Galactose-Containing Polymer-DOX Conjugates for Targeting Drug Delivery.

A novel multifunctional drug delivery system was fabricated by conjugating galactose-based polymer, methoxy-poly(ethylene glycol)-block-poly(6-O-methacryloyl-D-galactopyranose) (mPEG-b-PMAGP) with doxorubicin (DOX) via an acid-labile carbamate linkage. The mPEG-b-PMAGP-co-DOX nanoparticles were spherical in shape, and the diameter determined by dynamic light scattering (DLS) was 54.84 ± 0.58 nm, larger than that characterized by transmission electron microscopy (TEM). The in vitro drug release profiles were studied, and the release of DOX from the nanoparticles was pH-responsive. The cellular uptake behavior of free-DOX and mPEG-b-PMAGP-co-DOX nanoparticles by asialoglycoprotein (ASGP) receptor-positive cancer cell line (HepG2) and ASGP receptor-negative cancer cell lines (MCF-7 and A549 cells) was evaluated by confocal laser scanning microscopy (CLSM) and flow cytometry (FCM), respectively. The mPEG-b-PMAGP-co-DOX nanoparticles which contain galactose functional groups exhibited higher cellular uptake behavior via ASGP receptor-mediated endocytosis in HepG2 cells than in other two cancer cells. The in vitro cytotoxicity assay manifested that the mPEG-b-PMAGP-co-DOX nanoparticles exhibited higher anticancer efficacy against HepG2 cells than MCF-7 cells. These results indicated that the multifunctional mPEG-b-PMAGP-co-DOX nanoparticles possessing pH-responsible and hepatoma-targeting function have great potential to be used as a targeting drug delivery system for hepatoma therapy.

[Anthraquinones and triterpenoids from roots of Knoxia roxburghii].

Nine compounds were isolated from an ethanol extract of the roots of K. roxburghii by using a combination of various chromatographic techniques including column chromatography over silica gel, MCI gel, Sephadex LH-20, and reversed-phase HPLC. On the basis of physical-chemical properties and spectroscopic data analysis, their structures were identified as munjistin (1), 1-methoxy-3,6-dihydroxy-2-hydroxymethyl-9,10-anthraquinone (2), 1,2,3-trihydroxy-9,10-anthraquinone (3), arjunolic acid (4), hyptatic acid-A (5), hyptatic acid-B (6), 2α,3ß,24-trihydroxyurs-12-en-28-oic acid (7), 2α,3ß,23-trihydroxyurs-12-en-28-oic acid (8), and daucosterol (9). Compounds 1-9 were obtained from this genus for the first time.

Construction of a Robust Radiative Cooling Emitter for Efficient Food Storage and Transportation.

Nowadays, food safety is still facing great challenges. During storage and transportation, perishable goods have to be kept at a low temperature. However, the current logistics still lack enough preservation ability to maintain a low temperature in the whole. Hence, considering the temperature fluctuation in logistics, in this work, the passive radiative cooling (RC) technology was applied to package to enhance the temperature control capability in food storage and transportation. The RC emitter with selective infrared emission property was fabricated by a facile coating method, and Al2O3 was added to improve the wear resistance. The sunlight reflectance and infrared emittance within atmospheric conditions could reach up to 0.92 and 0.84, respectively. After abrasion, the sunlight reflection only decreased by 0.01, and the infrared emission showed a negligible change, revealing excellent wear resistance. During outdoor measurement, the box assembled by RC emitters (RC box) was proved to achieve temperature drops of ∼9 and ∼4 °C compared with the corrugated box and foam box, respectively. Besides, the fruits stored in the RC box exhibited a lower decay rate. Additionally, after printing with patterns to meet the aesthetic requirements, the RC emitter could also maintain the cooling ability. Given the superior optical properties, wear resistance, and cooling capability, the emitter has great potential for obtaining a better temperature control ability in food storage and transportation.

