Sentinel node biopsy versus elective neck dissection in early-stage oral cancer: a systematic review.

PURPOSE: To provide a summary of the evidence on the comparative effectiveness of two surgical treatment strategies, sentinel node biopsy (SNB) and elective neck dissection (END), in patients with T1-T2 oral cancer and clinically negative (cN0) neck, in terms of overall survival (OS), disease-free survival (DFS) and neck recurrence rates (NRRs). METHODS: A systematic review was performed by including studies published up to April 2019. Meta-analysis was performed to compare NRRs between SNB and END. A narrative summary of the results was generated for OS, DFS and morbidity outcomes. The certainty of evidence was assessed according to the GRADE methodology. RESULTS: No randomized studies were retrieved. Five observational studies were included in the comparative effectiveness analysis and four observational studies were included in the comparative morbidity analysis. The pooled risk ratio showed no differences in NRRs between SNB and END (10.5% vs 11.6%; pooled RR 1.09; 95% CI 0.67-1.76). No differences in OS or DFS between the two treatments were found. SNB appears to be associated with a lower rate of postoperative complications and lower shoulder dysfunction than END. Conversely, the results of the quality of life (QoL) questionnaires are not sufficient to advocate a particular strategy. CONCLUSION: Our review highlights the lack of well conducted and randomized studies comparing SNB to END, leading to poor clinical evidence. Although our findings suggest no significant differences in OS, DFS and NRR between the two strategies, the certainty of our evidence is too low to make it useful for clinical decision making.

Direct and Real-Time Quantification Of Bortezomib Release From Alginate Microparticles Using Boron (11B) Nuclear Magnetic Resonance Spectroscopy.

This study developed and validated a solution-state quantitative boron nuclear magnetic resonance (11B qNMR) method for the real-time quantification of boron containing bioactive agents with emerging therapeutic applications. Hence, this study may offer an alternative analytic method to estimate drug potency, purity, stability, or in vitro release kinetics of boron-containing pharmaceutical formulations/compounds, especially in cases where dialysis is typically required but limited. The 11B qNMR method was linear in the range tested, and the detection and quantification limits were 1.87 and 5.65 mM, respectively. The method was also specific, accurate, precise, and robust (%RSE < 2%). The 11B qNMR method was applied to the in vitro release study of a model drug, bortezomib (BTZ), from alginate microparticles, and results were compared to the traditional dialysis method. The alginate microparticles were prepared by spray drying, and the mean particle diameter was 2.36 ± 0.19 µm with a polydispersity index (PDI) of 0.253. The microparticles surface charge density was -57.1 ± 2.2 mV. More than 20% difference in the total amount of BTZ released from the microparticle formulation was observed between the direct 11B qNMR and dialysis methods. Furthermore, the dialysis method was not suitable to determine the initial burst release of BTZ from the microparticles. Throughout the release study, the dialysis method consistently underestimated the level of drug released, probably due to the separating membrane that can interfere with the real-time drug transport process. Overall, compared to the dialysis method, the direct 11B qNMR method was accurate and provided a direct and real-time quantification of BTZ for an effective study of drug release kinetics.

Preclinical Safety Evaluation of HIV-1 gp120 Responsive Microbicide Delivery System in C57BL/6 Female Mice.

Many novel vaginal/rectal microbicide formulations failed clinically due to safety concerns, indicating the need for the early investigation of lead microbicide formulations. In this study, the preclinical safety of an HIV-1 gp120 and mannose responsive microbicide delivery system (MRP) is evaluated in C57BL/6 mice. MRP was engineered through the layer-by-layer coating of calcium carbonate (CaCO3) with Canavalia ensiformis lectin (Con A) and glycogen. MRP mean particle diameter and zeta potential were 857.8 ± 93.1 nm and 2.37 ± 4.12 mV, respectively. Tenofovir (TFV) encapsulation and loading efficiencies in MRP were 70.1% and 16.3% w/w, respectively. When exposed to HIV-1 rgp120 (25 µg/mL), MRP released a significant amount of TFV (∼5-fold higher) in vaginal and seminal fluid mixture compared to the control (pre-exposure) level (∼59 µg/mL) in vaginal fluid alone. Unlike the positive control treated groups (e.g., nonoxynol-9), no significant histological damages and CD45+ cells infiltration were observed in the vaginal and major reproductive organ epithelial layers. This was probably due to MRP biocompatibility and its isosmolality (304.33 ± 0.58 mOsm/kg). Furthermore, compared to negative controls, there was no statistically significant increase in pro-inflammatory cytokines such as IL1α, Ilß, IL7, IP10, and TNFα. Collectively, these data suggest that MRP is a relatively safe nanotemplate for HIV-1 gp120 stimuli responsive vaginal microbicide delivery system.

