An Active Bio-Based Food Packaging Material of ZnO@Plant Polyphenols/Cellulose/Polyvinyl Alcohol: DESIGN, Characterization and Application.

Active packaging materials protect food from deterioration and extend its shelf life. In the quest to design intriguing packaging materials, biocomposite ZnO/plant polyphenols/cellulose/polyvinyl alcohol (ZnPCP) was prepared via simple hydrothermal and casting methods. The structure and morphology of the composite were fully analyzed using XRD, FTIR, SEM and XPS. The ZnO particles, plant polyphenols (PPL) and cellulose were found to be dispersed in PVA. All of these components share their unique functions with the composite's properties. This study shows that PPL in the composite not only improves the ZnO dispersivity in PVA as a crosslinker, but also enhances the water barrier of PVA. The ZnO, PPL and cellulose work together, enabling the biocomposite to perform as a good food packaging material with only a 1% dosage of the three components in PVA. The light shielding investigation showed that ZnPCP-10 can block almost 100% of both UV and visible light. The antibacterial activities were evaluated by Gram-negative Escherichia coli (E. coli) and Gram-positive staphylococcus aureus (S. aureus), with 4.4 and 6.3 mm inhibition zones, respectively, being achieved by ZnPCP-10. The enhanced performance and easy degradation enables the biocomposite ZnPCP to be a prospect material in the packaging industry.

Construction of Enzyme-Responsive Micelles Based on Theranostic Zwitterionic Conjugated Bottlebrush Copolymers with Brush-on-Brush Architecture for Cell Imaging and Anticancer Drug Delivery.

Bottlebrush copolymers with different chemical structures and compositions as well as diverse architectures represent an important kind of material for various applications, such as biomedical devices. To our knowledge, zwitterionic conjugated bottlebrush copolymers integrating fluorescence imaging and tumor microenvironment-specific responsiveness for efficient intracellular drug release have been rarely reported, likely because of the lack of an efficient synthetic approach. For this purpose, in this study, we reported the successful preparation of well-defined theranostic zwitterionic bottlebrush copolymers with unique brush-on-brush architecture. Specifically, the bottlebrush copolymers were composed of a fluorescent backbone of polyfluorene derivate (PFONPN) possessing the fluorescence resonance energy transfer with doxorubicin (DOX), primary brushes of poly(2-hydroxyethyl methacrylate) (PHEMA), and secondary graft brushes of an enzyme-degradable polytyrosine (PTyr) block as well as a zwitterionic poly(oligo (ethylene glycol) monomethyl ether methacrylate-co-sulfobetaine methacrylate) (P(OEGMA-co-SBMA)) chain with super hydrophilicity and highly antifouling ability via elegant integration of Suzuki coupling, NCA ROP and ATRP techniques. Notably, the resulting bottlebrush copolymer, PFONPN9-g-(PHEMA15-g-(PTyr16-b-P(OEGMA6-co-SBMA6)2)) (P2) with a lower MW ratio of the hydrophobic side chains of PTyr and hydrophilic side chains of P(OEGMA-co-SBMA) could self-assemble into stabilized unimolecular micelles in an aqueous phase. The resulting unimolecular micelles showed a fluorescence quantum yield of 3.9% that is mainly affected by the pendant phenol groups of PTyr side chains and a drug-loading content (DLC) of approximately 15.4% and entrapment efficiency (EE) of 90.6% for DOX, higher than the other micelle analogs, because of the efficient supramolecular interactions of π-π stacking between the PTyr blocks and drug molecules, as well as the moderate hydrophilic chain length. The fluorescence of the PFONPN backbone enables fluorescence resonance energy transfer (FRET) with DOX and visualization of intracellular trafficking of the theranostic micelles. Most importantly, the drug-loaded micelles showed accelerated drug release in the presence of proteinase K because of the enzyme-triggered degradation of PTyr blocks and subsequent deshielding of P(OEGMA-co-SBMA) corona for micelle destruction. Taken together, we developed an efficient approach for the synthesis of enzyme-responsive theranostic zwitterionic conjugated bottlebrush copolymers with a brush-on-brush architecture, and the resulting theranostic micelles with high DLC and tumor microenvironment-specific responsiveness represent a novel nanoplatform for simultaneous cell image and drug delivery.

