Nose-to-brain delivery of temozolomide-loaded PLGA nanoparticles functionalized with anti-EPHA3 for glioblastoma targeting

Glioblastoma is the most common malignant brain tumor. Efficient delivery of drugs targeting glioblastomas remains a challenge. Ephrin type-A receptor 3 (EPHA3) tyrosine kinase antibody-modified polylactide-co-glycolide (PLGA) nanoparticles (NPs) were developed to target glioblastoma via nose-to-brain delivery. Anti-EPHA3-modified, TBE-loaded NPs were prepared using an emulsion-solvent evaporation method, showed a sustained in vitro release profile up to 48 h and a mean particle size of 145.9 ± 8.7 nm. The cellular uptake of anti-EPHA3-modified NPs by C6 cells was significantly enhanced compared to that of nontargeting NPs (p < .01). In vivo imaging and distribution studies on the glioma-bearing rats showed that anti-EPHA3-modified NPs exhibited high fluorescence intensity in the brain and effectively accumulated to glioma tissues, indicating the targeting effect of anti-EPHA3. Glioma-bearing rats treated with anti-EPHA3-modified NPs resulted in significantly higher tumor cell apoptosis (p < .01) than that observed with other formulations and prolonged the median survival time of glioma-bearing rats to 26 days, which was 1.37-fold longer than that of PLGA NPs. The above results indicated that anti-EPHA3-modified NPs may potentially serve as a nose-to-brain drug carrier for the treatment of glioblastoma.     

Formulation development of albumin based theragnostic nanoparticles as a potential delivery system for tumor targeting

Background: Generally, chemotherapeutic drugs attack on both normal and tumor cells non-specifically causing life threatening side effects, necessitating targeted drug delivery to tumors.

Purpose: The purpose of this study is to formulate albumin-based nanoparticles for tumor targeted drug delivery and noninvasive diagnosis.

Methods: Albumin based nanoparticles (NPs) were developed as a potential tumor theragnostic agent by entrapping an anti cancer drug, doxorubicin and a near infrared dye, indocyanine green. Theragnostic nanoparticles were prepared using a well established coacervation/nanoprecipitation method followed by lyophilization. The formulation was optimized by varying process parameters using full factorial design of experiments. Release of dye and drug from NPs and physical state of the drug in NPs was studied using DSC. The NPs were injected into tumor bearing mice intravenously and imaged using a bio-imager.

Results: The optimized nanoparticle formulation had a particle size of 125.0?±?1.8?nm, poly dispersity index of 0.180?±?0.057 and zeta potential of ?32.7?±?0.9 mV. The release of dye and drug from the nanoparticles was determined to be quasi-fickian diffusion mediated. Differential scanning calorimetry (DSC) studies revealed the stability of drug in the NP. The in-vivo studies showed enhanced accumulation of the dye loaded NPs at the tumor site than the dye solution, thus allowing noninvasive tumor monitoring.

Conclusion: These results project the newly proposed and evaluated nanoparticle formulation as a potential tumor targeting and imaging delivery system.     

Brain-targeted delivery of doxorubicin using glutathione-coated nanoparticles for brain cancers

Abstract

Objectives: To prepare and characterize in vitro a novel brain-targeted delivery of doxorubicin using glutathione-coated nanoparticles (NPs) for the treatment of brain cancer.

Methods: Doxorubicin-loaded NPs were prepared by the nanoprecipitation method using PLGA-COOH (dl-lactide-co-glycolide). The NPs were coated with a glutathione-PEG conjugate (PEG-GSH) in order to target delivery to the brain. The NPs were characterized via in vitro studies to determine particle size, drug release, cellular uptake, immunofluorescence study, cytotoxic assay, and in vitro blood–brain barrier (BBB) assay.

Results: The NPs showed a particle size suitable for BBB permeation (particle size around 200?nm). The in vitro release profile of the NPs exhibited no initial burst release and showed sustained drug release for up to 96?h. The immunofluorescence study showed the glutathione coating does not interfere with the drug release. Furthermore, in vitro BBB Transwell? study showed significantly higher permeation of the doxorubicin-loaded NPs compared with the free doxorubicin solution through the coculture of rat brain endothelial (RBE4) and C6 astrocytoma cells (p?<?0.05).

