Associate Professor, Biomedical Engineering … · Associate Professor, Biomedical Engineering....

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Advanced Therapeutics Laboratory Craig Duvall, Ph.D. Associate Professor, Biomedical Engineering Vanderbilt University, Nashville, Tennessee, USA Breast Cancer Therapies DOD BCRP & NIH NCI R01 Vascular Graft Therapies NIH NHLBI R01 Improved siRNA Polyplex Chemistries for In Vivo Gene Knockdown Scaffolds and Cell Delivery NSF CAREER & NIH NIBIB R01 siRNA Lipid Conjugates for Carrier-Free Gene Silencing Overview “RAFT” Polymerization Allows Rational Design of Diverse Polymers Scaffolds for large tissue defects Microspheres for local, controlled drug release Nanoparticles for intracellular biologic drug delivery Polymeric Materials to Tackle Multi-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 Cellular Internalization pH-triggered Endosomal Escape Intracellular Release Clinical Application Nanoparticle Formulation Intracellular Delivery pH-responsive Polymer Therapeutic Peptide Electrostatic Complexation 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 graft harvest Ex vivo treatment Surgical Implantation Galectin-8 recruitment shows real time endosomal escape Peptide Nanoparticle 0 min 60 min Endosome Escape Screening ROS-Shielding Hydrogels for Therapeutic Cell Delivery Local Degradation Environmental Activation Thermal Gelation pH 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 CDMRP BCRP & PRORP 11 Fellowships since 2010 Osteoarthritis Therapies DOD PRORP Intra-articular Drug Delivery Treats Osteoarthritis Cartilage Damage (CII680) (x10 7 ) 5 8 PPS-MS Saline PPS Poly(Propylenesulfide) Emulsion Antioxidant Microspheres Antibody Conjugated Nanoparticles Target Damaged Cartilage Antioxidant Microspheres Provide Local Sustained Drug Delivery Normalized MMP-13 Expression No Tx mAbCII NP Bare NP No Tx 0.0 0.5 1.0 1.5 +OA ** * Intracellular Delivery of 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-YFP Reporter Cell Endosome Endosome Gal8-YFP Reporter Cell Alkyl Side Chains Modulate pH-dependent Hemolysis Graft Copolymer Library for Structure-Function Characterization PBS pAA 70:30 Octyl

Transcript of Associate Professor, Biomedical Engineering … · Associate Professor, Biomedical Engineering....

Page 1: Associate Professor, Biomedical Engineering … · Associate Professor, Biomedical Engineering. Vanderbilt University, Nashville, Tennessee, USA. Breast Cancer Therapies. ... Ex vivo

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