Mechanically Switchable Multifunctional Device for Regulating Passive Radiative Cooling and Solar Heating.

Energy consumption during cooling and heating poses a great threat to the development of society. Thermal regulation, as switchable cooling and heating in a single platform, is therefore urgently demanded. Herein, a switchable multifunctional device integrating heating, cooling, and latent energy storage was proposed for temperature regulation and window energy saving for buildings. A radiative cooling (RC) emitter, a phase-change (PC) membrane, and a solar-heating (SH) film were connected layer by layer to form a sandwich structure. The RC emitter exhibited selective infrared emission (emissivity in the atmospheric window: 0.81, emissivity outside the atmospheric window: 0.39) and a high solar reflectance (0.92). Meanwhile, the SH film had a high solar absorptivity (0.90). More importantly, both the RC emitter and the SH film displayed excellent wear resistance and UV resistance. The PC layer can control the temperature at a steady state under dynamic weather conditions, which could be verified by indoor and outdoor measurements. The thermal regulation performance of the multifunctional device was also verified by outdoor measurements. The temperature difference between the RC and SH models of the multifunctional device could reach up to 25 °C. The as-constructed switchable multifunctional device is a promising candidate for alleviating the cooling and heating energy consumption and realizing energy saving for windows.

Maleimide-functionalized phospholipid/Pluronic F127 mixed micelles for efficient ophthalmic delivery of voriconazole against Candida albicans.

Drugs that are topically applied on the eyes have low bioavailability, which has always been an important problem. In this study, maleimide functionalized, voriconazole (VCZ) loaded mixed micelles (Mal-VCZ-MM) were designed. Pluronic F127 and phospholipid were used as materials, and maleimide was used as an adhesive. The prepared Mal-VCZ-MM was nearly spherical with a particle size of 84.45 ± 1.39 nm and a zeta potential of - 20.3 ± 0.29 mV. The encapsulation efficiency of Mal-VCZ-MM was 95.33 ± 0.06%, and it had high stability with a critical micelle concentration value of 1.28 × 10-4 mg/mL. CCK-8 assay showed that its cytotoxicity was lower than that of free VCZ solution (VCZ-Sol). Both quantitative and qualitative analyses of the HCE-T cellular uptake showed that the cellular internalization of Mal-C6-MM was significantly stronger than that of C6-MM. The endocytosis pathway was macropinocytosis-mediated, cavernous-mediated, and energy-dependent. In vitro results against Candida albicans showed that the diameters of the antifungal inhibition zones of VCZ-Sol, VCZ-MM, and Mal-VCZ-MM were 15.5 ± 0.50 mm, 24.0 ± 0.71 mm, and 31.5 ± 1.12 mm, respectively. The antifungal effect of Mal-VCZ-MM was significantly higher than that of VCZ-Sol and VCZ-MM (P < 0.001). This study shows that Mal-VCZ-MM is a highly effective hydrophobic ophthalmic drug-delivery carrier that can improve the therapeutic effect of the drug.

N-acetylcysteine functionalized chitosan oligosaccharide-palmitic acid conjugate enhances ophthalmic delivery of flurbiprofen and its mechanisms.

An N-acetylcysteine functionalized chitosan oligosaccharide-palmitic acid conjugate (NAC-COS-PA) with bioadhesive and permeation promoting properties was synthesized to enhance transocular drug delivery. Flurbiprofen (FB) loaded self-assembled NAC-COS-PA nanomicelles (NAC-COS-PA-FB) were prepared and the drug loading was 7.35 ± 0.32%. Human immortalized corneal epithelial (HCE-T) cell cytotoxicity and hen's egg test-chorioallantoic membrane assays confirmed that the conjugate had good biocompatibility. The transportation efficiency of coumarin-6 (C6) loaded nanomicelles in the HCE-T cell monolayer was approximately 1.97 times higher than that of free C6. Decreased intracellular Ca2+ concentration and cell membrane potential, increased cell membrane fluidity, and reversible changes in the F-actin cytoskeleton are presumed to be responsible for the enhanced drug permeation. NAC-COS-PA exhibited strong binding capacity with mucin and rabbit eyeball. In vivo pharmacokinetics indicated that the area under the curve (AUC0-6 h) and the maximum concentration (Cmax) of NAC-COS-PA-FB were approximately 1.92 and 2.44 times that of the FB solution, respectively. NAC-COS-PA-FB demonstrated the best in vivo anti-inflammatory efficacy compared to unfunctionalized nanomicelles (COS-PA-FB) and FB solution. Consequently, NAC-COS-PA appears to be a promising bioadhesive carrier for ophthalmic delivery.