Conclusions: We conclude that the initial in vitro characterization of the NPs demonstrates potential in delivering doxorubicin to cancer cells with possible future application in targeting brain cancers in vivo.     

Surface modified kokum butter lipid nanoparticles for the brain targeted delivery of nevirapine

Abstract

Aim: The present work investigates the efficacy of Polysorbate 80(P80) coated Kokum butter (KB) solid lipid nanoparticles (P80NvKLNs) for the brain targeted delivery of Nevirapine (Nv).

Methods: Solid lipid nanoparticles (SLNs) were prepared by nanoprecipitation technique and evaluated for drug excipient compatibility studies, z- average particle size (nm), zeta potential (mv), percentage drug entrapment efficiency (%EE), surface morphology and in-vitro drug release properties. The in-vivo biodistribution and brain targeting efficiency of nanoparticles were studied in healthy male Wistar rat (150–200?g).

Results: P80NvKLNs were found to be smooth surfaced, spherical shaped having average particle size of 177.80?±?0.82?nm, zeta potential of ?8.91?±?4.36?mv and %EE of 31.32?±?0.42%. P80NvKLNs remained in blood circulation for 48?h maintaining a sustained release in brain for 24?h (p?<?0.05).

Conclusion: The study proves the efficacy of Polysorbate 80 coated Kokum butter nanoparticles for brain-targeted delivery of drugs providing ample opportunities for further study.     

Improvement of oral efficacy of Irinotecan through biodegradable polymeric nanoparticles through in vitro and in vivo investigations

Background: Irinotecan (IRN) (CPT-11) is a camptothecin derivative with low oral bioavailability due to active efflux by intestinal P-glycoprotein (p-gp) receptors. Hence, no oral formulation is marketed for IRN till date and its oral ingestion continues to remain a challenge.

Aim of study: The study aims to develop a nanoformulation i.e. Chitosan (CS)-coated-IRN-loaded-poly-lactic-co-glycolic acid (PLGA) nanoparticles (NPs) (CS-IRN-PLGA-NPs)in order to enhance oral bioavailability of IRN.

Results: Developed formulation revealed particle size, 166.9?±?13.63?nm, zeta potential, 14.67?±?1.08?mV and drug content (42.69?±?1.97 µg/mg), with spherical shape and smooth surface. Cytotoxicity studies, performed against human breast adenocarcinoma cell lines (MCF-7), confirmed the superiority of IRN-CS-PLGA-NPs over free IRN solution (IRN-S). Cellular transport conducted on human colon adenocarcinoma cell line (Caco-2) exhibited a higher permeability of 1.33 folds for IRN through CS-IRN-PLGA-NPs as compared to IRN-S (p?Discussion: CS-IRN-PLGA-NPs approach may be effectively utilised, to replace pre-existing intravenous therapy thus providing ‘patient care at home.     

Development,characterization and nasal delivery of rosmarinic acid-loaded solid lipid nanoparticles for the effective management of Huntington’s disease

Abstract

Objective: The objective of the present study was to investigate the potential use of solid lipid nanoparticles (SLNs) as a drug delivery system to enhance the brain-targeting efficiency of rosmarinic acid (RA) following intranasal (i.n.) administration.

Materials and methods: The RA-loaded SLNs was prepared by the hot homogenization technique, in which glycerol monostearate (GMS) as lipid, tween 80 and soya lecithin were used as surfactant along with hydrogenated soya phosphatidyl choline (HSPC) as a stabilizer, and were characterized for particle size, zeta potential (ZP), in vitro study. Nasal delivery of the developed formulation followed by the study of behavioral (locomotor, narrow beam, body weight) and biochemical parameters (glutathione, lipid peroxidation, catalase and nitrite) in wistar rat was carried out.

Results: Optimized RA-loaded SLNs using tween 80 (SLNPRT) have the mean size of (149.2?±?3.2?nm), ZP (?38.27?mV) entrapment efficiency (61.9?±?2.2%). 3-NP-treated rat significantly increased behavioral alterations, oxidative damage as compared with the control group. SLNPRT treatment significantly improved behavioral abnormalities and attenuated the oxidative stress in 3NP-treated rats. However, the nasal delivery of SLNPRT produced significant therapeutic action as compared to intravenous application. In the organ distribution study, brain drug concentration was found to be 5.69?µg, in pharmacokinetic study C_max, t_max, t_1/2, AUC values were found to be 0.284?µg/ml, 1.5?h, 3.17?h, and 1.505?µg/ml/h, respectively.

