Embed Size (px)
Citation preview
Keith Johnston Research GroupNanomaterials Chemistry/Colloid and Interface Science/Polymer Science
Protein stability and drug delivery
Morphology and protein-protein interactions
Rheology: subcutaneous injection
Adv. Functional Nanomaterials
(metals and metal oxides/polymers)Control morphology/crystallinity via nucleation/growth in sol’n
Colloidal stability (ligands and polymers on the surface)
Optical, magnetic, electrocatalytic properties = f (morphology)
Biodegradable photonic Au nanoclusters for cancer imaging
Nanoparticle Interact. with Liq. and Solid InterfacesOil/water and gas/water interfaces (emulsions and foams)
Solid surfaces (adsorption and transport in porous media)Φ(h)
h
vdW, depletion
attr.
elect. rep.
steric
5 n m5 n m
CollaboratorsTom Truskett, Nate LyndKostia Sokolov (Photonic nps- imaging)Keith Stevenson (Electrochemistry)
Masha Prodanovic, David DiCarlo George Hirasaki, Quoc Nguyen (Petr. Eng.)
Subcutaneous injection (SC) of concentrated monoclonal antibodies at 300 mg/ml is a major drug delivery challenge
• >20% of all biopharmaceuticals in clinical trials are mAbs
• cancer, allergies, asthma, inflammatory diseases, cardiovascular diseases, infectious diseases, etc.
• At high conc. spacings are small – specific short-ranged attraction cause association and high viscosity
– Hydrogen bonds, anisotropic elect. attraction
– Hydrophobic interactions
Agrawal et al, mAbs (16)Fukuda et al., Pharm Res (2015), Lilyestrom et al., JPCB (2013), Buck, et al., Mol Pharm (2012)
Name Indication Company Conc.ACTEMRA RA, juvenile arthritis Genetech 180mg/mL
Herceptin Breast and gastric cancer Roche 120 mg/mL
Static light scattering
Fv domains: light chain on left sideRed: exposed negative patches
Use co-solutes to mitigate attractive interactions to lower viscosity up to 10 x
3
1
10
100
1000
50 100 150 200 250 300
Vis
co
sit
y (
cP
)
mAb concentration (mg/mL)
15:40 His(HCl):Mannitol
DI water
40:50:17 Tre:His:CitrA
50:50:12 Tre:His:PhosA
Co-solute
Monomer solutionNetwork solution with
interaction sites
Agrawal et al, mAbs (16)), Shukla et al., JPCB (11), Hung et al., J Membr. Sci. (16)
• Local anisotropic electrostatic attraction• Hydrophobic interactions• Depletion attraction
Trehalose
Arginine Histidine
Research Goals• Characterize protein morphology, protein-protein interactions and
network structure for 200-250+ mg/mL mAb
– Static structure: SAXS/SANS, DLS, SLS, cryo-TEM/SEM
– Dynamic structure: DLS, shear and oscillatory rheology
– MD simulations
• Relate viscosity/stability to protein morphology and interactions
– Prot.-prot. interactions : (SAXS/SANS), kD (DLS), B22 (SLS), ζ-Potential
– Conformational stability: Diff. scanning calorimetry, circular dichroism
– Effect of mAb structure, pH, and ionic strength
– Develop design rules for cosolutes to achieve low viscosity (10 – 20 cP) and high stability
• Sponsors: NSF Inspire, Abbvie, Pfizer, Merck
4
Proposed: SAXS- Determine interactions from structure factor S(q) using 12 bead model for form factor P(q)
Godfrin, et al., JPCB (2016)
• Viscosity incr. by network formation of dimers w/ added salt. Dimer Conformations
0
0.001
0.002
0.003
0.004
0.005
0.006
0.001 0.01 0.1
I(q
)/c
Scattering Vector (A-1)
mAb1: 200 mg/ml
No Co-soluteEffective Co-soluteIneffective Co-solute
𝐼 𝑞 = 𝑐 ∗ Δρ 2 ∗ 𝑃 𝑞 ∗ 𝑆(𝑞)
Reversible Gold Nanoclusters for Imaging/Therapy
• Reversible equilibrium control of cluster size: self-limited growth
• NIR active nanoclusters with small particle spacing
• Design reversibility and lack of protein adsorption for clearance
Johnston, Sokolov, Truskett, Stover, Moaseri: ACS Nano (13), JACS (13), JPChem (14), Langmuir (16)
7
10
15
20
25
30
35
40
45
50
55
1 2 3 4 5 6
Hyd
rod
ynam
ic D
iam
ete
r(n
m)
Equilibrium Point
Growth of 16 nm Magnetic Nanoparticles with High Crystallinity to Yield Magnetic Susceptibility of 4!