Oral opening training increases oral opening in patients with oral submucous fibrosis. / å¼ å£è®­ç»ƒå¢žåŠ å£è ”é»è†œä¸‹çº¤ç»´æ€§å˜æ‚£è€ çš„å¼ å£åº¦.

OBJECTIVES: The mouth restriction of patients with oral submucous fibrosis (OSF) seriously affects their eating food and the quality of life. There are few reports about improving the oral opening degree in patients with OSF. This study aims to explore the effect of oral opening training on the improvement of mouth opening limitation in patients with OSF treated with local injection. METHODS: A total of 220 outpatients with limited mouth opening of OSF were collected from the Center of Stomatology, Xiangya Hospital, Central South University, and randomly divided into a control group and an experiment group (n=110). The control group were treated with local injection of Salvia miltiorrhiza and triamcinolone acetonide, once a week, and 8 times a course. The experimental group were treated with local injection combined with mouth opening training for 2 years. The degree of mouth opening was compared between the 2 groups at the end of local injection treatment, 1 year and 2 years after the treatment. The curative effect was evaluated according to the size of the opening, the lamellar structure of the mucosa, and the condition of the cords. RESULTS: A total of 197 patients completed the whole course of treatment, with 107 in the experimental group and 90 in the control group. At the end of treatment, 1 year and 2 years after the treatment, the degree of mouth opening in the experimental group was (36.14±2.62), (39.67±2.67), and (39.80±2.57) mm, respectively, which was significantly higher than that in the control group (24.71±1.97), (22.82±2.13), and (22.02±2.09) mm, respectively. The difference was significant (P<0.05). The increase of mouth opening in the experimental group was significantly better than that in the control group. Two years after local injection treatment, the effective rate of the experimental group was 97.1%, which was significantly higher than that of the control group (47.8%, P<0.05). CONCLUSIONS: Mouth opening training can significantly increase the degree of mouth opening in patients with OSF treated with local injection.

Micelles with Cyclic Poly(ε-caprolactone) Moieties: Greater Stability, Larger Drug Loading Capacity, and Slower Degradation Property for Controlled Drug Release.

Polymer topology exerts a significant effect on its properties and performance for potential applications. Cyclic topology and its derived structures have been recently shown to outperform conventional linear analogues for drug delivery applications. However, an amphiphilic tadpole-shaped copolymer consisting of a cylic hydrophobic moiety has rarely been explored. For this purpose, a tadpole-shaped amphiphilic diblock copolymer of poly(ethylene oxide)-b-(cyclic poly(ε-caprolactone)) (mPEG-b-cPCL) was synthesized successfully via ring-opening polymerization (ROP) of ε-CL using a mPEG-based macroinitiator with both a hydroxyl and an azide termini and subsequent intrachain Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAc) click cyclization. A comparison study on the self-assembly behaviors, in vitro drug loading and drug release profiles, and degradation properties of the resulting mPEG-b-cPCL (C) with those of the linear counterpart (mPEG-b-PCL, L) revealed that mPEG-b-cPCL micelles are a better formulation than the micelles formed by the linear counterparts in terms of micelle stability, drug loading capacity, and the degradation property. Interestingly, compared to the single degradation of L, C exhibited a slower two-stage degradation process including the topological change from tadpole shape to linear conformation and the subsequent degradation of a linear polymer. This study therefore uncovered the topological effect of a hydrophobic moiety on the properties of the self-assembled micelles and developed a complementary alternative to enhance the micelle stability by introducing a cyclic hydrophobic segment.

Fabrication of Hyperbranched Block-Statistical Copolymer-Based Prodrug with Dual Sensitivities for Controlled Release.

