Light-Activated Reactive Oxygen Species-Responsive Nanocarriers for Enhanced Photodynamic Immunotherapy of Cancer.

Exploring polymeric nanoplatforms combined with reactive oxygen species (ROS) responsiveness with mitochondria targeting has emerged as an effective strategy for enhanced photodynamic therapy (PDT). Amphiphilic copolymers were synthesized by reacting acrylamide thioketal (TK) linkers with amino-terminated triphenylphosphonium-polyethylene glycol and dodecylamine for encapsulating chlorin e6 (Ce6) via self-assembly. Then, anionic cladding with tumor targeting deshelled in tumor acidic microenvironments was surface-anchored by electrostatic forces (BioPEGDMA@RM). After sequential targeting to the mitochondria of cancerous cells, BioPEGDMA@RM could be light-activated with Ce6 released upon ROS cleavage of TK linkages. It was found that Ce6-loaded BioPEGDMA@RM exhibited higher cytotoxicity on CT26 cells and performed stronger ability on the production of ROS than that without TK linkers. Moreover, a minimum illumination of 3 and 5 min could be required for achieving the maximum release of Ce6 and high in vitro cytotoxicity for Ce6-loaded BioPEGDMA@RM, respectively. Furthermore, Ce6-loaded BioPEGDMA@RM showed 1.29-fold and 1.21-fold higher tumor inhibition on BALB/c nude mice and Kunming mice and stimulated immunologic reactions with more generation of IFN-γ and TNF-α and activation of CD3+, CD4+, and CD8+ T-lymphocytes and DCs than that of Ce6-loaded nanoparticles without TK bonds. This work provided an academic reference for the development of ROS-responsive drug delivery systems for advanced PDT efficiency.

pH-triggered polydopamine-decorated nanocellulose membranes for continuously selective separation of organic dyes.

Membrane separation technology has emerged as a powerful tool to separate organic dyes from industrial wastewater. However, continuously selective separation of organic dyes with similar molecular weight remains challenging. Herein, we presented a pH-triggered membrane composed of polydopamine-decorated tunicate-derived cellulose nanofibers (PDA@TCNFs) for selective separation of organic dyes. Such self-supporting membranes with nanoporous structure were fabricated by facile vacuum-assisted filtration of PDA@TCNF suspension. The incorporation of polydopamine not only enhanced the stability of the membranes, but also endowed membranes with excellent pH sensitivity, facilitating the continuously selective separation of organic dyes. These pH-triggered PDA@TCNF membranes could selectively separate Methyl Orange (MO) and Rhodamine B (RB) from the MO/RB mixed solution by switching the pH values. The continuously selective separation of the MO/RB mixed solution was demonstrated, where both MO and RB recovery ratios maintained at ∼99 % during 50 repeated cycles. This work provides a new strategy to develop a pH-triggered sustainable nanocellulose-based membrane for continuously selective separation of mixed dyes.

Applications and perspectives of quaternized cellulose, chitin and chitosan: A review.

Recently, increasing attention has been paid to natural polysaccharides for their low cost, biocompatibility and biodegradability. Quaternization is a modification method to improve the solubility and antibacterial ability of natural polysaccharides. Water-soluble derivatives of cellulose, chitin and chitosan offer the prospect of diverse applications in a wide range of fields, such as antibacterial products, drug delivery, wound healing, sewage treatment and ion exchange membranes. By combining the inherent properties of cellulose, chitin and chitosan with the inherent properties of the quaternary ammonium groups, new products with multiple functions and properties can be obtained. In this review, we summarized the research progress in the applications of quaternized cellulose, chitin and chitosan in recent five years. Moreover, ubiquitous challenges and personal perspectives on the further development of this promising field are also discussed.

Antibacterial nanocellulose membranes coated with silver nanoparticles for oil/water emulsions separation.

