Self-assembled amphiphilic chitosan: A time-dependent nanostructural evolution and associated drug encapsulation/elution mechanism.

This investigation reports the nanostructural evolution and associated encapsulation and elution of a hydrophobic drug, demethoxycurcumin (DMC), as a molecular probe, with the carboxymethyl-hexanoyl chitosan (CHC), which has been a technically interesting amphiphilic chitosan-based polymer successfully developed in this lab for years. The self-assembly nature of the CHC in neutral aqueous solutions allowed efficient encapsulation of various drugs without deteriorating or changing drugs' activity. However, its self-assembly behavior associated with nanostructural stability or variation, in terms of residence time in aqueous solution has not been well characterized and how the CHC nanostructure may be altered upon entrapping a drug, followed releasing out of the nanostructure. In this study, the CHC/DMC assembled model was used to evaluate entrapping efficiency, CHC-DMC interaction, and nanostructural variation while the drug being encapsulated and released from the CHC nanoparticles. Experimental outcomes showed a fractal transition between nanoparticulate and short fiber-like network evolution of the CHC as time elapsed, with the presence or absence of the DMC probe. This entrapment of DMC is relatively efficient upon CHC assembly and the associated DMC arrangement inside the helical CHC macromolecule gave largely increasing space over the resulting CHC/DMC assembly. Its excellent colloidal and nanostructural stability over a reasonably long period of time in testing environment suggests that this CHC/DMC assembly not only provides a crucial advantage for drug delivery application but also considers as a nanostructural model for better understanding of the mechanism upon drug encapsulation and elution which may be applicable to alternative amphiphilic polysaccharide-based macromolecules.

A new type of gadodiamide-conjugated amphiphilic chitosan nanoparticle and its use for MR imaging with significantly enhanced contrastability.

Magnetic resonance imaging (MRI) has been one of the most frequently-used diagnostic tools with high dimensional precision and positioning accuracy in clinical practices. To achieve contrast enhancement, utilization of high-efficient MR imaging contrast agents becomes a prime consideration and is indispensably reinforced the diagnosis precision, especially for the emerging precision medicine. Gadolinium (Gd)-based complexes has been widely used in current clinical MRI operations, however, numerous side effects were reported and highlighted in clinic. Those drawbacks render specific unmet needs to be clinically and technically improved with a new version of Gd-based compound. Here we report a newly-synthesized amphiphilic Gadodiamide-conjugated carboxymethyl-hexanoyl chitosan (termed as CHC-Gd) hybrid. The gadodiamide was selected is due to its smallest molecular size among other Gd-based complexes reported in literature, which assumed to give least influence on the resulting physicochemical properties such as colloidal stability, nanostructural evolution, and cytocompability, particularly self-assembly capability, of the resulting hybrid upon practical uses. Experimental outcomes showed a successful synthesis of the CHC-Gd hybrid using a one-pot synthesis protocol, where the gadodiamide complexes were covalently attached to the carboxyl groups along the CHC backbone. Self-assembly behavior can be observed to form a sphere-like nanoparticle of 100-200 nm in size as of amphiphilic native CHC macromolecule. Experimental outcomes indicated a largely improved cytocompatibility of the hybrid, compared with free Gd, suggesting the Gd+3 ions were well stabilized in the CHC nanostructure. Excellent contrastability in-vitro and in particular in vivo were measured, where for in-vivo test, a 10-40-folded reduction in dosage, compared with clinical Gd dose, was used and demonstrated a comparative-to-better imaging resolution and brightness. Therefore, from this preliminary investigation, a potential translation to clinical practice through the use of newly-synthesized amphiphilic CHC-Gd hybrid appears to be relatively promising.

Demethoxycurcumin-Loaded Chitosan Nanoparticle Downregulates DNA Repair Pathway to Improve Cisplatin-Induced Apoptosis in Non-Small Cell Lung Cancer.

