Weiren Cheng

Stimuli-responsive polymers for anti-cancer drug delivery.

Stimuli-responsive polymers are an important component for preparation of stimuli-responsive drug delivery systems with less side effects and improved efficacy for cancer treatment. There are endogenous stimuli and exogenous stimuli which can be explored. Here we review the developments in both endogenous stimuli- including redox-/pH-/enzyme-responsive polymers and exogenous stimuli- including thermo-/photo- and ultrasound-responsive polymers for delivery of anti-cancer drugs.

Redox-responsive hyperbranched poly(amido amine)s with tertiary amino cores for gene delivery.

Redox-responsive hyperbranched poly(amido amine)s (PAAs) with tertiary amino cores and amine, poly(ethylene glycol) (PEG) and hydroxyl terminal groups were prepared for DNA delivery respectively. The DNA condensation capability of PAAs was investigated using gel electrophoresis, and the results showed that PAA terminated with 1-(2-aminoethyl)piperazine (AEPZ) (BAA) is the most efficient in binding plasmid DNA (pDNA). The diameter and zeta-potential of polyplexes from PAAs were characterized using dynamic light scattering (DLS), and the morphology of the polyplexes was obtained using atomic force microscopy (AFM). All the PAAs were able to condense pDNA into nanoparticles with diameters between 50 and 200 nm with a positive surface charge when the weight ratio of polymer/DNA was higher than 20. Glutathione (GSH)-induced DNA release from polyplexes and the buffering capability of PAAs were investigated as well. Cytotoxicity of PAAs and in vitro gene transfection of polyplexes were evaluated in HEK293, COS-7, MCF-7 and Hep G2 cell lines, respectively. The results reflect that PAAs show remarkably low or even no cytotoxicity, and that PAA with amino terminal groups mediates the most efficient gene transfection with the transfection efficiency comparable to that of 25 kDa polyethylenimine. Further the effects of the presence of buthionine sulfoximine (BSO) on the transfection efficiency and cytotoxicity of BAA polyplexes were investigated.

Magnetic Resonance Imaging (MRI) Contrast Agents for Tumor Diagnosis

This review focuses on MRI contrast agents for tumor diagnosis. Several types of low molecular weight Gd3+-based complexes and dextran-coated superparamagnetic iron oxide (SPIO) nanoparticles have been used for clinical tumor diagnosis as longitudinal relaxation time (T1) and transverse relaxation time (T2) MRI contrast agents, respectively. To further improve the sensitivity of MRI, new types of chelates for T1 MRI contrast agents and combination of low molecular weight T1 MRI contrast agents with different types of carriers have been investigated. Different types of materials for forming secure coating layers of SPIO and novel superparamagnetic particles with higher relaxivity values have been explored. Various types of ligands were applied to improve the capability to target tumor for both T1 and T2 contrast agents. Furthermore, MRI contrast agents for detection of tumor metabolism were also pursued.

pH- and Redox-Responsive Poly(ethylene glycol) and Cholesterol-Conjugated Poly(amido amine)s Based Micelles for Controlled Drug Delivery

An optimized condition is identified to prepare linear poly(amido amine)s via Michael Addition polymerization of trifunctional amine, 4-(aminomethyl)piperidine (AMPD), with an equimolar diacrylamide, N,N-cystaminebis(acrylamide) (BAC). Poly(ethylene glycol) (PEG) and cholesterol (CE) are conjugated to linear poly(BAC-AMPD) through the reactions with the secondary amino groups in the backbone, respectively, to form poly(BAC-AMPD)-g-PEG-g-CE. The chemical structures of poly(BAC-AMPD) and poly(BAC-AMPD)-g-PEG-g-CE are characterized using NMR and gel permeation chromatography (GPC). Transmission electron microscopy (TEM), dynamic light scattering (DLS) and (1)H NMR results show that micelles with PEG shells and hydrophobic cores composed of poly(BAC-AMPD) and CE are formed via self-assembly of poly(BAC-AMPD)-g-PEG-g-CE in aqueous solution, and the micelles of poly(BAC-AMPD)-g-PEG-g-CE can be degraded by the presence of L-dithiothreitol and show a limited cytotoxicity in vitro. The anti-cancer drug, doxorubicin (DOX), can be loaded into the micelles. The DOX loaded micelles of poly(BAC-AMPD)-g-PEG-g-CE show pH- and redox-responsive drug release and redox-induced formation of aggregates, and it is shown that the DOX loaded micelles can deliver DOX into cells and show a higher efficacy in killing cancer cells than free drug.

