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Advanced Therapeutics LaboratoryCraig Duvall, Ph.D.
Associate Professor, Biomedical EngineeringVanderbilt University, Nashville, Tennessee, USA
Breast Cancer TherapiesDOD BCRP & NIH NCI R01
Vascular Graft TherapiesNIH NHLBI R01
Improved siRNA Polyplex Chemistries for In Vivo Gene Knockdown
Scaffolds and Cell DeliveryNSF CAREER & NIH NIBIB R01
siRNA Lipid Conjugates for Carrier-Free Gene Silencing
Overview
“RAFT” Polymerization Allows Rational Design of Diverse Polymers
Scaffoldsfor large tissue defects
Microspheresfor local, controlled
drug release
Nanoparticlesfor intracellular
biologic drug delivery
Polymeric Materials to TackleMulti-Scalar Drug Delivery Challenges
ROS-Responsive Materials Match Degradation to Tissue Infiltration
Polymer-enhanced Peptide Drug Delivery Prevents Vascular Graft Failure
In Vivo Luciferase Knockdown
Days
CellularInternalization
pH-triggered Endosomal Escape
Intracellular Release
Clinical Application
Nanoparticle Formulation Intracellular DeliverypH-responsive
Polymer
TherapeuticPeptide
ElectrostaticComplexation
Local Delivery of siRNA Modulates Tissue Healing The Advanced Therapeutics Laboratory focuses on
the design and applications of novel polymer-based materials for drug delivery
Improved Graft Patency
Vein graftharvest
Ex vivo treatment
SurgicalImplantation
Galectin-8 recruitment shows real time endosomal escape
Pept
ide
Nan
opar
ticle
0 min 60 min
Endosome Escape Screening
ROS-Shielding Hydrogels for Therapeutic Cell Delivery
Local Degradation Environmental Activation
Thermal GelationpH Responsive Hydrophobicity
Allows Many Polymer Backbone Architectures
Defined End Groups for Pre- or Post-Polymerization Conjugates
RAFT Chain Transfer Reagent Polymer
Initiator
Monomer (M)
= R Group = Z Group
“Smart” polymers can respond to changes in temperature, pH, reactive oxygen species, enzymes, and more!
PDN Hydrogels Solidify Upon Heating
CDMRPBCRP & PRORP
11 Fellowshipssince 2010
Osteoarthritis TherapiesDOD PRORP
Intra-articular Drug Delivery Treats Osteoarthritis
Cartilage Damage (CII680)
(x107)
5
8
PPS-
MS
Salin
e
PPSPoly(Propylenesulfide)
Emulsion
Antioxidant Microspheres
Antibody Conjugated Nanoparticles Target Damaged Cartilage
Antioxidant Microspheres Provide Local Sustained Drug Delivery
No
rma
lize
dM
MP
-13
E
xp
res
sio
n
No
Tx
mA
bC
II N
P
Ba
re N
P
No
Tx0 .0
0 .5
1 .0
1 .5
+ O A
* *
*
Intracellular Deliveryof siRNA
Targeted Accumulation in Joint Space
YFP
Gal8
Glycan
Gal8
YFP
Endosomal Membrane Intact; Gal8 binding blocked
EndosomalMembrane Disrupted; Gal8 binds and induces punctate fluorescence
Gal8-YFPReporter Cell
Endosome
Endosome
Gal8-YFPReporter Cell
Alkyl Side Chains Modulate pH-dependent Hemolysis
Graft Copolymer Library for Structure-Function Characterization
PBS pAA 70:30 Octyl
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