Zhongfan Jia

Polyacrylate Dendrimer Nanoparticles: A Self‐Adjuvanting Vaccine Delivery System

(Figure Presented) Special delivery: An effective group A streptococci vaccine is formed from a delivery device consisting of well-defined dendritic structures with nanoscale dimensions (see picture). The structures are designed to display multiple copies of the minimal B-cell epitopes, which were in the optimal conformation on the surface of the nanoparticles. The nanoparticles can be administered without the aid of an adjuvant.

One-Pot Conversion of RAFT-Generated Multifunctional Block Copolymers of HPMA to Doxorubicin Conjugated Acid- and Reductant-Sensitive Crosslinked Micelles

N-(2-Hydroxypropyl)methacrylamide (HPMA) containing polymers that are widely used as anticancer drug carriers. We have synthesized new amphiphilic block copolymers of HPMA with a functional monomer 2-(2-pyridyldisulfide)ethylmethacrylate (PDSM) via reversible addition-fragmentation chain transfer (RAFT) polymerization. In a one-pot reaction, the versatility of PDS groups on poly(PDSM)- b-poly(HPMA) was used to conjugate an anticancer drug, doxorubicin (DOX), and also simultaneously crosslink the micellar assemblies via acid-cleavable hydrazone bonds and reducible disulfide bonds. DOX-conjugated crosslinked micelles with an average diameter of approximately 60 nm were observed to be formed in aqueous medium. Disintegration of the micelles into unimers in the presence of a disulfide reducing agent confirmed the crosslinking via disulfide bonds. While the release of DOX from the crosslinked micelles at pH 5.0 was faster compared to the release at pH 7.4, a high proportion of released DOX was found to retain the original active structure. Overall results demonstrate the simplicity and the versatility of the poly(PDSM)- b-poly(HPMA) system, which are potentially important in the design of new generation of polymer therapeutics.

Synthesis of versatile thiol-reactive polymer scaffolds via RAFT polymerization

Well-defined polymer scaffolds convertible to (multi)functional polymer structures via selective and efficient modifications potentially provide an easy, versatile, and useful approach for a wide variety of applications. Considering this, a homopolymer scaffold, poly(pyridyldisulfide ethylmethacrylate) (poly(PDSM)), having pendant groups selectively reactive with thiols, was synthesized by reversible addition fragmentation chain transfer (RAFT) polymerization. Soluble polymers with controlled molecular weights and narrow PDIs were generated efficiently. The versatility of the scaffold to generate random co- and ter-polymers combining multiple functionalities with controlled-composition was shown by separate and simultaneous conjugation of different mercapto-compounds, including a tripeptide in one-step. Conversion of water-insoluble scaffold to peptide-containing water-soluble copolymers was observed to yield nanometer-size particles with narrow polydispersity. The overall results suggest that the well-defined PDSM homopolymer scaffold generated via RAFT polymerization can be a versatile building block for generation of new structures having potential for drug delivery applications via a straightforward synthetic approach.

A comparative study of the SET-LRP of oligo(ethylene oxide) methyl ether acrylate in DMSO and in H2O

A comparative analysis of the SET-LRP of oligo(ethylene oxide) methyl ether acrylate (OEOMEA) in DMSO and in H2O at 25 °C is reported. Both the catalysis with activated Cu(0) wire/Me6-TREN and with mimics of “nascent” Cu(0) nanoparticles/Me6-TREN resulted in a higher rate of polymerization in water than in DMSO. This result is consistent with the acceleration expected for SET-LRP by a more polar reaction solvent, and with the difference between the equilibrium constants of disproportionation of CuBr in DMSO (Kd = 1.4–4.4) and in water (Kd = 106 to 107), both much higher in the presence of Me6-TREN. The inefficient access of the Cu(0) catalyst to the hydrophobic reactive centers of the monomer and initiator assembled in micellar structures explains the induction time observed in the SET-LRP of OEOMEA in water. This induction period is longer for Cu(0) wire. The use of “nascent” Cu(0) nanoparticles prepared by the disproportionation of CuBr in DMSO, in combination with 5 mol% CuBr2, led to an extremely efficient SET-LRP of OEOMEA in water. This SET-LRP in water is fast and follows first order kinetics to complete monomer conversion with linear dependence of experimental Mn on conversion, and narrow molecular weight distribution. Under the polymerization conditions investigated in both water and DMSO, no reduction in the absorbance of CuBr2/Me6-TREN was observed by online UV-vis spectroscopy. This excludes the formation of CuBr by reduction of CuBr2 by Cu(0) during the SET-LRP in DMSO and in water.

An influenza virus-inspired polymer system for the timed release of siRNA

Small interfering RNA silences specific genes by interfering with mRNA translation, and acts to modulate or inhibit specific biological pathways; a therapy that holds great promise in the cure of many diseases. However, the naked small interfering RNA is susceptible to degradation by plasma and tissue nucleases and due to its negative charge unable to cross the cell membrane. Here we report a new polymer carrier designed to mimic the influenza virus escape mechanism from the endosome, followed by a timed release of the small interfering RNA in the cytosol through a self-catalyzed polymer degradation process. Our polymer changes to a negatively charged and non-toxic polymer after the release of small interfering RNA, presenting potential for multiple repeat doses and long-term treatment of diseases.