Layer-by-Layer Engineered Microbicide Drug Delivery System Targeting HIV-1 gp120: Physicochemical and Biological Properties.

The purpose of this study was to engineer a model anti-HIV microbicide (tenofovir) drug delivery system targeting HIV-1 envelope glycoprotein gp120 (HIV-1 g120) for the prevention of HIV sexual transmission. HIV-1 g120 and mannose responsive particles (MRP) were prepared through the layer-by-layer coating of calcium carbonate (CaCO3) with concanavalin A (Con A) and glycogen. MRP average particle size ranged from 881.7 ± 15.45 nm to 1130 ± 15.72 nm, depending on the number of Con A layers. Tenofovir encapsulation efficiency in CaCO3 was 74.4% with drug loading of 16.3% (w/w). MRP was non-cytotoxic to Lactobacillus crispatus, human vaginal keratinocytes (VK2), and murine macrophage RAW 264.7 cells and did not induce any significant proinflammatory nitric oxide release. Overall, compared to control, no statistically significant increase in proinflammatory cytokine IL-1α, IL-1ß, IL-6, MKC, IL-7, and interferon-γ-inducible protein 10 (IP10) levels was observed. Drug release profiles in the presence of methyl α-d-mannopyranoside and recombinant HIV-1 envelope glycoprotein gp120 followed Hixson-Crowell and Hopfenberg kinetic models, indicative of a surface-eroding system. The one Con A layer containing system was found to be the most sensitive (∼2-fold increase in drug release vs control SFS:VFS) at the lowest HIV gp120 concentration tested (25 µg/mL). Percent mucoadhesion, tested ex vivo on porcine vaginal tissue, ranged from 10% to 21%, depending on the number of Con A layers in the formulation. Collectively, these data suggested that the proposed HIV-1 g120 targeting, using MRP, potentially represent a safe and effective template for vaginal microbicide drug delivery, if future preclinical studies are conclusive.

Tenofovir Containing Thiolated Chitosan Core/Shell Nanofibers: In Vitro and in Vivo Evaluations.

It is hypothesized that thiolated chitosan (TCS) core/shell nanofibers (NFs) can enhance the drug loading of tenofovir, a model low molecular weight and highly water-soluble drug molecule, and improve its mucoadhesivity and in vivo safety. To test this hypothesis, poly(ethylene oxide) (PEO) core with TCS and polylactic acid (PLA) shell NFs are fabricated by a coaxial electrospinning technique. The morphology, drug loading, drug release profiles, cytotoxicity and mucoadhesion of the NFs are analyzed using scanning and transmission electron microscopies, liquid chromatography, cytotoxicity assays on VK2/E6E7 and End1/E6E7 cell lines and Lactobacilli crispatus, fluorescence imaging and periodic acid colorimetric method, respectively. In vivo safety studies are performed in C57BL/6 mice followed by H&E and immunohistochemical (CD45) staining analysis of genital tract. The mean diameters of PEO, PEO/TCS, and PEO/TCS-PLA NFs are 118.56, 9.95, and 99.53 nm, respectively. The NFs exhibit smooth surface. The drug loading (13%-25%, w/w) increased by 10-fold compared to a nanoparticle formulation due to the application of the electrospinning technique. The NFs are noncytotoxic at the concentration of 1 mg/mL. The PEO/TCS-PLA core/shell NFs mostly exhibit a release kinetic following Weibull model (r2 = 0.9914), indicating the drug release from a matrix system. The core/shell NFs are 40-60-fold more bioadhesive than the pure PEO based NFs. The NFs are nontoxic and noninflammatory in vivo after daily treatment for up to 7 days. Owing to their enhanced drug loading and preliminary safety profile, the TCS core/shell NFs are promising candidates for the topical delivery of HIV/AIDS microbicides such as tenofovir.