Conclusion: The encouraging results confirmed the developed optimized RA-loaded SLNs formulation following the non-invasive nose-to-brain drug delivery that is a promising therapeutic approach for the effective management in Huntington disease.     

Phytochemical screening and analgesic profile of the lyophilized aqueous extract obtained from Chrysobalanus icaco leaves in experimental protocols

Context: Chrysobalanus icaco L. (Chrysobalanaceae) has been used for the treatment of abdominal pain and cramps.

Objective: Assess the chemical and pharmacological profile of the lyophilized aqueous extract from C. icaco leaves (AEC).

Materials and methods: Chromatographic methods were used to assess compounds from AEC. Mice were treated with vehicle (control group) or AEC (100, 200 or 400?mg/kg, p.o.) (group with 7–8 mice) and the analgesic profile was assessed employing the acetic acid-induced writhing, formalin, hot plate tests and hyperalgesia induced by carrageenan (CG) or tumour necrosis factor-alpha. The animal motor performance was assessed using rota-rod and grip strength tests.

Results: The chromatographic profile of AEC demonstrated the presence of terpenoid compounds. The acute pretreatment with AEC, at all doses, produced a significant (p?<?0.01) inhibition of painful bahaviour (11.4?±?3.6; 10.3?±?2.8; 11.3?±?2.2) when compared to the control group (24.7?±?4.7) in acetic acid-induced writhing test. In the formalin test, AEC were effective in the second phase (p?<?0.01) (57.2?±?10.3; 56.3?±?9.2; 54.7?±?8.9) when compared to control group (121.9?±?18.5). No response was observed in the hot plate test. The higher dose of AEC produced a significant (p?<?0.01 or p?<?0.05) inhibitory effect on the mechanical hyperalgesia test. AEC did not affect the motor performance of the mice.

Discussion: The terpenoids from AEC are known for its analgesic and anti-inflammatory properties. So, these results corroborate the experiments using the AEC in inflammatory pain protocols.

Conclusion: Our results suggest that AEC act against inflammatory pain.     

Brain targeted nanoparticulate drug delivery system of rasagiline via intranasal route

The aim of the present study was to prepare and evaluate a rasagiline-loaded chitosan glutamate nanoparticles (RAS-CG-NPs) by ionic gelation of CG with tripolyphosphate anions (TPP). RAS-loaded CG-NPs were characterized for particle size, size distribution, encapsulation efficiency and in vitro drug release. The mean particles size, polydispersity index (PDI) and encapsulation efficiency was found to be 151.1?±?10.31, 0.380?±?0.01 and 96.43?±?4.23, respectively. Biodistribution of RAS formulations in the brain and blood of mice following intranasal (i.n.) and intravenous (i.v.) administration was performed using HPLC analytical method. The drug concentrations in brain following the i.n. of CG-NPs were found to be significantly higher at all the time points compared to both drug (i.n.) and drug CG-NPs (i.v.). The Cmax (999.25?ng/ml) and AUC (2086.60?ng?h/ml) of formulation CG-NPs (i.n) were found to be significantly higher than CG-NPs (i.v.) and RAS solution (i.n.). The direct transport percentage (DTP%) values of RAS-loaded CG-NPs (i.n.) as compared to drug solution (i.n.) increased from 66.27?±?1.8 to 69.27?±?2.1%. The results showed significant enhancement of bioavailability in brain, after administration of the RAS-loaded CG-NPs which could be a substantial achievement of direct nose to brain targeting in Parkinson's disease therapy.     

Optimization of nanostructured lipid carriers of lamotrigine for brain delivery: in vitro characterization and in vivo efficacy in epilepsy

Objective: The aim of the present work was to investigate the efficacy of nanostructured lipid carriers (NLCs) to enhance the brain targeting of lamotrigine (LMT) following intranasal (IN) administration.

