The inhibition of interaction with serum albumin enhances the physiological activity of curcumin by increasing its cellular uptake.

Based on the free drug hypothesis, we hypothesized that food compounds that bind stronger to BSA than CUR inhibit the binding between BSA and CUR, and that this results in...

Co-Delivery of Letrozole and Cyclophosphamide via Folic Acid-Decorated Nanoniosomes for Breast Cancer Therapy: Synergic Effect, Augmentation of Cytotoxicity, and Apoptosis Gene Expression

Breast cancer is one of the most prevalent causes of cancer mortality in women. In order to increase patient prognosis and survival rates, new technologies are urgently required to deliver therapeutics in a more effective and efficient manner. Niosome nanoparticles have been recently employed as therapeutic platforms capable of loading and carrying drugs within their core for both mono and combination therapy. Here, niosome-based nanoscale carriers were investigated as a targeted delivery system for breast cancer therapy. The platform developed consists of niosomes loaded with letrozole and cyclophosphamide (NLC) and surface-functionalized with a folic-acid-targeting moiety (NLCPFA). Drug release from the formulated particles exhibited pH-sensitive properties in which the niosome showed low and high release in physiological and cancerous conditions, respectively. The results revealed a synergic effect in cytotoxicity by co-loading letrozole and cyclophosphamide with an efficacy increment in NLCPFA use in comparison with NLC. The NLCPFA resulted in the greatest drug internalization compared to the non-targeted formulation and the free drug. Additionally, downregulation of cyclin-D, cyclin-E, MMP-2, and MMP-9 and upregulating the expression of caspase-3 and caspase-9 genes were observed more prominently in the nanoformulation (particularly for NLCPFA) compared to the free drug. This exciting data indicated that niosome-based nanocarriers containing letrozole and cyclophosphamide with controlled release could be a promising platform for drug delivery with potential in breast cancer therapy.

Bacteriomimetic Liposomes Improve Antibiotic Activity of a Novel Energy-Coupling Factor Transporter Inhibitor

Liposomes have been studied for decades as nanoparticulate drug delivery systems for cytostatics, and more recently, for antibiotics. Such nanoantibiotics show improved antibacterial efficacy compared to the free drug and can be effective despite bacterial recalcitrance. In this work, we present a loading method of bacteriomimetic liposomes for a novel, hydrophobic compound (HIPS5031) inhibiting energy-coupling factor transporters (ECF transporters), an underexplored antimicrobial target. The liposomes were composed of DOPG (18:1 (Δ9-cis) phosphatidylglycerol) and CL (cardiolipin), resembling the cell membrane of Gram-positive Staphylococcus aureus and Streptococcus pneumoniae, and enriched with cholesterol (Chol). The size and polydispersity of the DOPG/CL/± Chol liposomes remained stable over 8 weeks when stored at 4 °C. Loading of the ECF transporter inhibitor was achieved by thin film hydration and led to a high encapsulation efficiency of 33.19% ± 9.5% into the DOPG/CL/Chol liposomes compared to the phosphatidylcholine liposomes (DMPC/DPPC). Bacterial growth inhibition assays on the model organism Bacillus subtilis revealed liposomal HIPS5031 as superior to the free drug, showing a 3.5-fold reduction in CFU/mL at a concentration of 9.64 µM. Liposomal HIPS5031 was also shown to reduce B. subtilis biofilm. Our findings present an explorative basis for bacteriomimetic liposomes as a strategy against drug-resistant pathogens by surpassing the drug-formulation barriers of innovative, yet unfavorably hydrophobic, antibiotics.

Design and Optimization of Cationic Nanocapsules for Topical Delivery of Tretinoin: Application of the Box-Behnken Design, In Vitro Evaluation, and Ex Vivo Skin Deposition Study

Cationic nanocapsules represent a promising approach for topical delivery purposes. We elaborated on a novel formulation based on the cationic nanocapsules to enhance the pharmacodynamic efficacy, user compliance, and photostability of tretinoin (TTN). To achieve this goal, TTN nanocapsules were prepared by the nanoprecipitation method. In order to statistically optimize formulation variables, a Box-Behnken design, using Design-Expert software, was employed. Three independent variables were evaluated: total weight of the cationic acrylic polymer ( X 1 ), oil volume ( X 2 ), and TTN amount ( X 3 ). The particle size and encapsulation efficiency percent (EE%) were selected as dependent variables. The optimal formulation demonstrated spherical morphology under scanning electron microscopy (SEM), optimum particle size of 116.3 nm, and high EE% of 83.2%. TTN-loaded nanocapsules improved photostability compared to its methanolic solution. The in vitro release study data showed that tretinoin was released in a sustained manner compared to the free drug. The ex vivo skin permeation study demonstrated that greater drug deposition into the epidermal region rather than the deep skin was observed with a gel containing TTN-loaded nanocapsules than that of drug solution, respectively. The skin irritation test revealed that the nanoencapsulation of the drug decreased its irritancy compared to the free drug. These results revealed the promising potential of cationic nanocapsules for topical delivery of tretinoin