Dendrimer with hyperbranched structure and multivalent surface is regarded as one of the most promising candidates close to the ideal drug delivery systems, but the clinical translation and scale-up production of dendrimer has been hampered significantly by the synthetic difficulties. Therefore, there is considerable scope for the development of novel hyperbranched polymer that can not only address the drawbacks of dendrimer but maintain its advantages. The reversible addition-fragmentation chain transfer self-condensing vinyl polymerization (RAFT-SCVP) technique has enabled facile preparation of segmented hyperbranched polymer (SHP) by using chain transfer monomer (CTM)-based double-head agent during the past decade. Meanwhile, the design and development of block-statistical copolymers has been proven in our recent studies to be a simple yet effective way to address the extracellular stability vs intracellular high delivery efficacy dilemma. To integrate the advantages of both hyperbranched and block-statistical structures, we herein reported the fabrication of hyperbranched block-statistical copolymer-based prodrug with pH and reduction dual sensitivities using RAFT-SCVP and post-polymerization click coupling. The external homo oligo(ethylene glycol methyl ether methacrylate) (OEGMA) block provides sufficient extracellularly colloidal stability for the nanocarriers by steric hindrance, and the interior OEGMA units incorporated by the statistical copolymerization promote intracellular drug release by facilitating the permeation of GSH and H+ for the cleavage of the reduction-responsive disulfide bond and pH-liable carbonate link as well as weakening the hydrophobic encapsulation of drug molecules. The delivery efficacy of the target hyperbranched block-statistical copolymer-based prodrug was evaluated in terms of in vitro drug release and cytotoxicity studies, which confirms both acidic pH and reduction-triggered drug release for inhibiting proliferation of HeLa cells. Interestingly, the simultaneous application of both acidic pH and GSH triggers promoted significantly the cleavage and release of CPT compared to the exertion of single trigger. This study thus developed a facile approach toward hyperbranched polymer-based prodrugs with high therapeutic efficacy for anticancer drug delivery.

Facile Fabrication of 10-Hydroxycamptothecin-Backboned Amphiphilic Polyprodrug with Precisely Tailored Drug Loading Content for Controlled Release.

Polymeric prodrugs with precisely controlled drug loading content (DLC) and rapid intracellular destabilization generally require complicated chemistry that hinders large-scale manufacture. For this purpose, we reported in this study a facile construction of reduction-sensitive amphiphilic polyprodrugs with an anticancer drug, 10-hydroxycamptothecin (HCPT), and a hydrophilic poly(ethylene oxide) (PEG) moiety as the alternating building blocks of the multiblock copolymer using Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAc) click coupling between azide-SS-HCPT-SS-azide and alkyne-PEG-alkyne. Adoption of PEGs with two different molecular weights (MWs) of 400 and 1450 Da (PEG400 and PEG1450) afforded two polyprodrugs with different DLCs. Both formulations can self-assemble into spherical micelles with hydrodynamic diameter smaller than 200 nm, and exhibit glutathione (GSH)-triggered degradation for promoted drug release. A further comparison study revealed that the PEG1450-based polyprodrug is a better formulation than the analogue constructed from PEG400 in terms of in vitro drug release behaviors, and cytotoxicity. This work thus provides a facile yet efficient strategy toward polymeric prodrugs with precisely controlled DLC and reduction-triggered degradation for enhanced anticancer drug delivery.

Fabrication of Acidic pH-Cleavable Polymer for Anticancer Drug Delivery Using a Dual Functional Monomer.

The preparation of tumor acidic pH-cleavable polymers generally requires tedious postpolymerization modifications, leading to batch-to-batch variation and scale-up complexity. To develop a facile and universal strategy, we reported in this study design and successful synthesis of a dual functional monomer, a-OEGMA that bridges a methacrylate structure and oligo(ethylene glycol) (OEG) units via an acidic pH-cleavable acetal link. Therefore, a-OEGMA integrates (i) the merits of commercially available oligo(ethylene glycol) monomethyl ether methacrylate (OEGMA) monomer, i.e., hydrophilicity for extracellular stabilization of particulates and a polymerizable methacrylate for adopting controlled living radical polymerization (CLRP), and (ii) an acidic pH-cleavable acetal link for efficiently intracellular destabilization of polymeric carriers. To demonstrate the advantages of a-OEGMA ( Mn = 500 g/mol) relative to the commercially available OEGMA ( Mn = 300 g/mol) for drug delivery applications, we prepared both acidic pH-cleavable poly(ε-caprolactone)21- b-poly( a-OEGMA)11 (PCL21- b-P( a-OEGMA)11) and pH-insensitive analogues of PCL21- b-P(OEGMA)18 with an almost identical molecular weight (MW) of approximately 5.0 kDa for the hydrophilic blocks by a combination of ring-opening polymerization (ROP) of ε-CL and subsequent atom transfer radical polymerization (ATRP) of a-OEGMA or OEGMA. The pH-responsive micelles self-assembled from PCL21- b-P( a-OEGMA)11 showed sufficient salt stability, but efficient acidic pH-triggered aggregation that was confirmed by the DLS and TEM measurements as well as further characterizations of the products after degradation. In vitro drug release study revealed significantly promoted drug release at pH 5.0 relative to the release profile recorded at pH 7.4 due to the loss of colloidal stability and formation of micelle aggregates. The delivery efficacy evaluated by flow cytometry analyses and an in vitro cytotoxicity study in A549 cells further corroborated greater cellular uptake and cytotoxicity of Dox-loaded pH-sensitive micelles of PCL21- b-P( a-OEGMA)11 relative to the pH-insensitive analogues of PCL21- b-P(OEGMA)18. This study therefore presents a facile and robust means toward tumor acidic pH-responsive polymers as well as provides one solution to the trade-off between extracellular stability and intracellular high therapeutic efficacy of drug delivery systems using a novel monomer of a-OEGMA with dual functionalities.

