(12) United States Patent (1o) Patent No.: US 8,173,115 B2 Decuzzi et al. (45) Date of Patent: *May 8, 2012 (54) PARTICLE COMPOSITIONS WITH A OTHER PUBLICATIONS PRE-SELECTED CELL INTERNALIZATION International Search Report and Written Opinion mailed Jun. 3, MODE 2009, in PCT/US2008/071470, 15 pages. (75) Inventors: Paolo Decuzzi, Bari (IT); Mauro U.S. Appl. No. 12/110,515, filed Apr. 28, 2008, Ferrari et al. Ferrari, Houston, TX (US) Champion et al., "Making polymeric micro- and nanoparticles of complex shapes," PHAS, Jul. 17, 2007, 104(29):11901-11904. (73) Assignee: The Board of Regents of The Champion et al., "Role of target geometry in phagocytosis," PHAS, University of Texas System, Austin, TX Mar. 28, 2006, 103(13):4930-4934. Cohen et al., "Microfabrication of Silicon-Based Nanoporous Par- (US) ticulates for Medical Applications," Biomedical Microdevices, 2003, 5(3):253-259. (*) Notice: Subject to any disclaimer, the term of this Conner et al., "Regulated portals of entry into the cell," Nature, Mar. patent is extended or adjusted under 35 6, 2003, 422:37-44. U.S.C. 154(b) by 390 days. Decuzzi et al,. "The role of specific and non-specific interactions in This patent is subject to a terminal dis- receptor-mediated endocytosis of nanoparticles," Biomaterials, claimer. 2007, 28:2915-2922. Decuzzi et al., "A Theoretical Model for the Margination of Particles (21) Appl. No.: 12/181,759 within Blood Vessels," Annals of Biomedical Engineering, Feb. 2005, 33(2):179-190. (22) Filed: Jul. 29, 2008 Decuzzi et al., "Adhesion of Microfabricated Particles of Vascular Endothelium: A Parametric Analysis," Annals of Biomedical Engi- (65) Prior Publication Data neering, Jun. 2004, 32(6):793-802. Decuzzi et al., "The adhesive strength of non-spherical particles US 2010/0029785 Al Feb. 4, 2010 mediated by specific interactions," Biomaterials, 2006, 27:5307- 5314. (51) Int. Cl. Decuzzi et al., "The Effective Dispersion of Nanovectors Within the A61K47148 (2006.01) Tumor Microvasculature," Annals of Biomedical Engineering, 2006, (52) U.S. Cl . .................... 424/78.17; 525/54.1; 977/904; 34(4):633-641. 977/962 Decuzzi et al., "The Receptor-Mediated Endocytosis of Nonspheri- (58) Field of Classification Search ........................ None cal Particles," Biophysical Journal, May 2008, 94:3790-3797. See application file for complete search history. Ferrari, Mauro, "Cancer Nanotechnology: Opportunities and Chal- lenges," Nature Reviews, Mar. 2005, 5:1-11. (56) References Cited Ferrari, Mauro,"Nanovector therapeutics," Current Opinion in Chemical Biology, 2005, 9:343-346. U.S. PATENT DOCUMENTS Freund et al., "The role of binder mobility in spontaneous adhesive contact and implications for cell adhesion," Journal of the Mechanics 4,520,110 A 5/1985 Stryer et al. and Physics of Solids, 2004, 52:2455-2472. 4,888,176 A 12/1989 Langer et al. Ganong, William F., Review of Medical Physiology, 21st ed. New 4,933,185 A 6/1990 Wheatley et al. York: Lange Medical Books/McGraw-Hill Medical Publishing Divi- 5,010,167 A 4/1991 Ron etal. 5,651,900 A 7/1997 Keller et al. sion, 2003, Table of Contents, 9 pages. 5,770,076 A 6/1998 Chu et al. Gao et al., "Mechanics of receptor-mediated endocytosis," PNAS, 5,798,042 A 8/1998 Chu et al. Jul. 5, 2005, 102(27):9469-9474. 5,893,974 A 4/1999 Keller et al. Hanahan et al., "The Hallmarks of Cancer," Cell, Jan. 7, 2000, 5,938,923 A 8/1999 Tu et al. 100:57-70. 6,107,102 A 8/2000 Ferrari 6,858,184 B2 2/2005 Pelrine et al. (Continued) 7,091,041 B2 8/2006 Monahan et al. 2003/0114366 Al 6/2003 Martin et al. Primary Examiner Daniel C Garnett 2003/0205552 Al 11/2003 Hansford et al. (74) Attorney, Agent, or Firm Winstead PC 2004/0064050 Al 4/2004 Liu et al. 2005/0053590 Al 3/2005 Meininger 2005/0095174 Al 5/2005 Wolf (57) ABSTRACT 2006/0105032 Al 5/2006 Lynch et al. A method of formulating a particle composition having a 2007/0066138 Al 3/2007 Ferrari et al. 2007/0299340 Al 12/2007 Liu et al. pre-selected cell internalization mode involves selecting a 2008/0102030 Al 5/2008 Decuzzi et al. target cell having surface receptors and obtaining particles 2008/0206344 Al 8/2008 Decuzzi et al. that have i) surface moieties, that have an affinity for or are FOREIGN PATENT DOCUMENTS capable of binding to the surface receptors of the cell and ii) a preselected shape, where a surface distribution of the sur- WO WO 03/029403 A3 4/2003 face