Demethoxycurcumin (DMC), through a self-assembled amphiphilic carbomethyl-hexanoyl chitosan (CHC) nanomatrix has been successfully developed and used as a therapeutic approach to inhibit cisplatin-induced drug resistance by suppressing excision repair cross-complementary 1 (ERCC1) in non-small cell lung carcinoma cells (NSCLC). Previously, DMC significantly inhibited on-target cisplatin resistance protein, ERCC1, via PI3K-Akt-snail pathways in NSCLC. However, low water solubility and bioavailability of DMC causes systemic elimination and prevents its clinical application. To increase its bioavailability and targeting capacity toward cancer cells, a DMC-polyvinylpyrrolidone core phase was prepared, followed by encapsulating in a CHC shell to form a DMC-loaded core-shell hydrogel nanoparticles (DMC-CHC NPs). We aimed to understand whether DMC-CHC NPs efficiently potentiate cisplatin-induced apoptosis through downregulation of ERCC1 in NSCLC. DMC-CHC NPs displayed good cellular uptake efficiency. Dissolved in water, DMC-CHC NPs showed comparable cytotoxic potency with free DMC (dissolved in DMSO). A sulforhodamine B (SRB) assay indicated that DMC-CHC NPs significantly increased cisplatin-induced cytotoxicity by highly efficient intracellular delivery of the encapsulated DMC. A combination of DMC-CHC NPs and cisplatin significantly inhibited on-target cisplatin resistance protein, ERCC1, via the PI3K-Akt pathway. Also, this combination treatment markedly increased the post-target cisplatin resistance pathway including bax, and cytochrome c expressions. Thymidine phosphorylase (TP), a main role of the pyrimidine salvage pathway, was also highly inhibited by the combination treatment. The results suggested that enhancement of the cytotoxicity to cisplatin via administration of DMC-CHC NPs was mediated by down-regulation of the expression of TP, and ERCC1, regulated via the PI3K-Akt pathway.

Local co-administration of gene-silencing RNA and drugs in cancer therapy: State-of-the art and therapeutic potential.

Gene-silencing miRNA and siRNA are emerging as attractive therapeutics with potential to suppress any genes, which could be especially useful in combination cancer therapy to overcome multidrug resistant (MDR) cancer. Nanomedicine aims to advance cancer treatment through functional nanocarriers that delivers one or more therapeutics to cancer tissue and cells with minimal off-target effects and suitable release kinetics and dosages. Although much effort has gone into developing circulating nanocarriers with targeting functionality for systemic administration, another alternative and straightforward approach is to utilize formulations to be administered directly to the site of action, such as pulmonary and intratumoral delivery. The combination of gene-silencing RNA with drugs in nanocarriers for localized delivery is emerging with promising results. In this review, the current progress and strategies for local co-administration of RNA and drug for synergistic effects and future potential in cancer treatment are presented and discussed. Key advances in RNA-drug anticancer synergy and localized delivery systems were combined with a review of the available literature on local co-administration of RNA and drug for cancer treatment. It is concluded that advanced delivery systems for local administration of gene-silencing RNA and drug hold potential in treatment of cancer, depending on indication. In particular, there are promising developments using pulmonary delivery and intratumoral delivery in murine models, but further research should be conducted on other local administration strategies, designs that achieve effective intracellular delivery and maximize synergy and feasibility for clinical use.

Inhibition of Periodontitis Induction Using a Stimuli-Responsive Hydrogel Carrying Naringin.

BACKGROUND: Developing a drug carrier with favorable handling characteristics that can respond to environmental changes after inflammation, such as pH changes, may be beneficial for treating periodontitis. This study aims to investigate the preclinical feasibility of using naringin, a naturally derived polymethoxylated flavonoid compound with anti-inflammatory properties, to inhibit periodontitis induction via a thermogelling and pH-responsive injectable hydrogel. METHODS: The hydrogel was made of amphipathic carboxymethyl-hexanoyl chitosan (CHC), ß-glycerol phosphate (ß-GP), and glycerol. Thermogelling and pH-responsive characteristics of the hydrogel, as well as cell viability after treatment with the hydrogel containing naringin, were evaluated in vitro. Hydrogel was subgingivally delivered when experimental periodontitis was induced in vivo, and therapeutic effect was evaluated with microcomputed tomography imaging, histology, and expression of inflammation-associated genes, including toll-like receptor (TLR)2, the receptor for advanced glycation end products (RAGE), myeloid differentiation primary response gene-88, and tumor necrosis factor (TNF)-α. RESULTS: The hydrogel was consistently fluidic at 4°C but rapidly gelled at 37°C. Release of naringin was faster at pH 5.5 to 6.5, and viability was significantly promoted by treatment with 0.85% naringin. Naringin-carrying CHC-ß-GP-glycerol hydrogel sites showed significantly reduced periodontal bone loss (P <0.05) and inflammatory infiltration (P <0.01) as well as significantly downregulated TLR2 (P <0.05), RAGE (P <0.01), and TNF-α (P <0.05) relative to the sites with experimental periodontitis alone. CONCLUSION: Naringin-carrying CHC-ß-GP-glycerol colloidal hydrogel can be used to inhibit induction of experimental periodontitis with favorable handling and inflammation-responsive characteristics.