Sodium Acetate Coated Tenofovir-Loaded Chitosan Nanoparticles for Improved Physico-Chemical Properties.

PURPOSE: It is hypothesized that sodium acetate (SA) can be used for in situ coating of drug loaded chitosan NPs for improved physico-chemical properties. METHODS: Tenofovir (TFV) is used as a model drug. Uncoated chitosan NPs are prepared by ionic gelation. SA is generated in situ from half neutralization of acetic acid with sodium hydroxide, and coats chitosan NPs during freeze-drying. The NPs' physico-chemical properties [e.g., particle mean diameters (PMD) zeta potential (ζ), EE%, drug release profile, morphology] are characterized by dynamic light scattering, spectrophotometry, Korsmeyer-Peppas model, transmission electron microscopy (TEM), respectively. Melting point (MP), non-aqueous titration, Fourier transform infrared (FTIR) analysis, and powder X-ray diffractometry (XRD) pattern evaluate the SA coated chitosan NPs. The NPs' cytotoxicity on macrophages Raw 264.7 is assessed by neutral red, resazurin, nitrite oxide (NO) and cytokines assays. RESULTS: Collectively, FTIR, ζ, XRD, MP, and TEM data confirm that SA coats chitosan NPs. The PMD range is 136-348 nm (uncoated) and 171-379 nm (coated NPs). The ζ values range is +24.3-28.5 mV (uncoated) and 0.1-3.1 mV (coated NPs). The EE% ranges from 5.5 to 11.7% (uncoated NPs) and increased up to 86.3-92.7%(8-17-fold) after coating. The SA also prevents NPs aggregation during the freeze-drying and aqueous dispersion. The core-shell NPs exhibited a sustain release of TFV following anomalous transport mechanism (R(2) ~ 0.99). The coated NPs are non-cytotoxic (cell viability ~100%) and without any proinflammatory response. CONCLUSIONS: This SA coating chitosan NPs mechanism may be useful for (i) efficient encapsulation, (ii) stabilizing colloidal dispersions, (iii) controlling the release and solubility of bioactive agents.

Uptake and cytotoxicity of docetaxel-loaded hyaluronic acid-grafted oily core nanocapsules in MDA-MB 231 cancer cells.

PURPOSE: It is hypothesized that docetaxel (Doc)-loaded hyaluronic acid (HA)-polyethylene glycol/poly(ε-caprolactone)-grafted oily core nanocapsules (NCs) can enhance the drug cytotoxicity and uptake in CD44 expressing breast cancer (BC) cells (MDA-MB 231). METHODS: NCs were prepared, optimized and characterized by dynamic light scattering, transmission electron microscopy (TEM), and powder X-ray diffraction (PXRD). In vitro cytotoxicity tests [MTS, level of reactive oxygen species (ROS) and level of reduced glutathione (GSH)] were performed in BC cells. The contribution of CD44 to the NCs cellular uptake was elucidated using an anti CD44 antibody blockage and a CD44 negative NIH3T3 cell line. RESULTS: The optimum formulation of Doc-loaded HA oily core NCs had respective mean diameter, polydispersity, and drug encapsulation efficiency of 224.18 nm, 0.32, and 60.38%. The NCs appeared spherical with low drug crystallinity, while the drug release data fitted to first order equation. Compared to that of ungrafted NCs, the cytotoxicity of Doc-loaded HA-grafted NCs was significantly enhanced (p<0.05). A decrease of the intracellular level of ROS was reversely correlated with that of GSH. Interestingly, the cellular internalization of HA-grafted NCs mediated CD44 was dramatically enhanced (3 to 4-fold) with respect to the absence of specific biomarker or targeting ligand. CONCLUSIONS: The use of HA-grafted NCs enhanced the selective drug payload, cytotoxicity and uptake in MDA-MB 231 cells. Therefore, it could be a promising template for safe and effective delivery of Doc and similar chemotherapeutic agents in cancer cells.

Partial trisomy 3p24.3 and partial monosomy 5p15.33: case report and a literature review.