Multifunctional Nanoworms and Nanorods through a One-Step Aqueous Dispersion Polymerization

Producing synthetic soft worm and rod structures with multiple chemical functionalities on the surface would provide potential utility in drug delivery, nanoreactors, tissue engineering, diagnostics, rheology modifiers, enzyme mimics, and many other applications. Here, we have synthesized multifunctional worms and rods directly in water using a one-step reversible addition-fragmentation chain transfer (RAFT)-mediated dispersion polymerization at high weight fractions of polymer (>10 wt %). The chain-end functionalities included alkyne, pyridyl disulfide, dopamine, β-thiolactone, and biotin groups. These groups could further be converted or coupled with biomolecules or polymers. We further demonstrated a nanorod colorimetric system with good control over the attachment of fluorescent probes.

Stabilization of Polymer‐Hydrogel Capsules via Thiol–Disulfide Exchange

Polymer hydrogels are used in diverse biomedical applications including drug delivery and tissue engineering. Among different chemical linkages, the natural and reversible thiol-disulfide interconversion is extensively explored to stabilize hydrogels. The creation of macro-, micro-, and nanoscale disulfide-stabilized hydrogels commonly relies on the use of oxidizing agents that may have a detrimental effect on encapsulated cargo. Herein an oxidization-free approach to create disulfide-stabilized polymer hydrogels via a thiol-disulfide exchange reaction is reported. In particular, thiolated poly(methacrylic acid) is used and the conditions of polymer crosslinking in solution and on colloidal porous and solid microparticles are established. In the latter case, removal of the core particles yields stable, hollow, disulfide-crosslinked hydrogel capsules. Further, a procedure is developed to achieve efficient disulfide crosslinking of multilayered polymer films to obtain stable, liposome-loaded polymer-hydrogel capsules that contain functional enzymatic cargo within the liposomal subcompartments. This approach is envisaged to facilitate the development of biomedical applications of hydrogels, specifically those including fragile cargo.

Functionalized large pore mesoporous silica nanoparticles for gene delivery featuring controlled release and co-delivery

Novel mesoporous silica nanoparticles (LPMSNs) functionalised with degradable poly(2-dimethylaminoethyl acrylate) (PDMAEA) have been developed (PDMAEA-LPMSNs) as nano-carriers for gene delivery. The unique design of PDMAEA-LPMSNs has endowed this system with multiple functions derived from both the organic and inorganic moieties. The cationic polymer unit binds to genetic molecules and undergoes a self-catalyzed hydrolysis in water to form a non-toxic anionic polymer poly(acrylic acid), allowing controlled release of siRNA in the cells. The nanopores of the LPMSNs provide a reservoir for storage and release of chloroquine to facilitate endosomal escape. The PDMAEA-LPMSN composites were characterized by elemental analysis (EA), X-ray photoelectron spectroscopy (XPS), solid-state 13C magic-angle spinning nuclear magnetic resonance (MAS-NMR), thermogravimetric analysis (TGA), and nitrogen sorption techniques. Their siRNA delivery performance was tested in a KHOS cell line, showing promising potential for co-delivery of genes and drugs.

Functional Disulfide-Stabilized Polymer−Protein Particles

Polymer-protein hybrid particles (PPHPs) have a significant potential in drug delivery, diagnosis, and biomedical imaging applications. Herein, we describe a simple route to disulfide cross-linked, poly(ethylene glycol)-streptavidin hybrid particles with tunable diameters. These particles have great versatility and potential for a number of reasons. First, they possess free biotin binding sites on their streptavidin (SAv) coated surface, enabling the conjugation of any biotinylated-molecule such as biotinylated antibodies. Second, core-stabilization can easily be controlled using reversible disulfide cross-links, and third, thiol- and ene-reactive functionalities in the core are available for the conjugation of drugs and labels. In detail, micelles having a biotinylated poly(ethylene glycol) corona and a disulfide cross-linked, reactive core were formed using alpha-biotin PEG-b-poly(pyridyldisulfide ethylmethacrylate) block copolymers synthesized via RAFT polymerization. Functionalization of the micelle core was performed in a one-pot reaction concurrent with the micellization and cross-linking processes by using a thiol-reactive model compound (a maleimide derivative of a green fluorophore). The resultant micelles displayed spherical morphology with a diameter of 54 +/- 4 nm. Biotin functionality was largely exposed on the micelle corona (75 mol % availability), as determined by a streptavidin/HABA assay. The micelles were subsequently decorated with (red fluorophore-labeled) streptavidin (SAv) through the accessible biotins on the surface, yielding SAv-linked micelle aggregates with tunable dimensions (in the range between 350 nm and 2 microm), as determined by transmission electron microscopy. Fluorescent-labels on the particles were monitored using confocal microscopy, revealing that the SAv coats the periphery of the PPHPs.

An approach to biodegradable star polymeric architectures using disulfide coupling

The straightforward synthesis of biodegradable star polymers via both in situ polymerization from a trifunctional RAFT agent and post-polymerization conjugation of pyridyldisulfide-ended linear polymers to a trithiol precursor is described.