Preparation and in vitro evaluation of a folate-linked liposomal curcumin formulation

Curcumin (CUR), a plant-derived compound, exhibits versatile antitumor effects. However, its poor hydrophilic property limits its application. To circumvent these drawbacks, we encapsulated CUR in liposomes modified with folic acid for better solubility and enhanced tumor targeting. This novel formulation was prepared by a film-dispersion method and characterized by size, zeta potential, drug-loading efficiency, and physical-condition stability. In vitro, cellular uptake efficiency, cytotoxicity, and apoptosis analysis by flow cytometry were performed to evaluate tumor targeting and killing ability. Results showed that the folate-receptor (FR)-targeted liposomal CUR (F-CUR-L) performed with improved solubility, sufficient stability, and enhanced antitumor activity. Mean diameter, zeta potential, and drug-loading efficiency were 182?nm, ?26 mV, and 68%, respectively, and this formulation exhibited stability in storage at 4°C for 1 month. In vitro, FR-positive cells endocytosed more F-CUR-L than nontargeted liposomal CUR (CUR-L); thus, the former induced more cellular proliferation inhibition and higher apoptosis than the latter, and the enhanced targeting could be hindered by 1?mM of free folic acid. Further, KB cells were more sensitive to F-CUR-L, compared to Hela cells. Finally, the two kinds of tumor cells treated with F-CUR-L also showed dose- and time-dependent apoptosis.     

N-trimethyl chitosan chloride-coated liposomes for the oral delivery of curcumin

The aims of this study were to design the formulation of curcumin (CUR) liposomes coated with N-trimethyl chitosan chloride (TMC) and to evaluate in vitro release characteristics and in vivo pharmacokinetics and bioavailability of TMC-coated CUR liposomes in rats. The structure of synthesized TMC was examined by infrared spectroscopy, with the presence of trimethyl groups, and by proton nuclear magnetic resonance spectroscopy, indicating the high degree of substitution quaternization (65.6%). Liposomes, composed of soybean phosphotidylcholine, cholestrol, and D-α-tocopheryl polyethylene glycol 1000 succinate, were prepared by a thin-film dispersion method. Characteristics of the CUR liposomes, including entrapment efficiency (86.67%), drug-loading efficiency (2.33%), morphology, particle size (221.4?nm for uncoated liposomes and 657.7?nm for TMC-coated liposomes), and zeta potential (-9.63 mV for uncoated liposomes and +15.64 mV for TMC-coated liposomes) were investigated. Uncoated CUR liposomes and TMC-coated CUR liposomes showed a similar in vitro release profile. Nearly 50% of CUR was released from liposomes, whereas 80% of CUR was released from CUR propylene glycol solution. CUR incorporated into TMC-coated liposomes exhibited different pharmacokinetic parameters and enhanced bioavailability (C(max)?=?46.13 μg/L, t(1/2)?=?12.05 hours, AUC?=?416.58 μg/L·h), compared with CUR encapsulated by uncoated liposomes (C(max)?=?32.12 μg/L, t(1/2)?=?9.79 hours, AUC?=?263.77 μg/L·h) and CUR suspension (C(max)?=?35.46 μg/L, t(1/2)?=?3.85 hours, AUC?=?244.77 μg/L·h). In conclusion, oral delivery of coated CUR liposomes is a promising strategy for poorly water-soluble CUR.     

Enhancing the Antitumor Activity of Berberine Hydrochloride by Solid Lipid Nanoparticle Encapsulation

Berberine hydrochloride (BH) is an isoquinolin alkaloid with promising anticancer efficacies. Nevertheless, further development and application of this compound had been hampered by its poor aqueous solubility, low gastrointestinal absorption, and rapid metabolism in the body. In this study, a solid lipid nanoparticle (SLN)-based system was developed for efficient incorporation and persistent release of BH. The drug-loading SLNs (BH-loaded SLNs) were stable, with a mean particle size of 81.42 ± 8.48 nm and zeta potential of −28.67 ± 0.71 mV. BH-loaded SLNs showed desirable drug entrapment efficiency and drug-loaded, and the release of BH from SLNs was significantly slower than free BH. Importantly, our in vitro study indicated that BH-loaded SLNs more significantly inhibited cell proliferation on MCF-7, HepG 2, and A549 cancer cells. Meanwhile, clone formation, cellular uptake, cell cycle arrest, and cell apoptosis studies also demonstrated that BH-loaded SLNs enhanced the antitumor efficacies of BH on MCF-7 cancer cells. Taken together, our results suggest that this SLN formulation may serve as a novel, simple, and efficient system for the delivery of BH.KEY WORDS: antitumor evaluation, apoptosis, berberine hydrochloride, solid lipid nanoparticles     