We report on a preterm neonate with a deletion of the distal short arm of chromosome 5p15.33 and partial trisomy of the distal short arm of chromosome 3p24.3. The patient was the first-born monozygotic twin. There were no pertinent facial or physical features except a small lower lip hemangioma. The neonate presented with cardiac defects, which included a patent ductus arteriosus, an atrial septal defect and ventricular septal defects. After 94 days of age, however, the patient died from superior vena cava syndrome, recurrent chylothoraces and generalized anasarca. Array comparative genomic hybridization (aCGH) using a custom oligonucleotide microarray (Agilent 180,000 probe platform revealed a terminal duplication of 1,128 oligonucleotide probes from 3pter to 3p24.3, spanning approximately 20.4 megabases (Mb), and a terminal deletion of 271 oligonucleotide probes from 5pter to 5p15.33, spanning approximately 4.3 Mb. This is the first report of a patient with partial trisomy 3p24.3 and partial monosomy 5p15.33 without major dysmorphic features.

Fasting glucose and treatment outcome in breast and colorectal cancer patients treated with targeted agents: results from a historic cohort.

BACKGROUND: We investigated pretreatment fasting glucose as a predictor of patients' important outcomes in breast and colorectal cancers undergoing targeted therapies. PATIENTS AND METHODS: In a historic cohort of 202 breast and 218 colorectal cancers treated with targeted agents from 1998 to 2009, we used the Kaplan-Meier method and the log-rank test to estimate survival through tertiles of fasting glucose and the Cox proportional hazards model for multivariate analysis stratified by primary site of cancer and including gender, age and body mass index. RESULTS: The median follow-up was 20 months (1-128). At 60 months, 65% of patients in the lowest tertile of fasting glucose did not experiment disease progression compared with 34% in the highest tertile (P=0.001). Seventy-six percent of females in the lowest tertile showed no progression compared with 49% in the top tertiles (P=0.015). In multivariate analysis, fasting glucose was a significant predictor of time to disease progression only in breast cancer patients in the first tertile compared with the third (P=0.017). CONCLUSIONS: We found evidence of a predictive role of pretreatment fasting glucose in the development of resistance in breast cancer patients treated with targeted agents. Prospective studies are warranted to confirm our findings.

Circulating cytokines present in the serum of peripheral arterial disease patients induce endothelial dysfunction.

Peripheral arterial disease (PAD) is a chronic condition caused by atherosclerosis and is a severe complication of type 2 diabetes (T2D). We hypothesised that chronic condition of arterial disease engenders inflammation and endothelial damage in response to circulating cytokines released in the blood stream of PAD patients. We explored the levels of circulating cytokines in PAD patients with and without diabetes by multiplex cytokine array compared with non-PAD controls. Serum from PAD patients with or without diabetes showed high levels of VEGF, IFN-gamma, TNF-alpha, MCP-1, and EGF. VEGF levels correlated with TNF-alpha and IFN-gamma, significantly. Endothelial cells (ECs) were exposed to the different altered cytokines to evaluate changes in cell growth, migration and tubule-like formation, displaying impairment on proliferation, migration and tubule formation. Our findings demonstrate that a set of cytokines is significantly increased in the serum of PAD patients. These cytokines act to induce endothelial dysfunction synergistically. VEGF strongly correlated with TNF-alpha and IFN-gamma, opening new therapeutic perspectives.

Sensitive and rapid HPLC quantification of tenofovir from hyaluronic acid-based nanomedicine.

The purpose of this study was to develop and validate a rapid, sensitive, and specific reversed-phase high-performance liquid chromatography method for the quantitative determination of native tenofovir (TNF) for various applications. Different analytical performance parameters such as linearity, precision, accuracy, limit of quantification (LOQ), limit of detection (LOD), and robustness were determined according to International Conference on Harmonization (ICH) guidelines. A Bridge™ C18 column (150 × 4.6 mm, 5 µm) was used as stationary phase. The retention time of TNF was 1.54 ± 0.03 min (n = 6). The assay was linear over the concentration range of 0.1-10 µg/mL. The proposed method was sensitive with LOD and LOQ values equal to 50 and 100 ng/mL, respectively. The method was accurate with percent mean recovery from 95.41% to 102.90% and precise as percent RSD (relative standard deviation) values for intra-day, and inter-day precision were less than 2%. This method was utilized for the estimation of molar absorptivity of TNF at 259 nm (ε(259) = 12,518 L/mol/cm), calculated from linear regression analysis. The method was applied for determination of percentage of encapsulation efficiency (22.93 ± 0.04%), drug loading (12.25 ± 1.03%), in vitro drug release profile in the presence of enzyme (43% release in the first 3 h) and purification analysis of hyaluronic acid-based nanomedicine.