Methods: Formulation was optimized using four-factor three levels Box– Behnken design to establish the functional relationships between variables on responses, that is, particle size, entrapment efficiency (EE) and percentage cumulative drug release of LMT-loaded NLCs. NLCs were evaluated for particle size, surface morphology, %EE and in vitro release and ex vivo permeation. The developed formulation was subjected to stability study, in vivo efficacy and scintigraphic study in Wistar rat model.

Results: The NLCs had a mean particle size of 151.6 ± 7.6 nm, polydispersity index of 0.249 ± 0.035, zeta potential of 11.75 ± 2.96 mV and EE of 96.64 ± 4.27%. The drug release from NLCs followed Fickian diffusion with a flux value of 11.73 μgcm^?2h^?1. Sustained drug concentration was obtained in NLCs carrying LMT after IN administration after 24 h. γ scintigraphy studies further proved high accumulation of drug in brain.

Conclusion: Hence we can conclude that IN administration of LMT NLCs in rats is able to maintain higher brain concentration of LMT compared to IN and oral drug solution.     

聚水杨酸氧化还原响应型纳米载药系统的制备及体外评价

目的 将聚水杨酸(poly-salicylic acid,PSA)连接到羧甲基壳聚糖上,使其形成自组装纳米粒(nanoparticles,NPs),并进行表征和体外评价。方法 以O-羧甲基壳聚糖(O-carboxymethyl chitosan,OCMC)作为亲水骨链,通过二硫键将PSA连接在羧甲基壳聚糖上。利用核磁共振氢谱(¹H-NMR)、红外光谱(IR)确证聚合物的结构;采用超声法制备自组装NPs,并对其粒径、Zeta电位进行表征;采用芘荧光探针法测定NPs的临界聚集浓度(critical aggregation concentration,CAC);测定载DOX NPs包封率和载药量;MTT试验考察载药NPs的体外抗肿瘤活性。结果 OCMC二硫键连接PSA NPs(OCMC-SS-PSA NPs)的粒径为(148.5±2.3)nm;CAC值为(0.069 3±0.001 3)mg·mL^-1;还原响应性和pH敏感性良好。DOX/OCMC-SS-PSA NPs的粒径为(160.5±1.7)nm,载药量为(17.43±0.56)%,包封率为(89.67±1.23)%。MTT试验表明OCMC-SS-PSA NPs具有良好的生物安全性;细胞摄取试验表明DOX/OCMC-SS-PSA NPs在细胞内滞留时间更长。结论 OCMC-SS-PSA NPs粒径较小,具有良好的还原响应性、pH敏感性和生物安全性。OCMC-SS-PSA NPs可作为兼具还原响应性和pH敏感性的纳米给药系统。     

载姜黄素的透明质酸-熊果酸-硫辛酸交联纳米粒的制备及其体外抗肿瘤活性

目的 制备载姜黄素的透明质酸-熊果酸-硫辛酸交联纳米粒（Cur/cLA-HU NPs）,并进行体外抗肿瘤活性评价。方法 以载药量、包封率为指标,采用超声法,通过单因素考察优化Cur/cLA-HU NPs的制备工艺,并对Cur/cLA-HU NPs的粒径、Zeta电位、形态和体外释药情况进行评价。通过荧光倒置显微镜分析HepG2细胞对Cur/cLA-HU NPs的摄取,以MTT法考察Cur/cLA-HU NPs对HepG2细胞的毒性。结果 最佳载药工艺为：以甲醇为药物姜黄素有机溶剂,以药质比4∶10进行投料,超声于100 W下次数为3次,每次处理3 min,超声程序设置为开2 s、停4 s。Cur/cLA-HU NPs的包封率为（87.91±1.51）%,载药量为（16.64±0.45）%,粒径为（172.3±2.57）nm,PDI为（0.174±0.021）,分散均匀,Zeta电位为（−35.3±2.12）mV。Cur/cLA-HU NPs具有还原响应性,释放药物的快慢受到GSH浓度的影响;靶向肿瘤细胞,且被细胞快速摄取;对HepG2人肝癌细胞增殖具有明显抑制作用。结论 Cur/cLA-HU NPs载药量和包封率高,其体外抗肿瘤活性稍优于姜黄素,具有肿瘤靶向性。     

Smart thermosensitive chitosan hydrogel for nasal delivery of ibuprofen to treat neurological disorders

Background: The in-situ gelation of thermosensitive nasal formulations with desirable spray characteristics at room temperature and ability to undergo a phase change to a semi-solid state with mucoadhesive behavior at physiological temperature has the potential to efficiently deliver therapeutics to brain. However, their application in nasal spray generation with favorable characteristics has not been investigated.

