Preparation and in vitro characterization of 9-nitrocamptothecin-loaded long circulating nanoparticles for delivery in cancer patients

The purpose in this study was to investigate poly(ethylene glycol)-modified poly (d,l-lactide-co-glycolide) nanoparticles (PLGA-PEG-NPs) loading 9-nitrocamptothecin (9-NC) as a potent anticancer drug. 9-NC is an analog of the natural plant alkaloid camptothecin that has shown high antitumor activity and is currently in the end stage of clinical trial. Unfortunately, at physiological pH, these potent agents undergo a rapid and reversible hydrolysis with the loss of antitumor activity. Previous researchers have shown that the encapsulation of this drug in PLGA nanoparticles could increase its stability and release profile. In this research we investigated PLGA-PEG nanoparticles and their effect on in vitro characteristics of this labile drug. 9-NC-PLGA-PEG nanoparticles with particle size within the range of 148.5 ± 30 nm were prepared by a nanoprecipitation method. The influence of four different independent variables (amount of polymer, percent of emulsifier, internal phase volume, and external phase volume) on nanoparticle drug-loading was studied. Differential scanning calorimetry and X-ray diffractometry were also evaluated for physical characterizing. The results of optimized formulation showed a narrow size distribution, suitable zeta potential (+1.84), and a drug loading of more than 45%. The in vitro drug release from PLGA-PEG NPs showed a sustained release pattern of up to 120 hours and comparing with PLGA-NPs had a significant decrease in initial burst effect. These experimental results indicate that PLGA-PEG-NPs (versus PLGA-NPs) have a better physicochemical characterization and can be developed as a drug carrier in order to treat different malignancies

Tacrolimus phospholipid based nanomicelles as a potential local delivery system for corneal neovascularization therapy

Introduction: Tacrolimus, an immunosuppressive agent, has been shown to be an effective treatment against corneal neovascularization (CNV). However, the poor solubility of this compound restricts its clinical application. The goal of this study was to incorporate tacrolimus into phospholipid-bile salt mixed micelles. Methods and Results: Tacrolimus loaded phospholipid-bile salt mixed micelles were prepared, employing three different methods of direct dispersion, thin film hydration, and remote film loading, and the effects of various formulation parameters (type of dispersion medium, phospholipid to bile salt molar ratio, lipid-to-drug (L/D) molar ratio, time of probe sonication, and type of bile salt) on the physicochemical characteristics of the mixed micelles were assessed. Remote film loading method indicated higher efficacy for drug entrapment in comparison to the other methods. Encapsulation of tacrolimus within the micelles increased remarkably by the use of sodium taurocholate (NaTC) as bile salt, higher phospholipid percentage, and increasing the total lipid level. Atomic force microscopy (AFM) studies confirmed the size and size distribution of the mixed micelles and their spherical morphology. It was observed that release of tacrolimus from the micelles was in a controlled manner, without an initial burst. Conclusions: By adjusting process and formulation factors, phospholipid-bile salt mixed micelles with high entrapment efficiency of (99.5 %) and controlled release behavior were achieved, which possess great potential to be valuable carriers for ocular delivery of tacrolimus for the treatment of CNV.                                                                                                                                       &nbsp

Preparation and Optimization of Vancomycin hydrochloride Encapsulated Multivesicular Liposomes for Sustained Locoregional Delivery

Introduction: Osteomyelitis is a destructive inflammatory condition of the bone that is usually caused by a wide range of microorganisms especially Staphylococcus aureus. Considering the downsides of systemic antibiotic therapies as well as conventional local drug delivery systems such as using polymethylmethacrylate, this study aimed to develop, characterize and optimize vancomycin hydrochloride loaded multivesicular liposomes (MVLs) as a proper therapeutic option for the treatment of osteomyelitis. Methods and Results: A 23 full factorial design technique was applied to determine the effects of three variables (lipid to drug ratio, triolein content and cholesterol to phospholipid ratio) on the encapsulation efficiency and release profile of vancomycin hydrochloride loaded MVLs to optimize the final formulation. Further characterization was performed on the optimized formula by evaluating the morphology, size and storage stability. The average drug encapsulation efficiency and the mean diameter of the optimized formulation was 54.7 ± 0.3% and 9.019 ± 0.26 µm, respectively with a span value of 0.188. Additionally, the spherical and multivesicular nature of MVLs was visible using optical microscopy (x400). The optimized formula showed an in vitro sustained release characteristic with proper stability and insignificant change in size, morphology and EE% for 30 days at 4°C. Conclusion: This study suggests that vancomycin hydrochloride loaded MVLs might have the potential to be used in the treatment of chronic osteomyelitis as a biocompatible drug carrier with a high antibiotic entrapment capacity as well as controlled drug release

A 16 Month Survey of Cyclosporine Utilization Evaluation in Allogeneic Hematopoietic Stem Cell Transplant Recipients