Dodecylated lignin-g-PLA for effective toughening of PLA

A green approach to an effective toughening agent of the popular green plastic, polylactide (PLA), is established. Firstly an aqueous approach is developed to selectively graft dodecane to 100% of phenolic hydroxyl (OH) and 77% of carboxylic OH of alkaline lignin. The selective alkylation is characterized using 1H NMR, 31P NMR, FTIR and DSC. Then PLA is grafted from the remaining OH groups of dodecylated lignin. The grafting of PLA is characterized using 1H NMR, 31P NMR, and GPC. Note that Mn of the grafted PLA chains can reach more than 10 K Da. Subsequently lignin/PLA blends are prepared by mixing PLA and dodecylated lignin-g-PLA. On the basis of DSC results, it is suggested that there are three phases composed of bulk PLA, mixed bulk PLA and the grafted PLA, and dodecylated lignin, resepectively, in the blends. In comparison with PLA, the blends have similar thermal stability as reflected by TGA, are more hydrophobic as reflected by higher contact angles, and block UV light better. Impressively the elongation of the blends can be more than 40 times higher than PLA with certain improvements in Youngs modulus and tensile strength. This should be due to the well integrated dodecylated lignin units in the bulk PLA being able to disperse energy. This understanding can guide the development of new PLA toughening approaches.

Fluorescent carbon dot (C-dot) nanoclusters

Fluorescent carbon dot (C-dot) nanoclusters composed of C-dot-loaded hollow silica spheres are obtained via the dehydration of mannose, which is adsorbed onto hollow silica spheres or poly(ethylene glycol)-graft-hollow silica spheres (PEG-g-hollow silica). The structure of C-dot nanoclusters are confirmed using 1H NMR, FTIR, TEM and TGA. C-dot nanoclusters show a redshifted fluorescence emission with an increased excitation wavelength. Passivation with PEG diamines improve the quantum yields to ∼2%. Confocal laser scanning microscopy (CLSM) results reflect the fact that C-dot nanoclusters can provide good cytoplasm imaging of live Hep G2 cells and live MCF-7 cells, and the imaging obtained is brighter and more even than those from free C-dots. With their combination of good photostability and low cytotoxicity, C-dot nanoclusters are promising for the production of higher quality bioimaging.

A facile synthetic approach to a biodegradable polydisulfide MRI contrast agent

A polydisulfide MRI contrast agent was obtained by grafting diethylenetriaminepentaacetic (DTPA) to disulfide-containing poly(amido amine)s-graft-poly(ethylene glycol) (PEG) followed by Gd(iii) complexation. Self-assembly of the MRI contrast agent obtained occurs in aqueous solution forming nanosized micelles with PEG shells and ionic complex cores. The chemistry and structures of the MRI contrast agent and assembly were characterized using NMR, GPC and DLS. Thiol-induced degradation of the backbone and the assembly of the MRI contrast agent were investigated using GPC and DLS, respectively, and easy degradation was observed. Poly(BAC-AMPD)-g-PEG-g-Gd-DTPA also shows a low cytotoxicity and a high r1 value, so it is promising to provide better MRI imaging with fewer side effects.

Surfactant-Free Emulsion-Based Preparation of Redox-Responsive Nanogels

A surfactant-free emulsion-based approach is developed for preparation of nanogels. A water-in-oil emulsion is generated feasibly from a mixture of water and a solution of disulfide-containing hyperbranched PEGylated poly(amido amine)s, poly(BAC2-AMPD1)-PEG, in chloroform. The water droplets in the emulsion are stabilized and filled with poly(BAC2-AMPD1)-PEG, and the crosslinked poly(amido amine)s nanogels are formed via the intermolecular disulfide exchange reaction. FITC-dextran is loaded within the nanogels by dissolving the compound in water before emulsification. Transmission electron microscopy and dynamic light scattering are applied to characterize the emulsion and the nanogels. The effects of the homogenization rate and the ratio of water/polymer are investigated. Redox-induced degradation and FITC-dextran release profile of the nanogels are monitored, and the results show efficient loading and redox-responsive release of FITC-dextran. This is a promising approach for the preparation of nanogels for drug delivery, especially for neutral charged carbohydrate-based drugs.

Redox-responsive hydrogels

Abstract Stimuli-responsive polymers that undergo physical or chemical changes in response to environmental variations, when integrated into devices, can behave like living organisms to “sense and react” and produce intended responses once stimulated. Of all the different stimuli, change in the redox state is particularly attractive to polymer scientists because of well-documented redox variations in the body and the close association of unusual levels of redox potentials in certain diseases. Hydrogels, which are highly hydrophilic three-dimensional network of polymers, have always been regarded as one of the most promising biomaterials composite for biomedical applications, and redox-responsive hydrogels have been frequently employed in areas such as tissue engineering and drug delivery. Among the several different polymers used to prepare hydrogels, poly(amido amine)s being biocompatible and highly versatile have gained significant attention in recent years. Therefore, in this chapter, we would like to address the potential of poly(amido amine)s-based redox-responsive hydrogels. The synthesis mechanism of poly(amido amine)s via the Michael addition polymerization of bisacrylamide, such as N,N-cystaminebis(acrylamide), and trifunctional amines, such as 1-(2-aminoethyl)piperidine or 4-(aminomethyl)piperidine, will be discussed in detail. Different techniques to prepare the redox-responsive hydrogels will also be presented. Innovative approaches to nano/microgels, which possess both the advantageous properties of nanoparticles and hydrogels, are also highlighted. Lastly, the potential of redox-responsive hydrogels will be demonstrated in various biomedical applications.