Dual drug-loaded biofunctionalized amphiphilic chitosan nanoparticles: Enhanced synergy between cisplatin and demethoxycurcumin against multidrug-resistant stem-like lung cancer cells.

Lung cancer kills more humans than any other cancer and multidrug resistance (MDR) in cancer stem-like cells (CSC) is emerging as a reason for failed treatments. One concept that addresses this root cause of treatment failure is the utilization of nanoparticles to simultaneously deliver dual drugs to cancer cells with synergistic performance, easy to envision - hard to achieve. (1) It is challenging to simultaneously load drugs of highly different physicochemical properties into one nanoparticle, (2) release kinetics may differ between drugs and (3) general requirements for biomedical nanoparticles apply. Here self-assembled nanoparticles of amphiphilic carboxymethyl-hexanoyl chitosan (CHC) were shown to present nano-microenvironments enabling simultaneous loading of hydrophilic and hydrophobic drugs. This was expanded into a dual-drug nano-delivery system to treat lung CSC. CHC nanoparticles were loaded/chemically modified with the anticancer drug cisplatin and the MDR-suppressing Chinese herbal extract demethoxycurcumin, followed by biofunctionalization with CD133 antibody for enhanced uptake by lung CSC, all in a feasible one-pot preparation. The nanoparticles were characterized with regard to chemistry, size, zeta potential and drug loading/release. Biofunctionalized and non-functionalized nanoparticles were investigated for uptake by lung CSC. Subsequently the cytotoxicity of single and dual drugs, free in solution or in nanoparticles, was evaluated against lung CSC at different doses. From the dose response at different concentrations the degree of synergy was determined through Chou-Talalay's Plot. The biofunctionalized nanoparticles promoted synergistic effects between the drugs and were highly effective against MDR lung CSC. The efficacy and feasible one-pot preparation suggests preclinical studies using relevant disease models to be justified.

pH-Responsive Hydrogel With an Anti-Glycation Agent for Modulating Experimental Periodontitis.

BACKGROUND: Stimulus-responsive devices have emerged as a novel approach for local drug delivery. This study investigates the feasibility of a novel chitosan-based, pH-responsive hydrogel loaded with N-phenacylthiazolium bromide (PTB), which cleaves the crosslinks of advanced glycation end products on the extracellular matrix. METHODS: A chitosan-based hydrogel loaded with PTB was fabricated, and the in vitro release profile was evaluated within pH 5.5 to 7.4. BALB/cJ mice and Sprague-Dawley rats were used to evaluate the effects during the induction and recovery phases of periodontitis, respectively, and animals in each phase were divided into four groups: 1) no periodontitis induction; 2) ligature-induced experimental periodontitis (group PR); 3) experimental periodontitis plus hydrogel without PTB (group PH); and 4) experimental periodontitis plus hydrogel with PTB (group PP). The therapeutic effects were evaluated by microcomputed tomographic imaging of periodontal bone level (PBL) loss and histomorphometry for inflammatory cell infiltration and collagen density. RESULTS: PTB was released faster at pH 5.5 to 6.5 and consistently slower at pH 7.4. In the induction phase, PBL and inflammatory cell infiltration were significantly reduced in group PP relative to group PR, and the loss of collagen matrix was significantly reduced relative to that observed in group PH. In the recovery phase, PBL and inflammatory cell infiltration were significantly reduced, and significantly greater collagen deposition was noted in group PP relative to groups PR and PH at 4 and 14 days after silk removal. CONCLUSION: Chitosan-based, pH-responsive hydrogels loaded with PTB can retard the initiation of and facilitate the recovery from experimental periodontitis.