Abstract Objectives: Graft versus host disease (GVHD) is a life threatening reaction in the stem cell transplantation process. Nowadays Cyclosporine is the most commonly utilized agent for GVHD prophylaxis and it has a major role in successful transplantation. Cyclosporine has been applied for many years in this field but it could be stated that currently no general consensus is available for its optimal method of administration. Conditions related to cyclosporine administration and possible related adverse reactions observed closely in our patients with the aim of constructing a comprehensive practice guideline in the future. Patients and Methods: Allogeneic stem cell transplant recipients who have been taking cyclosporine were monitored during and after their hospitalization while recording all observations on predefined questionnaires on the basis of periodic clinical and laboratory examinations for a 16 month period. Results: Mean recorded duration of infusions was 1.44 ± 0.68 h and by twice daily administration, means intravenous and oral dose was 101.85 ± 22.03 mg and 219.28 ± 63.9 mg, respectively. A mean CsA trough level after about 12 h of specified unique doses was 223 ± 65 ng/mL. We found hypertension, nephrotoxicity, neurotoxicity, hypertension, and dyslipidemia in about 14, 20, 48, and 94 percent of patients. Conclusions: This study proposed that permanent guidance of healthcare team according to a fixed and standard method of cyclosporine administration routine with using efficient facilities and protocols would be helpful considerably for an optimal pharmacotherapy

Sirolimus-exuding core-shell nanofibers as an implantable carrier for breast cancer therapy: preparation, characterization, in vitro cell studies, and in vivo anti-tumor activity

OBJECTIVE: Breast cancer accounts for significant mortality worldwide. Here, we develop a localized, sustained-release delivery system for breast cancer therapy. METHODS: Sirolimus (SIR) core-shell nanofibers (NFs) are fabricated by coaxial electrospinning with poly(ε-caprolactone) (PCL) for the core and chitosan and PCL for the shell. The NFs were characterized by SEM, AFM, TEM, XRD, FTIR, water uptake, water contact angle, mechanical properties, drug content, and in vitro release. In vitro and in vivo anticancer effects were investigated. RESULTS: A sustained release behavior is observed during 480 h that is more extended compared to monoaxial NFs. In vitro cytotoxicity and Annexin V/propidium iodide assays indicate that SIR-loaded coaxial NFs are effective in inhibiting proliferation of 4T1 and MCF-7 cells. Implantation of SIR NFs in 4T1 breast tumor-bearing mice inhibits tumor growth significantly compared to free drug. Histopathological examination shows that suppression of tumor growth by SIR NFs is associated with apoptotic cell death. Furthermore, anti-cancer effects are also confirmed by decreased expression levels of Ki-67, MMP-2, and MMP-9. Histological observation of organs, serological analyses, and the lack of body weight changes indicate in vivo safety of SIR NFs. CONCLUSIONS: Altogether, we show here that incorporation of SIR into core-shell NFs could act as an effective drug release depot and induce a sustained antitumor response

Molecular docking, molecular dynamics simulation, preparation, and characterization of naltrexone-phospholipid complex: A novel cargo with improved loading into multivesicular liposomes

Naltrexone hydrochloride (NTX), a water-soluble opioid receptor antagonist, is prescribed widely for opioid and alcohol dependence and pain reduction. However, the significant limitations of NTX are low lipophilicity and extensive first-pass metabolism. This study aimed to design and prepare a novel phospholipid complex of NTX and load it into multivesicular liposomes (MVLs). In silico studies, including molecular docking and molecular dynamics (MD) simulation, were performed to determine the interactions between NTX and phospholipid and evaluate their best molar ratio to prepare the complex, respectively. The NTX phospholipid complex was prepared by solvent evaporation technique and characterized by PXRD, SEM, FTIR, 1HNMR, solubility study, and n-octanol/water partition coefficient analyses. NTX-SPC complex-loaded MVLs (NTX-SPC-MVLs) were prepared by the double-emulsion method and characterized by encapsulation efficiency (EE)%, size, PXRD, FTIR, SEM, and release pattern. MD simulation reported the 1:1.5 M ratio of NTX to phospholipid as the best molar ratio. Complexation led to reduced water solubility and enhanced n-octanol/water partition coefficient. Loading of NTX-SPC complex into MVLs enhanced EE and extended the release duration in comparison to NTX MVLs. Thus, the NTX-SPC complex may be an appropriate system to enhance the physicochemical features of NTX and improve the EE in vesicular drug delivery systems like MVLs

Piperine-loaded electrospun nanofibers, an implantable anticancer controlled delivery system for postsurgical breast cancer treatment

Tumorectomy followed by radiotherapy, hormone, and chemotherapy, are the current mainstays for breast cancer treatment. However, these strategies have systemic toxicities and limited treatment outcomes. Hence, there is a crucial need for a novel controlled release delivery system for implantation following tumor resection to effectively prevent recurrence. Here, we fabricated polycaprolactone (PCL)-based electrospun nanofibers containing piperine (PIP), known for chemopreventive and anticancer activities, and also evaluated the impact of collagen (Coll) incorporation into the matrices. In addition to physicochemical characterization such as morphology, hydrophilicity, drug content, release properties, and mechanical behaviors, fabricated nanofibers were investigated in terms of cytotoxicity and involved mechanisms in MCF-7 and 4T1 breast tumor cell lines. In vivo antitumor study was performed in 4T1 tumor-bearing mice. PIP-PCL75-Coll25 nanofiber was chosen as the optimum formulation due to sustained PIP release, good mechanical performance, and superior cytotoxicity. Demonstrating no organ toxicity, animal studies confirmed the superiority of locally administered PIP-PCL75-Coll25 nanofiber in terms of inhibition of growth tumor, induction of apoptosis, and reduction of cell proliferation compared to PIP suspension, blank nanofiber, and the control. Taken together, we concluded that PIP-loaded nanofibers can be introduced as a promising treatment for implantation upon breast tumorectomy