moieties on the particles and the shape of the particles are WO WO 2007/120248 A2 10/2007 WO WO 2008/021908 A2 2/2008 effective for the pre-selected cell internalization mode. WO WO 2008/041970 A2 4/2008 WO WO 2008/067049 A2 6/2008 13 Claims, 4 Drawing Sheets US 8,173,115 B2 Page 2 OTHER PUBLICATIONS Panes et al., "Regional differences in constitutive and induced ICAM-1 expression in vivo," Am. J. Physiol., 1995, Harris et al., "Influenza virus pleiomorphy characterized by 269(6Pt2):H1955-H1964. cryoelectron tomography," PNAS, Dec. 12, 2006, 103(50):19123- Prodan et al., "Low-frequency, low-field dielectric spectroscopy of 19127. living cell suspensions," Journal of Applied Physics, Apr. 1, 2004, Herant et al., "Mechanics of neutrophil phagocytosis experiments 95(7):3754-3756. and quantitative models," Journal of Cell Science, 2006, 119:1903- 1913. Rolland et al., "Direct Fabrication and Harvesting of Monodisperse, Herantetal., "Mechanics ofneutrophilphagocytosis: behavior ofthe Shape-Specific Nanobiomaterials," JACS, Jun. 21,2005,127:10096- cortical tension," Journal of Cell Science, 2006, 118:1789-1797. 10100. Hill, Terrell L., "An Introcution to Statistical Thermodynamics," Simson et al., "Membrane Bending Modulus andAdhesion Energy of 1960, Table of Contents, 5 pages. Wild-Type and Mutant Cells of Dictyostelium Lacking Talin or Hochmuth, Robert M., "Micropipette aspiration of living cells," Jour- Cortexillins," Biophysical Journal, Jan. 1998, 74:514-522. nal of Biomechanics, 2000, 33:15-22. Smith et al., "How Viruses Enter Animal Cells," Science, Apr. 9, Marsh et al., "Virus Entry: Open Sesame," Cell, Feb. 24, 2006, 2004,304:237-242. 124:729-740. Smythe et al., "Actin regulation in endocytosis," Journal of Cell May et al., "Phagocytosis and the actin cytoskeleton," Journal of Cell Science, 2006, 119(22):4589-4598. Science, Mar. 2001, 114(6):1061-1077. Sun et al., "Mechanics of Enveloped Virus Entry into Host Cells," Mukherjee et al., "Endocytosis," Physiol. Rev., Jul. 1997, 77(3):759- Biophysical Journal: Biophsical Letters, 2006, 90:L10-L 12. 803. Tasciotti et al., "Mesoporous silicon particles as amultistage delivery Oberd6rster et el., "Nanotoxicology: An Emerging Discipline Evolv- system for imaging and therapeutic applications," Nature ing from Studies of Ultrafine Particles," Environmental Health Per- Nanotechnology, Mar. 2008, 3:151-157. spectives, Jul. 2005, 113(7):823-839. Taylor, Richard F., Ed., "Protein Immobilization Fundamentals and Paik et al., "Micromachining of mesoporous oxide films for Applications," 1991, 109-110. microelectromechanical system structures," J. Mater. Res., Aug. Vasir et al., "Polymeric nanoparticles for gene delivery," Expert Opin. 2002,17(8):2121-2129. Drug Delivery, 2006, 3(3):325-344 U.S. Patent May 8, 2012 Sheet 1 of 4 US 8,173,115 B2 LL w U Ww U.S. Patent May 8, 2012 Sheet 2 of 4 US 8,173,115 B2 L d/ xewx 00 %D N 01 m — O O O O t e~ i~ X11 M c O d m oLn •~ N 0 y W `- c c N u- c4~ caY ~ 3; a N n ~ LIt .c V r F--I 7 Dl L c V N r — C 4J r F~ O~ O O O O O OI Das ^" 1 S•0 ' o U.S. Patent May 8, 2012 Sheet 3 of 4 US 8,173,115 B2 Nas Mi S'0 0 0 0 0 ° 0 ° Oo °o N N r- r- V1 C7 D n D D T M W h E_ uC C~ N u- Cr V D r- VI w I V 1 (r7 O O O O O O O UP, U.S. Patent May 8, 2012 Sheet 4 of 4 US 8,173,115 B2 l xewx a/ 111 Ln Ln Ln Ch m a% m 00 00 00 O O O O O O O is u1 M c O 0 Ln Y m cr- s ~ ic o c ~ w 0 N X 37 E a F--I LL ~1 .Q CL N 3 s V) s it _r Vi w r Z h~ 7 i r- a' _V 2 c rr G1 a O O O O c Q' c lqr m N wl- Q) Xas m I S'0 US 8,173,115 B2 1 2 PARTICLE COMPOSITIONS WITH A mode, which comprises a) selecting a cell having surface PRE-SELECTED CELL INTERNALIZATION receptors; and b) obtaining particles that have i) surface moi- MODE eties, that have an affinity for or are capable of binding to the receptors, and ii) a shape, wherein a surface distribution of the STATEMENT FOR FEDERALLY FUNDED 5 surface moieties and the shape are effective for the pre-se- RESEARCH lected cell internalization mode for the selected cell. Another embodiment is a method of treating or monitoring This invention was made with government support under a physiological condition comprising administering to a sub- Grant No. W311`4Q-07-1-0008, awarded by Defense ject in need thereof an effective amount of a particle compo- Advanced Research Projects Agency (DARPA); and under 10 sition having a pre-selected cell internalization mode.