Precise control over particle nucleation/growth to control particle size and crystallinity
Fe(CH3COO)2 dissociates rapidly at 210 C: high supersat.
for focused size distribution
crit. size is small for high monomer conc.
small particles grow faster than large onesarrest growth in focusing region
Applications: imaging- subsurface and biomedical, magnetic separations, sensors
3
𝜒𝑖 =𝑀
𝐻=𝜖𝜇0𝜋𝑀𝑑
2𝐷𝑝3
18𝑘𝐵𝑇
5 n m5 n m
Characterization: XRD (cryst. Structure), TEM: part. size, Mossbauer spectroscopy (Fe valence)
Colloidal stability of inorganic/polyelectrolyte hybrids at high salinity: grafting polymers from, to, and through
Reversible addition-fragmentation chain-transfer (RAFT) polymerization with “controlled” MW distribution
NH2
NH2
NH2H2N
H2N
NH2
NH2
H2N
Silica NP (20-30 nm)
0
20
40
60
80
100
120
0.000001 0.00001 0.0001 0.001 0.01 0.1 1 10
Hyd
rod
yn
am
ic D
iam
ete
r (nm
)
Ionic Strength (M)
-
-
--
-
-
--
-
-
--
--
----
--
-
-
-
-
-
-
-
-
-
--
-
-
-+ +
-
-+ +
Limited collapse for Ca2+ at high conc. and thus colloidal stability
10
Wormlike Micelles Impart Viscoelasticity for Ultra Dry Foams
Catanionic micelles:Jamming: slow drainage maintains thick lamellaeFameau et al., Ang. Chem. (11)
Stable foams at only 2% water: low drainage of viscoelastic lamellaethicker lamellae resist Ostwald ripening and coalescence
• 208 trillion m3 of CH4 in shale (world)• 2~5 million gallons of water/well for
disposal
0
20
40
60
80
100
120
140
67 77 87 97
Ap
pare
nt
Vis
co
sit
y c
P
Foam Quality %
90°C
50°C
Hardin, Johnston, K.P. et al. ; Highly Active LaNiO3, J. Phys. Chem. Let. 2013, Mefford, Hardin, Johnston, K.P. et al. ; LaMnO3 Pseudocapacitor, Nature Mater. 2014Hardin, Mefford, Johnston, K.P. et al. ; Perovskite Active Site Variation, Chem. Mater. 2014, Nature Comm. 2016
Oxygen Evolution Reaction (OER)4OH- → 2H2O + 4e- + O2
Nanostructured Perovskite Oxides for Electrocatalysis:
batteries, supercapacitors, water splitting
Subst. of Sr2+ for La3+ creates O vacancies: high covalency of Co-O bond
OER rate correlated to O vacancy conc.
Novel paradigam for supercapacitors: OH- vacancy mediated redox
supercapacitance
High Surface Area to raise activity
Metal 3d and Oxygen 2p density of states should overlap!
Destination of PhD Students
• Gupta Auburn
• Balbuena Texas A + M
• Meredith Ga. Tech.
• Yates U. Rochester
• Da Rocha Virginia Tech.