Methods: Thermosensitive chitosan (CS)-based formulations with different viscosities were prepared for intranasal delivery of ibuprofen using CS of various molecular weights. The formulation developed was optimized with regards to its physicochemical, rheological, biological properties and the generated aerosol characteristics.

Results: The formulations showed rapid gelation (4–7 min) at 30–35°C, which lies in the human nasal cavity temperature spectrum. The decrease in CS molecular weight to 110–150 kDa led to generation of optimum spray with lower Dv₅₀, wider spray area, and higher surface area coverage. This formulation also showed improved ibuprofen solubility that is approximately 100× higher than its intrinsic aqueous solubility, accelerated ibuprofen transport across human nasal epithelial cells and transient modulation of tight junctions.

Conclusions: A thermosensitive CS-based formulation has been successfully developed with suitable rheological properties, aerosol performance and biological properties that is beneficial for nose-to-brain drug delivery.     

Folate-decorated poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) nanoparticles for targeting delivery: optimization and in vivo antitumor activity

Abstract

Context: Doxorubicin (DOX)-loaded folate-targeted poly(3-hydroxybutyrate-co-3-hydroxyoctanoate) [P(HB-HO)] nanoparticles [DOX/FA-PEG-P(HB-HO) NPs] have potential application in clinical treatments for cervical cancer due to specific affinity of folate and folate receptor in HeLa cells.

Objective: The aim of this study was to develop an optimized formulation for DOX/FA-PEG-P(HB-HO) NPs, and investigate the targeting and efficacies of the nanoparticles.

Materials and methods: DOX/FA-PEG-P(HB-HO) NPs were prepared by W₁/O/W₂ solvent extraction/evaporation method, and an orthogonal experimental design [L₉ (3⁴)] was applied to establish the optimum conditions. The physico–chemical characteristics, microscopic observation and in vivo antitumor study of the nanoparticles were evaluated.

Results: The optimum formulation was obtained with DOX 10% (w/v), FA-PEG-P(HB-HO) 6.5% (w/v), PVA 3%(w/v) and oil phase/internal water phase volume ratio of 3/1. The size distribution, drug loading and encapsulation efficiency of the optimized nanoparticles were 150–350?nm, 29.6?±?2.9% and 83.5?±?5.7%, respectively. In vitro release study demonstrated that 80% of the drug could release from the nanoparticles within 11 days. Furthermore, in vitro microscopic observation and in vivo antitumor study showed that DOX/FA-PEG-P(HB-HO) NPs could inhibit HeLa cells effectively, and the tumor inhibition rate (TIR) in vivo was 76.91%.

Discussion and conclusions: DOX/FA-PEG-P(HB-HO) NPs have been successfully developed and optimized. In vitro drug release study suggested a sustained release profile. Moreover, DOX/FA-PEG-P(HB-HO) NPs could effectively inhibit HeLa cells with satisfying targeting, and reduce side effects and toxicity to normal tissues. DOX/FA-PEG-P(HB-HO) NPs were superior in terms of inhibiting HeLa tumor over non-targeted formulations therapy.     

Formulation,development and optimization of raloxifene-loaded chitosan nanoparticles for treatment of osteoporosis

Abstract

Context: Osteoporosis (OP) is a disease of skeletal system and is associated with fragility fracture at the hip, spine and wrist. Various drugs have been used to treat OP. One of them is raloxifene hydrochloride (RLX), a second-generation selective estrogen receptor modulator (SERM) approved by the USFDA. RLX possesses only 2% absolute bioavailability (BA) by oral route due to its extensive first-pass metabolism.

Objective: The purpose of the current research work was to develop and evaluate RLX-loaded chitosan nanoparticles (CS-NPs) for treatment of OP with enhanced BA.

Materials and methods: The RLX-loaded CS-NPs were prepared by gelation of CS with tripolyphosphate (TPP) by ionic cross-linking. Formulation was optimized and in vitro drug release and in vivo study were performed.