Fabrication of Thermosensitive Cyclic Brush Copolymer with Enhanced Therapeutic Efficacy for Anticancer Drug Delivery.

Adaptation of cyclic brush polymer for drug delivery applications remains largely unexplored. Herein, cyclic brush copolymer of poly(2-hydroxyethyl methacrylate-g-poly(N-isopropylacrylamide-st-N-hydroxyethylacrylamide)) (cb-P(HEMA-g-P(NIPAAm-st-HEAAm))), comprising a cyclic core of PHEMA and thermosensitive brushes of statistical copolymer of P(NIPAAm-st-HEAAm), is designed and synthesized successfully via a graft-from approach using atom transfer free radical polymerization from a cyclic multimacroinitiator. The composition of the brush is optimized to endow the resulting cyclic brush copolymer with a lower critical solution temperature (LCST) slightly above the physiological temperature, but lower than the localized temperature of tumor tissue, which is suitable for the hyperthermia-triggered anticancer drug delivery. Critical aggregation concentration determination reveals better stability for the unimolecular nanoparticle formed by the cyclic brush copolymer than that formed by the bottlebrush analogue. The dramatically increased size with elevated temperatures from below to above the LCST confirms hyperthermia-induced aggregation for both formulations. Such structural destabilization promotes significantly the drug release at 40 °C. Most importantly, the drug-loaded cyclic brush copolymer shows enhanced in vitro cytotoxicity against HeLa cells than the bottlebrush counterpart. The better stability and higher therapeutic efficacy demonstrates that the thermosensitive cyclic brush copolymer is a better formulation than bottle brush copolymer for controlled drug release applications.

Papillary squamous cell carcinoma of the oral mucosa: a clinicopathologic and immunohistochemical study of 12 cases and literature review.

Papillary squamous cell carcinoma (SCC) (PSCC) of the oral mucosa is a relatively rare but distinct variant of SCC of head and neck. The objectives of this study were to describe the clinicopathologic and immunohistochemical features of a series of patients with oral PSCC and to review the literature on this topic. Retrospective review of patients with clinical and pathologic diagnosis of PSCC (n = 12) between 2000 and 2008 in our institution was conducted. The outcome analysis in a mean follow-up of 56 months (range, 24-131 months) was performed. These patients were 7 women and 5 men, and the mean age at diagnosis was 72.9 years (range, 53-83 years). The cheek and the gingiva were the predominant sites of involvement. At the end of follow-up, 4 patients were found to have local recurrence, and 3 were dead of disease. The estimated 3- and 5-year survival was 91.7% and 76.4% for the whole series, respectively. Histopathologically, the papillary pattern consisted of multiple, thin, delicate filiform, finger-like papillary projections with fibrovascular cores. Besides, the exophytic pattern consisted of the broad-based bulbous to "cauliflower-like" exophytic growth with rounded projections. Immunohistochemically, positivity for CKpan, CKhmw (high molecular weight), and p53, yet negativity for CK8, vimentin, desmin, smooth muscle actin, and S-100 was observed in PSCC. In conclusion, 2 specific histopathologic growth patterns of oral PSCC were identified to separate from conventional SCC. Patients with PSCC have a favorable outcome in relation to exophytic nature and limited invasion of the tumor.

5-aminolevulinic acid photodynamic therapy for extensive oral leukoplakia with concomitant oral submucous fibrosis: A case report.