• Lee U. S. California
• Ziegler U. Florida
• Lu Nat. Univ. Singapore
• Elhag Petroleum Inst. (Abu Dhabi)
• Shah Pfizer• Pham Sematech• Chen Abbott• Dickson Exxon-Mobil• Smith Exxon-Mobil• Overhoff Schering-Plough• Engstrom Bristol-Meyers-Squibb• Matteucci Dow• Gupta Exxon-Mobil• Tam Bristol-Meyers-Squibb• Patel Lam Research• Ma Dupont• Miller Medimmune• Slanac Dupont• Murthy Roche• Chen Dow• Xue Ecolab• Borwankar Bristol-Meyers-Squibb• Worthen Exponent
Protein therapeuticsJessica HungBart [email protected]
Gold imaging nanoclustersEhsan [email protected]
Subsurface nanotechnologyCarson DaChola DandamudiShehab [email protected]
Energy storage (electrochemistry)Will HardinCaleb [email protected]
NSF Inspire ProgramDOE CFSES, DOE NETLAdvanced Energy Consortium, AbbVie,Pfizer, Merck
Welch FoundationAbu Dhabi Nat. Oil. Co.GOMRI, NSF CBET,NIH
• K. Y. Yoon et al., Control of magnetite primary particle size in aqueous dispersions of nanoclusters for high magnetic susceptibilities. Journal of Colloid and Interface Science 462, 359 (Jan 15, 2016).
• Z. Xue et al., Ultradry Carbon Dioxide-in-Water Foams with Viscoelastic Aqueous Phases. Langmuir 32, 28 (Jan 12, 2016).
• A. J. Worthen, V. Tran, K. A. Cornell, T. M. Truskett, K. P. Johnston, Steric stabilization of nanoparticles with grafted low molecular weight ligands in highly concentrated brines including divalent ions. Soft Matter 12, 2025 (2016).
• E. E. Urena-Benavides et al., Low Adsorption of Magnetite Nanoparticles with Uniform Polyelectrolyte Coatings in Concentrated Brine on Model Silica and Sandstone. Ind. Eng. Chem. Res. 55, 1522 (2016).
• R. J. Stover et al., Formation of Small Gold Nanoparticle Chains with High NIR Extinction through Bridging with Calcium Ions. Langmuir 32, 1127 (2016).
• J. T. Mefford, W. G. Hardin, S. Dai, K. P. Johnston, K. J. Stevenson, Anion charge storage through oxygen intercalation in LaMnO3 perovskite pseudocapacitor electrodes. Nat. Mater. 13, 726 (2014).
• W. G. Hardin et al., Tuning the Electrocatalytic Activity of Perovskites through Active Site Variation and Support Interactions. Chem. Mater. 26, 3368 (2014).
• L. M. Foster et al., High Interfacial Activity of Polymers "Grafted through" Functionalized Iron Oxide Nanoparticle Clusters. Langmuir 30, 10188 (2014).
• A. K. Murthy et al., Charged Gold Nanoparticles with Essentially Zero Serum Protein Adsorption in Undiluted Fetal Bovine Serum. Journal of the American Chemical Society 135, 7799 (2013).
• A. K. Murthy et al., Equilibrium Gold Nanoclusters Quenched with Biodegradable Polymers. ACS Nano 7, 239 (2013).
• A. U. Borwankar et al., Tunable equilibrium nanocluster dispersions at high protein concentrations. Soft Matter 9, 1766 (2013).
• M. A. Miller et al., Antibody nanoparticle dispersions formed with mixtures of crowding molecules retain activity and In Vivo bioavailability. J. Pharm. Sci. 101, 3763 (Oct, 2012).
• K. P. Johnston et al., Concentrated Dispersions of Equilibrium Protein Nanoclusters That Reversibly Dissociate into Active Monomers. ACS Nano 6, 1357 (Feb, 2012).
