Nanomedicine and chemotherapeutics drug delivery: challenges and opportunities.

Cancer is considered as one of the biggest threats to humans worldwide. Researchers suggest that tumour is not just a single mass, it comprises cancerous cells surrounded by noncancerous cells such as immune cells, adipocytes and cancer stem cells (CSCs) in the extracellular matrix (ECM) containing distinct components such as proteins, glycoproteins and enzymes; thus tumour microenvironment (TME) is partially complex. Multiple interactions happen in the dynamic microenvironment (ME) lead to an acidic, hypoxic and stiff ME that is considered as one of the major contributors to cancer progression and metastasis. Furthermore, TME involves in drug resistance mechanisms and affects enhanced permeability and retention (EPR) in tumours. In such a scenario, the first step to accomplish satisfying results is the identification and recognition of this ME. Then designing proper drug delivery systems can perform selectively towards cancerous cells. In this way, several targeting and stimuli/enzyme responsive drug delivery systems have been designed. More importantly, it is necessary to design a drug delivery system that can penetrate deeper into the tumours, efficiently and selectively. Various drug delivery systems such as exosomes and size-switchable nanocarriers (NCs) could decrease side effects and increase tumour treatment results by selective accumulation in tumours. In this review, TME features, current drug delivery approaches, challenges and promising strategies towards cancer treatment are discussed.

In vitro and in vivo evaluation of paclitaxel-lapatinib-loaded F127 pluronic micelles.

The aim of this study was to evaluate the in vitro and in vivo efficacy of paclitaxel-lapatinib-loaded Pluronic micelles. Lapatinib and pluronic sensitize the cancerous cells to paclitaxel via efflux pump inhibition. In addition, pluronic polymers can trigger intrinsic apoptosis pathways. Furthermore, micellar system can passively target the chemotherapeutic agents by enhanced permeability and retention effect. The paclitaxel-lapatinib-loaded micelles were characterized in means of encapsulation efficacy and size. The in vitro analyses were performed by MTT assay and uptake studies. Real-time imaging and in vivo anti-tumor efficacy studies were also performed. The prepared micelles have acceptable encapsulation ratio and size. Hemolysis assay confirmed that the micelles are hemo-compatible. MTT assay demonstrated that drug-loaded micelles have superior cytotoxicity compared with the naked drugs. The confocal microscopy and flowcytometry analyses showed that micelles are mainly internalized by endocytosis. According to the results of the in vivo imaging, the micelles are accumulated within liver. In vivo anti-tumor efficacy studies confirmed that tumor inhibition of drug-loaded micelles was significant compared to Intaxel®.

Preparation and Bioavailability Analysis of Ferrous Bis Alanine Chelate as a New Micronutrient for Treatment of Iron Deficiency Anemia.

Purpose: One of the most nutritional disorders around the world is iron deficiency. A novel iron compound was synthesized by chelating ferrous ions with alanine for prevention and treatment of iron deficiency anemia. Methods: The newly synthesized compound was characterized both qualitatively and quantitatively by Fourier Transform Infrared (FT-IR) spectroscopy. The bioavailability of newly synthesized iron micronutrient was evaluated in four groups of Wistar rats. The group I was a negative control group and the other three groups received three different iron formulations. After 14 days, the blood samples were taken and analyzed accordingly. Results: Calculations showed that more than 91.8% of iron was incorporated in the chelate formulation. In vivo studies showed that serum iron, total iron binding capacity and hemoglobin concentrations were significantly increased in group IV, which received ferrous bis alanine chelate compared with the negative control group (p<0.05) and also group II, which received ferrous sulfate.7H2O (p<0.05). It indicates that the new formulation considerably improves the blood iron status compared with the conventional iron compounds. There were no significant differences (p<0.05) in the serum iron between group IV and group III, which received ferrous bis glycine. Conclusion: The results showed better bioavailability of ferrous bis alanine as a new micronutrient for treatment of iron deficiency anemia in comparison with ferrous sulfate. Ferrous bis alanine could be considered as a suitable supplement for prevention and treatment of iron deficiency anemia.

Development and Validation of a Rapid RP-HPLC-DAD Analysis Method for the Simultaneous Quantitation of Paclitaxel and Lapatinib in a Polymeric Micelle Formulation.

A robust and rapid analysis method was developed and validated for the simultaneous assay of paclitaxel (PTX) and lapatinib (LPT) in a polymeric micelle formulation as a novel drug delivery system using high-performance liquid chromatography (HPLC). The assay was performed using the C18 MZ-Analytical Column (5 µm, 150 × 4.6 mm, OSD-3) which was protected with the C18 pre-column (5 µm, 4.0 × 4.6 mm, OSD-3). The mobile phase was composed of acetonitrile and water (70/30; V/V) with a flow rate of 0.5 mL/min and detection wavelength of 227 nm. Accuracy was reported as the relative error and was found to be less than 6.8%. The interday assay was evaluated to be 3.22% and 5.76% RSD for PTX and LPT, respectively. The intraday precision was found to be at its maximum value of 5.83% RSD. The limit of detection for both PTX and LPT was found to be 1 µg/mL by means of the newly developed method. The limit of quantitation for PTX and LPT was found to be 5 µg/mL. The calibration curves for both drugs were linear in the concentration range of 5 to 80 µg/mL. In vitro release for both drugs from the polymeric micelle was evaluated using the newly developed analysis method.

