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Sorafenib, marketed under the brand name Nexavar ® , is a multiple tyrosine kinase inhibitor drug that has been actively used in the clinical setting for the treatment of several cancers. However, the low solubility and bioavailability of sorafenib constitute a significant barrier to achieving a good therapeutic outcome. We developed a sorafenib-loaded self-nanoemulsifying drug delivery system (SNEDDS) formulation composed of capmul MCM, tween 80, and tetraglycol, and demonstrated that the SNEDDS formulation could improve drug solubility with excellent self-emulsification ability. Moreover, the sorafenib-loaded SNEDDS exhibited anticancer activity against Hep3B and KB cells, which are the most commonly used hepatocellular carcinoma and oral cancer cell lines, respectively. Subsequently, to improve the storage stability and to increase the possibility of commercialization, a solid SNEDDS for sorafenib was further developed through the spray drying method using Aerosil ® 200 and PVP K 30. X-ray diffraction and differential scanning calorimeter data showed that the crystallinity of the drug was markedly reduced, and the dissolution rate of the drug was further improved in formulation in simulated gastric and intestinal fluid conditions. In vivo study, the bioavailability of the orally administered formulation increases dramatically compared to the free drug. Our results highlight the use of the solid-SNEDDS formulation to enhance sorafenib's bioavailability and outlines potential translational directions for oral drug development., Competing Interests: Conflict of interest The authors have no competing interests to declare. Declaration of interests The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Photothermal therapy using gold nanorods (AuNRs) has gained great attention for cancer therapy because AuNRs emit heat and induce tumor cell death responding to the near infrared light. However, the anticancer efficiency of AuNRs alone is undermined by its poor in vivo stability and potential toxicity. The prime purpose of this study was to send more AuNRs into tumors to more fully ablate them. For this, we fabricated hybrid albumin nanoparticles encapsulating small AuNRs (AuNRs-Alb-NPs), which take advantage of biocompatible albumin as a carrier, with better tumor targetability and high in vivo photothermal activity. The sizes of length/width of AuNRs were approximately 20.5 nm and 4.6 nm, respectively, showing a 4.5 aspect ratio, and the size of the resulting AuNRs-Alb-NPs was ˜130 nm, all of which are favorable for glomerular filtration and passive tumor targeting via extravasation. We chose the best formulation for AuNRs-Alb-NPs by in vitro cytotoxicity based on photothermal conversion efficiency considering the incorporated number of AuNRs. Visualized by a photothermal camera, the local tumor temperature of mice treated with AuNRs-Alb-NPs increased to 57℃, which was sufficient for the hyperthermal effect with 808 nm laser irradiation. Subsequently, AuNRs-Alb-NPs displayed remarkably better tumor ablation vs. naïve formulation of AuNRs (tumor volume: 73.8 ± 105.8 vs. 1455.3 ± 310.4 mm 3 at day 8) in the glioblastoma N2a tumor-bearing mice. Most of all, we demonstrated, using photoacoustic imaging and inductively coupled plasma mass spectrometry, that this much better tumor ablation was due to enhanced tumor targeting with albumin nanoparticles. We believe our AuNRs-Alb-NPs should be considered promising photothermal agents that are safer, have good targetability, and exhibit excellent tumor ablation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Photothermal therapy (PTT) is an effective means of treating tumors because tumor cells are sensitive to heat. Gold and carbon nanoparticles are used as efficient PTT materials. However, development of a non-toxic biodegradable PTT agent remains a challenge. Here, we developed a hemoglobin (Hb) hydrogel that exhibited excellent PTT effects in vitro and in vivo. Unlike conventional PTT agents, which are toxic and do not decompose completely in the body, the Hb hydrogel was manufactured using only two components: (i) Hb, a natural substance derived from the human body, and (ii) PEG, an FDA-approved polymer. The gelation time of the Hb hydrogels could be controlled by changing the Hb concentration. Because Hb is present at a high concentration (150 mg/ml) in the body, the Hb hydrogel decomposed and was eliminated in vivo without toxicity. The Hb hydrogel showed an excellent PTT effect