Zi-Chen Li

Multi-responsive nanogels containing motifs of ortho ester, oligo(ethylene glycol) and disulfide linkage as carriers of hydrophobic anti-cancer drugs

A family of multi-responsive nanogels with different compositions and crosslinking degrees have been prepared by the miniemulsion copolymerization of monomethyl oligo(ethylene glycol) acrylate (OEGA) and an ortho ester-containing acrylic monomer, 2-(5,5-dimethyl-1,3-dioxan-2-yloxy) ethyl acrylate (DMDEA), with bis(2-acryloyloxyethyl) disulfide (BADS) as a crosslinker. These nanogels are thermoresponsive and labile in the weakly acidic or reductive environments. The thermoresponsive behaviors, acid-triggered hydrolysis, and reduction-induced degradation of these nanogels were studied by means of dynamic light scattering (DLS), transmission electron microscopy (TEM) and atomic force microscopy (AFM). The results indicate that the volume phase transition temperature (VPTT), thermally induced deswelling ratio, and acid-triggered swelling ratio of the nanogels are closely relevant to their compositions and crosslinking degrees. Although these nanogels could be reductively disrupted by dithiothreitol (DTT), single polymer chains with sizes smaller than 20 nm were not detected by DLS. This is probably due to the existence of some unbreakable linkages formed by chain transfer to the disulfide bond during the radical polymerization. These nanogels are capable of encapsulating hydrophobic compounds. The loading capability of the nanogels for Nile Red (NR), paclitaxel (PTX), and doxorubicin (DOX), and the release behaviors of the drug-loaded nanogels were investigated by UV-vis spectrometry and HPLC. As expected, drug release can be greatly accelerated by a cooperative effect of both acid-triggered hydrolysis and DTT-induced degradation. Finally, the PTX-loaded nanogels exhibit a concentration-dependent toxicity to MCF-7 cells while the intact unloaded nanogels are non-toxic, thereby they may be used as potential carriers for hydrophobic anticancer drugs.

One-pot synthesis of polyamides with various functional side groups via Passerini reaction

Polyamides with various functional side groups were synthesized via Passerini reaction in a one-pot approach. The polymerization conditions and kinetics as well as the resulting polymer structures were thoroughly investigated. The facile introduction of various pendant groups, especially alkynyl and alkenyl groups, provides a platform for efficient post-polymerization modification by click chemistry.

Targeted minicircle DNA delivery using folate-poly(ethylene glycol)-polyethylenimine as non-viral carrier

Targeted gene delivery systems have attracted great attention due to their potential in directing the therapeutic genes to the target cells. However, due to their low efficiency, most of the successful applications of polymeric vectors have been focused on genes which can achieve robust expression. Minicircle DNA (mcDNA) is a powerful candidate in terms of improving gene expression and prolonging the lifespan of gene expression. In this study, we have combined folate/poly(ethylene glycol) modified polyethylenimine and mcDNA as a new tumor gene delivery system. We found that folate-labeled polyplexes were homogenous, with a size ranging from 60 to 85 nm. mcDNA increased folate-labeled vector based gene expression 2-8 fold in folate receptor-positive cells. Results of folic acid competition assay indicated that mcDNA mediated by folate-labeled vector were internalized into cells through receptor-mediated endocytosis. The investigation of the endocytosis pathway of the polyplexes showed that a large portion of them escaped from endo/lysosome and the polyplexes were associated before being separated in the nucleus. Furthermore, in vivo optical imaging and luciferase assays demonstrated that systemic delivery of the folate-labeled polyplexes resulted in preferential accumulation of transgenes in folate receptor-positive tumors, and mcDNA mediated approach achieved 2.3 fold higher gene expressions in tumors than conventional plasmid. Cytotoxicity assays showed that PEG-shielding of the polyplexes reduced the toxicity of PEI.