N-trimethyl chitosan chloride-coated liposomes for the oral delivery of curcumin

The aims of this study were to design the formulation of curcumin (CUR) liposomes coated with N-trimethyl chitosan chloride (TMC) and to evaluate in vitro release characteristics and in vivo pharmacokinetics and bioavailability of TMC-coated CUR liposomes in rats. The structure of synthesized TMC was examined by infrared spectroscopy, with the presence of trimethyl groups, and by proton nuclear magnetic resonance spectroscopy, indicating the high degree of substitution quaternization (65.6%). Liposomes, composed of soybean phosphotidylcholine, cholestrol, and D-α-tocopheryl polyethylene glycol 1000 succinate, were prepared by a thin-film dispersion method. Characteristics of the CUR liposomes, including entrapment efficiency (86.67%), drug-loading efficiency (2.33%), morphology, particle size (221.4?nm for uncoated liposomes and 657.7?nm for TMC-coated liposomes), and zeta potential (–9.63 mV for uncoated liposomes and +15.64 mV for TMC-coated liposomes) were investigated. Uncoated CUR liposomes and TMC-coated CUR liposomes showed a similar in vitro release profile. Nearly 50% of CUR was released from liposomes, whereas 80% of CUR was released from CUR propylene glycol solution. CUR incorporated into TMC-coated liposomes exhibited different pharmacokinetic parameters and enhanced bioavailability (C_max?=?46.13 μg/L, t_1/2?=?12.05 hours, AUC?=?416.58 μg/L·h), compared with CUR encapsulated by uncoated liposomes (C_max?=?32.12 μg/L, t_1/2?=?9.79 hours, AUC?=?263.77 μg/L·h) and CUR suspension (C_max?=?35.46 μg/L, t_1/2?=?3.85 hours, AUC?=?244.77 μg/L·h). In conclusion, oral delivery of coated CUR liposomes is a promising strategy for poorly water-soluble CUR.     

Factorial design based curcumin ethosomal nanocarriers for the skin cancer delivery: in vitro evaluation

Abstract

Melanoma is the most deadly and life-threatening form of skin cancer with progressively higher rates of incidence worldwide. The objective of the present investigation is to develop and to statistically optimize and characterize curcumin (CUR) loaded ethosomes for treatment of melanoma. A two factor, three level (3²) factorial design approach was employed for the optimization of ethosomes. The prepared ethosomes were evaluated for size, zeta potential, entrapment efficiency, in vitro skin permeation and deposition ability. The optimized ethosomal formulation was evaluated for in vitro cytotoxicity and cellular uptake studies using A375 human melanoma cells. The optimized formulation has imperfect round shaped unilamellar structures with a mean vesicle size of 247?±?5.25?nm and an entrapment efficiency of 92.24?±?0.20%. The in vitro skin permeation studies proved the superiority of ethosomes over the traditional liposomes in terms of the amount of drug permeated and deposited in skin layers. Fluorescence microscopy showed the enhanced penetration of ethosomes into the deeper layers of the skin. In vitro cytotoxicity and cellular uptake studies revealed that curcumin ethosomes have significantly improved cytotoxicity and cellular uptake in A375 human melanoma cell lines. The colony formation assay results showed that curcumin ethosomes have a superior antiproliferative effect as they effectively inhibit the clonogenic ability of A375 cells. The flow cytometry results indicate that curcumin ethosomes induce cell death in A375 cells by apoptosis mechanism. The present study provides a strong rationale and motivation for further investigation of newly developed curcumin ethosomes as a potential therapeutic strategy for melanoma treatment.     