Mucoadhesive phenylboronic acid conjugated chitosan oligosaccharide-vitamin E copolymer for topical ocular delivery of voriconazole: Synthesis, in vitro/vivo evaluation, and mechanism.

Topical eye drops still face challenges of low-drug treatment effects and frequent dosing in ophthalmic applications due to the low preocular retention rate and low transcorneal permeability. Thus, we designed and synthesized a phenylboronic acid conjugated chitosan oligosaccharide-vitamin E copolymer (PBA-CS-VE) for use in mucoadhesive voriconazole (VRC)-loaded nanomicelles for fungal keratitis. In vitro mucin binding and ex vivo eyeball adhesion tests show that the copolymer has strong mucoadhesion. The transportation of coumarin-6 (C6) across a monolayer of HCE-T cells and 3D cell spheroids confirm the strong corneal penetration ability of PBA-CS-VE. The mechanism of promoting corneal penetration was studied in terms of intracellular calcium-ion concentration, cell membrane potential, cell membrane fluidity, and the tight junctions of cells. The pharmacokinetics in the aqueous humor were examined to evaluate the ability of nanomicelles in promoting corneal penetration and prolonging ocular retention. VRC-loaded PBA-CS-VE nanomicelles (PBA-CS-VE-VRC) yielded a very favorable therapeutic effect on a rabbit model of fungal keratitis in vivo as compared to the free drug. Overall, the results indicate that PBA-CS-VE nanomicelles are a mucoadhesive candidate with enhanced transcorneal permeability and prolonged preocular retention for efficient delivery of topical ocular drugs. STATEMENT OF SIGNIFICANCE: Although eye drops are widely used in ocular drug delivery, the disadvantages such as short retention time and weak corneal penetrating ability still seriously affect the therapeutic effect of the drug. Therefore, the mucoadhesive carrier seems to be an interesting strategy for ocular drug delivery. Herein, a novel phenylboronic acid conjugated chitosan oligosaccharide-vitamin E copolymer was designed and constructed as mucoadhesive nanomicelles loaded with voriconazole for fungal keratitis. These nanomicelles were able to improve the in vitro mucin binding and to prolong the residence time of the drug on the surface of the eyeball. Moreover, the nanomicelles exhibited an enhanced drug permeability in cell monolayer models and 3D cell culture models. This work provides a promising ocular drug delivery system.

The physico-chemical characterization of casein-modified surfaces and their influence on the adhesion of spores from a Geobacillus species.

To gain a better understanding of the factors influencing spore adhesion in dairy manufacturing plants, casein-modified glass surfaces were prepared and characterized and their effect on the adhesion kinetics of spores from a Geobacillus sp., isolated from a dairy manufacturing plant (DMP) was assessed using a flow chamber. Surfaces were produced by initially silanizing glass using (3-glycidyloxypropyl) trimethoxysilane (GPS) or (3-aminopropyl) triethoxysilane to form epoxy-functionalized (G-GPS) or amino-functionalized glass (G-NH(2)) substrata. Casein was grafted to the G-GPS directly by its primary amino groups (G-GPS-casein) or to G-NH(2) by employing glutaraldehyde as a linking agent (G-NH(2)-glutar-casein). The surfaces were characterised using streaming potential measurements, contact angle goniometry, infrared spectroscopy and scanning electron microscopy. The attachment rate of spores suspended in 0.1 M KCl at pH 6.8, was highest on the positively charged (+14 mV) G-NH(2) surface (333 spores cm(-2) s(-1)) compared to the negatively charged glass (-22 mV), G-GPS (-20 mV) or G-GPS-casein (-21 mV) surfaces (162, 17 or 6 spores cm(-2) s(-1) respectively). Whilst there was a clear decrease in attachment rate to negatively charged casein-modified surfaces compared to the positively charged amine surface, there was no clear relationship between surface hydrophobicity and spore attachment rate.