in response to 808 nm near-infrared (NIR) laser irradiation and had excellent anticancer effects against A549 lung cancer cells both in vitro and in vivo. Blood hematology and blood biochemical assay results from an animal model treated with Hb hydrogel were similar to those of the control group. Importantly, toxicity was not observed based on H&E staining of major organs (heart, liver, spleen, kidneys and lung). Tumors of A549 cell-xenografted mice treated with Hb hydrogel and 808 nm NIR laser irradiation were significantly smaller than those of the control group (23.1 mm 3 versus 746.5 mm 3 , respectively). This is a first report of a biocompatible photothermal hydrogel based on hemoglobin, and our overall results suggest that Hb hydrogels are commercially-promising PTT systems that have excellent anti-cancer effects., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Chlorin e6 (Ce6) has attracted considerable interest as a promising second-generation photosensitizer for photodynamic therapy (PDT). However, the in vivo availability of Ce6 is significantly restricted by its low water solubility and poor ability to target tumors. We sought to overcome the limitations of Ce6 by using albumin nanoparticles with nab ™ (nanoparticle albumin-bound) technology. The fabricated albumin nanoparticles consisted of bovine serum albumin (BSA), Ce6-BSA, and beta-carotene as a carrier, photosensitizing agent, and cross-linker, respectively. These albumin nanoparticles (Ce6-BSA-BC-NPs) did not include any toxic chemotherapeutics but instead contained naturally safe beta-carotene and Ce6, which was activated only upon irradiation with 660-nm laser light. Ce6-BSA-BC-NPs were ∼120 nm in size and spherical, similar to Abraxane ® , and showed good physicochemical stability. The nanoparticles showed significant cytotoxicity toward 4T1 cells as evaluated by MTT, Live/Dead, and TUNEL assays. In particular, results of the TUNEL assay demonstrated that cell death induced by Ce6-BSA-BC-NPs and light irradiation (660 nm) occurred through the apoptotic pathway. Ce6-BSA-BC-NPs displayed a remarkably enhanced tumor suppression effect when irradiated by 660-nm light compared with free Ce6 (tumor volume 90 ± 39 versus 487 ± 69 mm 3 respectively). Overall, this improved in vivo antitumor efficacy seemed to be due to the targetability of albumin nanoparticles. We believe that our Ce6-BSA-BC-NPs with PDT offer a promising new potential therapeutic platform for breast cancer treatment., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Albumin nanoparticles are well-known as effective drug carriers used to deliver hydrophobic chemotherapeutic agents. Albumin nanoparticles encapsulating curcumin and doxorubicin were fabricated using slightly modified nanoparticle albumin-bound (nab™) technology, and the synergistic effects of these two drugs were examined. Albumin nanoparticles encapsulating curcumin, doxorubicin, and both curcumin and doxorubicin were prepared using a high pressure homogenizer. The sizes of albumin nanoparticles were ∼130nm, which was considered to be suitable for the EPR (enhanced permeability and retention) effect. Albumin nanoparticles gradually released drugs over a period of 24h without burst effect. To confirm the synergistic effect of two drugs, in vitro cytotoxicity assay was performed using B16F10 melanoma cells. The cytotoxic effect on B16F10 melanoma cells was highest when co-treated with both curcumin and doxorubicin compared to single treatment of either curcumin and doxorubicin. The combined index calculated by medium-effect equation was 0.6069, indicating a synergistic effect. Results of confocal laser scanning microscopy and fluorescence-activated cell sorting corresponded to results from an in vitro cytotoxicity assay, indicating synergistic cytotoxicity induced by both drugs. A C57BL/6 mouse model induced by B16F10 lung metastasis was used to study in vivo therapeutic effects. When curcumin and doxorubicin were simultaneously treated, the metastatic melanoma mass in the lungs macroscopically decreased compared to curcumin or doxorubicin alone. Albumin nanoparticles encapsulating two anticancer drugs were shown to have an effective therapeutic result and would be an excellent way to treat resistant lung cancers., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In this study, we report a gas-forming drug carrier engineered using the liposomal magnetoporation method. The liposomes that were magnetoporated under a magnetic shear stress possessed an opened lipid bilayer