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