Saina Yang

Dual-stimuli sensitive keratin graft PHPMA as physiological trigger responsive drug carriers

Keratin graft poly(N-(2-hydroxypropyl)methacrylamide) (K-g-PHPMA) copolymers were synthesized and characterized. On account of the thiol groups of keratin and the amphiphilicity of the graft copolymers, micelles with cleavable cross-links on a keratin core were fabricated in water. The K-g-PHPMA micelles can efficiently encapsulate doxorubicin (DOX) and can be used as a drug carrier. The DOX content in the micelles increases with the keratin content of the graft copolymers. The release of the encapsulated DOX in the micelles is sensitive to the physiological environment. Redox trigger glutathione (GSH), especially at the intracellular level, and trypsin can effectively trigger the release of the encapsulated DOX. In vitro cellular uptake experiments indicate that the DOX released from the DOX-loaded K-g-PHPMA micelles can be efficiently internalized into cells. Under higher GSH condition, the DOX shows a much faster release into the nucleus of the cells. The K-g-PHPMA copolymers have promising applications as drug carriers for enhanced intracellular drug delivery in cancer therapy.

Injectable tissue adhesive composite hydrogel with fibroblasts for treating skin defects

In this work, an injectable composite hydrogel was synthesized via a unique way of crosslinking glycol chitosan (GC) with silica nano-particles (SiNP) through non-chemical interactions, and was then applied as a kind of wound dressing. Gelation was achieved through the incorporation of SiNPs with the GC segments in aqueous solution, therefore strictly confining the movement of the solubilized polymer chains. Rheology tests showed that the sol-gel transition and the moduli of the hydrogel were influenced by the composition of the two components, the size of the nano-particles and the conformation of the polymers. Using such a strategy, tissue adhesion properties of GC were well-preserved in the GC/SiNP hydrogel and therefore it gains gluey properties toward biological tissues as demonstrated through the adhesion of two pieces of mouse skin, obtaining a lap-shear stretching force of ca. 90 kPa. This characteristic, together with the injectability, allowed the hydrogel to be administrated directly on the wound site and to fill the wound area. Meanwhile, the hydrogel also works as a carrier of protein and cells. The in situ encapsulation of fibroblasts enabled the promising properties of the GC/SiNP hydrogel to be used for treating full-thickness skin defects in a mouse model, resulting in the favorable growth of hair follicles and microvessels, hence reducing the risk of scar formation.

Fibril-shaped aggregates of doxorubicin with poly-L-lysine and its derivative

Complex formation between polymers and organic molecules is an interesting topic in polymer physics. Compared to the influence of small molecules on polymer assembly, there are fewer examples demonstrating the effect of polymers on the supramolecular structures formed by organic molecules. In this paper, we first prove that doxorubicin (DOX), a common anti-tumour drug, assembles into fibril-like aggregates in phosphate buffer (pH 7.4) and then show that the assembly of DOX was influenced by the complexation with an amphiphilic poly (amino acid) derivative, i.e. cholate-grafted poly-L-lysine (PLL-CA). With PLL-CA, the DOX fibrils converted to helix structured nano-spindles, whilst the presence of PLL led to minor change on the morphology of PLL/DOX complex compared to the DOX aggregates, which is attributed to the amplitude of intermolecular interactions. As a DNA intercalating agent, the aggregation of DOX on its biofunctionality was also investigated, showing that the formation of fibril assemblies was unfavourable for the cellular internalization of DOX and caused lower cytotoxicity to DOX resistance MCF-7 cells, whereas the polymer/DOX complexes gained an improved cell uptake on the MCF-7/ADR cell line due to an enhanced electrostatic interaction between the complexes and the cell membrane.

pH gradient difference around ischemic brain tissue can serve as a trigger for delivering polyethylene glycol-conjugated urokinase nanogels.

BACKGROUND AND PURPOSE pH-sensitive polyethylene glycol-conjugated urokinase nanogels (PEG-UKs) were previously reported to be a new form of UK nanogels that could release UK at certain pH values. In this study, we evaluated the effect of PEG-UK targeted to ischemic tissue with microcirculation failure in rat model of ischemic stroke and investigated the possible mechanisms of action. METHODS Surgeries were performed to induce persistent middle cerebral artery (MCA) occlusion in adult Sprague-Dawley rats. The pH distribution in the brain was mapped 1h after ischemia using a needle-type pH micro sensor. The release curve of active UK from PEG-UK was also mapped by a continuous measurement of the peripheral blood. The thrombolytic effects of PEG-UK, when it was administrated 1h after occlusion, including dynamic changes in the D-dimer level, neurological deficits and infarction volume, were observed. Next, the possible mechanisms underlying these effects were explored, including the BBB integrity and the extent of apoptosis and neurotoxicity. Additionally, the long-term effects of PEG-UK during the four weeks after treatment were evaluated using the dynamic changes in the body weights and clinical scores and the numbers of deaths and hemorrhagic transformations (HTs). To evaluate the systemic side effects of PEG-UK, the fluctuations of cytokines in the liver and kidney were evaluated. RESULTS On average, MCA occlusion for 1h induced an approximately 0.49 decline in the pH value (from 7.12 to 6.73), and the lowest value was 6.32 in the predominantly affected region around the cortex. PEG suspended the release of UK from PEG-UK into the circulation. When it was administrated 1h after occlusion, PEG-UK treatment clearly reduced the severity of neurological deficits in the acute phase (P=0.001). The relative infarct volume also decreased significantly in PEG-UK rats (P<0.001). As to the integrity of BBB, the EB leakage in the PEG-UK group was reduced (P=0.001). Maintenance of the expression of TIMP-1 (P=0.032) and claudin5 (P<0.001) and inhibition of MMP9 upregulation (P<0.001) were observed through both immunohistochemistry and Western blot in the PEG-UK group. Moreover, the expression of both NMDAR1 (P<0.001) and Caspase9 (P=0.013) in PEG-UK-treated rats was reduced. As to the long-term prognosis, the rats in PEG-UK group recovered faster and better, and the numbers of deaths and HTs were not increased. No significant fluctuation in IL-1β and TNF-α was found in the PEG-UK-treated rats during the four post-treatment weeks. When PEG-UK was administrated 2.5h after occlusion, no clearly better outcomes were observed; however, the number of HTs was not increased. CONCLUSIONS Treatment with PEG-UK decreased the severity of ischemic stroke by improving ischemic brain tissue and protecting the BBB and by inhibiting apoptosis and decreasing neurotoxicity. PEG-UK could further inhibit HT through its BBB protection effect. The administration of PEG-UK also improved the long-term prognosis and had no obvious systemic side effects in rats. Our data provide new insights into the thrombolytic treatment of ischemic stroke.