Hyaluronic acid-coated liposomes for targeted delivery of paclitaxel, in-vitro characterization and in-vivo evaluation.

Breast cancer is the leading cause of cancer death in women. Chemotherapy is regarded as the most essential strategy in inhibiting the proliferation of tumor cells. Paclitaxel is a widely used taxane; however, the side effects of available Cremophor-based formulations and also the limitations of passive targeting uncovered an essential need to develop tumor-specific targeted nanocarriers. A hyaluronic acid targeted liposomal formulation of paclitaxel was prepared in which, hyaluronic acid was electrostatistically attracted to the surface of liposomes. Liposomes, had a particle size of 106.4±3.2nm, a weakly negative zeta potential of -9.7±0.8mV and an acceptable encapsulation efficiency of 92.1±1.7%. The release profile of liposomes in buffer showed that 95% of PTX was released during 40h. Confocal laser scanning microscopy and flow cytometry analysis showed the greater cellular internalization of coumarin-loaded liposomes compared to free coumarin. MTT assay on 4T1 and T47D cells demonstrated the stronger cytotoxic activity of liposomes in comparison to free paclitaxel. Cell cycle analysis showed that cells were mainly blocked at G2/M phases after 48h treatment with liposomes. In vivo real time imaging on 4T1 tumor-bearing mice revealed that the liposomal formulation mainly accumulated in the tumor area. Liposomes also had better antitumor efficacy against Cremophor-based formulation. In conclusion, hyaluronic acid targeted paclitaxel liposome can serve as a promising targeted formulation of paclitaxel for future cancer chemotherapy.

Liposomal formulation for co-delivery of paclitaxel and lapatinib, preparation, characterization and optimization.

Paclitaxel (PTX) is one of the most promising natural anticancer agents with a wide therapeutic range which is limited by its hydrophobic nature, low therapeutic index and more importantly, the emergence of multidrug resistance (MDR). Lapatinib (LPT) is a dual tyrosine kinase inhibitor with a significant potential to inhibit p-glycoproteins which form one of the main groups of proteins responsible for efflux pump mediated MDR. To overcome the PTX related MDR, a novel liposomal formulation was optimized for co-delivery of PTX and LPT by applying the D-optimal response surface methodology. The encapsulation efficiency (EE%) of the optimized formulation for LPT and PTX was 52 ± 3% and 68 ± 5, respectively. The optimized formulation showed a narrow size distribution with the average of 235 ± 12 nm. The transmission electron microscopy image showed that liposomes were round in shape and discrete. The release profile exhibited 93% and 71% drug release for PTX and LPT after 40 h in the sink condition. The differential scanning calorimetry analysis indicated the conversion of both drugs from crystalline state to molecular state in the optimized lyophilized formulation. The cytotoxicity of the prepared formulation was studied against 4T1 murine mammary cells. The liposomal formulation showed better cytotoxicity in comparison to the binary mixture of free drugs.

Hyaluronic acid based micelle for articular delivery of triamcinolone, preparation, in vitro and in vivo evaluation.

A novel triamcinolone loaded polymeric micelle was synthesized based on hyaluronic acid and phospholipid for articular delivery. The newly developed micelle was characterized for physicochemical properties including size, zeta potential, differential scanning calorimetry (DSC) analysis and also morphology by means of transmission electron microscopy. The biocompatibility of micelle was explored by histopathological experiment in rat model. Also biological fate of micelle was investigated in rat by means of real time in vivo imaging system. Triamcinolone loaded micelle was in the size range of 186 nm with negative zeta potential charge. Micelles were spherical in shape with core shell like structure. Triamcinolone was released from micelle during 76 h with almost low burst effect. DSC analysis showed the conversion of crystalline triamcinolone from its crystalline state. Histopathological analysis showed no evidence of tissue damage or phagocytic accumulation in knee joint of rat. The real time in vivo imaging analysis suggested at least three days retention time of micellar system in knee joint post injection.

Comparison of depression, anxiety, stress, and related factors among women and men with human immunodeficiency virus infection.

