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Nanostructured Materials for Long Acting Biologic Delivery
Tejal A. Desai, PhDErnest L Prien Professor and ChairDirector, UCSF Engineering and Applied Sciences InitiativeDept. of Bioengineering and Therapeutic Sciences
7 February 2020
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Conflicts
Zordera, Inc. VasaRx, Inc.
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Therapeutic biomaterials for mitigating disease
• Drug Delivery and Targeting
• Cell Therapy and Immune Modulation
• Implants and Drug/Device combinations
We design and fabricate micro and nanomaterial solutions for:
The Desai Laboratory for Therapeutic Microtechnology and Nanotechnology
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TopographyDevices
Thin FilmsNanoparticles
The Desai Laboratory for Therapeutic Microtechnology and Nanotechnology
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Can we use material “structure” to achieve long
term biologic delivery?
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Age-related Macular Degeneration
Major cause of vision impairment in elderly Significant visual impact to fine detail 2.07 million individuals affected in US
Normal Vision Degenerated Macula
National Eye Institute, Age-Related Macular Degeneration (AMD) Data and Statistics; www.nei.nih.gov
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Wet-AMD Therapeutics – Disrupting VEGF
Lucentis (ranibizumab)~48kDa antibody fragment
0.5 mg injection monthly
First intraocular injection for wAMD
Binds and inhibits VEGF-A
Eylea (aflibercept)~115kDa fusion protein
After loading dose, 2 mg injection bimonthly
VEGF-R1 & VEGF-R2 extracellular domains + IgG1 Fc
Avastin (bevacizumab)~150kDa antibody
1.25 mg injection monthly
used off label
cost-effective alternative to Lucentis/Eylea
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Clinical Need for Better Delivery Systems for wet-AMD
Current therapies all use intravitrealinjection- On average patients dosed 7.7 times per year- Peaks and troughs lead to poorer outcomes- Repeated injection results in risk of infection,
retinal detachment, and cataracts- Maximum dose is limited by inflammation
and elimination from eye
Requirements?- extended delivery duration (at least 4-6 mos)- A large drug depot- Syringe deployable- Device degrades at the end of use (no explant)
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Concentration Dependent Delivery
“Single File”Constrained Delivery
Pore Size > Molecular Size Pore Size ~ Molecular Size
Achieving Constant Rate Delivery: Tuning the pore size
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Modeling Device Pharmacokinetics
Continuous delivery can sustain therapeutic concentrations with equivalent payloads
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Polycaprolactone Thin Films
Three core film types- Non-porous- Microporous (PEG porogen)- Nanoporous (ZnO Template)
27 January 2020
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Device Fabrication
Can be flat, packet/sachet, cylindrical Load liquid, powder, compressed drug pellet
27 January 2020
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Nanostructured films enable linear release kinetics for range of proteins
Bernards DA, 2012, Lance K et al, 2015
k0 ≈ 1.6 ug/day
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Thin Film Devices for Eyelea (anti-VEGF)
Schlesinger et al., DDTR 2019
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Ocular tolerability
• Post-implantation inflammation
- resolved 2-3 weeks
• No glaucoma or cataract formation seen
• Retina: no biomicroscopic or OCT abnormalities
Overall, intravitrealdevices well-tolerated over study period
McDonald-Shattuck score
IOP
mm
Hg
Flar
e ph
otom
etry
day
0da
y 28
day
56da
y 70
da
y 84
African green monkeys6 test eyes (drug device)8 placebo eyes (sucrose/PEG device)
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Challenges in Glaucoma Drug Delivery
Studies show 50% of patients are not adherent over 75% of the time
Risk population (high age) have difficulty following dosing regimen and properly using eye droppers
1) Patient Compliance 2) Physiological Barriers
Robin et al (2011) & Zhang et al (2012)Layers of the cornea
(CRFA & Robertson et al, 2005)
Tight junctional complexes retard paracellular drug permeation
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Kim K et al., Investigative ophthalmology & visual science 57 (10), 4341-4346; Kim J et al. Evaluation of polycaprolactone implant for long-term treatment of glaucoma: pilot study, JCR
In vitro
Glaucoma : intracameral device (DE-117)In vivo
Jean Kim 1
Cornea112244814262.283.96688.576.242.3Iris-ciliary body112244813634.915919228430086.4Vitreous humor11224481.554.260.691999999999999950.677000000000000051.421.39Retina-choroid11224487.81999999999999762.823.214.410.66.968.81
Time [weeks]
DE-117 [ng/g or ng/mL]
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Intracameral Device for Glaucoma:Combination therapy: timolol and brimonodine
Timolol BrimonidineRelease rate (µg/day) 2.09 ± 0.04 0.60 ± 0.02Target rate (µg/day) 3.00 0.90
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Scaling Down
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What else can we do with thin film delivery?
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Chiang N, Serhan CN. Mol. Asp. Med. 2015
Specialized Lipid Mediators (SPM) Drive Resolution
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Vascular Effects of SPM
Reduced chemotaxis/migration of VSMC Reduce cytokine-stimulated leukocyte adhesion to EC, VSMC Reduce cytokine stimulated NF-kB activation and downstream
inflammatory gene expression Reduce cytokine stimulated ROS generation Modest anti-proliferative effects in VSMC
Ho KJ et al; Am J Pathology 2010 Akagi D et al. FASEB J 2015
Miyahara T et al ; FASEB J 2013 Wu B et al. J Vasc Surg 2016
Chatterjee A et al; PLoS One 2014 Lance K et al. J Biomed Mater Res A 2016
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SPM-Eluting Biodegradable Film
Locally deliver SPM to sites of surgical/vascular injury to enhance repair
Developed a thin (e.g.