Injectable insulin-lysozyme-loaded nanogels with enzymatically-controlled degradation and release for basal insulin treatment: In vitro characterization and in vivo observation.

Diabetes is a common global disease that causes immense suffering for individuals and huge costs for the health care system. To minimize complications such as organ degeneration, diabetic patients are required to undergo treatments to maintain the blood glucose level in the normal range, ideally mimicking normal insulin secretion. The normal physiological insulin secretion pattern in healthy individuals consists of a base (basal) level through the day and increased secretion after meals (bolus insulin). Thus effective treatments may combine long acting, low-level insulin therapy with boosts of short acting insulin and/or oral agents. To achieve long term management of basal insulin level, an injectable insulin-loaded gel composed of self-assembled nanoparticles from carboxymethyl-hexanoyl chitosan (CHC) and integrated lysozyme for controlled biodegradation and insulin release was developed. In vitro characterizations and evaluations confirmed that lysozyme was active on CHC and that the amount of lysozyme in a CHC hydrogel determined the degradation and insulin release rate. The degradation products were found to be highly cytocompatible using a cell assay. In vivo evaluation of the system in a diabetic mouse model revealed that the fasted blood glucose level could be maintained in the normal range for 10days with a single injection of insulin-loaded CHC-lysozyme gel. The insulin-loaded CHC-lysozyme gels clearly show promise for use as a novel injectable long-acting insulin delivery system, with potential to manage the basal insulin level for many days with a single injection.

Demethoxycurcumin-carrying chitosan-antibody core-shell nanoparticles with multitherapeutic efficacy toward malignant A549 lung tumor: from in vitro characterization to in vivo evaluation.

Targeting controlled release core-shell nanocarriers with the potential to overcome multidrug resistant (MDR) lung cancer were prepared based on demethoxycurcumin (DMC) loaded amphiphilic chitosan nanoparticles coated with an anti-EGFR antibody layer. The nanocarriers were characterized with regard to size with dynamic light scattering, SEM, and TEM. The characterization confirmed the nanocarriers to have a surface coating of the anti-EGFR antibody and a final size excellently suited for circulating targeting nanocarriers, i.e., <200 nm in diameter. In vitro drug release revealed extended quasi-Fickian release from the nanocarriers, with the anti-EGFR layer further reducing the release rate. Cell culture experiments using normoxic and MDR hypoxic cells overexpressing EGFR confirmed improved DMC delivery for anti-EGFR coated particles and revealed that the DMC was delivered to the cytoplasmic region of the cells, forming nanoprecipitates in lysosomes and endosomes. The effective endocytosis and targeting of the core-shell nanoparticles resulted in the nanocarriers achieving high cytotoxicity also against MDR cells. The therapeutic potential was further confirmed in an A549 xenograft lung tumor mouse model, where DMC loaded core-shell nanocarriers achieved about 8-fold reduction in tumor volume compared with control group over the 8 weeks of the investigation. Both in vitro and in vivo data suggest the anti-EGFR coated core-shell nanocarriers as highly promising for treatment of hypoxic MDR cancers, especially for non-small cell lung cancer.

Enhanced antioxidant capacity of dental pulp-derived iPSC-differentiated hepatocytes and liver regeneration by injectable HGF-releasing hydrogel in fulminant hepatic failure.