1-Benzyl-3,5-bis-(4-methyl-benzyl-idene)-4-oxopiperidin-1-ium chloride acetic acid monosolvate.

In the title solvated mol-ecular salt, C(28)H(28)NO(+)·Cl(-)·C(2)H(4)O(2), the central piperidinium ring of the cation adopts an envelope conformation with the N atom displaced by 0.798 (2) Šfrom the mean plane of the five C atoms. In the crystal, the components are linked by N-H⋯Cl and O-H⋯Cl hydrogen bonds into trimeric assemblies. C-H⋯Cl and C-H⋯π inter-actions further consolidate the packing.

Cell penetrating peptide TAT-functionalized liposomes for efficient ophthalmic delivery of flurbiprofen: Penetration and its underlying mechanism, retention, anti-inflammation and biocompatibility.

In treating eye diseases, topical administration on the ocular surface is the most convenient and acceptable route. However, the intraocular efficiency of non-invasive drug delivery systems is still considerably hampered by the eye's defense barriers. In this work, cell-penetrating peptide TAT-functionalized, flurbiprofen-loaded liposomes (TAT-FB-Lip) were designed to enable transcorneal drug delivery and prolong ocular surface retention. The corneal penetration-promoting properties of TAT-functionalized liposomes (TAT-Lip) were confirmed in vitro using a corneal permeability assay and the HCE-T cell sphere model and in vivo by aqueous humor pharmacokinetics assessment. TAT-Lip induced an increase in intracellular calcium ion concentration and membrane potential depolarization. F-actin images of HCE-T cells treated with TAT-Lip show the tight junctions between cells partly opened. The cellular internalization pathway mainly depended on the electrostatic interaction between TAT-Lip and the cell membrane, and there is a certain degree of energy dependence. The pharmacokinetics of flurbiprofen in tears demonstrated TAT-Lip could reduce the drug loss rate. Moreover, the anti-inflammatory effect of TAT-FB-Lip was enhanced by markedly suppressing PGE2, IL-6, and TNF-α production in tears and aqueous humor in a rabbit conjunctivitis model. In conclusion, this work demonstrates that TAT-Lip is an effective ocular drug carrier system that facilitates transcorneal delivery.

A NAG-Guided Nano-Delivery System for Redox- and pH-Triggered Intracellularly Sequential Drug Release in Cancer Cells.

AIM: Sequential treatment with paclitaxel (PTXL) and gemcitabine (GEM) is considered clinically beneficial for non-small-cell lung cancer. This study aimed to investigate the effectiveness of a nano-system capable of sequential release of PTXL and GEM within cancer cells. METHODS: PTXL-ss-poly(6-O-methacryloyl-d-galactopyranose)-GEM (PTXL-ss-PMAGP-GEM) was designed by conjugating PMAGP with PTXL via disulfide bonds (-ss-), while GEM via succinic anhydride (PTXL:GEM=1:3). An amphiphilic block copolymer N-acetyl-d-glucosamine(NAG)-poly(styrene-alt-maleic anhydride)58-b-polystyrene130 acted as a targeting moiety and emulsifier in formation of nanostructures (NLCs). RESULTS: The PTXL-ss-PMAGP-GEM/NAG NLCs (119.6 nm) provided a sequential in vitro release of, first PTXL (redox-triggered), then GEM (pH-triggered). The redox- and pH-sensitive NLCs readily distributed homogenously in the cytoplasm. NAG augmented the uptake of NLCs by the cancer cells and tumor accumulation. PTXL-ss-PMAGP-GEM/NAG NLCs exhibited synergistic cytotoxicity in vitro and strongest antitumor effects in tumor-bearing mice compared to NLCs lacking pH/redox sensitivities or free drug combination. CONCLUSION: This study demonstrated the abilities of PTXL-ss-PMAGP-GEM/NAG NLCs to achieve synergistic antitumor effect by targeted intracellularly sequential drug release.