Results and discussions: CS-NPs were formed by the ionic gelation method. The particle size, entrapment efficiency and loading efficiency varied from 216.65 to 1890?nm, 32.84 to 97.78% and 23.89 to 62.46%, respectively. Release kinetics showed diffusion-controlled and Fickian release pattern. In vivo study indicated higher plasma drug concentration with NPs administered intranasally as compared to drug suspension administered through oral route (p?<?0.05). A significantly higher drug concentration in plasma was achieved in 10?min after nasal administration with respect to oral administration.

Conclusion: The results suggest that RLX-loaded CS-NPs have better BA and would be a promising approach for intranasal (i.n.) delivery of RLX for the treatment of OP.     

Effects of polysaccharide from Physalis alkekengi var. francheti on liver injury and intestinal microflora in type-2 diabetic mice

Context: Diabetic liver injury is a serious diabetic complication. The alterations of intestinal microbiota play an important role in induction and promotion of liver injury progression. Physalis alkekengi L. var. francheti (Mast.) Makino (Solanaceae) has been used as a water decoction for treating diabetes.

Objective: To study the effects of a polysaccharide (PPSB) from Physalis alkekengi var. francheti on liver injury and intestinal microflora in type-2 diabetic mice.

Materials and methods: Streptozotocin (160?mg/kg) was injected i.p. for 3?days to build model. The diabetic mice were randomly divided into four groups together with control group (10 mice in each group). The doses of PPSB were 50 and 100?mg/kg, respectively. After 5 weeks administration, level of blood glucose, ALT and AST were measured. Alterations of intestinal microflora, and protein expression of TGF-β1, TNF-α and DCN were detected.

Results: Level of blood glucose decreased from (25.38?±?2.21) mmol/L to (18.01?±?2.53) mmol/L, ALT and AST decreased to (24.67?±?4.86) U/L and (30.84?±?7.50) U/L in PPSB-H group. Lactobacillus, Clostridium butyricum, and Bacteroides increased remarkably with increasing concentration of PPSB, but Enterobacter was inhibited. The relative expression of TGF-β1 and TNF-α decreased to (0.70?±?0.17) and (0.39?±?0.06), and the expression of DCN increased to (0.65?±?0.13).

Discussion and conclusions: Probiotics have been promoted by PPSB, and protein expressions have been modulated in the progression of liver injury. PPSB could be used as a natural agent for treating diabetic liver injury and intestinal microflora imbalance.     

Immunoadjuvant potential of cross-linked dextran microspheres mixed with chitosan nanospheres encapsulated with tetanus toxoid

Context: Nasal mucosa is a desirable route for mucosal vaccine delivery. Mucosal co-administration of chitosan nanoparticles with absorption enhancers such as cross-linked dextran microspheres (CDM, Sephadex^®) is a promising antigen delivery system.

Objective: In the current study, the chitosan nanospheres loaded with tetanus toxoid (CHT:TT NPs) was prepared and characterized. The immune responses against tetanus toxoid after nasal administration of CHT:TT NPs alone or mixed with CDM were also determined.

Materials and methods: Chitosan nanospheres were prepared by ionic gelation method. Particle size, releasing profile and antigen stability were evaluated by dynamic light scattering, diffusion chamber and SDS-PAGE methods, respectively. Rabbits were nasally immunized with different formulations loaded with 40 Lf TT. After three times immunizations with 2 weeks intervals, sera IgG titres and nasal lavage sIgA titres were determined.

Results: Mean size of CHT NPs and CHT:TT NPs were 205?±?42?nm and 432?±?85?nm, respectively. The release profile showed that 42.4?±?10.5% of TT was released after 30?min and reached to a steady state after 1.5?h. Stability of encapsulated TT in nanospheres was confirmed by SDS-PAGE. The antibody titres showed that CHT:TT NPs-induced antibody titres were higher than TT solution. CHT NPs mixed with CDM induced the systemic IgG and nasal lavage sIgA titres higher than intranasal administration of TT solution (p?Discussion and conclusion: As the results indicated, these CHT:TT NPs when co-administered with CDM were able to induce more immune responses and have the potential to be used in mucosal immunization.     