Synergistically fabricated polymeric nanoparticles featuring dual drug delivery system to enhance the nursing care of cervical cancer

We have developed a new methodology to attain treatment-actuated modifications in a tumor microenvironment by utilizing synergistic activity between two potential anticancer drugs. Dual drug delivery of curcumin (CUR) and 7-ethyl-10-hydroxycamptothecin (SN38) exhibits a great anti-cancer potential, as CUR enhances the effect of SN38 treatment of human cervical cells by providing microenvironment stability. However, encapsulation of CUR and SN38 obsessed by polyethylene glycol (PEG) and poly (lactic-co-glycolic acid (PLGA)-based nanoparticles (NPs) is incompetent owing to unsuitability between the binary free CUR and SN38 moieties and the polymeric system. Now, we display that SN38 can be prepared by hydrophobic covering of the drug centers with dioleoylphosphatidic acid (DOPA). The DOPA-covered SN38 can be co-encapsulated in PEG-PLGA NPs alongside CUR to stimulate excellent anticancer property. The occurrence of the SN38 suggestively enhanced the encapsulations of CUR into PEG-PLGA NPs (CUR-SN38 NPs). Formation of the nanocomposite (CUR-SN38 NPs) was confirmed by FTIR and X-ray spectroscopic techniques. Further, the morphology of CUR NPs, SN39 NPs, and CUR-SN38 NPs and nanoparticle size was examined by transmission microscopy (TEM), respectively. Furthermore CUR-SN38 NPs induced significant apoptosis in human cervical HeLa cancer cells in vitro. The morphological observation and apoptosis were confirmed by the various biochemical assayes such as acridine orange-ethidium bromide (AO-EB), Nuclear Staining and Annexin V-FITC). The results suggest that CUR-SN38 NPs are one of the promising nursing cares for human cervical cancer therapeutic candidates worthy of further investigations.     

Pluronic F68-Linoleic Acid Nano-spheres Mediated Delivery of Gambogic Acid for Cancer Therapy

Gambogic acid (GA), a natural compound from gamboge resin, has been introduced as a promising antitumor drug contributing to its broad spectrum of antitumor activity. However, the poor aqueous solubility and short half-life hinder its clinical application. Pluronic F68 (F68) is a well-known amphiphilic block copolymer consisting of hydrophobic propylene oxide units and hydrophilic ethylene oxide. Although F68 has an amphiphilic structure, its short propylene oxide segment limits its dilution stability and drug-loading capacity. To overcome this limitation, we modified F68 by conjugating linoleic acid, a hydrophobic fatty acid, to increase the hydrophilic-hydrophobic interaction and thus improve the stability of F68 nano-spheres. This F68-linoleic acid (F68-LA) conjugate was synthesized and was used to load GA to improve its anticancer effects. GA-loaded F68-LA nano-spheres were stable for 6 days, with a mean diameter of 159.3 nm and zeta potential of ?23.2 mV. The entrapment efficiency of GA in F68-LA nano-spheres was as high as 92.0%. Furthermore, F68-LA/GA nano-spheres exhibited an enhanced cytotoxic activity and proapoptotic effect against human ovarian cancer A2780 cells, compared with free GA. Our results showed that the F68-LA/GA nano-spheres might be a promising cancer-targeted drug delivery system in ovarian cancer therapy.     

Development of a More Efficient Albumin-Based Delivery System for Gambogic Acid with Low Toxicity for Lung Cancer Therapy

Gambogic acid (GA) has been proven to be a potent chemotherapeutic agent for the treatment of lung cancer in clinical trials. However, GA is limited in its therapeutic value by properties such as poor water solubility and low chemical stability. In clinical trials, cationic arginine (Arg) was added to solubilize GA, and this may also cause other side effects. Here, we have designed and developed a more efficient human serum albumin (HSA)-based delivery system for GA with low toxicity which helps improve its solubility, chemical stability and increases its antitumor efficacy. The GA-HSA nanoparticles (NPs) were prepared by albumin-bound (nab^TM) technology, with a particle size of 135.2?±?35.03 nm, a zeta potential of ?21.81?±?1.24 mV, and a high entrapment efficiency. Compared with GA-Arg solution, the physical and chemical stability of the NPs were improved when stored at pH 7.4 in PBS or freeze-dried. The in vitro drug release showed that GA-HSA NPs had a more sustained release than GA-Arg solution. Furthermore, HSA NPs improved the therapeutic efficacy of GA and were less toxic compared with GA-Arg solution in A549-bearing mice. Therefore, this delivery system is a promising polymeric carrier for GA when used for tumor therapy.     