Enhanced transdermal delivery of lornoxicam by nanostructured lipid carrier gels modified with polyarginine peptide for treatment of carrageenan-induced rat paw edema.

Background: Nanostructured lipid carriers (NLCs) are emerging as attractive drug carriers in transdermal drug delivery. The surface modification of NLCs with cell-penetrating peptides (CPPs) can enhance the skin permeation of drugs. Purpose: The objective of the current study was to evaluate the ability of the cell-penetrating peptide (CPP) polyarginine to translocate NLCs loaded with lornoxicam (LN) into the skin layers and to evaluate its anti-inflammatory effect. Methods: The NLCs were prepared using an emulsion evaporation and low temperature solidification technique using glyceryl monostearates, triglycerides, DOGS-NTA-Ni lipids and surfactants, and then six histidine-tagged polyarginine containing 11 arginine (R11) peptides was modified on the surface of NLCs. Results: The developed NLCs formulated with LN and R11 (LN-NLC-R11) were incorporated into 2% HPMC gels. NLCs were prepared with a particle size of (121.81±3.61)-(145.72±4.78) nm, and the zeta potential decreased from (-30.30±2.07) to (-14.66±0.74) mV after the modification of R11 peptides. The encapsulation efficiency and drug loading were (74.61±1.13) % and (7.92±0.33) %, respectively, regardless of the surface modification. Cellular uptake assays using HaCaT cells suggested that the NLC modified with R11 (0.02%, w/w) significantly enhanced the cell internalization of nanoparticles relative to unmodified NLCs (P<0.05 or P<0.01). An in vitro skin permeation study showed better permeation-enhancing ability of R11 (0.02%, w/w) than that of other content (0.01% or 0.04%). In carrageenan-induced rat paw edema models, LN-NLC-R11 gels inhibited rat paw edema and the production of inflammatory cytokines compared with LN-NLC gels and LN gels (P<0.01). Conclusion: In our investigation, it was strongly demonstrated that the surface modification of NLC with R11 enhanced the translocation of LN across the skin, thereby alleviating inflammation.

Redox-sensitive micelles based on retinoic acid modified chitosan conjugate for intracellular drug delivery and smart drug release in cancer therapy.

Novel chitosan-cystamine-retinoic acid conjugate (CS-SS-RA) was synthesized and could self-assemble into redox-sensitive micelles in aqueous environment with low critical micelle concentration value. CS-SS-RA micelles were characterized with spherical shape, desirable particle size, negative zeta potential, high paclitaxel (PTX) loading and encapsulation efficiency and redox-sensitivity. Hemolysis and cytotoxicity studies proved the safety of CS-SS-RA micelles for intravenous administration. Cytotoxicity study against HepG2 cells and the growth inhibition study on three-dimensional multicellular tumor spheroids (MCTSs) revealed that PTX-loaded CS-SS-RA micelles exhibited higher antitumor activity than free PTX. The in vitro cellular uptake profiles of FITC-labeled CS-SS-RA micelles evaluated via confocal laser scanning microscopy and flow cytometry indicated that CS-SS-RA micelles could enhance cellular uptake efficiency of PTX, and their internalization by HepG2 cells were mediated by clathrin-mediated endocytosis and macropinocytosis. These results demonstrated that CS-SS-RA micelles could be developed as a promising platform for intracellular delivery of hydrophobic antitumor agents.