BACKGROUND: Oral leukoplakia and oral submucous fibrosis are potentially malignant disorders of the oral cavity, with high rates of recurrence and malignant transformation. Notably, the malignant transformation rate of oral leukoplakia with concomitant oral submucous fibrosis is significantly higher than that of oral submucous fibrosis or oral leukoplakia alone. However, the management of these conditions is not well defined. Photodynamic therapy is a minimally invasive treatment modality that effectively targets oral potentially malignant disorders, such as oral leukoplakia, erythroleucoplakia, and verrucous hyperplasia, with the advantages of being repeatable and leaving no scarring. CASE PRESENTATION: We report the case of a 42-year-old man with concomitant oral leukoplakia and oral submucous fibrosis almost involving the entire right buccal mucosa, who underwent six sessions of topical 5-aminolevulinic acid-mediated photodynamic therapy. RESULTS: Photodynamic therapy successfully eradicated whitish plaques and improved mouth opening without any adverse effects. Although photodynamic therapy failed to completely reverse the pathological changes, grading of epithelial dysplasia did not progress and clinical recurrence was not found during the 10-month follow-up. CONCLUSION: In conclusion, topical 5-aminolevulinic acid-mediated photodynamic therapy appears safe and has excellent clinical efficacy against oral leukoplakia-concomitant oral submucous fibrosis, but long-term follow-up is necessary.

Synthesis of enzyme-responsive theranostic amphiphilic conjugated bottlebrush copolymers for enhanced anticancer drug delivery.

Synthesis of polyfluorene (PF) based theranostic amphiphilic copolymers with simultaneously high drug loading efficiency and tumor microenvironment-specific responsiveness for promoted intracellular drug release and enhanced cancer therapy has been rarely reported likely due to the lack of efficient synthetic approaches to integrate these desirable properties. In this work, we recorded the successful preparation of well-defined theranostic amphiliphilic bottlebrush copolymers composing of fluorescent backbone of PF and tunable enzyme-degradable side chains of polytyrosine (PTyr) and POEGMA by integrating Suzuki coupling, NCA ROP and ATRP techniques. Notably, the resulting copolymer, PF25-g-(PTyr26-b-(POEGMA28)2 (P4) with two branched POEGMA brushes tethered to one PTyr termini for each unit could form steady unimolecular micelles with higher fluorescence quantum yield of 18.3% in aqueous and greater entrapment efficiency (EE) of 91.0% for DOX ascribed to the efficient π-π stacking interactions between PTyr blocks and drug molecules and the unique structure of branched hydrophilic brushes with a moderate chain length. DOX@P4 micelles revealed visualization of intracellular trafficking and accelerated drug release due to the enzyme-triggered degradation of PTyr blocks with proteinase K and subsequent deshielding of POEGMA corona for micelle destruction. In vitro and In vivo animal study further verified the intensive therapeutic efficiency with attenuated systematic toxicity. Taken together, we provided a universal strategy toward multifunctional polymeric delivery vehicles based on conjugated PF and biocompatible and degradable polypeptide by integratied Suzuki coupling and NCA ROP, and identified the branched structure of hydrophilic brushes for better performance of bottlebrush copolymers-based micelles for drug delivery applications. STATEMENT OF SIGNIFICANCE: Synthesis of polyfluorene (PF)-based theranostic amphiphilic copolymers with simultaneously high drug loading efficiency and tumor microenvironment-specific responsiveness for promoted intracellular drug release and enhanced cancer therapy has been rarely reported likely due to the lack of efficient synthetic approaches to integrate these desirable properties. We reported herein successful preparation of enzyme-responsive theranostic amphiliphilic bottlebrush copolymers with simultaneously high drug loading efficiency and tumor microenvironment-specific responsiveness for enhanced chemotherapy in vivo. This study therefore not only developed a universal strategy for the construction of multifunction polymeric vehicles based on the conjugated polymer of PF and degradable polypeptide by integrated Suzuki coupling and NCA ROP, but also emphasized the better stability of micelles endowed by the branched hydrophilic brushes than linear ones.

Research trends and characteristics of oral lichen planus: A bibliometric study of the top-100 cited articles.