hole. A photosensitizing model drug (chlorin e6: Ce6) and 1H-1H-2H-perfluoro-1-hexene (PFH, as a volatile gas-forming agent) were efficiently loaded into the opened holes of the magnetoporated liposomes. PFH in the liposomes is vaporized at 50°C and can initiate liposome destabilization. The experimental results demonstrated that the liposomes were destabilized at 50°C efficiently released Ce6 and enhanced Ce6-mediated phototoxicity against KB tumor cells. As a result, these liposomes induced a significantly increased in vitro and in vivo photodynamic tumor inhibition., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Anticancer drug targeting to liver asialoglycoprotein receptors (ASGPR) is viewed as a good approach for hepatocellular carcinoma (HCC) treatment. Lactose residue is a promising ASGPR ligand due to its high receptor affinity. Herein, we introduce doxorubicin and paclitaxel co-bound lactosylated albumin (Lac-BSA) nanoparticles (Dox/Pac Lac-BSA NPs) with good liver targetability. Lac-BSA was synthesized by conjugating lactobionic acid to naïve BSA then characterized by mass spectrometry. Dox/Pac Lac-BSA NPs were fabricated utilizing high-pressure homogenization and evaporation with Nab ® (nanoparticle albumin bound) technology. Dox/Pac Lac-BSA NPs were spherical and well-dispersed, with a 148.7±13.8nm particle size and -54.1±0.7mV zeta potential at a 100% Lac-BSA feed ratio. Combined Dox and Pac synergistic cytotoxicity was confirmed in Hep G2 cells. Specifically, the inhibitory concentration (IC 50 ; 0.21±0.02μg/ml) for Dox/Pac Lac-BSA NPs was 3.2 time lower than plain Dox/Pac BSA NPs (IC 50 ; 0.68±0.04μg/ml). Also, Dox/Pac Lac-BSA NPs exhibited better internalizing in Hep G2 cells (61.8% vs. 14.4% for Dox) and spheroids compared to Dox/Pac BSA NPs. Finally, Dox/Pac Lac-BSA NPs displayed much greater localization into ICR mice livers compared to Dox/Pac BSA NPs. This was indicated by the presence of NP lactose residues revealed by a galactose inhibition study. Based on these results, we suggest that lactose-modified albumin-based nanoparticles fabricated with the Nab ® technique can be a potential therapeutic vector for treating HCC via hepatocyte targeting., (Copyright © 2017 Elsevier B.V. All rights reserved.)

In this study, we report the development of extremely small-sized globular poly(ethylene glycol) (gPEG) that can specifically recognize tumor acidic pH. gPEG coupled with chlorin e6 (Ce6, a photosensitizing drug) and 2,3-dimethylmaleic acid (DMA, as a pH-responsive moiety) (gPEG-Ce6-DMA, particle size: 3-4nm in diameter) was easily dispersed in phosphate buffered saline (PBS) without any of the nanoparticle fabrication steps. We observed that gPEG-Ce6-DMA displayed pH-dependent zeta-potential changes due to coupling (at pH 7.4) or decoupling (at pH 6.8-6.0) of DMA. As a result, the uptake of gPEG-Ce6-DMA was significantly increased in tumors at acidic pH, likely due to the decoupling of DMA (backing cationic primary amines). As a result, the preferential cellular uptake of gPEG-Ce6-DMA at acidic pH allowed for a significant enhancement of in vitro/in vivo photodynamic tumor cell ablation under light illumination., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Albumin has been viewed as one of the most attractive biomacromolecules for making nanoparticulate systems due to its biocompatibility and chemical functionality. Thus far, albumin nanoparticles (NPs) are prepared by several limited methods, such as, desolvation, emulsification or high-pressure homogenization. In this article, we introduce a new albumin NPs prototype fabricated via a 'host' (β-cyclodextrin)-'guest' (adamantane) supramolecular association. These NPs (GC-CD/HSA-ADA NPs) consisted of β-cyclodextrin-modified glycol chitosan (GC-CD) and adamantane-conjugated human serum albumin (HSA-ADA) (GC-CD/HSA-ADA NPs) that were facilely prepared by a consequent dropwise mixing and sonication method. Doxorubicin-loaded GC-CD/HSA-ADA NPs exhibited an appropriate particle size (∼260nm), good physicochemical stability (∼48h), significant HCT116 cell cytotoxicity (IC50: 0.32μg/ml) and cell internalization. Furthermore, GC-CD/HSA-ADA NPs showed excellent tumor targetability probably due to gp60-mediated transcytosis mechanism because it was markedly accumulated in the tumor site of a HCT116 cell-xenograft mouse. Based on these results, these albumin NPs will be promising for a new NP platform that can be applied for cancer therapy or imaging., (Copyright © 2016 Elsevier B.V. All rights reserved.)