Formulation Optimization and In-vitro and In-vivo Evaluation of Lornoxicam Ethosomal Gels with Penetration Enhancers.

BACKGROUND: Ethosomes, a novel type of percutaneous drug delivery carrier with a lipid bilayer structure, penetrate the skin barrier due to their deformability and malleability, and presence of ethanol that fluidizes lipids in the skin. In order to further enhance the delivery of drugs through the skin, penetration enhancers are widely used. OBJECTIVE: The objective of this work was to develop an optimized formulation of lornoxicam ethosomal gels, investigate skin permeability with the addition of penetration enhancers, and evaluate the invivo pharmacodynamics of these formulations. METHODS: Lornoxicam ethosomes were prepared by the ethanol injection method and optimized using the orthogonal design method. Lornoxicam ethosomal gels with enhancers were prepared and optimized using in-vitro transdermal delivery experiments. Experiments on lornoxicam ethosomal gels containing various enhancers such as azone, menthol, lauryl alcohol, and oleic acid were conducted using vertical Franz diffusion cells to measure the percutaneous permeability of the different formulations. Furthermore, the in-vivo analgesic effects of the optimized lornoxicam ethosomal gels were examined using the hot-plate and acetic acid-induced writhing tests. Anti-inflammatory activity was investigated using the dimethylbenzene-induced mouse ear swelling method. RESULTS: The results showed that compared to other formulations, the optimized lornoxicam ethosomal gels with 5 % menthol significantly increased transdermal penetration. Meanwhile, the optimized lornoxicam ethosomal gels showed remarkably anti-nociceptive and anti-inflammatory activity compared with the plain lornoxicam gels. CONCLUSION: These results suggest that the optimized ethosomal gel formulated in this study is a promising lornoxicam carrier in transdermal delivery systems to enhance anti-nociceptive and antiinflammatory efficiency.

Oral delivery of human growth hormone: Preparation, characterization, and pharmacokinetics.

Daily subcutaneous injection of human growth hormone has been used for the treatment of growth hormone deficiency and growth failure but has led to poor patient compliance and renal toxicity. Thus, it is crucial to develop favorable growth hormone delivery systems to improve patient compliance. In the present study, to increase the oral bioavailability of growth hormone and improve patient compliance, enteric-coated capsules filled with monomethoxyl poly(ethylene glycol)-b-poly(L-lactide-co-glycolide) nanoparticles were prepared to facilitate oral growth hormone delivery. The nanoparticles were less than 100 nm in size, exhibited narrow polydispersity indices < 0.3, and showed a zeta potential of -4.87 mV. The highest efficiency of growth hormone encapsulation achieved in this study was nearly 70%. An in vitro release experiment showed that adequate amounts of growth hormone were retained under simulated gastric conditions and significant amounts of growth hormone were released under simulated intestinal conditions. The bioavailability of encapsulated growth hormone relative to subcutaneously injected growth hormone in Sprague-Dawley rats was 11.06%. Thus, the use of poly(ethylene glycol)-b-poly(L-lactide-co-glycolide) nanoparticles yielded promising results, and these agents should be investigated further regarding their potential as an oral growth hormone delivery system in the future.

A shell-crosslinked polymeric micelle system for pH/redox dual stimuli-triggered DOX on-demand release and enhanced antitumor activity.