Comparing different sterol containing solid lipid nanoparticles for targeted delivery of quercetin in hepatocellular carcinoma

Quercetin (QT) is a potential chemotherapeutic drug with low solubility that seriously limits its clinical use. The aim of this study was enhancing cellular penetration of QT by sterol containing solid lipid nanoparticles (SLNs) which make bilayers fluent for targeting hepatocellular carcinoma cells. Three variables including sterol type (cholesterol, stigmasterol and stigmastanol), drug and sterol content were studied in a surface response D-optimal design for preparation of QT-SLNs by emulsification solvent evaporation method. The studied responses included particle size, zeta potential, drug loading capacity and 24?h release efficiency (RE₂₄%). Scanning electron and atomic force microscopy were used to study the morphology of QT-SLNs and their thermal behavior was studied by DSC analysis. Cytotoxicity of QT-SLNs was determined by MTT assay on HepG-2 cells and cellular uptake by fluorescence microscopy method. Optimized QT-SLNs obtained from cholesterol and QT with the ratio of 2:1 that showed particle size of 78.0?±?7.0?nm, zeta potential of??22.7?±?1.3?mV, drug loading efficiency of 99.9?±?0.5% and RE₂₄ of 56.3?±?3.4%. IC₅₀ of QT in cholesterol SLNs was about six and two times less than free QT and phytosterol SLNs, respectively, and caused more accumulation of QT in HepG2 cells. Blank phytosterol SLNs were toxic on cells.     

Functionalized amphiphilic hyperbranched polymers for targeted drug delivery

Amphiphilic hyperbranched core-shell polymers with folate moieties as the targeting groups were synthesized and characterized. The core of the amphiphilic polymers was hyperbranched aliphatic polyester Boltorn H40. The inner part and the outer shell of the amphiphilic polymers were composed of hydrophobic poly(epsilon-caprolactone) segments and hydrophilic poly(ethylene glycol) (PEG) segments, respectively. To achieve tumor cell targeting property, folic acid was further incorporated to the surface of the amphiphilic polymers via a coupling reaction between the hydroxyl group of the PEG segment and the carboxyl group of folic acid. The polymers were characterized by (1)H NMR, (13)C NMR, and combined size-exclusion chromatography and multiangle laser light scattering analysis. The nanoparticles of the amphiphilic polymers prepared by dialysis method were characterized by transmission electron microscopy and particle size analysis. Two antineoplastic drugs, 5-fluorouracil and paclitaxel, were encapsulated into the nanoparticles. The drug release property and the targeting of the drug-loaded nanoparticles to different cells were evaluated in vitro. The results showed the drug-loaded nanoparticles exhibited enhanced cell inhibition because folate targeting increased the cytotoxicity of drug-loaded nanoparticles against folate receptor expressing tumor cells.     

Starch-based microspheres for sustained-release of curcumin: Preparation and cytotoxic effect on tumor cells

Curcumin (CUR) has been proved to be highly cytotoxic against different tumor cell lines. However, its poor solubility in aqueous medium and fast degradation in physiological pH are the common drawbacks preventing its efficient practical use. Herein, we report the development of original microspheres based on the biopolymer starch crosslinked with N,N-methylenebisacrylamide (MBA) to be applied as an efficient delivering system for CUR. The starch-based microspheres showed high loading efficiency even in loading solution with different CUR concentrations. In vitro release assays data showed that the CUR release is governed by anomalous transport (n = 0.73) and it is pH-dependent. Cytotoxicity assays showed that starch microspheres could improve the cytotoxicity of CUR toward Caco-2 and HCT-116 tumor cell lines up to 40 times than that found for pure CUR. This behavior was attributed to the slowly and sustained release of CUR from the microspheres.     