Intelligent nucleic acid delivery systems based on stimuli-responsive polymers

Despite significant advances in the past two decades, gene therapy is still in the stage of clinical trials worldwide mainly due to the lack of safe and efficient delivery vehicles for therapeutic nucleic acids. Among the various attempts to develop clinically applicable gene therapy, polymer-based nucleic acid delivery systems have attracted great interest, especially for the exciting RNAi-based gene therapy. Regarding in vivo nucleic acid delivery, in particular via intravenous injection, there are many extra- and intracellular obstacles, some of which are conflicting. Virus-mimicking nucleic acid delivery systems that combine multiple and programmable functions are thought to be very promising for conquering these challenging barriers. In this review article, we highlight recent progress in stimuli-responsive polymers that have been applied in fabrication of non-viral multi-functional nucleic acid vehicles, which are categorized by the type of stimulus: reduction potential, pH, temperature, and others. In each section, intelligent pDNA delivery systems are introduced first, followed by summarizing various responsive polymer-based siRNA vehicles. Considering the great potential of RNAi-based gene therapy, we devote some space to the recent progress of multi-functional siRNA delivery systems. In addition, different requirements in designing polymer-based siRNA and pDNA carriers are also specified in this review.

Oxidation-responsive polymers for biomedical applications

Reactive oxygen species (ROS) play key roles in many physiological processes, such as cell signaling and host innate immunity. However, when they are overproduced, ROS may damage biomolecules in vivo and cause diseases such as cardiovascular or neurodegenerative diseases, cancer, and so forth. Oxidative stress is usually implicated in various inflammatory tissues, representing an important target for the development of various therapeutic strategies. Therefore, various probes for the in vitro detection of ROS or the in vivo diagnosis of the oxidative stress-relevant diseases have been developed. Oxidation-responsive polymers have also attracted great interest due to their potential applications in biomedical fields. In this feature article, we summarize six types of oxidation-responsive polymers based on different oxidation-responsive motifs. Poly(propylene sulfide)s, selenium-based polymers, aryl oxalate- and phenylboronic ester-containing polymers are discussed in detail, while poly(thioketal)s and proline-containing polymeric scaffolds are briefly introduced.

Facile synthesis of multi-block copolymers containing poly(ester–amide) segments with an ordered side group sequence

We report a facile method for the synthesis of multi-block copolymers consisting of poly(ethylene glycol) (PEG) and poly(ester–amide) segments with an ordered side group sequence via multicomponent polymerization based on the Passerini reaction (PR). The technique involves the polymer supported liquid-phase synthesis of three PEG diacid macromonomers (M1–M3) via stepwise PR with tert-butyl isocyanoacetate and a functional aldehyde followed by selective hydrolysis, and the final multicomponent polymerization of M1–M3 with phenylacetaldehyde and 1,6-diisocyanohexane.

Active control of surface properties and aggregation behavior in amino acid-based Gemini surfactant systems

Two types of Gemini surfactants containing a disulfide bond in the spacer, sodium dilauroyl cystine (SDLC) and sodium didecamino cystine (SDDC), were synthesized, and their surface properties and aggregation behavior in aqueous solution were studied by means of surface tension measurements, dynamic light scattering (DLS), transmission electron microscopy (TEM), and fluorescence. During the transition of the Gemini surfactants to their corresponding monomers through the reduction of disulfide bonds, the surface tensions of their aqueous solutions, as well as their aggregation behavior, changed greatly. The reduction of SDLC and SDDC led to disruption of the vesicle, and the oxidation of corresponding monomers to Gemini surfactants led to vesicle re-formation. These results demonstrated the control of surface properties and aggregation behavior by the reversible transition between the Gemini surfactant and its monomer via reduction/oxidation reactions.