The effect of tracheostomy on swallowing function in open partial horizontal laryngectomies: preliminary experience.

OBJECTIVE: Tracheostomy is required to ensure a safe airway in open partial horizontal laryngectomies. The presence of the tracheostomy tube can contribute to post-operative dysphagia. This study aimed to evaluate the effects of a circumferential tracheostomy technique on swallowing. METHODS: A retrospective study was conducted of patients who underwent open partial horizontal laryngectomies between April 2018 and June 2019. Patients were divided into two groups based on the tracheostomy technique: group 1 had two stitches from the inferior tracheal ring to the skin; group 2 had circumferential fixation of the trachea to the skin. Demographic information, surgical data, post-operative rehabilitation course and complication details were collected and analysed. RESULTS: Twenty-four patients were enrolled. Patients in group 2 had significant improvement in the initial phases of swallowing rehabilitation. CONCLUSION: Tracheostomy with anchorage of the trachea to the skin by circumferential stitches could allow early removal of the tracheal tube, with a better swallowing outcome.

Rheological analysis of a novel phenylboronic acid-closomer gel.

This study aims to characterize the rheological behavior of a novel phenylboronic acid (PBA)-based closomer nanoconjugate (Closogel) with potential application in pharmaceutical formulation. PBA was used as a cross-linking agent and model (antiviral) drug. The PBA loaded Closogel chemical structure was analyzed by boron (11B) NMR and Fourier transform infrared (FTIR) spectroscopy. The Closogel and control hydroxyethyl cellulose (HEC) gel were analyzed under oscillatory and continuous shear rheometry followed by mathematical modeling to characterize the gel flow behavior. The chemical analysis confirmed the existence of characteristic borate esters peaks and Boron chemical shifts within Closogel spectra. Due to its more flexible molecular structure, undiluted Closogel exhibited lower, yield stress, viscosity and relaxation time (30 Pa &163 Pa.s & 0.21 s vs 45 Pa &301 Pa.s & 0.39 s for HEC). Both Closogel and HEC gels exhibited a thixotropic behavior. The plastic undiluted and pseudoplastic 2.5 % w/v aqueous Closogels were more viscous than elastic (tan (δ) > 1) in the linear viscoelastic range. The Herschel-Bulkley model showed a significant fitting to all experimental data (R2 > 0.95). The 0.25 % w/v aqueous Closogel nearly exhibited a Newtonian behavior with a flow index of 0.93. These data suggest that PBA loaded Closomer-based gels have similar rheological behavior, with lower complex modulus than that of HEC gels, and they can be a promising platform used for delivery of topical antiviral or other bioactive agents.

Partial trisomy 10p12.33 and partial monosomy 13q32.1: case report and a literature review.

We report on a preterm neonate with a deletion of the distal long arm of chromosome 13q32.1 and partial trisomy of the short arm of chromosome 10p12.33. The patient has intrauterine growth retardation, microphthalmia, macrocephaly, holoprosencephaly, patent ductus arteriosus, aortic isthmus hypoplasia, right renal agenesis, imperforate anus, ambiguous genitalia, pleural effusion and vertebral anomaly. Analysis using an oligonucleotide microarray (U-array Cyto6000 array platform (Human Genome build: hg 18) indicated that there was a partial trisomy of chromosome 10(19.5 Mb gain) involving 298 oligonucleotides from 10pter to 10p12.33, and a partial monosomy of chromosome 13(18.3 Mb deleted) involving 313 oligonucleotides from 13q32.1 to 13qter. This is the first report of a patient with partial trisomy 10p12.33 and partial monosomy 13q32.1.

Self-Assembled Nanomicelles to Enhance Solubility and Anticancer Activity of Etoposide.