Pharmacokinetics and analgesic effect of ketorolac floating delivery system

Abstract

Objectives: The efficacy of ketorolac tromethamine (KT) floating alginate beads as a drug delivery system for better control of KT release was investigated. The formulation with the highest drug loading, entrapment efficiency, swelling, buoyancy, and in vitro release would be selected for further in vivo analgesic effect in the mice and pharmacokinetics study in rats compared to the tablet dosage form.

Methods: KT floating alginate beads were prepared by extrusion congealing technique. KT in plasma samples was analyzed using a UPLC MS/MS assay.

Results: The percentage yield, drug loading and encapsulation efficiency were increased proportionally with the hydroxypropylmethyl cellulose (HPMC) polymer amount in the KT floating beads. A reverse relationship was observed between HPMC amount in the beads and the KT in vitro release rate. F3-floating beads were selected, due to its better in vitro results (continued floating for >8?h) than others. A longer analgesic effect was observed for F3 in fed mice as compared to the tablets. After F3 administration to rats, the C_max (2.2?±?0.3?µg/ml) was achieved at ～2?h and the decline in KT concentration was slower. F3 showed a significant increase in the AUC (1.89 fold) in rats as compared to the tablets.

Conclusion: KT was successfully formulated as floating beads with prolonged in vitro release extended to a better in vivo characteristic with higher bioavailability in rats. KT in floating beads shows a superior analgesic effect over tablets, especially in fed mice.     

Cytotoxicity evaluation of electronic cigarette vapor extract on cultured mammalian fibroblasts (ClearStream-LIFE): comparison with tobacco cigarette smoke extract

Abstract

Context: Electronic cigarettes (ECs) are used as alternatives to smoking; however, data on their cytotoxic potential are scarce.

Objective: To evaluate the cytotoxic potential of 21 EC liquids compared to the effects of cigarette smoke (CS).

Methods: Cytotoxicity was evaluated according to UNI EN ISO 10993-5 standard. By activating an EC device, 200?mg of liquid was evaporated and was extracted in 20?ml of culture medium. CS extract from one cigarette was also produced. The extracts, undiluted (100%) and in five dilutions (50%, 25%, 12.5%, 6.25% and 3.125%), were applied to cultured murine fibroblasts (3T3), and viability was measured after 24-hour incubation by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assay. Viability of less than 70% was considered cytotoxic.

Results: CS extract showed cytotoxic effects at extract concentrations above 12.5% (viability: 89.1?±?3.5% at 3.125%, 77.8?±?1.8% at 6.25%, 72.8?±?9.7% at 12.5%, 5.9?±?0.9% at 25%, 9.4?±?5.3% at 50% and 5.7?±?0.7% at 100% extract concentration). Range of fibroblast viability for EC vapor extracts was 88.5–117.8% at 3.125%, 86.4–115.3% at 6.25%, 85.8–111.7% at 12.5%, 78.1–106.2% at 25%, 79.0–103.7% at 50% and 51.0–102.2% at 100% extract concentration. One vapor extract was cytotoxic at 100% extract concentration only (viability: 51.0?±?2.6%). However, even for that liquid, viability was 795% higher relative to CS extract.

Conclusions: This study indicates that EC vapor is significantly less cytotoxic compared tobacco CS. These results should be validated by clinical studies.     

负载阿霉素的黄芩苷纳米粒的制备及其体外性能评价

目的 制备负载阿霉素的黄芩苷纳米粒（DOX/SA-SS-BAI NPs）,并评价其体外性能。方法 构建以胱胺为连接臂的海藻酸钠–黄芩苷聚合物,并负载阿霉素,得到DOX/SA-SS-BAI NPs。对DOX/SA-SS-BAI NPs的理化性质进行表征;采用HepG2细胞进行MTT实验验证其细胞毒性。结果 DOX/SA-SS-BAI NPs粒径为（158.2±2.8）nm,PDI为（0.241±0.008）,Zeta电位为（-24.1±0.3）m V,包封率为（64.34±0.25）%,载药量为（16.22±0.06）%。体外释放显示载药纳米粒具有良好的还原响应性;MTT实验证明DOX/SA-SS-BAINPs对HepG2细胞具有良好的抑制作用;细胞摄取实验表明DOX/SA-SS-BAI NPs在HepG2细胞内较快地释放阿霉素。结论 制备的DOX/SA-SS-BAI NPs具有较好的理化性质和体外抗癌作用。