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Sustained and directional elution of RvD1 from a biodegradable wrap
Directional ElutionSustained Elution
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Wu B, et al J Vasc Surg 2016
Angio veh-gel
Perivascular delivery of SPM in an acute arterial injury model (rat)
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Bypass Only Veh Gel RvD1 Gel Veh Wrap RvD1 Wrap
Wu B, et al. J Vasc Surg 2018; 68 (6S):188S-200S
Local RvD1 Treatment Reduces Vein Graft Hyperplasia -Rabbit Carotid Interposition Graft at 28 days
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Can we design materials to modulate the local immune
environment long term?
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Features vs. Challenges
Small signaling protein
Received interest in for
cancer & autoimmune
disease
Short half-life
Not bioavailable
Pleiotropic>30% require hospitalization
IFNγTNFαIL-2
Local Immune Activation via Cytokine Therapy
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Endogenous cytokine complexes with
antibody
Localized, cell specific
activationCellular influx
Loose networkformation
Subcutaneous injection
T= 0 T= minutes
T= hours T= days
- Receptor A
- Receptor B
a b c d
Nanostructures as an injectable cytokine trap
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Sprent et al., 2012
Can we use this strategy to activate T cells specifically and locally?
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Conjugated Nanowire Fabrication
Zamecnik et al., ACS Nano 2017.
Scale Bar 20μm
45 kDa PCL is blended with short chain PCL containing a maleimide end groups
a
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Lymph Node
Na
no
wi r
es
Ab
Na
no
wi r
es
Ab
on
l y
0
1 0
2 0
3 0
4 0
%K
i6
7+
N a t u r a l K i l l e r
* * * p < 0 . 0 0 0 1
Na
no
wi r
es
Ab
Na
no
wi r
es
Ab
on
l y
0
2 0
4 0
6 0
8 0
%C
D1
22
+
C D 8
* * p < 0 . 0 0 5 * p < 0 . 0 5
Na
no
wi r
es
Ab
Na
no
wi r
es
Ab
on
l y
4 0
5 0
6 0
7 0
8 0
%C
D2
5+
T r e g
Na
no
wi r
es
Ab
Na
no
wi r
es
Ab
on
l y
0
1 0
2 0
3 0
4 0
5 0
%K
i6
7+
N a t u r a l K i l l e r
Na
no
wi r
es
Ab
Na
no
wi r
es
Ab
on
l y
0
2
4
6
8
%C
D1
22
+
C D 8
* p < 0 . 0 0 3
* p < 0 . 0 5
Na
no
wi r
es
Ab
Na
no
wi r
es
Ab
on
l y
4 0
4 5
5 0
5 5
6 0
6 5
%
CD
25
+
T r e g
SkinIL-2S4B6
Strong signal Weak signal
CD122 + CD25
CD8 Memory T cells, NK
Cells
Regulatory T Cells
CD122
S4B6 antibody-conjugated wires locally activate NK and CD8 Cells in vivo
Zamecnik et al., ACS Nano 2017.
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T-reg specific nanowires for autoimmune applications
Zamecnik et al., Biomaterials 2019
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Nanorods persist in vivo for >6 weeks
2 week 4 week 6 week
DAPI
F4/80
NWs
Scale bar -100μm
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Decreased epithelial hyperplasia and myeloid infiltrate observed in vivo
Zamecnik et al., Biomaterials 2019.
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Harnessing micro- and nanoscale cues for therapy
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Acknowledgements
• NIH • NSF• JDRF• Thome Foundation• Al Mann Institute• CIRM• Eli Lily• SPARC
The Therapeutic Micro and Nanotechnology Laboratory
Nanostructured Materials for Long Acting Biologic DeliveryConflictsThe Desai Laboratory for Therapeutic Microtechnology and NanotechnologySlide Number 4Can we use material “structure” to achieve long term biologic delivery?Age-related Macular DegenerationWet-AMD Therapeutics – Disrupting VEGFClinical Need for Better Delivery Systems for wet-AMD Achieving Constant Rate Delivery: Tuning the pore sizeModeling Device Pharmacokinetics�Polycaprolactone Thin FilmsDevice FabricationNanostructured films enable linear release kinetics for range of proteinsThin Film Devices for Eyelea (anti-VEGF)�Ocular tolerabilityChallenges in Glaucoma Drug DeliveryGlaucoma : intracameral device (DE-117)Intracameral Device for Glaucoma:�Combination therapy: timolol and brimonodineScaling DownWhat else can we do with thin film delivery?Specialized Lipid Mediators (SPM) Drive ResolutionVascular Effects of SPMSPM-Eluting Biodegradable FilmSustained and directional elution of RvD1 from a biodegradable wrapPerivascular delivery of SPM in an acute arterial injury model (rat)Local RvD1 Treatment Reduces Vein Graft Hyperplasia -Rabbit Carotid Interposition Graft at 28 daysCan we design materials to modulate the local immune environment long term?Local Immune Activation via Cytokine TherapyNanostructures as an injectable cytokine trapCan we use this strategy to activate T cells specifically and locally?�Conjugated Nanowire Fabrication S4B6 antibody-conjugated wires locally activate NK and CD8 Cells in vivoT-reg specific nanowires for autoimmune applicationsNanorods persist in vivo for >6 weeks�Decreased epithelial hyperplasia and myeloid infiltrate observed in vivoHarnessing micro- and nanoscale cues for therapy�Acknowledgements