Presentation Title

Microgel Core/Shell Architectures for Targeted Delivery of Thrombolytic Agents

Location

Room 2904 B

Session Format

Paper Presentation

Research Area Topic:

Natural & Physical Sciences - Chemistry

Co-Presenters, Co- Authors, Co-Researchers, Mentors, or Faculty Advisors

Dr. Andrew Lyon

Abstract

(for a powerpoint presentation)

The design of targeted methodologies for delivery of fibrinolytic agents such as plasminogen activators, to intravascular thrombi for clot dissolution via lysis of the fibrin network, has gained interest for several years. This is primarily because off target effects of these agents can cause hemorrhagic conditions due to their effects on circulating plasminogen. The work presented here involves the development of microgel constructs for targeted delivery of tissue plasminogen activator (tPA).

Microgels or hydrogel microparticles have been demonstrated to be useful for the encapsulation and delivery of therapeutics like siRNA and growth factors1,2. They are advantageous for biological applications because of their versatility with respect to size, functionality, architecture and biocompatibility. The polymer-based microgels used in this project were synthesized primarily from the monomer N-Isopropylmethacrylamide in three size ranges, with hydrodynamic diameters of approximately 200 nm, 800 nm and 1.2 µm as measured by Dynamic Light Scattering (DLS). Differential localization of microgels within the clot based on dissimilarities between clot porosity and microgel dimensions can cause differential clot lysis, making it crucial to study microgels of different sizes. The microgels were synthesized to generate a core/shell architecture, and the shell was synthesized with acrylic acid (AAc) as a co-monomer to facilitate bioconjugation. Atomic Force Microscopy on the microgels revealed their spherical profile and DLS measurements demonstrated their pH responsivity, thus verifying the incorporation of AAc. The microgels were then conjugated to two different fibrin-specific peptides (cysteine terminated knob ‘A’ and knob ‘B’ peptide mimics) via a maleimide containing cross-linker. Current studies involve further characterization of the microgels along with experiments relating to flow of the microgel solutions through a fibrin clot followed by analysis of the eluent to elucidate differences in residence of the microgels within the clot. Additionally, microfluidic experiments are being conducted to observe a concentration gradient of the microgels as they flow through the clot. Parallel studies comprise production of positively charged Green Fluorescent Protein for examining loading and release from the microgels as a proof of concept, following which similar investigations with tPA will be done. Future work will involve studies of clot degradation over time using tPA loaded, targeting peptide-decorated microgels.

  1. Dickerson, E. B. et al. (2010). BMC CANCER 10
  2. Kim, P. H. et al. (2014). J CONTROL RELEASE 187: 1-13

Keywords

Microgels, Core, Shell, Fibrin, Targeted thrombolytic therapy, Microgel localization

Presentation Type and Release Option

Presentation (Open Access)

Start Date

4-24-2015 9:30 AM

End Date

4-24-2015 10:30 AM

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Apr 24th, 9:30 AM Apr 24th, 10:30 AM

Microgel Core/Shell Architectures for Targeted Delivery of Thrombolytic Agents

Room 2904 B

(for a powerpoint presentation)

The design of targeted methodologies for delivery of fibrinolytic agents such as plasminogen activators, to intravascular thrombi for clot dissolution via lysis of the fibrin network, has gained interest for several years. This is primarily because off target effects of these agents can cause hemorrhagic conditions due to their effects on circulating plasminogen. The work presented here involves the development of microgel constructs for targeted delivery of tissue plasminogen activator (tPA).

Microgels or hydrogel microparticles have been demonstrated to be useful for the encapsulation and delivery of therapeutics like siRNA and growth factors1,2. They are advantageous for biological applications because of their versatility with respect to size, functionality, architecture and biocompatibility. The polymer-based microgels used in this project were synthesized primarily from the monomer N-Isopropylmethacrylamide in three size ranges, with hydrodynamic diameters of approximately 200 nm, 800 nm and 1.2 µm as measured by Dynamic Light Scattering (DLS). Differential localization of microgels within the clot based on dissimilarities between clot porosity and microgel dimensions can cause differential clot lysis, making it crucial to study microgels of different sizes. The microgels were synthesized to generate a core/shell architecture, and the shell was synthesized with acrylic acid (AAc) as a co-monomer to facilitate bioconjugation. Atomic Force Microscopy on the microgels revealed their spherical profile and DLS measurements demonstrated their pH responsivity, thus verifying the incorporation of AAc. The microgels were then conjugated to two different fibrin-specific peptides (cysteine terminated knob ‘A’ and knob ‘B’ peptide mimics) via a maleimide containing cross-linker. Current studies involve further characterization of the microgels along with experiments relating to flow of the microgel solutions through a fibrin clot followed by analysis of the eluent to elucidate differences in residence of the microgels within the clot. Additionally, microfluidic experiments are being conducted to observe a concentration gradient of the microgels as they flow through the clot. Parallel studies comprise production of positively charged Green Fluorescent Protein for examining loading and release from the microgels as a proof of concept, following which similar investigations with tPA will be done. Future work will involve studies of clot degradation over time using tPA loaded, targeting peptide-decorated microgels.

  1. Dickerson, E. B. et al. (2010). BMC CANCER 10
  2. Kim, P. H. et al. (2014). J CONTROL RELEASE 187: 1-13