Acute hepatic failure (AHF) is a severe liver injury leading to sustained damage and complications. Induced pluripotent stem cells (iPSCs) may be an alternative option for the treatment of AHF. In this study, we reprogrammed human dental pulp-derived fibroblasts into iPSCs, which exhibited pluripotency and the capacity to differentiate into tridermal lineages, including hepatocyte-like cells (iPSC-Heps). These iPSC-Heps resembled human embryonic stem cell-derived hepatocyte-like cells in gene signature and hepatic markers/functions. To improve iPSC-Heps engraftment, we next developed an injectable carboxymethyl-hexanoyl chitosan hydrogel (CHC) with sustained hepatocyte growth factor (HGF) release (HGF-CHC) and investigated the hepatoprotective activity of HGF-CHC-delivered iPSC-Heps in vitro and in an immunocompromised AHF mouse model induced by thioacetamide (TAA). Intrahepatic delivery of HGF-CHC-iPSC-Heps reduced the TAA-induced hepatic necrotic area and rescued liver function and recipient viability. Compared with PBS-delivered iPSC-Heps, the HGF-CHC-delivered iPSC-Heps exhibited higher antioxidant and antiapoptotic activities that reduced hepatic necrotic area. Importantly, these HGF-CHC-mediated responses could be abolished by administering anti-HGF neutralizing antibodies. In conclusion, our findings demonstrated that HGF mediated the enhancement of iPSC-Hep antioxidant/antiapoptotic capacities and hepatoprotection and that HGF-CHC is as an excellent vehicle for iPSC-Hep engraftment in iPSC-based therapy against AHF.

Synergistic hierarchical silicone-modified polysaccharide hybrid as a soft scaffold to control cell adhesion and proliferation.

In this study, a new type of polydimethylsiloxane-modified chitosan (PMSC) amphiphilic hydrogel was developed as a soft substrate to explore cellular responses for dermal reconstruction. The hydrogel wettability, mechanical stiffness and topography were controllable through manipulation of the degree of esterification (DE) between hydrophobic polydimethylsiloxane (PDMS) and hydrophilic N,O-(carboxymethyl)-chitosan (NOCC). Based on microphase separation, the incorporation of PDMS into NOCC increased the stiffness of the hybrid through the formation of self-assembled aggregates, which also provided anchor sites for cell adhesion. As the DE exceeded 0.39, the size of the PDMS-rich aggregates changed from nanoscale to microscale. Subsequently, the hierarchical architecture resulted in an increase in the tensile modulus of the hybrid gel up to fourfold, which simultaneously provided mechano-topographic guidance and allowed the cells to completely spread to form spindle shapes instead of forming a spherical morphology, as on NOCC (DE=0). The results revealed that the incorporation of hydrophobic PDMS not only impeded acidic damage resulting from NOCC but also acted as an adhesion modification agent to facilitate long-term cell adhesion and proliferation on the soft substrate. As proved by the promotion on long-term type-I collagen production, the PMSC hybrid with self-assembled mechano-topography offers great promise as an advanced scaffold material for use in healing applications.

A temperature-induced and shear-reversible assembly of latanoprost-loaded amphiphilic chitosan colloids: characterization and in vivo glaucoma treatment.

Hydrogels composed of assembled colloids is a material class that is currently receiving much interest and shows great promise for use in biomedical applications. This emerging material class presents unique properties derived from the combination of nanosized domains in the form of colloidal particles with a continuous gel network and an interspersed liquid phase. Here we developed an amphiphilic chitosan-based, thermogelling, shear-reversible colloidal gel system for improved glaucoma treatment and addressed how preparation procedures and loading with the anti-glaucoma drug latanoprost and commonly used preservative benzalkonium chloride influenced the mechanical properties of and drug release from the colloidal gels. The results highlight that incorporated substances and preparation procedures have effects both on mechanical properties and drug release, but that the release of drug loaded in the colloidal carriers is mainly limited by transport out of the carriers, rather than by diffusion within the gel. The developed colloidal chitosan based gels hold outstanding biomedical potential, as confirmed by the ease of preparation and administration, low cytotoxicity in MTT assay, excellent biocompatibility and lowering of intraocular pressure for 40 days in a rabbit glaucoma model. The findings clearly justify further investigations towards clinical use in the treatment of glaucoma. Furthermore, the use of this shear-reversible colloidal gel could easily be extended to localized treatment of a number of critical conditions, from chronic disorders to cancer, potentially resulting in a number of new therapeutics with improved clinical performance.

Highly electrostatically-induced detection selectivity and sensitivity for a colloidal biosensor made of chitosan nanoparticle decorated with a few bare-surfaced gold nanorods.

