Application of carrier and plasticizer to improve the dissolution and bioavailability of poorly water-soluble baicalein by hot melt extrusion.

The objective of this study was to develop a suitable formulation for baicalein (a poorly water-soluble drug exhibiting high melting point) to prepare solid dispersions using hot melt extrusion (HME). Proper carriers and plasticizers were selected by calculating the Hansen solubility parameters, evaluating melting processing condition, and measuring the solubility of obtained melts. The characteristic of solid dispersions prepared by HME was evaluated. The dissolution performance of the extrudates was compared to the pure drug and the physical mixtures. Physicochemical properties of the extrudates were characterized by differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and Fourier transform infrared spectroscopy (FTIR). Relative bioavailability after oral administration in beagle dogs was assessed. As a result, Kollidon VA64 and Eudragit EPO were selected as two carriers; Cremophor RH was used as the plasticizer. The dissolution of all the extrudates was significantly improved. DSC and PXRD results suggested that baicalein in the extrudates was amorphous. FTIR spectroscopy revealed the interaction between drug and polymers. After oral administration, the relative bioavailability of solid dispersions with VA64 and EPO was comparative, about 2.4- and 2.9-fold greater compared to the pure drug, respectively.

Amyloid Protein-Biofunctionalized Polydopamine Nanoparticles Demonstrate Minimal Plasma Protein Fouling and Efficient Photothermal Therapy.

Polydopamine (PDA) shows great application potential in photothermal therapy (PTT) of tumors due to its excellent photothermal performance. However, PDA rich in a large number of catechin structures, with strong adhesion, can readily attach to plasma proteins in blood to form protein corona, which greatly hinders the transfer efficiency to tumors and reduces the bioavailability. In this paper, a simple, rapid phase-transitioned albumin biomimetic nanocorona (TBSA) is used for the surface camouflage of PDA nanoparticles for minimal plasma protein fouling and efficient PTT. TBSA coating is formed by the BSA-derived amyloid through the hydrophobic aggregation near the isoelectric point and the rupture of disulfide bonds by tris(2-carboxyethyl) phosphine. The stable PDA@TBSA complexes are formed by camouflaging TBSA onto the surface of PDA through hydrophobic, electrostatic, and covalent binding between TBSA and PDA, which showed excellent anti-plasma protein adsorption properties profited from the surface charge of PDA@TBSA approaching equilibrium and the surface passivation of BSA. The plasma protein thickness of the PDA@TBSA surface is 6 times lower than that of PDA at adsorption saturation. In vitro and in vivo experiments have revealed that PDA@TBSA has an excellent photothermal antitumor effect compared to PDA. Both PDA and PDA@TBSA treatment plus 808 nm laser irradiation result in more than 70% inhibition on tumor cell proliferation. In addition, PDA@TBSA does not cause a significant inflammatory response and tissue damage. Taken together, the TBSA coating endows PDA with low-fouling functions in blood and improves the residence time of PDA in blood and enrichment in the tumor tissue. This work offers a novel and efficient strategy for the design of functional nanosystems exploiting the speciality of the biomolecular corona formation around nanomaterials.

Self-assembly and chiroptical property of poly(N-acryloyl-L-amino acid) grafted celluloses synthesized by RAFT polymerization.

Three amphiphilic poly(N-acryloyl-L-amino acid) grafted celluloses were prepared by RAFT polymerization of N-acryloyl-L-amino acid, where amino acid is alanine, proline or glutamic acid, onto cellulose backbones. The chemical structure and solution properties of the brush copolymers were characterized with FTIR, NMR and wide angle X-ray diffraction (WAXD). The thermal stability of the brush copolymers was estimated by thermal gravimetric analysis (TGA). Circular dichroism (CD) and specific rotation measurements confirmed that these grafted celluloses had characteristic chiroptical properties. The amphiphilic brush copolymers self-assembled into micelles in the aqueous solution as confirmed by transmission electron microscopy (TEM) and dynamic light scattering (DLS) analyses. The micellar aggregates showed a tunable pH-responsive property and disaggregated to form unimolecular micelles at higher pH in diluted solutions. The brush copolymers have potential applications in controlled drug release and high-performance liquid chromatography, and so forth.

A low-molecular-weight heparin-coated doxorubicin-liposome for the prevention of melanoma metastasis.