AIMS: To compare depression, anxiety, stress, and related factors among women and men with human immunodeficiency virus (HIV) infection. SETTINGS AND DESIGN: In this cross-sectional survey conducted between November and September 2013, 200 participants with HIV/acquired immune deficiency syndrome (AIDS) attending Consultation Centers. MATERIALS AND METHODS: Participants with HIV/AIDS were interviewed using the Depression, Anxiety and Stress Scales questionnaire (DASS21 ). RESULTS: There were significant associations between marital status of women and the level of depression (P < 0.05). However, the mean depression and anxiety in women are greater than men (P < 0.05), and the mean stress in men is greater than women (P < 0.05). CONCLUSIONS: HIV infection is related with psychiatric disorders. According to the results, women are more vulnerable to depression and anxiety and they need more care. Management of these psychiatric disorders is very important and requires innovative comprehensive approaches.

Pluronic F127 polymeric micelles for co-delivery of paclitaxel and lapatinib against metastatic breast cancer: preparation, optimization and in vitro evaluation.

The aim of this study was to develop and characterize the paclitaxel (PTX)-lapatinib (LPT) loaded micelles for simultaneous delivery against metastatic breast cancer. Efflux pump-mediated drug resistance influences the efficacy of chemotherapeutic regimens. However, in the newly developed delivery system, LPT was selected to act as chemosensetizer. LPT increases the intracellular level of PTX by inhibition of efflux pumps. Pluronic F127 was selected for the preparation of the micelles, and its critical micelle concentration was determined to be 0.012 mg/ml. D-optimal design was used to analyze the impact of different experimental parameters on PTX and LPT encapsulation ratio. PTX encapsulation ratio was optimized at 68.3%, while LPT encapsulation ratio found to be 70.1%. Transmission electron microscope analyses demonstrate that micelles possess a good core-shell structure without any sharp edge. Laser scattering method results indicated that size of the optimized micelles is 64.81 nm with acceptable polydispersity index (0.309). In vitro release studies showed a sustain release pattern. PTX-LPT-loaded micelles suppressed the proliferation of resistant T-47D cell line (IC50 = 0.6 ± 0.1 µg/ml) compared to binary mixture of PTX and LPT (IC50 = 6.7 ± 1.2 µg/ml). Therefore, it is concluded that the developed formulation might increase the therapeutic efficacy in drug resistant metastatic breast cancer.

Development and Validation of Rapid Stability-Indicating RP-HPLC-DAD Method for the Quantification of Lapatinib and Mass Spectrometry Analysis of Degraded Products.

A rapid, simple and stability-indicating high-performance liquid chromatography assay method was developed and validated for quantitative analysis of lapatinib (LPT) in bulk pharmaceuticals. The newly developed method was assessed using a C18 MZ-Analytical column (5 µm, 150 × 4.6 mm, OSD-3), which was protected by a (5 µm, 4.0 × 4.6 mm, OSD-3) pre-column with mobile phase that was composed of acetonitrile and water (70/30, v/v) and a detection wave length of 227 nm. The method was validated according to the ICH guidelines with respect to precision, accuracy, linearity, robustness, specificity and system suitability. Forced degradation studies were also performed for LPT to determine the stability-indicating aspect of developed method. The method was found to be specific for LPT in the presence of degradation products. The retention time of LPT was ∼4 min. Accuracy of the method was found to be 2.20% bias for all tested samples. The inter- and intra-day precision of the novel method were found to be 2.84 and 2.78%, respectively. The calibration curve was linear over the concentration range of 5-80 µg/mL with a regression coefficient of 0.9990. The limits of detection and quantification were also found to be 1 and 5 µg/mL, respectively. Mass spectrometry analysis was performed in order to better characterize degraded products.

Synthesis and optimization of a novel polymeric micelle based on hyaluronic acid and phospholipids for delivery of paclitaxel, in vitro and in-vivo evaluation.

Novel polymeric micelles were synthesized based on hyaluronic acid (HA) and phospholipids (PEs) including 1,2-dimiristoyl phosphatidylethanolamine (DMPE) and 1,2-distearoyl phosphatidylethanolamine (DSPE). The newly developed micelles evaluated for the physicochemical properties including structural analysis by means of FTIR. Micelles were optimized for delivery of paclitaxel (PTX). The D-optimal design was applied in order to reach micelles with high entrapment efficiency (EE %) and minimum size, simultaneously. In this design the independent variables were the co-polymer type, the drug to polymer ratio and the formulation temperature, whereas the dependent variables were EE% and micelle size. The EE% of the optimized micelles was 46.8% and 59.9% for HA-DMPE and HA-DSPE micelles, respectively. The size of the optimized micelles was in the range of around 250 nm. In vitro release study of the optimized micelles showed that PTX was released from HA-DMPE and HA-DSPE micelles as long as 23 h and 34 h, respectively. Differential scanning calorimetry (DSC) studies showed a conversion of the crystalline PTX molecules into the amorphous form in the micelles. In vivo real time image analysis showed that micellar system was mostly accumulated in the liver, spleen and heart. Accelerated stability studies represented that PTX loaded micelle formulations were stable both physically and chemically at least in 6 months' time.