Metallic nanoparticles have been utilized as an analytical tool to detecting a wide variety of organic analytes. Among them, gold nanoparticles demonstrating outstanding surface plasmonic resonance property have been well recognized and received wide attention for plasmon-based sensing applications. However, in literature, gold-based nanosensor has to be integrated with specific "ligand" molecule in order to gain molecular recognition ability. However, "ligand" molecules, included proteins, peptides, nucleic acids, etc. are expensive and vulnerable to environmental change, in the meantime, anchoring procedure of the "ligand" molecules to gold surface may be cost-ineffective and endangered to the ligand's activity, making a final analytic probe less reliable and risk in production capability. Here, we develop a new approach by designing a colloid-type sensor using a few "bare" Au nanorods deposited on the surface of a colloidal chitosan carrier. By tuning the solution pH, the resulting colloidal nanoprobe is capable of detecting proteins, i.e., human serum albumin and lysozyme, with high specificity and sensitivity. This new approach allows a new type of the molecular probes to be well manipulated to monitor important biomolecules for medical detection, diagnosis, and bioengineering applications.

A pH-responsive amphiphilic chitosan-pyranine core-shell nanoparticle for controlled drug delivery, imaging and intracellular pH measurement.

A pH-responsive multifunctional core-shell nanoparticle, named CHC-PY nanoparticle, was successfully synthesized through electrostatic interaction of a thin shell of fluorescent pyranine dye (PY) with amphiphilic carboxymethylhexanoyl chitosan (CHC) nanoparticles. Upon encapsulating an anticancer drug, camptothecin (CPT), the CHC-PY nanoparticles exhibited an excellent drug loading efficiency (>95%). The resulting CPT-loaded CHC-PY nanoparticles also exhibited efficient cell internalization and good pH-responsive behavior. After being internalized (via efficient endocytosis pathway), the presence of fluorescent PY shell showed a pH-dependent emission characteristic which allowed the internalized CHC-PY nanoparticles acting as an indicator to distinguish the acidic microenvironment of cancerous cells, compared with normal cells. The pH-sensitive PY shell also acted as a modulator to control the CPT release wherein a higher release rate was detected at lower pH value, which is essentially a potential therapeutic niche for anticancer purposes. This new type of CHC-PY core-shell nanoparticle provides multiple functionality, where a synergistic performance of nanotherapeutics, imaging and even diagnosis at a cellular resolution can be achieved simultaneously.

Epigenetic regulation of the miR142-3p/interleukin-6 circuit in glioblastoma.

Epigenetic regulation plays a critical role in glioblastoma (GBM) tumorigenesis. However, how microRNAs (miRNAs) and cytokines cooperate to regulate GBM tumor progression is still unclear. Here, we show that interleukin-6 (IL-6) inhibits miR142-3p expression and promotes GBM propagation by inducing DNA methyltransferase 1-mediated hypermethylation of the miR142-3p promoter. Interestingly, miR142-3p also suppresses IL-6 secretion by targeting the 3' UTR of IL-6. In addition, miR142-3p also targets the 3' UTR and suppresses the expression of high-mobility group AT-hook 2 (HMGA2), leading to inhibition of Sox2-related stemness. We further show that HMGA2 enhances Sox2 expression by directly binding to the Sox2 promoter. Clinically, GBM patients whose tumors present upregulated IL-6, HMGA2, and Sox2 protein expressions and hypermethylated miR142-3p promoter also demonstrate poor survival outcome. Orthotopic delivery of miR142-3p blocks IL-6/HMGA2/Sox2 expression and suppresses stem-like properties in GBM-xenotransplanted mice. Collectively, we discovered an IL-6/miR142-3p feedback-loop-dependent regulation of GBM malignancy that could be a potential therapeutic target.

Electrophoretic coating of amphiphilic chitosan colloids on regulating cellular behaviour.

In this communication, we report a facile nanotopographical control over a stainless steel surface via an electrophoretic deposition of colloidal amphiphilic chitosan for preferential growth, proliferation or migration of vascular smooth muscle cells (VSMCs) and human umbilical vein endothelial cells (HUVECs). Atomic force microscopy revealed that the colloidal surface exhibited a deposition time-dependent nanotopographical evolution, wherein two different nanotopographic textures indexed by 'kurtosis' (Rkur) value were easily designed, which were termed as 'sharp' (i.e. high peak-to-valley texture) surface and 'flat' (i.e. low peak-to-valley texture) surface. Cellular behaviour of VSMCs and HUVECs on both surfaces demonstrated topographically dependent morphogenesis, adherent responses and biochemical properties in comparison with bare stainless steel. The formation of a biofunctionalized surface upon a facile colloidal chitosan deposition envisions the potential application towards numerous biomedical devices, and this is especially promising for cardiovascular stents wherein a new surface with optimized texture can be designed and is expected to create an advantageous environment to stimulate HUVEC growth for improved healing performance.