BACKGROUND: Bibliometric analysis highlights the key topics and research trends which have shaped the understanding and management of a concerned disease. The objective of this study was to identify and characterize the most-cited articles on oral lichen planus (OLP), and highlight the analysis of key topics and research trends. METHODS: A comprehensive search was performed and identified in the Scopus database from 1907 to 5 March 2019 for the top-100 most-cited articles on OLP. RESULTS: The number of citations of the 100 selected articles varied from 101 to 570, with a mean of 178.7 citations per article. Malignant potential, immunopathogenesis, and topical drug therapy were the top-3 study topics, and the majority of high-quality articles were the research of the 3 topics. Journal of Oral Pathology and Medicine (n = 19) and Oral Surgery Oral Medicine Oral Pathology Oral Radiology (n = 14) were 2 journals with the most articles published. Both van der Waal I. and Scully C. were the most frequently contributing authors (n = 9). United States (n = 27) and Academic Centre for Dentistry Amsterdam (n = 7) was the most contributing country and institution, respectively. Systematic reviews (n = 2), randomized controlled trial (n = 1), cohort studies (n = 17) were study designs with higher evidence level, but the large majority (n = 80) were considered lower level. CONCLUSIONS: The results of this first citation analysis of the 100 most cited articles on OLP provide a historical perspective on scientific evolution, and suggest further research trends and clinical practice in the field of OLP.

Synthesis of cyclic graft polymeric prodrugs with heterogeneous grafts of hydrophilic OEG and reducibly conjugated CPT for controlled release.

Fabrication of cyclic graft (cg) copolymer-based polymeric prodrugs by conjugation of drug molecules to cg copolymers via a dynamic covalent bond capable of responding to biorelevant signals integrates simultaneously the merits of cg copolymers and polymeric prodrugs for enhanced stability of nanocarriers and precise modulation of drug release kinetics. To completely eliminate the compromised drug conjugation efficiency due to the steric hindrance of hydrophilic grafts, it will be useful to develop cg polymeric prodrugs with heterogeneous grafts composed of hydrophilic polymers and drug species, respectively. For this purpose, we reported in this study the synthesis of cyclic graft polymeric prodrugs with heterogeneous grafts of hydrophilic oligo (ethylene glycol) (OEG) and reducibly conjugated camptothecin (CPT), cg-poly(oligo(ethylene glycol) monomethyl ether methacrylate)-b-poly((2-hydroxyethyl methacrylate)-disulfide link-camptothecin) (cg-P(OEGMA)-b-P(HEMA-SS-CPT), cg-prodrugs), via an integrated strategy of a previously reported diblock copolymer-based template and post-polymerization intermolecular click conjugation of a reducible CPT prodrug. The micelles self-assembled from cg-prodrugs on one hand had sufficient salt stability due to the branched cg structure, and on the other hand showed a reduction-triggered cleavage of the disulfide link for a promoted CPT release. Most importantly, we uncovered two interesting phenomena of the cg-based polymeric prodrugs as delivery vehicles: (i) the dimensions of both self-assemblies formed by the cg and bottlegraft (bg) polymers depend substantially on the molecular size of the cg and bg polymers likely due to the steric hindrance of the grafted structures of the cg and bg molecules and relatively low aggregation number of the self-assembled structures, and (ii) cg-prodrug-based micelles exhibited greater in vitro cytotoxicity against cancer cells despite the lower drug loading content (DLC) than the bg-based analogues, which results primarily from the faster reduction-triggered degradation and drug release as well as the greater cellular uptake efficiency of the former micelle prodrugs. Taken together, the developed cg-prodrugs provide great potential for chemotherapy, and the aforementioned interesting results will definitely inspire more upcoming studies on the future design and development of novel cg polymers for biomedical applications.

Modulation of cyclic topology toward enhanced drug delivery, from linear and tadpole-like to dumbbell-shaped copolymers.

In this study, an efficient strategy for the synthesis of dumbbell-shaped amphiphilic copolymers with cyclic moieties as the two bells was developed and the enhanced performance of dumbbell-shaped copolymers for controlled drug release because of the simultaneous introduction of two macrocycles was disclosed.

Fabrication of biocleavable shell cross-linked hybrid micelles for controlled drug release using a reducible silica monomer.

We report in this communication the first preparation of triblock copolymer-based biocleavable shell cross-linked (SCL) hybrid micelles using a reducible silica monomer that integrates a polymerizable methacrylate structure and in situ cross-linkers of silica precursors via a disulfide bond. The monomer developed herein offers a highly straightforward and robust strategy toward bioreducible silica-based hybrid nanoparticles for controlled drug release.