We have developed nanomedicine vehicle based on a biocompatible tri-block copolymer, poly(ethylene glycol)-block-poly(lactic acid)-block-poly(ethylene glycol) (PEG-PLA-PEG) by simple approach without toxic linker to escalate therapeutic efficacy of anticancer agent by enhanced targeting to metastasized breast cancers. The synthesized ABA type copolymer had a low polydispersity index and formed small, highly stable spherical micelles. Furthermore, a functional group at the end site of the copolymer can be decorated with imaging agents and targeting moieties. The doxorubicin loaded micelles (DLM) showed higher drug-loading capacity, faster drug release, and better cell toxicity compared to those using di-block copolymers. DLM efficiently delivered to the metastatic breast cancers in brain and bone and suppressed growing of metastasis. In demonstration of treating metastasized animal model, we present a tri-block copolymer as a potential nanomedicine vehicle to efficiently deliver anticancer drug and to effectively treat metastatic breast cancer., (Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.)

Albumin has gained considerable interest as a material for fabricating nanoparticulate systems due to its biomedical advantages, such as biocompatibility and chemical functionality. Here, we report a new pH-sensitive albumin nanocomplex prototype with a zinc-imidazole coordination bond. Albumin was conjugated with 1-(3-aminopropyl)imidazole and mPEG10kDa-NHS, and the resulting albumin conjugate (PBI) was then modified with either Cy5.5 or BHQ-3. The newly formed albumin nanocomplex (C/BQ-PBI Zn NCs: ∼116nm) system was facilely self-assembled around pH 7.4 in the presence of Zn(2+), but it quickly disassembled in an acidic environment (∼pH 5.0). Based on this pH-sensitivity, C/BQ-PBI Zn NCs emitted strong near-infrared fluorescence and released Zn(2+), turning "off" at pH ∼7.4 (e.g., plasma) and "on" at pH ∼5.0 (e.g., endo/lysosomes in tumor cells) on account of fluorescence resonance energy transfer. C/BQ-PBI Zn NCs displayed significant cytotoxicity due to an increase in cellular Zn(2+) in response to endosomal pH (∼5.0) in breast cancer MCF-7 cells and lung adenocarcinoma A549 cells. Particularly, confocal laser scanning microscopic images showed a strong fluorescence signal caused by the disassembly of C/BQ-PBI Zn NCs in the endosomal region of MCF-7 cells. Based on these results, we believe that this albumin nanocomplex is an attractive biocompatible tumor targeting probe carrier for the theranostic purpose., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Sophisticated control of the assembly of nano-sized structures to achieve desired properties is one of the most efficient techniques in drug carrier design. In this study, we hypothesized that under magnetic shear stress, high-density superparamagnetic Fe3O4 nanoparticles dispersed in a liposome would apply a high load in a particular direction to a liposome membrane and ultimately generate open lipid bilayer holes. Indeed, the designed experimental conditions enabled the formation of one or multiple open pore sites in liposome membranes. With this evidence, open lipid bilayer holes in liposome membranes were further used as open entrances for proteins (bovine serum albumin or insulin) into the liposomes prior to the natural recovery (i.e., closing) of the lipid bilayer holes. This trial will provide potential opportunities for the engineering of functional liposomes for protein drug delivery., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objectives: This study sought to investigate the efficacy of (11)C-Pittsburgh B (PiB) positron emission tomography (PET)/computed tomography (CT) in the diagnosis of cardiac amyloidosis., Background: The PiB compound has been promising for detection of amyloid deposits in the brain., Methods: A total of 22 consecutive patients were enrolled in this prospective pilot study of monoclonal gammopathy patients with suspected cardiac amyloidosis. The study consisted of a series of (11)C-PiB PET/CT, echocardiography, cardiac magnetic resonance, and endomyocardial biopsy within a 1-month period. In addition, 10 normal subjects were recruited to determine the most optimal cut-off value for a positive (11)C-PiB PET/CT scan., Results: Among the 22 patients, 