It is hypothesized that etoposide/VP-16 nanomicellar formulation (VP-16 NMF) utilizing D-α-Tocopherol polyethylene glycol 1000 succinate (TPGS) can improve etoposide solubility and anticancer activity. The following four different concentrations of TPGS: 3, 6, 8, and 10 wt% were used to solubilize the drug. Among these four formulations, 10 wt% of TPGS loaded with VP-16 NMF dramatically enhanced etoposide apparent solubility by 26-folds compared with the native drug. The physicochemical properties of the optimized formulation were further analyzed by dynamic light scattering, X-ray powder diffraction, scanning electron microscopy, proton nuclear magnetic resonance (1HNMR) and Fourier transform infrared spectroscopy. Liquid chromatography tandem-mass spectrometry (LC-MS/MS) was used to assess solubility and intracellular uptake of the drug from the NMF. Cell viability assay ([3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H tetrazolium solution [MTS]) was performed on MCF-7 and MCF-10A cell lines to assess intracellular uptake and anticancer activity of etoposide. The MTS assay results showed that the VP-16 NMF platform provides a higher anticancer activity than the native VP-16 on the MCF-7 cells line as it integrates a dual anticancer activity of VP-16 and TPGS. LC-MS/MS data showed a threefold increase in cellular uptake of VP-16 NMF in MCF-7 cell line compared with the native etoposide. These data suggest that an optimal TPGS concentration can improve VP-16 bioavailability and efficacy with potential benefits for chemotherapy.

Fluorine (19F) Nuclear Magnetic Resonance Spectroscopy For Real Time Maraviroc Analysis From Microparticulate Systems.

Real time analysis of pharmaceuticals in controlled release nano and microsystems remains a challenge. It is hypothesized that fluorine 19 nuclear magnetic resonance (19F qNMR) can be used for real time quantification and in vitro release of maraviroc (MVC). The release of maraviroc was analyzed in simulated body fluids from spray dried sodium alginate microspheres (MS) using the 19F qNMR method. Calibration produced a linearity curve in concentration range (0.42 mg/ml - 15 mg/ml), and the limits of detection and quantification values were 0.97 mg/ml and 2.93 mg/ml, respectively. The method was confirmed to be specific, accurate, precise, and robust (%RSE > 2%). MVC was successfully microencapsulated (18% w/w) as evidenced by the FT-IR spectra and SEM images. The MS had an average diameter of 2.522 ± 0.15 µm, with a zeta potential of - 61.31 ± 2.1 mV. Overall, the 19F qNMR method enabled a direct and real time quantification of MVC for an efficient drug release kinetics. This approach could be potentially used to quantify fluorinated drug potency, purity, and stability, and evaluate in vitro release kinetic from different formulations.

Enhancing Etoposide Aqueous Solubility and Anticancer Activity with L-Arginine.

It is hypothesized that L-arginine (ARG) can improve etoposide (VP-16) water solubility while preserving its anticancer activity. Factorial design is used to identify conditions for optimum drug aqueous solubility after freeze-drying. The physicochemical properties of the optimized formulation is further analyzed by X-ray powder diffraction, scanning electron microscopy, proton nuclear magnetic resonance, and fourier transform infrared spectroscopy. Drug stability in formulation is analyzed using mass spectrometry based fragmentation analysis. Liquid chromatography tandem mass spectrometry and cell viability assay on Michigan Cancer Foundation-7 (MCF-7) cell line are performed to assess the drug cellular uptake and the anticancer activity, respectively. At the VP-16: ARG ratio of 4:10 (w/w), the drug apparent solubility increased significantly (∼65-folds) with a 3.5-fold improvement in the drug dissolution rate. The interaction between VP-16 and ARG transforms the drug from crystalline to amorphous solid state. VP-16-ARG complex in lower native drug concentration range (50-300 µM) has lower anticancer activity compared with native VP-16, due to reduced intracellular transport of the more hydrophilic complex as indicated by the cell viability assay and confirmed by cell uptake study. However, at higher drug concentrations (500 µM) the complex's higher anticancer activity is ascribed to the synergistic effect between ARG and VP-16. These data suggest that an optimal ARG concentration can have positive effects with potential benefits for chemotherapy.

Analysis of process parameters affecting spray-dried oily core nanocapsules using factorial design.