Fabrication of supramolecular star-shaped amphiphilic copolymers for ROS-triggered drug release.

Star-shaped copolymers with branched structures can form unimolecular micelles with better stability than the micelles self-assembled from conventional linear copolymers. However, the synthesis of star-shaped copolymers with precisely controlled degree of branching (DB) suffers from complicated sequential polymerizations and multi-step purification procedures, as well as repeated optimizations of polymer compositions. The use of a supramolecular host-guest pair as the block junction would significantly simplify the preparation. Moreover, the star-shaped copolymer-based unimolecular micelle provides an elegant solution to the tradeoff between extracellular stability and intracellular high therapeutic efficacy if the association/dissociation of the supramolecular host-guest joint can be triggered by the biologically relevant stimuli. For this purpose, in this study, a panel of supramolecular star-shaped amphiphilic block copolymers with 9, 12, and 18 arms were designed and fabricated by host-guest complexations between the ring-opening polymerization (ROP)-synthesized star-shaped poly(ε-caprolactone) (PCL) with 3, 4, and 6 arms end-capped with ferrocene (Fc) (PCL-Fc) and the atom transfer radical polymerization (ATRP)-produced 3-arm poly(oligo ethylene glycol) methacrylates (POEGMA) with different degrees of polymerization (DPs) of 24, 30, 47 initiated by ß-cyclodextrin (ß-CD) (3Br-ß-CD-POEGMA). The effect of DB and polymer composition on the self-assembled properties of the five star-shaped copolymers was investigated by dynamic light scattering (DLS), transmission electron microscopy (TEM), and fluorescence spectrometery. Interestingly, the micelles self-assembled from 12-arm star-shaped copolymers exhibited greater stability than the 9- and 18-arm formulations. The potential of the resulting supramolecular star-shaped amphiphilic copolymers as drug carriers was evaluated by an in vitro drug release study, which confirmed the ROS-triggered accelerated drug release from the doxorubicin (DOX)-loaded supramolecular star-shaped micelles due to the oxidation-induced dissociation of ß-CD/Fc pair and the consequent loss of the colloidal stability of the star-shaped micelles. Studies of the delivery efficacy by an in vitro cytotoxicity study further indicated that higher DBs and longer hydrophilic arm compromised the therapeutic efficacy of the DOX-loaded supramolecular star-shaped micelles, resulting in significantly reduced cytotoxicity, as measured by increased IC50 value. Overall, our results revealed that the screening of hydrophilic block by DB and MW for an optimized star-shaped copolymer should balance the stability versus therapeutic efficacy tradeoff for a comprehensive consideration. Therefore, the 12-arm star-shaped copolymer with POEGMA30 is the best formulation tested.

Hydroxyl-Functional Groups on Graphene Trigger the Targeted Delivery of Antitumor Drugs.

An efficient and targeted treatment for tumor cells is demonstrated. This targeting is based upon the strong affinity between hydroxyl-functional groups on graphene and acidic tumors. The hydroxylated graphene (GOH) with a unique 2D architecture further improve the targeting capacity of the system via an enhanced permeability and retention (EPR) process. Polyethylene glycol (PEG) was employed for better biocompatibility and the antitumor drug doxorubicin (DOX) was then incorporated. These additions created a biocompatible system with a superior pH-dependent drug release property. Its proficiency was due to its ability to pass through cell membranes via a process of endocytosis and exocytosis. The results from a Transwell co-culture system discovered that the PEG-GOH-DOX system had a large impact on tumor cell viability (less than 10% survived after treatment) and little influence on normal cells (more than 80% survived). An in vitro 3D tumor model study demonstrated that the size of the PEG-GOH-DOX treated tumor was 50% less than that of the pristine DOX treated tumor. In vivo data indicated that the PEG-GOH-DOX system was able to inhibit the size of tumors by a factor of 6.5 when compared to the untreated tumors.

Fabrication of Reduction-Sensitive Amphiphilic Cyclic Brush Copolymer for Controlled Drug Release.