15 patients were diagnosed as cardiac amyloidosis by endomyocardial biopsy and 5 patients had undergone chemotherapy previously before the (11)C-PiB PET/CT. There were no differences in echocardiographic parameters between patients with versus without cardiac amyloidosis, except for a marginal difference in the left ventricular end-diastolic dimension (median 41.0 mm [range 33.0 to 49.0 mm] vs. 50.0 mm [range 38.0 to 55.0 mm], p = 0.066). (11)C-PiB PET/CT was positive in 13 of 15 biopsy-proven cardiac amyloidosis patients, whereas none of the patients without cardiac amyloidosis demonstrated positive (11)C-PiB PET/CT scan results. The maximal myocardium-to-blood cavity ratio was significantly different between patients with versus without cardiac amyloidosis (median 3.9 [range 1.7 to 19.9] vs. 1.0 [range 0.8 to 1.2], p < 0.001). In association with the significant difference of (11)C-PiB uptake in the myocardium between the chemotherapy naïve versus the previous chemotherapy group (median 10.4 [range 1.7 to 19.9] vs. 2.3 [range 1.7 to 3.8], p = 0.014), all except 1 patient among the 5 previously treated patients had responded to chemotherapy by serum free light chain assay results at the time of (11)C-PiB PET/CT scan., Conclusions: (11)C-PiB PET/CT may be valuable for the diagnosis of cardiac amyloidosis noninvasively. Whether (11)C-PiB PET/CT may be a good surrogate marker of active light chain deposition in the myocardium warrants further investigation in a larger number of patients., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

In this study, we report a novel pH-responsive nanoparticle composed of poly(γ-cyclodextrin) [poly(γCD)] conjugated with functional 3-diethylaminopropyl (DEAP) groups [poly(γCD-DEAP)]. The design of the nanoparticle takes advantage of the biocompatible functional poly(γCD) as the backbone polymer and the unique pH-responsive feature of DEAP as either a hydrophobic moiety (non-ionic DEAP) at pH 7.4 or a hydrophilic moiety (ionic DEAP) at acidic pH. Poly(γCD) was coupled with DEAP and utilized for fabricating pH-responsive nanoparticles for antitumor drug (doxorubicin: DOX) delivery. The experimental results reveal that the poly(γCD-DEAP) nanoparticles increased the release of the encapsulated DOX content when the pH of the solution was decreased to 6.0. This event caused significant increases in the efficiency of cellular DOX uptake and in vitro tumor inhibition. Furthermore, these nanoparticles allow the encapsulation of multiple antitumor drugs into the nanoparticles [utilizing the hydrophobic interactions (between non-ionic DEAP moieties and drugs) and inclusive interactions (between poly(γCD)s and drugs)], thereby suggesting their potential for use in drug combination therapy., (Copyright © 2014 Elsevier B.V. All rights reserved.)

In this study, we report the development of a novel pH-responsive nanoparticle composed of hyaluronic acid (HA) grafted with functional 3-diethylaminopropyl (DEAP) groups (HA-g-DEAP). The pH-responsive nanoparticles were fabricated by a self-assembled arrangement of a hydrophilic block (HA) and a hydrophobic block (non-protonated DEAP) of HA-g-DEAP at pH 7.4. HA-g-DEAP was prepared by a simple conjugation of the carboxylic acid groups of HA and the free amine groups of DEAP. The HA-g-DEAP nanoparticles displayed pH-dependent changes in their physicochemical properties. We observed nanoparticle destabilization because of the protonation of DEAP when the pH of the solution decreased to 5.0. This phenomenon resulted in the release of the encapsulated content (model drug, doxorubicin: DOX) from the nanoparticle core. In addition, the degradation of HA by hyaluronidase (Hyal) significantly accelerated the DOX release rate, which may allow for increased drug release in diseased cells with acidic endosomal pH (∼pH 5.0) in the presence of Hyal. Overall, a significant improvement in the drug release rate was evident when this nanoparticle system was stimulated by both an acidic pH and specific enzymes., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Decanoic acid-modified glycol chitosan (DA-GC) hydrogels containing tightly adsorbed palmitic acid-modified exendin-4 (Ex4-C16) were prepared, and their pharmaceutical abilities as a long-acting sustained-release exendin-4 system for the