The superhydrophilic/underwater superoleophobic nanocellulose-based membranes show great potential in oil/water emulsion separation. However, nanocellulose composed of polysaccharides inevitably suffered from bacterial erosion during use or storage, resulting in structural damage or reduced separation efficiency. In this work, silver nanoparticles (AgNPs) as effective bactericidal materials are uniformly deposited on tunicate cellulose nanocrystals (TCNCs) by in situ hydrothermal reduction of silver nitrate. TCNCs not only act as reducing agents for silver ions, but also work as dispersant and stabilizers of AgNPs. Nanocomposite membranes are fabricated by vacuum-assisted filtrating of AgNPs@TCNC suspension, which exhibit nanoporous structure, superhydrophilicity, and underwater superoleophobicity. These membranes could efficiently separate oil/water microemulsion with water flux (>324 L m-2 h-1 bar-1) and oil rejection (>99%). Importantly, these membranes show excellent antibacterial efficacy against E. coli and S. aureus, benefiting to their long-term use and storage.

Targeted Recruitment and Degradation of Estrogen Receptor α by Photothermal Polydopamine Nanoparticles for Breast Tumor Ablation.

The major challenges of photothermal therapy (PTT) toward clinical application are the severe skin injury and inflammation response associated with high power laser irradiation. Herein, polydopamine nanoparticles (PDA-EST and PDA-RAL) targeted to estrogen receptor α (ERα) for efficient ablation of breast tumor under a low irradiation density of 0.1 W cm-2 are reported. These nanoparticles are capable of recruiting ERα on their surface and induce a complete ERα degradation via localized heat. Owing to the ERα targetability, PDA-EST and PDA-RAL strongly suppress the proliferation of breast cancer cells without causing significant inflammation. This work provides a generalized method for enhancing PTT efficacy under low irradiation density.

A pH/ROS-responsive, tumor-targeted drug delivery system based on carboxymethyl chitin gated hollow mesoporous silica nanoparticles for anti-tumor chemotherapy.

A new nanosystem was prepared by coating ROS-cleavable thioketal (TK) bonded hollow mesoporous silica nanoparticles with carboxymethyl chitin via electrostatic interaction and further surface-anchored with glucose-regulated protein 78 binding peptide for targeted-delivery of doxorubicin (DOX) and α-tocopheryl succinate (α-TOS). The nanosystem (HMSN-TK-CMCH-GRP78P) showed an average size of 265 nm after loading DOX and α-TOS with a drug loading content of 4.06 % and 7.64 %, respectively. The in vitro release studies revealed the pH/ROS dual-responsibility of DOX/α-TOS loaded HMSN-TK-CMCH-GRP78P. The released α-TOS increased the intracellular ROS concentration, which could induce the cleavage of TK linkages and in turn accelerate DOX release. Moreover, the nanosystem could target to 4T1 cells, causing cell death in vitro and suppress tumor growth in vivo in 4T1-bearing BALB/c mice with reduced side effects, which illustrated that the nanosystem led to an effective anti-tumor efficacy and exhibited as a promising carrier to deliver chemotherapeutic agents for chemotherapy.

Sequential-targeting nanocarriers with pH-controlled charge reversal for enhanced mitochondria-located photodynamic-immunotherapy of cancer.