Formulation and Optimization of Doxorubicin and Biochanin A Combinational Liposomes for Reversal of Chemoresistance

Circumvention of drug resistance still remains a challenge in the development of anticancer therapeutics. Combinational nano-formulations provide many avenues for effective cancer therapy and reversal of drug resistance. In the current study, combination of biochanin A (BioA) and doxorubicin (DOX) in liposomes were prepared and studied for its potential to reverse DOX resistance in COLO205 cells. After development and validation of DOX resistant cells of COLO205 (ColoR), dosing ratio of DOX and BioA for reversal of DOX resistance was determined by co-treatment in ColoR cells. As limited solubility and analytical data available for BioA, therefore solubility was studied for BioA and analytical method was developed for the combination. Combinational liposomes were prepared and optimized for both lipid content and surface charge by evaluating size, polydispersity index, zeta potential, and encapsulation efficiency. The optimized formulation had a size about 125 nm; zeta potential of ?19.5 mV and 70% encapsulation efficiency (EE) for BioA. Thus, prepared combinational liposomes of DOX and BioA were evaluated for its cellular uptake and efficacy to reverse DOX resistance. From the study, increased DOX uptake and promising effect for reversal of DOX resistance was observed.     

Folate receptor-targeted aggregation-enhanced near-IR emitting silica nanoprobe for one-photon in vivo and two-photon ex vivo fluorescence bioimaging

A two-photon absorbing (2PA) and aggregation-enhanced near-infrared (NIR) emitting pyran derivative, encapsulated in and stabilized by silica nanoparticles (SiNPs), is reported as a nanoprobe for two-photon fluorescence microscopy (2PFM) bioimaging that overcomes the fluorescence quenching associated with high chromophore loading. The new SiNP probe exhibited aggregate-enhanced emission producing nearly twice as strong a signal as the unaggregated dye, a 3-fold increase in two-photon absorption relative to the DFP in solution, and approximately 4-fold increase in photostability. The surface of the nanoparticles was functionalized with a folic acid (FA) derivative for folate-mediated delivery of the nanoprobe for 2PFM bioimaging. Surface modification of SiNPs with the FA derivative was supported by zeta potential variation and (1)H NMR spectral characterization of the SiNPs as a function of surface modification. In vitro studies using HeLa cells expressing a folate receptor (FR) indicated specific cellular uptake of the functionalized nanoparticles. The nanoprobe was demonstrated for FR-targeted one-photon in vivo imaging of HeLa tumor xenograft in mice upon intravenous injection of the probe. The FR-targeting nanoprobe not only exhibited highly selective tumor targeting but also readily extravasated from tumor vessels, penetrated into the tumor parenchyma, and was internalized by the tumor cells. Two-photon fluorescence microscopy bioimaging provided three-dimensional (3D) cellular-level resolution imaging up to 350 μm deep in the HeLa tumor.     

Dual-targeting multifunctional hyaluronic acid ligand-capped gold nanorods with enhanced endo-lysosomal escape ability for synergetic photodynamic–photothermal therapy of cancer

Au nanorods (AuNRs) have attracted considerable interest as drug delivery systems because of their enhanced cell internalization and stronger drug-loading ability. In addition, the incorporation of photodynamic therapy (PDT) and photothermal therapy (PTT) into one nanosystem presents great promise to defect multiple drawbacks in cancer therapy. Herein, we fabricated a multifunctional and dual-targeting nanoplatform based on hyaluronic acid-grafted-(mPEG/triethylenetetramine-conjugated-lipoic acid/tetra(4-carboxyphenyl)porphyrin/folic acid) polymer ligand capped AuNRs (AuNRs@HA-g-(mPEG/Teta-co-(LA/TCPP/FA)) for combined photodynamic–photothermal therapy of cancer. The prepared nanoparticles displayed high TCPP loading capacity and excellent stability in different biological media. Furthermore, AuNRs@HA-g-(mPEG/Teta-co-(LA/TCPP/FA)) not only could produce a localized hyperthermia to conduct PTT, but also generate cytotoxic singlet oxygen (¹O₂) to perform PDT under laser irradiation. Confocal imaging results disclosed that this nanoparticle endowing the specific function of polymeric ligand could enhance cellular uptake, accelerate endo/lysosomal escape, as well as produce higher reactive oxygen species. Importantly, this combination therapy strategy could also induce higher anticancer potential than PDT or PTT only against MCF-7 tumor cells in vitro. Therefore, this work presented an AuNRs-based therapeutic nanoplatform with great potential in dual-targeting and photo-induced combination therapy of cancer.     

