Multifunctional Dendritic Sialopolymersomes as Potential Antiviral Agents: Their Lectin Binding and Drug Release Properties

Abstract

Polymer vesicles, commonly referred to as polymersomes, are self-organized materials that result from the self-assembly of amphiphilic copolymers in solution. Recently, there has been increasing interest in biomedical applications of polymersomes due to the different functions that can be imparted through encapsulation of molecules within the core or membrane or through the introduction of bioactive molecules to the polymersome surface. We describe here the development and study of poly(ethylene oxide)-polycaprolactone polymersomes designed to interact with influenza viruses at two different stages in the infection process. First, the conjugation of the sialic acid N-acetylneuraminic acid (Neu5Ac) to the polymersome surface was designed to inhibit the binding of viral hemagglutinin to sialic acids on host cells, thus preventing viral entry. Second, the incorporation of the neuraminidase inhibitor zanamivir into the polymersome core was designed to prevent the release of progeny virus from the host cells, thus inhibiting viral replication. With the aim of maximizing multivalent effects at the polymersome surface, polyester dendrons functionalized with Neu5Ac were synthesized and conjugated to polymersomes. Binding of the resulting dendritic sialopolymersomes to Limax flavus agglutinin was studied and compared to the sialodendron and a monovalent Neu5Ac derivative using an enzyme-linked lectin inhibition assay. It was found that while the sialodendron exhibited a 17-fold enhancement (per sialoside) relative to the small molecule, the dendritic sialopolymersomes resulted in an almost 2000-fold enhancement in binding affinity. It was also demonstrated that encapsulation of zanamivir into the dendritic sialopolymersomes could be performed with the same efficiency as for naked polymersomes to provide a drug loading of ~35 wt %. Drug release rates were similar for both systems with sustained release over a period of 4 days. Overall, these results suggest the promise of using a multifunctional polymersome system for interaction with and inhibition of influenza viruses.

Multivalent Peptide–Nanoparticle Conjugates for Influenza‐Virus Inhibition

“…High molecular‐weight scaffolds displaying a large number of low affinity SA derived ligands were used to achieve high HA avidity. Over the years several carrier systems were employed as scaffolds ranging from polymers,6, 8, 9 dendrimers,10, 11, 12, 13 liposomes,5, 14 proteins,15 to gold nanoparticles 16. The most affine binders reported to date consist of SA tethered to linear polyacrylamide polymers 6.…”

Nanomimics of Host Cell Membranes Block Invasion and Expose Invasive Malaria Parasites

“…27 So far, polymersomes have been designed to present viral receptors on their surface for virusassisted loading of polymersomes 28 or to study viral protein binding. 29 In addition, heparin has been used at the surface of solid nanoparticles to achieve long circulation times in the bloodstream for drug delivery in cancer therapy. 30,31 Here, we introduce nanomimics based on polymersomes that present attachment receptors and thus mimic RBC membranes as a nanotechnological strategy for blocking invasion (drug action) and increased exposure of the infective form of P. falciparum to the immune system (vaccine-like action) (Scheme 1).…”

Polyester Dendrimers: Smart Carriers for Drug Delivery

“…Drug release rates were similar for both systems with sustained release over a period of 4 days. The results described in this paper indicate that multifunctional polymersome systems can be used for the interaction with and inhibition of influenza viruses [103].…”

“…Polymersomes can be readily accessed from a wide range of block copolymers and they typically exhibit much lower critical aggregation concentrations and enhanced thermodynamic and kinetic stabilities [222,223]. Recently, Gillies and coworkers exploited the multivalent and multifunctional capabilities of polymersomes in a dendritic sialopolymersome system designed to interact with the influenza virus at two different stages in the infection process [103]. First, the sialic acid N-acetylneuraminic acid (Neu5Ac) was conjugated to the polymersome surface in order to inhibit the binding of viral hemagglutinin to sialic acids on host cells, thus preventing viral entry.…”

“…Conventionally, nanoscale therapeutics is derived from polymer-drug conjugates, in which a drug is covalently bound through cleavable linkages such as the pH sensitive cis-aconityl, hydrazine, and acetal linkages [56,[90][91][92][93][94][95][96][97][98]. On the other hand, supramolecular drug delivery systems based on block copolymer micelles or dendritic systems have shown great promise and utility for tumor targeting and drug delivery [8,19,[99][100][101][102][103]. Both covalent and non-covalent systems can utilize the enhanced permeability and retention (EPR) phenomenon [9][10][11].…”