Targeting delivery of photosensitizers to mitochondria as the most sensitive cellular organelles to reactive oxygen species (ROS) by positively charged polymeric nanocarriers (NCs) is one of the useful methods for efficient photodynamic therapy (PDT). However, the NCs with positively charged mitochondria-targeting moieties are easily cleaned during circulation, restricting their in vivo applications. Herein, to address this issue and enhance in vivo PDT efficacy, we developed a sequential-targeting delivery system consisting of mitochondria-targeting micelles as the core prepared from the cationic amphiphilic copolymer for loading chlorin e6 (Ce6) and a tumor-targeting pH-dependent charge transformational layer as the shell obtained from 2,3-dimethylmaleic anhydride modified Biotin-PEG4000-NH2 (BioPEGDMA) via electrostatic interaction. Concealed by the anionic shell, the as-prepared NCs showed longer retention within the first stage of tumor-targeting. Then, the accumulated NCs conversed to positive charge in tumor extracellular microenvironment (pH ∼ 6.5), which could be more effectively internalized by tumor cells, and the re-exposed triphenylphosphonium (TPP) groups endowed their second-stage targetability to the mitochondria. In vivo experiments revealed that the Ce6-loaded NCs exhibited remarkable tumor inhibition rates of 84.1% and 93.2% on BALB/c nude mice and Kunming mice, respectively, under 660 nm NIR irradiation, and stimulated immune responses with upregulated expression of IFN-γ, TNF-α and CD3+ in tumor tissues, and enhanced activation of CD3+/CD4+, CD3+/CD8+ T lymphocytes and DCs in both tumor tissues and lymph glands. This work provided a new pathway for the development of smart drug delivery system with advanced PDT efficacy. STATEMENT OF SIGNIFICANCE: Although the existing targeting delivery of photosensitizers to mitochondria by positively charged nanocarriers (NCs) have efficiently enhanced photodynamic therapy (PDT), their positive charges caused rapid clearance during circulation, which has restricted their in vivo applications. Therefore, we fabricated a novel sequential-targeting NC to solve the problem. The tumor accumulated NCs conversed to positive charge in tumor extracellular microenvironment, and the re-exposed triphenylphosphonium groups initiated second-stage targetability to mitochondria. This system exhibited remarkable tumor inhibition efficiency both in vitro and in vivo. Moreover, as we hypothesized, mitochondria-located PDT could promote immune response, resulting in improvement of PDT. The strategy of sequential targeting-based PDT in combination with augmented immune response showed a novel pathway for the development of smart drug delivery system with advanced PDT.

Dendrimer-grafted bioreducible polycation/DNA multilayered films with low cytotoxicity and high transfection ability.

Controlled release of incorporated foreign DNA from multilayered films plays an important role in surface-mediated gene delivery. Herein, multilayered polyelectrolyte complex thin films, composed of dendrimer-grafted bio-reducible cationic poly(disulfide amine) and plasmid DNA, were fabricated via layer-by-layer (LBL) assembly for in vitro localized gene delivery. The UV absorbance and thickness of the LBL films were found to have linear correlation with the numbers of poly(disulfide amine)/DNA bilayers. Although LBL films were stable in PBS buffer, their degradation could be triggered by reducing agents (i.e. glutathione, GSH). The degradation rate of the films is directly proportional to the GSH concentration, which in turn affected the corresponding gene expression. All poly(disulfide amine)/DNA films exhibited lower cytotoxicity and higher transfection activity in comparison with PEI/DNA multilayered films. Moreover, LBL films showed the highest transfection efficiency in the presence of 2.5 mM GSH when cultured with 293T cells, with ~36% GFP-positive 293T cells after 5-days of co-culture. These DNA-containing reducible films could potentially be useful in gene therapy and tissue engineering by controlling the release of incorporated DNA.

Doxorubicin loaded tumor-triggered targeting ammonium bicarbonate liposomes for tumor-specific drug delivery.

Ammonium bicarbonate (ABC) liposomes can only release drugs extracellularly while intracellular drug delivery could be more promising than extracellular release in chemotherapy. The purpose of this work was to endow the ABC liposomes with tumor-triggered targeting effect, to realize the intracellular drug release and retain the long circulation characteristics of the liposomes. The tumor-triggered targeting ABC (TT-ABC) liposomes were proposed to improve uptake of tumor cells owing to folate (FA) - specific binding. To retain the long circulation characteristics of the TT-ABC liposomes, we synthesized PEGylated phospholipid with a pH-sensitive imine bond (DSPE-PEG5000) and added it to the liposomes. After endocytosis by tumor cells via active targeting, the TT-ABC liposomes produced carbon dioxide (CO2) bubbles at elevated temperature or in the acidic endo/lysosome. The permeable defects could be created in the phospholipid bilayer by the generating CO2 bubbles, so the liposomes could quickly release the drugs intracellularly. Doxorubicin (DOX) loaded TT-ABC (DOX@TT-ABC) liposomes exhibited good stability at physiological pH (7.4) and released DOX quickly at reduced pH (6.4) and hyperthermia (42 °C). DOX@TT-ABC liposomes showed significantly enhanced cellular uptake, intracellular accumulation of DOX, and cytotoxicity at pH 6.4 and 42 °C.

Polyaniline promotes peripheral nerve regeneration by enhancement of the brain­derived neurotrophic factor and ciliary neurotrophic factor expression and activation of the ERK1/2/MAPK signaling pathway.