treatment of diabetes were evaluated. Glycol chitosan (GC) was conjugated with N-hydroxysuccinimide-activated decanoic acid (DA) in anhydrous 0.4% dimethylaminopyridine/dimethylsulfoxide at different feed ratios. DA-GC hydrogels formed by physical self-assembly during dialysis vs. deionized water, and their inner network structures, swelling or gel-forming abilities and release properties were examined. The hypoglycemia caused by Ex4-C16-loaded DA-GC hydrogels was evaluated by subcutaneous administration in type 2 diabetic db/db mice. The results obtained showed that GC prepared at a DA:GC feed ratio of 1:100 had optimal properties with respect to hydrogel swelling, stiffness and Ex4-C16 incorporation, whereas DA-GC hydrogels prepared at a feed ratio of greater than 1:100 formed gels that were too stiff. The in vitro and in vivo release of Ex4-C16 from DA-GC hydrogels was dramatically delayed compared with native Ex4 probably due to strong hydrophobic interactions. In particular, Ex4-C16 in DA-GC hydrogels was found to be present around the injection site up to 10 days after subcutaneous administration, whereas Ex4 in DA-GC hydrogels was cleared from injection sites in ≈ 2 days in ICR mice. Finally, the hypoglycemia induced by Ex4-C16 DA-GC hydrogels was maintained for >7 days. Our findings demonstrate that Ex4-C16 DA-GC hydrogels offer a potential delivery system for the long-term treatment of type 2 diabetes., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Four-arm polyethylene glycol (PEG) cross-linked hyaluronic acid (HA) hydrogels containing PEGylated tumor necrosis factor-related apoptosis-inducing ligand (PEG-TRAIL) were fabricated, and their antitumor effects were evaluated in pancreatic cell (Mia Paca-2)-xenografted mice. HA was conjugated with 4-arm PEG(10k)-amine (a cross-linker) at ratios of 100:1 and 100:2 using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride as a cross-linker, and TRAIL or PEG-TRAIL was incorporated into these HA hydrogels. HA hydrogels at a 100:1 ratio were prepared in good yields (>88%), were moderately stiff, and gradually released PEG-TRAIL over ~14 days in vitro and over ~7 days in vivo (as determined by high-pressure liquid chromatography and infrared imaging). The released PEG-TRAIL was found to have obvious apoptotic activity in Mia Paca-2 cells. PEG-TRAIL HA hydrogels displayed remarkably more antitumor efficacy than TRAIL HA hydrogels in Mia Paca-2 cell-xenografted mice in terms of tumor volumes (size) and weights (453.2mm(3) and 1.03 g vs. 867.5mm(3) and 1.86 g). Furthermore, this improved antitumor efficacy was found to be due to the apoptotic activity of PEG-TRAIL in vivo (determined by a TUNEL assay) despite its substantially lower cytotoxicity than native TRAIL (IC50 values: 71.8 and 202.5 ng ml(-1), respectively). This overall enhanced antitumor effect of PEG-TRAIL HA hydrogels appeared to be due to the increased stability of PEGylated TRAIL in HA hydrogels. These findings indicate that this HA hydrogel system combined with PEG-TRAIL should be considered a potential candidate for the treatment of pancreatic cancer., (Copyright © 2013 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Advanced materials that have controllable pH-responsive properties when submerged in the lysosome have a great potential in intracellular drug delivery. We developed novel poly(L-amino acid) nanogels that were prepared by a facile cross-linking of poly[L-aspartic acid-g-(3-diethylaminopropyl)]-b-poly(ethylene glycol)-maleimide [poly(L-Asp-g-DEAP)-b-PEG-Mal] and poly(L-aspartic acid-g-ethyl thiol)-b-PEG [poly(L-Asp-SH)-b-PEG] in an oil/water emulsion condition. Interestingly, these nanogels (~125 nm in diameter) modulated volume expansion (~375 nm in diameter) in a lysosomal pH (~pH 5.0) due to an extensive proton absorption of DEAP at a low pH, which mediated lysosome swelling and the subsequent lysosome destabilization. In the in vitro tumor cell cytotoxicity test, they encouraged tumor cell death, probably owing to the leakage of lysosomal enzymes. Furthermore, encapsulating antitumor drug (e.g., doxorubicin, DOX) into these nanogels enhanced tumor cell cytotoxicity. We conclude that this nanogel system will have great potential for tumor therapy., (Copyright © 2012 Elsevier B.V. All rights reserved.)