The cyclic brush polymers, due to the unique topological structure, have shown in the previous studies higher delivery efficacy than the bottlebrush analogues as carriers for drug and gene transfer. However, to the best of knowledge, the preparation of reduction-sensitive cyclic brush polymers for drug delivery applications remains unexplored. For this purpose, a reduction-sensitive amphiphilic cyclic brush copolymer, poly(2-hydroxyethyl methacrylate-g-poly(ε-caprolactone)-disulfide link-poly(oligoethyleneglycol methacrylate)) (P(HEMA-g-PCL-SS-POEGMA)) with reducible block junctions bridging the hydrophobic PCL middle layer and the hydrophilic POEGMA outer corona is designed and synthesized successfully in this study via a "grafting from" approach using sequential ring-opening polymerization (ROP) and atom transfer free radical polymerization (ATRP) from a cyclic multimacroinitiator PHEMA. The resulting self-assembled unimolecular core-shell-corona (CSC) micelles show sufficient salt stability and efficient destabilization in the intracellular reducing environment for a promoted drug release toward a greater therapeutic efficacy relative to the reduction-insensitive analogues. The overall results demonstrate the reducible cyclic brush copolymers developed herein provides an elegant solution to the tradeoff between extracellular stability and intracellular high therapeutic efficacy toward efficient anticancer drug delivery.

Influence of formulation factors on methyl-ALA-induced protoporphyrin IX accumulation in vivo.

Photodynamic therapy (PDT) is a medical treatment by which a combination of a photosensitising drug and visible light cause the destruction of selected cells. Thick lesions, such as nodular basal cell carcinomas (BCCs), or lesions with overlying keratinous debris, are reported as being difficult to eradicate using 5-aminolevulinic acid-based photodynamic therapy (ALA-PDT). Such treatment failures have been attributed to the shallow penetration of water-soluble drugs like ALA. In addition, the current scarcity of sophisticated drug delivery research centered on PDT applications has meant that accurate comparison of similar clinical studies is difficult. This paper investigates, for the first time, novel drug delivery systems for controlled drug delivery of methyl-ALA (M-ALA). Pressure sensitive adhesive (PSA) and bioadhesive patches containing defined M-ALA loadings and a standard cream containing equivalent amounts of drug were applied to the skin of mice for defined periods of time and the fluorescence of the protoporphyrin IX (PpIX) induced measured over 24h. Of major importance, the PSA patches containing low drug loadings induced high PpIX levels, which were limited to the site of application, after only 1h applications. Such systems have the potential to improve selectivity of PpIX accumulation, increase simplicity of treatment and, due to the low drug loadings required, reduce costs of clinical PDT. PSA patches would be most suitable for application to areas of dry skin, while bioadhesive patches would be suitable for moist areas, such as the mouth or lower female reproductive tract and have been shown here to induce significant PpIX production at the site of application after 4h applications of patches containing high drug loadings.

Multifunctional chitosan/polyvinyl pyrrolidone/45S5 Bioglass® scaffolds for MC3T3-E1 cell stimulation and drug release.

Novel chitosan-polyvinyl pyrrolidone/45S5 Bioglass® (CS-PVP/BG) scaffolds were prepared via foam replication and chemical cross-linking techniques. The pristine BG, CS-PVP coated BG and genipin cross-linked CS-PVP/BG (G-CS-PVP/BG) scaffolds were synthesized and characterized in terms of chemical composition, physical structure and morphology respectively. Resistance to enzymatic degradation of the scaffold is improved significantly with the use of genipin cross-linked CS-PVP. The bio-effects of scaffolds on MC3T3-E1 osteoblast-like cells were evaluated by studying cell viability, adhesion and proliferation. The CCK-8 assay shows that cell viability on the resulting G-CS-PVP/BG scaffold is improved obviously after cross-linking of genipin. Cell skeleton images exhibit that well-stretched F-actin bundles are obtained on the G-CS-PVP/BG scaffold. SEM results present significant improvement on the cell adhesion and proliferation for cells cultured on the G-CS-PVP/BG scaffold. The drug release performance on the as-synthesized scaffold was studied in a phosphate buffered saline (PBS) solution. Vancomycin is found to be released in burst fashion within 24h from the pristine BG scaffold, however, the release period from the G-CS-PVP/BG scaffold is enhanced to 7days, indicating improved drug release properties of the G-CS-PVP/BG scaffold. Our results suggest that the G-CS-PVP/BG scaffolds possess promising physicochemical properties, sustained drug release capability and good biocompatibility for MC3T3-E1 cells' proliferation and adhesion, suggesting their potential applications in areas such as MC3T3-E1 cell stimulation and bone tissue engineering.