A previous study has demonstrated a progression in the nerve regeneration by polyaniline/cellulose (PANI/RC), although the underlying mechanism was not elucidated. In the present study, regenerated nerves were investigated, using histological techniques, functional assays and western blot analysis. The triceps surae muscle weight ratio percentages of the sham, regenerated cellulose (RC) and the PANI/RC groups were 38.88±4.76 and 76.32±7.11%, respectively. The thickness of the myelin sheath for the aforementioned groups were as follows: 1.2±0.27; 0.49±0.21 and 0.93±0.28 µl. Western blot analysis demonstrated that the ciliary neurotrophic factor (CNTF) and brain­derived neurotrophic factor (BDNF) were highly expressed in the regenerated nerve in the presence of polyaniline. Phosphorylated extracellular kinase (p­ERK)1/2 expression in the PANI/RC group was significantly elevated compared with the RC group (1.83­fold) and the sham group (4.92­fold). The expression of the axon sprout­associated proteins, such as Tau, α­tubulin and growth associated protein­43, were increased (1.64, 1.59 and 1.24­fold, respectively) compared with the RC group. The results demonstrated that PANI enhances the expression and secretion of BDNF and CNTF, activates the ERK1/2 signaling pathway and increases the expression levels of the GAP­43, Tau and α­tubulin, suggesting an insight into nerve regeneration and possible clinical interventions in nerve injury.

Biocompatible cellulose-based superabsorbent hydrogels with antimicrobial activity.

Current superabsorbent hydrogels commercially applied in the disposable diapers have disadvantages such as weak mechanical strength, poor biocompatibility, and lack of antimicrobial activity, which may induce skin allergy of body. To overcome these hassles, we have developed novel cellulose based hydrogels via simple chemical cross-linking of quaternized cellulose (QC) and native cellulose in NaOH/urea aqueous solution. The prepared hydrogel showed superabsorbent property, high mechanical strength, good biocompatibility, and excellent antimicrobial efficacy against Saccharomyces cerevisiae. The presence of QC in the hydrogel networks not only improved their swelling ratio via electrostatic repulsion of quaternary ammonium groups, but also endowed their antimicrobial activity by attraction of sections of anionic microbial membrane into internal pores of poly cationic hydrogel leading to the disruption of microbial membrane. Moreover, the swelling properties, mechanical strength, and antibacterial activity of hydrogels strongly depended on the contents of quaternary ammonium groups in hydrogel networks. The obtained data encouraged the use of these hydrogels for hygienic application such as disposable diapers.

An Examination of Differences in the New Bone Formation Promoted by Different Doses of Recombinant Human Parathyroid Hormone during Mandibular Distraction Osteogenesis.

BACKGROUND: The administration of different doses of parathyroid hormone to promote mandibular distraction osteogenesis remains unclear. The objective of the present study was to examine the effects of recombinant human parathyroid hormone on new bone formation during mandibular distraction osteogenesis and to investigate the dose-effect relationship associated with this phenomenon. METHODS: A total of 45 rabbits were used to establish the mandibular distraction osteogenesis model. The rabbits were divided into a control group (that received a subcutaneous injection of 1 ml of saline every other day) and experimental groups A, B, C, and D (that received subcutaneous injections of 10, 20, 30, and 40 µg/kg of recombinant human parathyroid hormone, respectively, every other day). On days 1, 7, and 14 of the consolidation period after the distraction had been completed, new bone in the distraction region was examined through histomorphometric investigation and bone mineral density testing. RESULTS: On days 1, 7, and 14 of the fixation period, the number of osteoblasts, trabecular bone area, and bone mineral density were greater in each experimental group than in the control group. On day 1 of the consolidation period, group C featured the highest average number of osteoblasts. On day 14 of the consolidation period, group C exhibited the highest bone mineral densities and largest trabecular bone areas. CONCLUSIONS: Intermittent subcutaneous injections of recombinant human parathyroid hormone can promote new bone formation during mandibular distraction osteogenesis. Different doses of recombinant human parathyroid hormone promoted mandibular distraction osteogenesis to differing extents.