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Gold nanoparticles (size 10 nm) were designed to store and release nitric oxide (NO), by functionalizing their surfaces with functional polymers modified with NO-donor molecules. Firstly, block copolymer chains consisting of poly(oligoethylene glycol methyl ether methacrylate)-b-poly(vinyl benzyl chloride) (P(OEGMA)-b-PVBC)) were prepared using RAFT polymerization. The chloro-functional groups were then reacted with hexylamine, to introduce secondary amine groups to the copolymer chains. The block copolymers were then grafted onto the surface of gold nanoparticles, exploiting the end-group affinity for gold – attaining grafting densities of 0.6 chain per nm2. The secondary amine functional groups were then converted to N-diazeniumdiolate NO donor molecules via exposure to NO gas at high pressure (5 atm). The NO-bearing, gold nanoparticles were characterized using a range of techniques, including transmission electron microscopy, dynamic light scattering (DLS), thermal gravimetric analysis (TGA), and X-ray photoelectron spectroscopy (XPS). The nanoparticles displayed slow release of the nitric oxide in biological media. Proof of potential utility was then demonstrated in two different application areas: Pseudomonas aeruginosa biofilm dispersal and cancer cell cytotoxicity.

In this paper, we describe the synthesis of asymmetric functional POEGMA-b-P(ST-co-VBA) copolymers in methanol, yielding in one-pot polymerization a range of nanoparticle morphologies, including spherical micelles, worm-like, rod-like micelles and vesicles. The presence of the aldehyde group was then exploited to form crosslinks or to conjugate chemotherapy compounds, such as doxorubicin, via pH-breakable bonds (Schiff base or imine) directly to the preformed nanoparticles. The influence of the nanoparticle morphologies on the MCF-7 breast cancer cell line uptake was investigated using flow cytometry and confocal microscopy. Finally, the IC50 of DOX, following nanoparticle delivery, was studied showing significant influence of the nanoparticle carrier morphology on therapeutic efficacy for breast cancer.

A library of magnetic nanoparticles was generated using in situ co-precipitation of ferrous (Fe2+) and ferric (Fe3+) ions from aqueous solutions in the presence of functional block copolymers. Three different iron oxide anchoring groups, viz., phosphonic acid, carboxylic acid or glycerol were incorporated into well-defined diblock copolymers of poly(oligoethylene glycol acrylate) employed to stabilize the iron oxide nanoparticles. The [copolymer] : [Fe] ratio was varied to wield control over nanoparticle diameters within the range of 7–20 nm. The relationship between colloidal stability and nanoparticle crystallinity was investigated using dynamic light scattering, transmission electron microscopy and X-ray diffraction measurements. The amount of polymer employed during the co-precipitation proved critical in governing crystallinity and colloidal stability. We report a correlation between the polymer grafting density and the chemical structure of the anchoring group. Finally, the transverse relaxivity of the iron oxide nanoparticles in water, was investigated using a 9.4T magnetic resonance imaging scanner yielding values varying from 70 to 370 mM−1 s−1.

International audience; Click and drug: A combination of orthogonal click reactions is employed for the preparation of functional iron oxide nanoparticles (IONPs) that show unprecedented hyperthermia-induced drug release through a magnetically stimulated retro-Diels–Alder (rDA) process. Magnetic stimulation induces sufficient local energy in close proximity to the cycloadduct to initiate the rDA process.

We describe the synthesis of iron oxide nanoparticles (IONPs) with excellent colloidal stability in both water and serum, imparted by carefully designed grafted polymer shells. The polymer shells were built with attached aldehyde functionality to enable the reversible attachment of doxorubicin (DOX) via imine bonds, providing a controlled release mechanism for DOX in acidic environments. The IONPs were shown to be readily taken up by cell lines (MCF-7 breast cancer cells and H1299 lung cancer cells), and intracellular release of DOX was proven using in vitro fluorescence lifetime imaging microscopy (FLIM) measurements. Using the fluorescence lifetime difference exhibited by native DOX (~1 ns) compared to conjugated DOX (~4.6 ns), the intracellular release of conjugated DOX was in situ monitored in H1299 and was estimated using phasor plot representation, showing a clear increase of native DOX with time. The results obtained from FLIM were corroborated using confocal microscopy, clearly showing DOX accumulation in the nuclei. The IONPs were also assessed as MRI negative contrast agents. We observed a significant change in the transverse relaxivity properties of the IONPs, going from 220 to 390 mM(-1) s(-1), in the presence or absence of conjugated DOX. This dependence of MRI signal on IONP-DOX/water interactions may be exploited in future theranostic applications. The in vitro studies were then extended to monitor cell uptake of the DOX loaded IONPs (IONP@P(HBA)-b-P(OEGA) + DOX) into two 3D multicellular tumor spheroids (MCS) grown from two independent cell lines (MCF-7 and H1299) using multiphoton excitation microscopy.