Based on targeted amphiphilic block copolymer N-acetyl glucosamine-poly (styrene-alt-maleic anhydride)58-b-polystyrene130 (NAG-P(St-alt-MA)58-b-PSt130), a pH/redox dual-triggered shell-crosslinked polymeric micelle system was constructed. The shell-crosslinked micelles (CLM) were prepared by post-crosslinking method to regulate drug release kinetics using cystamine as linkers between carboxy groups of the shell. Compared with non-crosslinked micelles (NCLM), CLM showed spherical shapes with little increased mean diameter of 102.40±0.54nm, low polydispersity index (PDI) of 0.19±0.36, enlarged zeta potential value from -41.46±0.99 to -9.31±0.50mV, indicating the successful modification of disulfide bonds in shell. In vitro drug release study clearly exhibited a pH and redox dual-sensitive drug release profile with significantly accelerated drug release under pH 5.0 and 10mM GSH conditions (46.84% in 96h) without burst release. Both CLM and NCLM showed quite different release profiles between physiological (pH 7.4) and tumoral microenvironment (pH 5.0), effectively avoiding the premature drug leakage and realizing on-demand drug release. The MTT assay implied that CLM presented a time- and concentration-dependent manner to inhibit proliferation of A549 and MCF-7 cells and much lower IC50 values in comparison with that of NCLM after 72h incubation. Both FCM and CLSM results showed that CLM displayed much higher cellular uptake efficiency and anti-tumor activities than NCLM and free DOX. CLM and NCLM could be internalized by energy-dependent endocytosis mechanism due to similar surface properties. Overall, this dual-stimuli triggered micelle system provided a promising tumor-responsive platform for cancer therapy.

Tumor-targeted polymeric nanostructured lipid carriers with precise ratiometric control over dual-drug loading for combination therapy in non-small-cell lung cancer.

Gemcitabine (GEM) and paclitaxel (PTX) are effective combination anticancer agents against non-small-cell lung cancer (NSCLC). At the present time, a main challenge of combination treatment is the precision of control that will maximize the combined effects. Here, we report a novel method to load GEM (hydrophilic) and PTX (hydrophobic) into simplex tumor-targeted nanostructured lipid carriers (NLCs) for accurate control of the ratio of the two drugs. We covalently preconjugated the dual drugs through a hydrolyzable ester linker to form drug conjugates. N-acetyl-d-glucosamine (NAG) is a glucose receptor-targeting ligand. We added NAG to the formation of NAG-NLCs. In general, synthesis of poly(6-O-methacryloyl-d-galactopyranose)-GEM/PTX (PMAGP-GEM/PTX) conjugates was demonstrated, and NAG-NLCs were prepared using emulsification and solvent evaporation. NAG-NLCs displayed sphericity with an average diameter of 120.3±1.3 nm, a low polydispersity index of 0.233±0.04, and accurate ratiometric control over the two drugs. A cytotoxicity assay showed that the NAG-NLCs had better antitumor activity on NSCLC cells than normal cells. There was an optimal ratio of the two drugs, exhibiting the best cytotoxicity and combinatorial effects among all the formulations we tested. In comparison with both the free-drug combinations and separately nanopackaged drug conjugates, PMAGP-GEM/PTX NAG-NLCs (3:1) exhibited superior synergism. Flow cytometry and confocal laser scanning microscopy showed that NAG-NLCs exhibited higher uptake efficiency in A549 cells via glucose receptor-mediated endocytosis. This combinatorial delivery system settles problems with ratiometric coloading of hydrophilic and hydrophobic drugs for tumor-targeted combination therapy to achieve maximal anticancer efficacy in NSCLC.

Biodegradable Self-Assembled Nanoparticles of Galactose-Containing Amphiphilic Triblock Copolymers for Targeted Delivery of Paclitaxel to HepG2 Cells.

Biodegradable self-assembled polymeric nanoparticles (NPs) composed of poly(6-O-methacryloyl-D-galactopyranose)-b-poly(L-lactide)-b-poly(6-O-methacryloyl-D-galactopyranose) (PMAGP-b-PLA-b-PMAGP) are prepared as carriers for the hydrophobic anticancer drug paclitaxel (PTX), to achieve target delivery to hepatoma cells. PTX can be encapsulated by the NPs with various molar ratios of L-lactide (LA) and 6-O-methacryloyl-D-galactopyranose (MAGP) during the process of self-assembly, and the resulting NPs exhibit high drug loading efficacy and substantial stability in aqueous solution. The size, size distribution, and morphology of the NPs are characterized using a Zetasizer Nano ZS and transmission electron microscopy. The hemolysis assay and cell cytotoxicity assay indicate that the polymeric NPs are biocompatible and non-toxic. The cellular uptake assay demonstrates that the galactose-containing NPs can be selectively recognized and subsequently accumulate in HepG2 cells. All of these results demonstrate that galactose-containing polymeric NPs are potential carriers for hepatoma-targeted drug delivery and liver cancer therapy in clinical medicine.