In order to develop a novel functional poly(L-amino acid) that can dissolve in volatile organic solvents, we prepared poly[L-aspartic acid-g-(3-diethylaminopropyl)]-b-poly(ethylene glycol) [poly(L-Asp-g-DEAP)-b-PEG] via the conjugation of 3-diethylaminopropyl (DEAP) to carboxylate groups of poly(L-Asp) (M(n) 4 K)-b-PEG (M(n) 2 K). This poly(L-aspartic acid) derivative evidenced a relatively high solubility in volatile organic solvents such as dichloromethane, chloroform, and acetone. We fabricated a model nanostructure (i.e., polymeric micelle) using poly(L-Asp-g-DEAP)-b-PEG by the film rehydration method, which involves the simple removal of the volatile organic solvent (dichloromethane) used to dissolve polymer, reducing concerns about organic solvents remaining in a nano-sized particle. Interestingly, this micelle showed the pH-stimulated release of encapsulated model drug [i.e., doxorubicin (DOX)] due to the protonation of DEAP according to the pH of the solution. We expect that this poly(L-aspartic acid) derivative promises to provide pharmaceutical potential for constituting a new stimuli-sensitive drug carrier for various drug molecules., (Copyright © 2012 Elsevier B.V. All rights reserved.)

The purpose of this study was to fabricate porous poly(lactide-co-glycolide) (PLGA) microparticles for efficient pulmonary deposition and increased therapeutic duration of the antioxidant anthocyanin (ATH). These microparticles were prepared by a water-in-oil-in-water (W(1)/O/W(2)) multi-emulsion method with vaporizing ammonium bicarbonate (AB) as a porogen and starch as a viscous additive. High porosity achieved by the decomposition reaction of AB to the base of ammonia, carbon dioxide, and water vapor at 50°C enabled efficient deposition of ATH throughout the entire lung in BALB/c mice. In addition, the porous microparticles incorporating starch showed sustained ATH release characteristics (up to 5 days) and protracted antioxidant activity (up to 5 days) for 2,2-diphenyl-1-pikryl-hydrazyl (DPPH) radicals, which was comparable to that of the porous microparticles without starch which completely released ATH in 2h. Furthermore, these porous microparticles incorporating starch led to longer ATH residence (up to 20 days) in in vivo lung epithelium. We believe that this system has great pharmaceutical potential as a long-acting antioxidant for continuously relieving oxidative stress in pulmonary diseases like chronic obstructive pulmonary disease (COPD)., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Herein, we describe magnetic cell levitation models using conventional polymeric microparticles or nanoparticles as a substrate for the three-dimensional tumor cell culture. When the magnetic force originating from the ring-shaped magnets overcame the gravitational force, the magnetic field-levitated KB tumor cells adhered to the surface area of magnetic iron oxide (Fe(3)O(4))-encapsulated nano/microparticles and concentrated clusters of levitated cells, ultimately developing tumor cells to tumor spheroids. These simple cell culture models may prove useful for the screening of anticancer drugs and their formulations., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Polysaccharidic nanogels were fabricated with bovine serum albumin (BSA) and a glycol chitosan (GCS) grafted with functional 3-diethylaminopropyl (DEAP) groups. These nanogels were investigated to evaluate their cellular uptake in HeLa cells and in vivo fate in nude mice tumor model. Unlike free BSA, GCS-g-DEAP/BSA nanogels improved cellular uptake of BSA. Furthermore, this system led to an enhanced blood circulation and a high accumulation of BSA in the tumor site. Our collective results strongly support that GCS-g-DEAP/BSA nanogel is a potential carrier system for high molecular weight proteins., (Copyright © 2011 Elsevier B.V. All rights reserved.)