Tumor metastasis is the biggest challenge in cancer therapy. During the metastasis process, metastatic cells could acquire stealth ability toward immune system through the formation of a protection cloak by hijacking platelets (PTs). Heparins, a heterogeneous mixture of glycosaminoglycans, can inhibit metastatic cascades by blocking P-selectin-mediated intercellular adhesion between tumor cells and PTs. In this study, low-molecular-weight heparin-coated doxorubicin-loaded liposome (LMWH-DOX-Lip) was developed for metastasis preventative therapy. The formation of LMWH-DOX-Lip was based on electrostatic interactions between the negatively charged heparins and cationic lipids. LMWH-DOX-Lip prepared at the optimum prescription possessed high entrapment efficiency, ideal particle size and zeta potential. Morphology of LMWH-DOX-Lip was characterized by atomic force microscopy and transmission electron microscopy. The results of confocal microscopic observations and flow cytometry analysis indicated that LMWH-DOX-Lip mediated an efficient cellular uptake in B16F10 melanoma cell line. Besides, LMWH-DOX-Lip displayed an increased cytotoxic over their unmodified counterparts. Furthermore, the inhibition effect of LMWH-DOX-Lip on adhesion between tumor cells and PTs/P-selectin was observed. In vivo study performed on a pulmonary melanoma mouse model revealed a substantially tumor metastasis prevention by LMWH-DOX-Lip. All these results suggested that LMWH-DOX-Lip could significantly inhibit metastasis through preventing the tumor cell-platelet interactions and in the meantime suppressed tumor growth.

Polybrene: Observations on cochlear hair cell necrosis and minimal lentiviral transduction of cochlear hair cells.

Polybrene is widely used to enhance viral transduction; however, little is known about the utility thereof, in enhancing lentiviral transduction of cochlear cells. In the present study, we examined the cytotoxic effects of polybrene, and the further effects thereof, on lentiviral transduction of cochlear cells, especially sensory hair cells. Cochlear basilar membranes of newborn rats were cultured and treated with 0.1-10 µg/mL polybrene for 24h to explore the potential development of ototoxicity. PI staining and TUNEL detection were used to evaluate necrosis or apoptosis of hair cell. Various doses of lentivirus-GFP were added to cochlear organotypic cultures with safe concentrations of polybrene, incubated for 24h, and cultured (in the absence of the virus and polybrene) for a further 48 h. Transduction efficiencies were evaluated. The results showed that polybrene at 0.1 µg/mL was safe to cochlear cells, and 0.5-10 µg/mL concentration induced hair cell necrosis in a dose-dependent manner. However, supporting cells were not damaged. Lentiviral vectors transduced into cochlear cells and 0.1 µg/mL polybrene enhanced transduction efficiency. However, hair cells were hardly transduced with lentiviral vectors either alone or in the presence of 0.1 µg/mL polybrene. The use of polybrene to aid lentiviral transduction of cochlear hair cells requires further attention.

PFA-fixed Hsp60sp-loaded dendritic cells as a vaccine for the control of mouse experimental allergic encephalomyelitis.

We have shown that Hsp60sp-loaded immature dendritic cells (DC/sp) can protect mice from the induction of experimental allergic encephalomyelitis (EAE) by inducing Qa-1-restricted CD8(+) T regulatory (Treg) cells. The binding half-life between Qa-1 and Hsp60sp is particularly short and leads to an unstable Qa-1/peptide complex that significantly decreases the efficacy of this vaccination. To prevent Qa-1/Hsp60sp complex dissociation, we utilized paraformaldehyde (PFA) fixation to stabilize the formation of the Qa-1/Hsp60sp complex and maximize the function of DC/sp as a vaccine to control autoimmune diseases. Compared with the non-fixed DC/sp, the fixed DC/sp (FDC/sp) showed an enhanced ability to activate Qa-1-restricted Hsp60sp-specific CD8(+)T cells in vitro and prevented EAE in vivo. Importantly, the FDC/sp maintained immune activity following cryopreservation for 1 week or after storage for 72 h at 4 °C. These results indicate that PFA fixation can sustain or increase the efficacy of DC/sp by improving the stability of the Qa-1/Hsp60sp complex on the surface of the DC/sp. In addition, PFA fixation creates a time window for DC/sp storage, transport and application. Our data suggest a potential clinical use of FDC/sp as a vaccine for the prevention and treatment of autoimmune disease.