Polymer Based Bioresponsive Delivery of Macromolecules
September 1, 2015
Research Personnel: Dr. Ritu Goyal, Manessa Lormejuste, Jamal Keyes (REU summer student)
Collaborator: Dr. David Devore
Funding: Department of Defense
Biological macromolecules including peptides and oligonucleotides are being developed as next generation therapeutics, yet a major barrier to their translation exists: delivery of the active biological macromolecule to cells in a quantity that is biologically effective and in a form that is functionally intact, yet non-toxic. The delivery problem is quite challenging due to the presence of both systemic and cellular barriers and is compounded by the susceptibility of the therapeutics to enzymatic breakdown.
We have developed a family of novel graft copolymers that is designed to overcome both systemic and cellular delivery barriers. The graft copolymers are anionic polyelectrolytes with hydrophobic backbone groups and amphiphilic polyetheramine pendent chains that impart “smart” pH-sensitive behavior. The combination of functional groups provides a balance of hydrophilic and lipophilic properties necessary to keep the nanovectors stable in aqueous environments, protect the bound therapeutic biologics from serum degradation, facilitate their transport through tissues and across cell membranes, and enable their release with high biological activity. GRAPLON is an acronym for self-assembled ternary complexes of GRAft copolymers, cationic Peptides or Liposomes, and Oligonucleotide Nanovectors. GRAPLONs are prepared by self-assembly of the graft copolymer with the therapeutic biologic, which may optionally be encapsulated first in a liposome or peptide complex.
We are using the GRAPLON approach in two distinct applications. The GRAPLON nanovectors were rationally designed and developed initially for the delivery of antisense oligonucleotides and short interfering RNA, both of which are capable of performing therapeutic gene silencing. We have utilized GRAPLONs adsorbed onto liposomes to deliver antisense molecules silencing the bcl-2 oncogene in multiple cell types and in xenograft ovarian carcinomas in vivo. We have also used them to deliver siRNA to glioma cancer stem cells (CSCs) as probes to interrogate the CSC microenvironment and potentially provide novel avenues of therapy. In addition, we have utilized GRAPLONs directly with cationic peptides to provide protection from enzymatic degradation and controlled release for wound healing antibacterial therapy.