Coordinated pH/redox dual-sensitive and hepatoma-targeted multifunctional polymeric micelle system for stimuli-triggered doxorubicin release: Synthesis, characterization and in vitro evaluation.

Multifunctional polymeric micelles self-assembled from a DOX-conjugated methoxypolyethylene glycols-b-poly (6-O-methacryloyl-D-galactopyranose)-disulfide bond-DOX (mPEG-b-PMAGP-SS-DOX) copolymer were prepared as an antitumor carrier for doxorubicin delivery, of which the chemical modification with disulfide bonds and hydrazone bonds allowed micelles to release doxorubicin (DOX) selectively at acidic pH and high redox conditions. The resulting micelles exhibited coordinated pH/redox dual-sensitive and hepatoma-targeted multifunction with sustaining stability in aqueous media. The multifunctional micelles showed spherical shapes with a mean diameter of 93 ± 2.08 nm, a low polydispersity index (PDI) of 0.21, a low CMC value of 0.095 mg/mL, a high drug grafting degree of 56.9% and a drug content of 39.0%. Remarkably, in vitro drug release studies clearly exhibited a pH and redox dual-sensitive drug release profile with significantly accelerated drug release treated with pH 5.0 and 10mM GSH (88.4% in 72 h) without drug burst release. The tumor proliferation assays indicated that DOX-grafted micelles, along with low cytotoxicity and well biocompatibility to normal cells up to a concentration of 10 µg/mL, inhibited the proliferation of HepG2 cells in a formulation-, time- and concentration-dependent manner in comparison with MCF-7 cells which was similar to free DOX. Anticancer activity releaved that the disulfide-modified micelles possessed much higher anti-hepatoma activity with a low IC50 value of 1.1 µg/mL following a 72 h incubation. Furthermore, the intracellular uptake tested by CLSM and FCM demonstrated that multifunctional polymeric micelles could be more efficiently taken up by HepG2 cells compared with MCF-7 cells, agreed well with MTT assays, suggesting these well-defined micelles provide a potential drug delivery system for dual-responsive controlled drug release and enhanced anti-hepatoma therapy.

Multifunctional mesoporous silica nanoparticles modified with tumor-shedable hyaluronic acid as carriers for doxorubicin.

In this paper, a CD44-targeted and redox-responsive drug delivery system based on mesoporous silica nanoparticles (MSNs) was synthesized by conjugating tumor-shedable hyaluronic acid (HA) on the surface of MSNs via disulfide bonds. Doxorubicin hydrochloride (DOX·HCl) was physically encapsulated into HA modified MSNs (MSNs/SS/HA@DOX) as a model drug. MSNs/SS/HA@DOX (40nm) had a high drug loading (14.1%) and redox-responsive drug release property. The cellular uptake behaviors of MSNs/SS/HA@DOX by HeLa and LO2 cells were evaluated by confocal laser scanning microscopy (CLSM) and flow cytometry (FCM). MSNs/SS/HA@DOX exhibited higher cellular uptake efficacy via CD44-mediated endocytosis by HeLa cells (CD44 over-expressed cells) than by LO2 cells (CD44 deficient cells). The in vitro cytotoxicity assay demonstrated that MSNs/SS/HA@DOX exhibited higher cytotoxicity to HeLa cells than to LO2 cells. These results indicated that MSNs/SS/HA@DOX might be promising as a multifunctional drug delivery system to improve the anti-tumor efficacy of chemotherapeutic drugs.