Polysaccharide-lecithin reverse micelles with enzyme-degradable triglyceride shell for overcoming tumor multidrug resistance.

A newly-designed drug carrier with enzyme-triggered release behavior and the ability to circumvent multidrug resistance was successfully developed. By optimizing the ratio of lecithin and polysaccharide in reverse micelles, encapsulation efficiency and encapsulation stability can be significantly improved.

A novel multifunctional nano-platform with enhanced anti-cancer and photoacoustic imaging modalities using gold-nanorod-filled silica nanobeads.

The novel nano-seaurchin structure is characteristic of high-density and well-dispersed gold nanorods in one mesoporous silica nanobead. This nanoplatform provided increased photothermal stability, stable photoacoustic signal and highly efficient hyperthermia effect both in vitro and in vivo, indicating a powerful theranostic modality.

Corneal repair by human corneal keratocyte-reprogrammed iPSCs and amphiphatic carboxymethyl-hexanoyl chitosan hydrogel.

Induced pluripotent stem cells (iPSCs) have promising potential in regenerative medicine, but whether iPSCs can promote corneal reconstruction remains undetermined. In this study, we successfully reprogrammed human corneal keratocytes into iPSCs. To prevent feeder cell contamination, these iPSCs were cultured onto a serum- and feeder-free system in which they remained stable through 30 passages and showed ESC-like pluripotent property. To investigate the availability of iPSCs as bioengineered substitutes in corneal repair, we developed a thermo-gelling injectable amphiphatic carboxymethyl-hexanoyl chitosan (CHC) nanoscale hydrogel and found that such gel increased the viability and CD44+proportion of iPSCs, and maintained their stem-cell like gene expression, in the presence of culture media. Combined treatment of iPSC with CHC hydrogel (iPSC/CHC hydrogel) facilitated wound healing in surgical abrasion-injured corneas. In severe corneal damage induced by alkaline, iPSC/CHC hydrogel enhanced corneal reconstruction by downregulating oxidative stress and recruiting endogenous epithelial cells to restore corneal epithelial thickness. Therefore, we demonstrated that these human keratocyte-reprogrammed iPSCs, when combined with CHC hydrogel, can be used as a rapid delivery system to efficiently enhance corneal wound healing. In addition, iPSCs reprogrammed from corneal surgical residues may serve as an alternative cell source for personalized therapies for human corneal damage.

Forming of demethoxycurcumin nanocrystallite-chitosan nanocarrier for controlled low dose cellular release for inhibition of the migration of vascular smooth muscle cells.

We report an efficient therapeutic approach to inhibit the migration and growth of vascular smooth muscle cells (VSMCs) via a low-dose sustained elution of a water-insoluble drug, demethoxycurcumin (DMC), through a self-assembled amphiphilic carbomethyl-hexanol chitosan (CHC) nanomatrix. Manipulating the cellular internalization and controlled cytotoxic effect of DMC-CHC nanoparticles over the VSMCs was elucidated. The DMC-CHC nanoparticles, which were systematically characterized in terms of structural morphology, surface potential, encapsulation efficiency, and DMC nanocrystallite distribution, exhibited rapid cellular uptake efficiency and considerably improved cytotoxic potency by 2.8 times compared to the free DMC. Under a cytotoxic evaluation, an improved antiproliferative effect and effective inhibition of VSMC migration as a result of highly efficient intracellular delivery of the encapsulated DMC in comparison to free DMC was achieved, which also was confirmed with a subsequent protein analysis. Cellular drug release and distribution of DMC after internalization into VSMCs was experimentally determined. This work may open a potential intracellular medicinal strategy with improved biological and therapeutic efficacy using the DMC-CHC nanoparticles illustrated in this work.