One-Step Bulk Preparation of Calcium Carbonate Nanotubes and Its Application in Anticancer Drug Delivery

Bulk fabrication of ordered hollow structural particles (HSPs) with large surface area and high biocompatibility simultaneously is critical for the practical application of HSPs in biosensing and drug delivery. In this article, we describe a smart approach for batch synthesis of calcium carbonate nanotubes (CCNTs) based on supported liquid membrane (SLM) with large surface area, excellent structural stability, prominent biocompatibility, and acid degradability. The products were characterized by transmission electron micrograph, X-ray diffraction, Fourier transform infrared spectra, UV-vis spectroscopy, zeta potential, and particle size distribution. The results showed that the tube-like structure facilitated podophyllotoxin (PPT) diffusion into the cavity of hollow structure, and the drug loading and encapsulation efficiency of CCNTs for PPT are as high as 38.5 and 64.4 wt.%, respectively. In vitro drug release study showed that PPT was released from the CCNTs in a pH-controlled and time-dependent manner. The treatment of HEK 293T and SGC 7901 cells demonstrated that PPT-loaded CCNTs were less toxic to normal cells and more effective in antitumor potency compared with free drugs. In addition, PPT-loaded CCNTs also enhanced the apoptotic process on tumor cells compared with the free drugs. This study not only provides a new kind of biocompatible and pH-sensitive nanomaterial as the feasible drug container and carrier but more importantly establishes a facile approach to synthesize novel hollow structural particles on a large scale based on SLM technology.     

Design of a liquid nano-sized drug delivery system with enhanced solubility of rivaroxaban for venous thromboembolism management in paediatric patients and emergency cases

Abstract

The increasing incidence of venous thromboembolism (VTE) in paediatric population has stimulated the development of liquid anticoagulant formulations. Thus our goal is to formulate a liquid formulation of poorly-water soluble anticoagulant, rivaroxaban (RIVA), for paediatric use and to assess the possibility of its intravenous administration in emergencies. Self-nanoemulsifying drug delivery systems (SNEDDSs) were developed and characterized. SNEDDS constituents were estimated from the saturated solubility study followed by plotting the corresponding ternary phase diagrams to determine the best self-emulsified systems. Thermodynamic stability, emulsification, dispersibility, robustness to dilution tests, in vitro dissolution, particle size, and zeta potential were executed to optimize the formulations. The optimized formulation, that composed of Capryol 90:Tween 20:PEG 300 (5:45:50), increased RIVA solubility (285.7-fold than water), it formed nanoemulsion with a particle size of 16.15?nm, PDI of 0.25 and zeta potential of ?21.8. It released 100.83?±?2.78% of RIVA after 5?min. SNEDDS was robust to dilution with oral and parenteral fluids and showed safety to human RBCs. SNEDDS showed enhanced bioavailability after oral and intravenous administration than the oral drug suspension (by 1.25 and 1.26-fold, respectively). Moreover, it exhibited enhanced anticoagulant efficacy in the prevention and treatment of carrageenan-induced thrombosis rat model.     

Wogonin enhances antitumor activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo through ROS-mediated downregulation of cFLIPL and IAP proteins

Combination of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) with other agents is a promising strategy to overcome TRAIL resistance in malignant cells. Wogonin, a flavonoid originated from Scutellaria baicalensis Georgi, has been shown to enhance TRAIL-induced apoptosis in malignant cells in in vitro studies. However, whether wogonin enhances TRAIL’s antitumor activity in vivo has never been studied. In this study, the effect of combination of TRAIL and wogonin was tested in a non-small-cell lung cancer xenografted tumor model in nude mice. Consistent with the in vitro study showing that wogonin sensitized A549 cells to TRAIL-induced apoptosis, wogonin greatly enhanced TRAIL-induced suppression of tumor growth, accompanied with increased apoptosis in tumor tissues as determined by TUNEL assay. The expression levels of antiapoptotic proteins including long form of cellular FLICE-like inhibitory protein (cFLIP_L), X-linked inhibitor of apoptosis protein (XIAP), and cellular inhibitor of apoptosis protein 1 and 2 (cIAP-1 and cIAP-2) were markedly reduced in both cultured cells and xenografted tumor tissues after co-treatment with wogonin and TRAIL. The down-regulation of these antiapoptotic proteins was likely mediated by proteasomal degradation that involved intracellular reactive oxygen species (ROS), because wogonin robustly induced ROS accumulation and ROS scavengers butylated hydroxyanisole (BHA) and N-acetyl-l-cysteine (NAC) and the proteasome inhibitor MG132 restored the expression of these antiapoptotic proteins in cells co-treated with wogonin and TRAIL. These results show for the first time that wogonin enhances TRAIL’s antitumor activity in vivo, suggesting this strategy has an application potential for clinical anticancer therapy.     