General rules for the scaling behavior of linear wormlike micelles formed in catanionic surfactant systems

We report in this work on the scaling behavior of wormlike micelles formed in a series of mixed systems of oppositely charged surfactants, including sodium decanote (SD)/hexadecyltrimethylammonium bromide (CTAB), sodium laurate (SL)/hexadecyltrimethylammonium bromide, sodium didecaminocystine (SDDC)/hexadecyltrimethylammonium bromide, and sodium dilauraminocystine (SDLC)/hexadecyltrimethylammonium bromide. Steady and dynamic rheological measurements were performed to characterize these wormlike micelles. The scaling behavior for these systems at various mixing ratios was systematically investigated and was compared with that given by the Cates model. It was found that the Cates law can be applied in these systems simply by manipulating the mixing ratio or the surfactant structure. Energetic analysis demonstrates that the scaling behavior of wormlike micelles in nonequimolar mixed cationic and anionic surfactant systems can be close to that predicted by the Cates model, if the electrostatic contribution is below a threshold value.

Facile Synthesis of Acid-Labile Polymers with Pendent Ortho Esters

This work presents a facile approach for preparation of acid-labile and biocompatible polymers with pendent cyclic ortho esters, which is based on the efficient and mild reactions between cyclic ketene acetal (CKA) and hydroxyl groups. Three CKAs, 2-ethylidene-1,3-dioxane (EDO), 2-ethylidene-1,3-dioxolane (EDL), and 2-ethylidene-4- methyl-1,3-dioxolane (EMD) were prepared from the corresponding cyclic vinyl acetals by catalytic isomerization of the double bond. The reaction of CKAs with different alcohols and diols was examined using trace of p-toluenesulfonic acid as a catalyst. For the monohydroxyl alcohols, cyclic ortho esters were formed by simple addition of the hydroxyl group toward CKAs with ethanol showing a much greater reactivity than iso-propanol. When 1,2- or 1,3-diols were used to react with the CKAs, we observed the isomerized cyclic ortho esters besides the simple addition products. Biocompatible polyols, that is, poly(2-hydroxyethyl acrylate) (PHEA) and poly(vinyl alcohol) (PVA) were then modified with CKAs, and the degree of substitution of the pendent ortho esters can be easily tuned by changing feed ratio. Both the small molecule ortho esters and the CKA-modified polymers demonstrate the pH-dependent hydrolysis profiles, which depend also on the chemical structure of the ortho esters as well as the polymer hydrophobicity.

Thermoresponsive behavior of an LCST-type polymer based on a pyrrolidone structure in aqueous solution

Poly(3-ethyl-N-vinyl-2-pyrrolidone) (C2PVP) is a new type of thermoresponsive polymer which exhibits phase separation in water above the lower critical solution temperature (LCST) at about 26 °C. The thermoresponsive mechanism of C2PVP during the heating–cooling cycle has been investigated by means of temperature-dependent FTIR in combination with a two-dimensional correlation (2Dcos) technique and density functional theory (DFT) calculations. Compared with a secondary-amide thermoresponsive polymer such as poly(N-isopropyl acrylamide) (PNIPAM), the unusual phenomenon of an asymmetrical-to-symmetrical transition of the CO peak shape is observed in the conventional IR spectra of tertiary-amide polymer C2PVP. 2Dcos results confirmed that two species of CO groups (CO⋯2D2O and CO⋯D2O) mainly coexist at the initial heating, and they change to the other two CO groups involving the free CO and CO⋯DOD⋯OC after heating, with the latter predominant above the LCST. A slight hysteresis is observed in the cooling process attributed to the existence of a weak “crosslinking” point originating from the structure of CO⋯DOD⋯OC. Based on 2Dcos results, the dehydration process of different groups could be described in the following order: ethyl groups > CO groups > CH2 groups in ring (“>” means prior to), and the reversible sequence is observed during hydration process. In PNIPAM system, CH2 groups usually change prior to CO groups, while for C2PVP the dehydrated rate of CH2 groups (in ring) lags behind that of CO groups because of the steric hindrance of pyrrolidone structures. It is worth noting that cononsolvency of C2PVP can be found in water/methanol mixed solvents. The LCST of C2PVP in water/methanol mixture shifts from 29.5 to 16 °C as the methanol volume fraction reaches 50% and the phase separation totally disappears when the content of methanol is higher than 60%.