The purpose of this work was to optimize the process parameters required for the production of spray-dried oily core nanocapsules (NCs) with targeted size and drug yield using a two-level four-factor fractional factorial experimental design (FFED). The coded process parameters chosen were inlet temperature (X(1)), feed flow rate (X(2)), atomizing air flow (X(3)), and aspiration rate (X(4)). The produced NCs were characterized for size, yield, morphology, and powder flowability by dynamic light scattering, electron microscope, Carr's index, and Hausner ratio measurement, respectively. The mean size of produced NCs ranged from 129.5 to 444.8 nm, with yield varying from 14.1% to 31.1%. The statistical analysis indicated an adequate model fit in predicting the effect of process parameters affecting yield. Predicted condition for maximum yield was: inlet temperature 140°C, atomizing air flow 600 L/h, feed flow rate 0.18 L/h, and aspiration air flow set at 100%, which led to a yield of 30.8%. The morphological analysis showed the existence of oily core and spherical nanostructure. The results from powder flowability analysis indicated average Carr's index and Hausner ratio of 42.77% and 1.76, respectively. Spray-dried oily core NCs with size lower than 200 nm were successfully produced, and the FFED proved to be an effective approach in predicting the production of spray-dried NCs of targeted yield.

Formulation of dacarbazine-loaded cubosomes. Part III. Physicochemical characterization.

The purpose of this study was to investigate the physicochemical properties of dacarbazine-loaded cubosomes. The drug-loaded cubosome nanocarriers were prepared by a fragmentation method and then freeze dried. They were then characterized for size, morphology, thermal behavior, and crystallography using dynamic light scattering, transmission electron microscopy (TEM), differential scanning calorimetry (DSC), and powder X-ray diffraction (PXRD), respectively. The drug loading and encapsulation efficiency were determined by UV spectrophotometry. The results showed that the prepared dacarbazine-loaded cubosomes had mean diameters ranging from 86 to 106 nm. In addition to the TEM, the characteristic peaks from PXRD data suggested that the freeze-dried nanoformulations were indeed cubic in nature. DSC and PXRD analysis suggested the 0.06 or 0.28% w/w actual drug loaded inside cubosomes was in the amorphous or molecular state. These physicochemical characteristics would affect the nanoformulation shelf-life, efficacy, and safety.

Hyperthermic isolated perfusion with tumor necrosis factor-alpha and doxorubicin for the treatment of limb-threatening soft tissue sarcoma: the experience of the Italian Society of Integrated Locoregional Treatment in Oncology (SITILO).

BACKGROUND: Tumor necrosis factor-alpha (TNFalpha)-based hyperthermic isolated limb perfusion (HILP) is routinely carried out at most oncological institutions in the treatment of locally advanced soft tissue limb sarcoma (STS), employing high TNFalpha dosages. After a phase I-II study, the SITILO (Italian Society of Integrated Locoregional Therapies in Oncology) centers began to employ the lower dose of 1 mg of TNFalpha. The aim of this paper is to report on the results obtained in 75 patients with limb-threatening STS treated with a low TNFalpha dose and doxorubicin (Dx). PATIENTS AND METHODS: HILP with TNFalpha (at a dosage of either 1 mg) and Dx was administered to 75 patients with limb-threatening STS: 37 males and 38 females; median age 50 years; tumor in the lower and upper limbs in 58 and 17 patients, respectively; primary and recurrent tumors in 45 and 30 patients, respectively. Most tumors (77%) were high grade. Tumor resection was carried out 6 to 8 weeks after HILP. RESULTS: The grade of limb toxicity was mild to moderate in the vast majority of patients (76%). Grades IV and V were observed, but only when high muscle temperatures were recorded and high TNFalpha dosages were employed. Systemic toxicity was also mild to moderate and there were no postoperative deaths. Complete and partial tumor responses were 34% and 48%, respectively, with an overall response of 82% . Limb sparing surgery was carried out in 85.3% of patients. At a median follow-up of 28 months, 16 recurrences (21.3%) were recorded, with a 5-year locoregional disease-free survival of 63% . The 5-year disease-free survival and overall survival were 36.7% and 61.6%, respectively. CONCLUSION: HILP with 1 mg of TNFalpha is an effective neoadjuvant therapy resulting in a high rate of limb sparing in limb-threatening STS, with acceptable local reactions and negligible systemic toxicity.