S
authors.lastname: D'Angelo
authors.affiliation: Bioscience Division, Los Alamos National Laboratory, Los Alamos, NM 87545;
authors.forename: Fortunato
authors.initials: F
authors.lastname: Ferrara
authors.affiliation: David H. Koch Center, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030;
authors.forename: Bettina
authors.initials: B
authors.lastname: Proneth
authors.affiliation: Oncothyreon, Seattle, WA 98121;
authors.forename: Yu-Shen
authors.initials: YS
authors.lastname: Lin
authors.affiliation: Center for Micro-Engineered Materials, University of New Mexico, Albuquerque, NM 87131; Sandia National Laboratories, Albuquerque, NM 87106;
authors.forename: Darren R
authors.initials: DR
authors.lastname: Dunphy
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131;
authors.forename: Prashant
authors.initials: P
authors.lastname: Dogra
authors.affiliation: Department of Imaging Physics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77054;
authors.forename: Marites P
authors.initials: MP
authors.lastname: Melancon
authors.affiliation: Department of Imaging Physics, The University of Texas M.D. Anderson Cancer Center, Houston, TX 77054;
authors.forename: R Jason
authors.initials: RJ
authors.lastname: Stafford
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8656, Japan;
authors.forename: Kohei
authors.initials: K
authors.lastname: Miyazono
authors.affiliation: Department of Biomedical Engineering, Wayne State University, Detroit, MI 48201;
authors.forename: Juri G
authors.initials: JG
authors.lastname: Gelovani
authors.affiliation: Department of Molecular Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8656, Japan; Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Tokyo 113-8656, Japan;
authors.forename: Kazunori
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Center for Micro-Engineered Materials, University of New Mexico, Albuquerque, NM 87131; Sandia National Laboratories, Albuquerque, NM 87106; Department of Chemical and Nuclear Engineering, University of New Mexico, Albuquerque, NM 87131;
authors.forename: C Jeffrey
authors.initials: CJ
authors.lastname: Brinker
authors.affiliation: Harvard Medical School and Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA 02215; richard_sidman@hms.harvard.edu warap@salud.unm.edu rpasqual@salud.unm.edu.
authors.forename: Richard L
authors.initials: RL
authors.lastname: Sidman
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Hematology/Oncology, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131 richard_sidman@hms.harvard.edu warap@salud.unm.edu rpasqual@salud.unm.edu.
authors.forename: Wadih
authors.initials: W
authors.lastname: Arap
authors.affiliation: University of New Mexico Comprehensive Cancer Center, Albuquerque, NM 87131; Division of Molecular Medicine, Department of Internal Medicine, University of New Mexico School of Medicine, Albuquerque, NM 87131; richard_sidman@hms.harvard.edu warap@salud.unm.edu rpasqual@salud.unm.edu.
authors.forename: Renata
authors.initials: R
authors.lastname: Pasqualini
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000175:diagnosis* / Q000188:drug therapy*; D004195:Disease Models, Animal; D016503:Drug Delivery Systems; D005260:Female; D007259:Infrared Rays; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D064847:Multimodal Imaging; D036103:Nanotechnology; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000188:drug therapy*; D020349:Surface Plasmon Resonance
chemical_list: D000970:Antineoplastic Agents
keywords: ligand receptor; mathematical modeling; nanoparticle; phage display; photothermal therapy
references.citation: Nanomedicine (Lond). 2015;10(8):1315-26
references.pmid: 25955125
references.citation: Proc Natl Acad Sci U S A. 2009 Feb 17;106(7):2182-7
references.pmid: 19168626
references.citation: Science. 2012 Nov 16;338(6109):903-10
references.pmid: 23161990
references.citation: Cancer Res. 1986 Dec;46(12 Pt 1):6387-92
references.pmid: 2946403
references.citation: J Drug Target. 2016;24(3):179-91
references.pmid: 26061298
references.citation: Adv Genet. 2010;69:115-33
references.pmid: 20807605
references.citation: Adv Drug Deliv Rev. 2013 Mar;65(3):348-56
references.pmid: 22820525
references.citation: J Am Chem Soc. 2009 Feb 4;131(4):1354-5
references.pmid: 19173660
references.citation: Colloids Surf B Biointerfaces. 2014 Apr 1;116:17-25
references.pmid: 24441178
references.citation: Adv Healthc Mater. 2012 May;1(3):348-53
references.pmid: 23184753
references.citation: Acc Chem Res. 2013 Mar 19;46(3):792-801
references.pmid: 23387478
references.citation: Proc Natl Acad Sci U S A. 2006 Jan 31;103(5):1215-20
references.pmid: 16434473
references.citation: J Math Biol. 2009 Apr;58(4-5):485-510
references.pmid: 18781304
references.citation: Curr Opin Biotechnol. 2013 Aug;24(4):620-6
references.pmid: 23465756
references.citation: ACS Nano. 2013 Dec 23;7(12):11174-82
references.pmid: 24187963
references.citation: J Drug Target. 2013 Dec;21(10):904-13
references.pmid: 24079419
references.citation: ACS Nano. 2011 Feb 22;5(2):738-47
references.pmid: 21275414
references.citation: ACS Nano. 2012 Mar 27;6(3):2174-88
references.pmid: 22309035
references.citation: Methods Mol Biol. 2007;357:385-406
references.pmid: 17172704
references.citation: Int J Nanomedicine. 2015;10:4099-109
references.pmid: 26124662
references.citation: Adv Drug Deliv Rev. 2015 Aug 30;91:3-6
references.pmid: 25579058
references.citation: PLoS One. 2008;3(5):e2242
references.pmid: 18493583
references.citation: Anal Chem. 2006 Sep 1;78(17):6232-7
references.pmid: 16944906
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 11;100(23):13549-54
references.pmid: 14597719
references.citation: Proc Natl Acad Sci U S A. 2013 Aug 27;110(35):14266-71
references.pmid: 23940372
references.citation: J Clin Invest. 2014 Apr;124(4):1525-36
references.pmid: 24614108
references.citation: Nano Today. 2012 Dec 1;7(6):606-618
references.pmid: 23243460
references.citation: Proc Natl Acad Sci U S A. 2015 Mar 24;112(12):3776-81
references.pmid: 25762070
references.citation: Biochem Biophys Res Commun. 2015 Dec 18;468(3):411-8
references.pmid: 26315266
references.citation: Int J Nanomedicine. 2015;10:1001-18
references.pmid: 25678788
references.citation: Nat Rev Cancer. 2002 Oct;2(10):750-63
references.pmid: 12360278
references.citation: Mol Pharm. 2013 Jan 7;10(1):59-68
references.pmid: 23110441
references.citation: Angew Chem Int Ed Engl. 2015 Jun 15;54(25):7436-40
references.pmid: 25940402
references.citation: Nat Mater. 2011 May;10(5):389-97
references.pmid: 21499315
references.citation: Nanomedicine. 2013 Feb;9(2):194-201
references.pmid: 22687896