In this communication, we report an easy method for introducing functional groups into polymer structures by successively reacting two different activated ester functionalities (pentafluorophenyl (PFP) ester and azlactone (AZ)) with different functional amine compounds. By exploiting the difference in reactivity of the two activated esters (PFP and AZ) toward different amino compounds, we demonstrate, for the first time, a selective modification of the different activated ester groups, thereby introducing functional groups to the polymer backbone in a controlled manner. Statistical and block copolymers of vinyl dimethyl azlactone (VDM) and pentafluorophenyl acrylate (PFPA), i.e.,(p(VDM-stat-PFPA)) and (p(VDM-block-PFPA)), were prepared using reversible addition–fragmentation transfer (RAFT) polymerization and subsequently modified using a library of amino compounds, yielding macromolecules with bespoke functionality. In additional work, the functional macromolecules were self-assembled into nanoparticles.

Superparamagnetic iron oxide nanoparticles (IONPs) have been studied extensively as negative contrast agents to enhance MRI efficacy. For optimal effective clinical use in T2/T2* weighted MRI imaging, the aim is to maximize relaxivity (r2) of IONPs, and minimize r1 relaxivity. A prerequisite for successful clinical use of magnetic nanoparticles is colloidal stability in biologically relevant media; biocompatible polymers with antifouling properties such as poly(ethylene glycol) (PEG) can be coated on the surface of IONPs, to improve stability and to impart longer blood circulation times. Our research aim was to optimize IONPs for use as contrast agents by achieving high grafting density and therefore colloidal stability, while retaining the magnetic properties of the IONP core. To attain the optimal material design the chemical functionalities and chain length of the polymeric layer must be precisely controlled. In this paper we describe the synthesis of poly(oligoethylene glycol acrylate) (P(OEGA)) funct...

IPI-504 (retaspimycin hydrochloride) is an Hsp90 inhibitor that is the subject of multiple clinical trials for the treatment of cancer. IPI-504 is an aqueous soluble (>200 mg/ml) hydroquinone hydrochloride salt of 17-(allylamino)-17-demethoxygeldanamycin (17-AAG), a quinone derivative also undergoing clinical evaluation, albeit with suboptimal formulations that address its inferior aqueous solubility (∼50 µg/ml). IPI-504 interconverts with 17-AAG in vivo through oxidation-reduction reactions that result in a dynamic redox equilibrium. The development challenges associated with redox active molecules are significant due to the pH, oxygen, and temperature sensitivities associated with such chemotypes. The API and sterile drug product manufacturing processes thus warrant the monitoring and control of these key variables. Furthermore, the pharmaceutical development challenges associated with cancer agents that are often fast-tracked due to unmet medical needs mandate a rapid development cycle with associated regulatory hurdles. Drug Dev Res 71: 429–438, 2010. © 2010 Wiley-Liss, Inc.

Biofilms are increasingly recognized as playing a major role in human infectious diseases, as they can form on both living tissues and abiotic surfaces, with serious implications for applications that rely on prolonged exposure to the body such as implantable biomedical devices or catheters. Therefore, there is an urgent need to develop improved therapeutics to effectively eradicate unwanted biofilms. Recently, the biological signaling molecule nitric oxide (NO) was identified as a key regulator of dispersal events in biofilms. In this paper, we report a new class of core cross-linked star polymers designed to store and release nitric oxide, in a controlled way, for the dispersion of biofilms. First, core cross-linked star polymers were prepared by reversible addition-fragmentation chain transfer polymerization (RAFT) via an arm first approach. Poly(oligoethylene methoxy acrylate) chains were synthesized by RAFT polymerization, and then chain extended in the presence of 2-vinyl-4,4-dimethyl-5-oxazolone monomer (VDM) with N,N-methylenebis(acrylamide) employed as a cross-linker to yield functional core cross-linked star polymers. Spermine was successfully attached to the star core by reaction with VDM. Finally, the secondary amine groups were reacted with NO gas to yield NO-core cross-linked star polymers. The core cross-linked star polymers were found to release NO in a controlled, slow delivery in bacterial cultures showing great efficacy in preventing both cell attachment and biofilm formation in Pseudomonas aeruginosa over time via a nontoxic mechanism, confining bacterial growth to the suspended liquid.