Pluronics with different structural compositions and properties are used for several applications, including drug delivery systems. We developed a binary mixing system with two Pluronics, L121/P123, as a nano-sized drug delivery carrier. The lamellar-forming Pluronic L121 (0.1 wt%) was incorporated with Pluronic P123 to produce nano-sized dispersions (in case of 0.1 and 0.5 wt% P123) with high stability due to Pluronic P123 and high solubilization capacity due to Pluronic L121. The binary systems were spherical and less than 200-nm diameter, with high thermodynamic stability (at least 2 weeks) in aqueous solution. The CMC of the binary system was located in the middle of the CMC of each polymer. In particular, the solubilization capacity of the binary system (0.1/0.1 wt%) was higher than mono-systems of P123. The main advantage of binary systems is overcoming limitations of mono systems to allow tailored mixing of block copolymers with different physicochemical characteristics. These nano-sized systems may have potential as anticancer drug delivery systems with simple preparation method, high stability, and high loading capacity., (Copyright © 2010 Elsevier B.V. All rights reserved.)

In this study, a novel pH-responsive nanogel composed of glycol chitosan (GCS) grafted with functional 3-diethylaminopropyl (DEAP) groups (denoted as GCS-g-DEAP hereafter) was fabricated. The GCS-g-DEAP was designed to have a self-assembled arrangement consisting of hydrophilic block (GCS) and hydrophobic block (DEAP) at physiological pH. As the pH decreased to tumor extracellular pH (pH(e)), the nanogel was destabilized due to the protonation of DEAP. The pH-responsive property of the nanogel at tumor extracellular pH (pH(e)) was characterized in drug-release kinetic studies. The release of doxorubicin (DOX) from DOX-loaded nanogels was significantly accelerated at lower pH values, which allowed for increased DOX uptake by non-small lung carcinoma A546 cells under a slightly acidic pH condition, as in tumor pH(e)., (Copyright 2010 Elsevier B.V. All rights reserved.)

The rapid elimination of glucagon-like peptide-1 (GLP-1) is the main impediment to its anti-diabetic utility. Here, we tried to improve its poor pharmacokinetic/pharmacodynamic profiles using PEGylation. The site-specific (Lys(34)) PEGylated GLP-1s were synthesized with PEGs of 2, 5, and 10 kDa, respectively. Oral glucose tolerance tests using db/db mice showed that these three PEGylated GLP-1s (5 nmol/kg) specifically stabilized plasma glucose levels when intraperitoneally (i.p.) administered at 30, 30-120, or 120-360 min preoral glucose treatment, respectively (total hypoglycemic degree: 60.5 +/- 5.0%, approximately 67.2 +/- 2.3%, and approximately 59.4 +/- 4.3%, respectively). Particularly, Lys(34)-PEG(10K)-GLP-1 showed an stable hypoglycemic efficacy when administered up to 360 min preglucose. The different anti-diabetic effects of PEGylated GLP-1s were attributed to their augmented pharmacokinetics and metabolic resistance. These analogs had higher metabolic stabilities in rat plasma, liver and kidney homogenates, and extended pharmacokinetic profiles with the greater circulating half-lives (26.6, 64.5, and 105.5 min for Lys(34)-PEG(2,5,10 K)-GLP-1s, respectively, vs. 8.5 min for GLP-1, at elimination phases after i.p. injections) in ICR mice. Our findings suggest that GLP-1 substituted with a PEG of an appropriate Mw at Lys(34) could be used as a promising type 2 anti-diabetic agent to timely control postprandial glucose levels.

Porous microparticles (PMs) with a low density (<0.4 g/cm3) for pulmonary protein delivery were prepared by the water-in-oil-in-water (W1/O/W2) multi-emulsion method using a cyclodextrin derivative as a porogen. The complexation of positively charged lysozyme (Lys) and negative-charged hyaluronate (HA) was investigated for long-term protein release from PMs. The interaction of Lys and HA not only increased protein encapsulation efficiency but also stabilized Lys against a denaturing organic solvent (dichloromethane). Furthermore, PMs with Lys/HA complexes increased the Lys release period up to 7 days, as opposed to a 4h Lys release time from PMs without Lys/HA complexes. In particular, PMs containing 10mg of HA and 50mg of Lys showed almost zero-order Lys release kinetic for 7 days and preserved the bioactivity of Lys more than 98% during its entire release period. This result suggests that PMs with Lys/HA complexes may be applied in long-term pulmonary administration of protein or peptide drugs, including those that require particles to arrive at a deep lung epithelium with the help of low density (high porosity) of PMs.