Radical Polymerization and Copper(0) Mediated Polymerization): From Fundamentals to Bioapplications Cyrille Boyer,*,†,‡ Nathaniel Alan Corrigan,‡ Kenward Jung,‡ Diep Nguyen,‡ Thuy-Khanh Nguyen,‡ Nik Nik M. Adnan,†,‡ Susan Oliver,†,‡ Sivaprakash Shanmugam,‡ and Jonathan Yeow†,‡ †Australian Centre for Nanomedicine, and ‡Centre for Advanced Macromolecular Design (CAMD), School of Chemical Engineering, University of New South Wales, Sydney 2052, Australia

Copper-Mediated Living Radical Polymerization (Atom Transfer Radical Polymerization and Copper(0) Mediated Polymerization): From Fundamentals to Bioapplications

Star polymers: Advances in biomedical applications

Stimulus-responsive polymeric nanogels as smart drug delivery systems.

Poly(oligoethylene glycol) methyl ether acrylate was polymerized via reversible addition fragmentation transfer polymerization (RAFT), and then chain extended in the presence of both a cross-linker and vinyl benzaldehyde (VBA), yielding monodisperse star polymers. The presence of aldehyde groups in the core was exploited to attach doxorubicin. The drug loading was controlled by the amount of VBA incorporated (until 28 wt% in drug). The doxorubicin release was studied at pH = 5.5 and 7.4; conditions representative of endosomal and extra cellular environments. In vitro studies revealed that the doxorubicin-conjugated star polymers had a level of cytotoxicity comparable to that found for free doxorubicin. Confocal microscopy and flow cytometry studies confirmed efficient cell uptake of the star polymers.

Synthesis of functional core, star polymers via RAFT polymerization for drug delivery applications.

A series of well-defined star-shaped polypeptides were successfully synthesised by the ring opening polymerisation (ROP) of the N-carboxyanhydride (NCA) of e-carbobenzyloxy-L-lysine (ZLL) using a range of generations of polypropylene imine (PPI) dendrimers as multifunctional initiators. The monomer feed ratio and dendrimer generation were varied to afford a series of polypeptide dendrimer hybrids with superior structural versatility and functionality. Subsequent protecting group removal yielded star-shaped poly(lysine) of controlled variation in polypeptide chain length and arm multiplicity. Star-shaped PLL polymers were used to prepare pDNA and siRNA to form “polyplexes” to determine their ability to complex different nucleic acid cargoes and were compared with linear PLL polyplex controls. Significant differences in size and surface charge were seen between star-shaped PLL polyplexes and linear PLL polyplexes for both cargoes. The star-shaped polypeptides were capable of more effective complexation of both nucleic acids at low N/P ratios compared to linear PLL as evidenced by zeta potential and electrophoretic data. This was particularly evident in siRNA polyplexes as linear PLL failed to completely complex siRNA into nanocomplexes of appropriate size for cell transfection i.e. <200 nm in size, while star poly(lysine) formed siRNA polyplexes <100 nm at certain N/P ratios, albeit strongly dependent on the particular molecular weight and architecture, as analysed by dynamic light scattering (DLS). Atomic force microscopy (AFM) identified discrete spherically shaped polyplexes for all star-shaped polypeptide-based polyplexes while linear PLL formed elongated irregular shaped complexes. This difference in morphology may go some way towards explaining the 300-fold increase in luciferase expression seen for star-shaped PLL polyplexes G5(64)-PLL40 compared to linear PLL pGLuc polyplexes in epithelial cells. Each of the PPI-PLL polymers appeared to be capable of protecting the nucleic acid cargoes from degradation by the relevant nuclease enzyme as effectively as the positive control polyethyleneimine (PEI) polyplexes. Overall the promising nucleic acid complexation, sizing, morphology and protection capacity of two different genetic “cargoes” highlight the potential of polypeptide dendrimer hybrids as gene delivery vectors.

Molecular weight and architectural dependence of well-defined star-shaped poly(lysine) as a gene delivery vector

There is a growing demand for the simultaneous, site-localized delivery and expression of tandem functionality within the human body. [1–7] The benefits of dual delivery of functional cargos such as two (synergistic) therapeutics, [8,9] a therapeutic and an imaging agent, [4,10] or dual-mode imaging agents [11,12] have all been recently reported. For many medical applications requiring such in vivo expression of exogenous functional materials, the use of polymeric nanoparticle delivery vehicles of increasingly complex design is envisioned. Currently, organic nanoparticle platforms under development for these purposes include liposomes, [13] dendrimers,[14] and micelles. [15] Alternatively, star polymers (unimolecular, globular, polymer architectures) are an increasingly attractive class of organic nanoparticles for biomedical research purposes. [16–18] Although topographically similar to dendrimers (i.e., a high local density of polymeric arms, surface functionality, and interstitial regions), they lack the synthetic and structural limitations of dendrimers [19,20] and the dynamic instability of micelles [21] and liposomes. [22] Nanogel star polymers, i.e., those with polymer “arms” emanating from a cross-linked polymer core, [23,24] in particular, offer a potential for variation in nanoparticle structure and surface functional, i.e., arm density but are among the most synthetically demanding of polymeric nanostructures to develop. [25–29]

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Nanogel Star Polymer Architectures: A Nanoparticle Platform for Modular Programmable Macromolecular Self-Assembly, Intercellular Transport, and Dual-Mode Cargo Delivery

Melia Tjio

Papers

Nanogel Star Polymer Architectures: A Nanoparticle Platform for Modular Programmable Macromolecular Self-Assembly, Intercellular Transport, and Dual-Mode Cargo Delivery