Targeted delivery of quercetin loaded mesoporous silica nanoparticles to the breast cancer cells

BackgroundMesoporous silica nanoparticles (MSNs) have been promising vehicles for drug delivery. Quercetin (Q), a natural flavonoid, has been reported to have many useful effects. However, poor water solubility as well as less bioavailability has confined its use as a suitable anti-cancer drug. Therefore, profound approach is required to overcome these drawbacks.MethodsWe have synthesized folic acid (FA) armed mesoporous silica nanoparticles (MSN-FA-Q) loaded with quercetin and then characterized it by DLS, SEM, TEM and FTIR. MTT, confocal microscopy, flow cytometry, scratch assay and immunoblotting were employed to assess the cell viability, cellular uptake, cell cycle arrest, apoptosis, wound healing and the expression levels of different signalling molecules in breast adenocarcinoma cells. Nanoparticle distribution was investigated by using ex vivo optical imaging and CAM assay was employed to assess tumor regression.ResultsMSN-FA-Q facilitates higher cellular uptake and allows more drug bioavailability to the breast cancer cells with over-expressed folate receptors. Our experimental results suggest that the newly synthesized MSN-FA-Q nanostructure caused cell cycle arrest and apoptosis in breast cancer cells through the regulation of Akt & Bax signalling pathways. Besides, we also observed that MSN-FA-Q has a concurrent anti-migratory role as well.ConclusionThis uniquely engineered quercetin loaded mesoporous silica nanoparticle ensures a targeted delivery with enhanced bioavailability.General significanceEffective targeted therapeutic strategy against breast cancer cells.     

Design, synthesis, and biological evaluation of folic acid targeted tetraphenylporphyrin as novel photosensitizers for selective photodynamic therapy

Photodynamic therapy (PDT) is a cancer treatment involving systemic administration of a tumor-localizing photosensitizer; this, when activated by the appropriate light wavelength, interacts with molecular oxygen to form a toxic, short-lived species known as singlet oxygen, which is thought to mediate cellular death. Targeted PDT offers the opportunity of enhancing photodynamic efficiency by directly targeting diseased cells and tissues. Two new conjugates of three components, folic acid/hexane-1,6-diamine/4-carboxyphenylporphyrine 1 and folic acid/2,2'-(ethylenedioxy)-bis-ethylamine/4-carboxyphenylporphyrine 2 were synthesized. The conjugates were characterized by 1H NMR, MALDI, UV-visible spectroscopy, and fluorescence quantum yield. The targeted delivery of these photoactive compounds to KB nasopharyngeal cell line, which is one of the numerous tumor cell types that overexpress folate receptors was studied. It was found that after 24 h incubation, conjugates 1 and 2 cellular uptake was on average 7-fold higher than tetraphenylporphyrin (TPP) used as reference and that 1 and 2 cellular uptake kinetics increased steadily over the 24 h period, suggesting an active transport via receptor-mediated endocytosis. In corresponding results, conjugates 1 and 2 accumulation displayed a reduction of 70% in the presence of a competitive concentration of folic acid. Survival measurements demonstrated that KB cells were significantly more sensitive to conjugated porphyrins-mediated PDT. Under the same experimental conditions and the same photosensitizer concentration, TPP displayed no photocytotoxicity while conjugates 1 and 2 showed photodynamic activity with light dose values yielding 50% growth inhibition of 22.6 and 6.7 J/cm2, respectively.