Synthesis and properties of CO2-switchable Dex-g-PAHMA copolymers

Dextran graft poly((N-amidino)hexyl methacrylamide) (Dex-g-PAHMA) copolymers were synthesized by free radical polymerization in aqueous solution and characterized. Dex-g-PAHMA copolymers can self-assemble into micelles with the PAHMA rich core and dextran rich shell in aqueous media. The CO2 sensitivity of the micelles was investigated by dynamic light scattering (DLS), conductivity and zeta potential. The results confirmed that the Dex-g-PAHMA copolymer micelles have reversible CO2 sensitivity. The micelles can be used as doxorubicin (DOX) carriers and DOX molecules are mainly located in the core of the micelles. The MTT assay indicated that the Dex-g-PAHMA graft copolymers are non-toxic to cells in the copolymer concentration range of 5–1000 μg mL−1, whereas the relative cell viability is greatly reduced with the increase of copolymer concentration for DOX-loaded micelles. The DOX-loaded micelles can be endocytosed by MCF-7 cells and the DOX can release from micelles and diffuse into the cell nucleus. The Dex-g-PAHMA copolymers have promising applications as drug carriers for cancer therapy.

Surface patterned hydrogel film as a flexible scaffold for 2D and 3D cell co-culture

Herein we report a facile route for the preparation of surface patterned dynamic hydrogel films, which are not only a matrix to encapsulate one type of cell in 3D but also a substrate to support aligned aggregates of magnetic silica rods to adhere another type of cell in 2D. This enables the composite hydrogel films to be flexible scaffolds for engineering multi-cellular tissues.

Nano-rods of doxorubicin with poly(L-glutamic acid) as a carrier-free formulation for intratumoral cancer treatment

In addition to intravenous injections (i.v.), topical dosing of doxorubicin hydrochloride (DOX) has also been the focus of cancer treatment recently, although it normally requires well-designed drug carriers. In this work, we found that DOX could form fibril-shaped DOX aggregates via self-assembly in phosphate buffer (PB) and then co-assemble with poly(l-glutamic acid) (PGA) at a proper polymer-drug ratio, giving a unique nano-rod-shaped microstructure. The release rate of DOX from the PGA/DOX nano-rods was thus easily controlled at a slower release rate without being encapsulated by any classic carrier. In vitro cell culture demonstrated that the PGA/DOX nano-rods were not favorably taken up by cancer cells, which can be attributed to the negatively charged nature and the non-spherical shape of the aggregates. These features suggest great potential for the PGA/DOX assemblies for a sustained delivery through the intratumoral pathway (i.t.) as a carrier-free formulation. In the mouse model it diminished organ damage at a dose level of 30 mg kg-1via i.t. injections compared to the serious cardiotoxicity and renal toxicity via typical multiple i.v. dosage of free drug solution at 5 mg kg-1. As a result, the PGA/DOX formulation showed efficient anti-tumor activity. The survival rate of tumor bearing mice was significantly increased by over 35% compared to the i.v. injections of DOX solutions. Therefore, PGA/DOX nano-rods may provide a new and safe delivery route of the common anti-tumor drug.

Janus Nanocage toward Platelet Delivery

The platelet-shaped Janus nanocages with a mesoporous silica shell are prepared. PEG moiety onto the exterior surface is responsible for good dispersity in water. The graphene sheet inside the cavity is responsible for hydrophobic performance to selectively capture hydrophobic species, and photothermal effect by NIR irradiation. As a biocompatible DOX-loaded Janus platelet delivery, HeLa cell cytotoxicity is greatly enhanced under NIR irradiation. There exists a synergetic effect between the chemotherapy and photothermal therapy.

Enhanced acaricidal activity of ricinine achieved by the construction of nano-formulation using amphiphilic block copolymer

Efficient control of Tetranychus cinnabarinus (B.) is in challenge worldwide. Herein we report the use of an amphiphilic block copolymer, poly(ethylene oxide)-b-poly(caprolactone) (PEO–PCL), as a micellar carrier to make formulations of ricinine, a water insoluble botanical pesticide, and the tests of their physical properties and moreover the acaricidal activity on Vigna unguiculata (L). Compared to the formulations made from small molecular surfactant, e.g. Tween-80, the polymer formulations showed differentiated spreading property on T. cinnabarinus (B.) and V. unguiculata (L.) leaf surfaces, i.e. having slightly lower contact angle on the mites integument. This contributes a relatively easy wash-off performance of the polymer formulations from the V. unguiculata (L.) leaf and meanwhile an enhanced protection to the plant in the simulated field trial. Our work thus suggests favorable characteristic of amphiphilic polymer in the future development of insecticides.