ABSTRACT
Herein, we present the design, synthesis, and characterization of fully degradable, hybrid, star-branched dendritic polyols. First multiarmed polyphosphazenes were prepared as a star-branched scaffold which upon functionalization produced globular branched hydroxyl-functionalized polymers with over 1700 peripheral functional end groups. These polyols with unique branched architectures could be prepared with controlled molecular weights and relatively narrow dispersities. Furthermore, the polymers are shown to undergo hydrolytic degradation to low molecular weight degradation products, the rate of which could be controlled through postpolymerization functionalization of the phosphazene backbone.
ABSTRACT
The chemical synthesis and biological activity of novel functionalized imidazoquinoline derivatives (ImQ) to generate Toll-like receptor (TLR) 7/8 specific prodrugs are presented. In vivo activity of ImQs to induce inflammation was confirmed in zebrafish larvae. After covalent ligation to fully biodegradable polyphosphazenes (ImQ-polymer), the macromolecular prodrugs were designed to undergo intracellular pH-sensitive release of ImQs to induce inflammation through binding to endosomal TLR7/8 (danger signal). We showed ImQ dissociation from prodrugs at a pHâ 5 pointing towards endosomal prodrug degradability. ImQ-polymers strongly activated ovalbumin-specific Tâ cells in murine splenocytes as shown by increased proliferation and expression of the IL-2 receptor (CD25) on CD8+ Tâ cells accompanied by strong IFN-γ release. ImQ prodrugs presented here are suggested to form the basis of novel nanovaccines, for example, for intravenous or intratumoral cancer immunotherapeutic applications to trigger physiological antitumor immune responses.
Subject(s)
Prodrugs/chemistry , Toll-Like Receptor 7/antagonists & inhibitors , Toll-Like Receptor 8/antagonists & inhibitors , Animals , Animals, Genetically Modified/metabolism , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/metabolism , Dendritic Cells/cytology , Dendritic Cells/drug effects , Dendritic Cells/metabolism , Hydrogen-Ion Concentration , Inflammation/etiology , Interferon-gamma/metabolism , Larva/drug effects , Larva/metabolism , Mice , Microscopy, Confocal , NF-kappa B/metabolism , Prodrugs/chemical synthesis , Prodrugs/toxicity , Quinolines/chemical synthesis , Quinolines/chemistry , Quinolines/toxicity , Receptors, Interleukin-2/genetics , Receptors, Interleukin-2/metabolism , Toll-Like Receptor 7/metabolism , Toll-Like Receptor 8/metabolism , Zebrafish/growth & developmentABSTRACT
A novel series of peptide based hybrid polymers designed to undergo enzymatic degradation is presented, via macrosubstitution of a polyphosphazene backbone with the tetrapeptide Gly-Phe-Leu-Gly. Further co-substitution of the hybrid polymers with hydrophilic polyalkylene oxide Jeffamine M-1000 leads to water soluble and biodegradable hybrid polymers. Detailed degradation studies, via 31P NMR spectroscopy, dynamic light scattering and field flow fractionation show the polymers degrade via a combination of enzymatic, as well as hydrolytic pathways. The peptide sequence was chosen due to its known property to undergo lysosomal degradation; hence, these degradable, water soluble polymers could be of significant interest for the use as polymer therapeutics. In this context, we investigated conjugation of the immune response modifier imiquimod to the polymers via the tetrapeptide and report the self-assembly behavior of the conjugate, as well as its enzymatically triggered drug release behavior.