Combined Hemoperfusion and Continuous Veno-Venous Hemofiltration for Carbamazepine Intoxication

<b><i>Introduction:</i></b> Carbamazepine (CBZ) is a widely used anticonvulsant with a low molecular weight that allows for extracorporeal removal of free drug by both dialytic and hemoperfusion techniques, particularly in a massive overdose where serum protein binding is saturated. This report presents a case of CBZ intoxication where we were able to compare the mass removal of CBZ using hemoperfusion, with the mass removal of CBZ achieved with continuous renal replacement therapy (CRRT) during combined treatment. <b><i>Methods:</i></b> The Jafron HA230 resin hemoperfusion cartridge was applied in series with the continuous veno-venous hemofiltration (CVVH) circuit. Baseline and ongoing serum drug levels along with further samples from pre- and post-hemoperfusion cartridges and from CVVH effluent were collected. <b><i>Results:</i></b> Combined CVVH and resin hemoperfusion therapy in series was associated with a 50% reduction in the CBZ level from 16 mg/L to 8 mg/L over 3 h, far more rapid than that observed with CVVH alone or in the absence of extracorporeal drug clearance in the preceding hours. The combination therapy removed close to 35 mg/h of CBZ. <b><i>Conclusion:</i></b> The combination of CRRT and hemoperfusion can be easily deployed, appears safe, and is able to combine the CBZ mass removal achieved with each technique, thus to maximize CBZ extraction.

Inhibition of Neovascularization and Inflammation in a Mouse Model of Corneal Alkali Burns Using Cationic Liposomal Tacrolimus

Eye drops account for more than 90% of commercialized ophthalmic drugs. However, eye drops have certain shortcomings, such as short precorneal retention time and weak corneal penetration. The requirement of frequent instillation of eye drops also causes poor patient compliance, which may lead to further aggravation of the disease. We aimed to develop a cationic liposome formulation to increase the bioavailability of the therapeutic agent and solve the aforementioned problems. In the present study, we prepared cationic liposomal tacrolimus (FK506) with a surface potential of approximately +30 mV, which could bind to the negatively charged mucin layer of the ocular surface. Our results showed that the content of FK506 in the cornea was increased by 93.77, 120.30, 14.24, and 20.36 times at 5, 30, 60, and 90 min, respectively, in the FK506 liposome group (0.2 mg/ml) compared with the free drug group (0.2 mg/ml). Moreover, FITC-labeled FK506 liposomes significantly prolonged the ocular surface retention time to 50 min after a single dose. In addition, the results of the Cell Counting Kit-8 assay, live and dead cell assay, sodium fluorescein staining, and hematoxylin and eosin staining all indicated that FK506 liposomes had good biological compatibility in both human corneal epithelial cells and mouse eyeballs. Compared with the free drug at the same concentration, FK506 liposomes effectively inhibited vascular endothelial growth factor-induced green fluorescent protein-transduced human umbilical vein endothelial cell migration and tube formation in vitro. In a mouse corneal neovascularization model induced by alkali burns, FK506 liposomes (0.2 mg/ml) enhanced corneal epithelial recovery, inhibited corneal neovascularization, and reduced corneal inflammation, and its therapeutic effect was better than those of the commercial FK506 eye drops (1 mg/ml) and the free drug (0.2 mg/ml). Collectively, these results indicate that cationic FK506 liposomes could increase the efficacy of FK506 in the corneal neovascularization model. Therefore, cationic FK506 liposomes can be considered as a promising ocular drug delivery system.

Liposomes as Vancomycin Hydrochloride Delivery System

Liposomes are being used as unique drug delivery systems due to their ability to encapsulate both hydrophilic and hydrophobic drugs, as well as for the fact that they improve the disadvantages of free drug administration. However, liposomes have a significant disadvantage - low encapsulation efficiency. In the research carried out, 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC) and cholesterol (Chol), in the ratio (n/n) of 2:1, 3:1 and 4:1 respectively, were used to prepare the liposomes. Blank liposomes (LIP) and vancomycin hydrochloride (VANKA) containing liposomes (VANKA-LIP) were prepared for each of the DSPC and Chol compositions. The aim of our study was to evaluate the effect of liposome composition on the VANKA encapsulation efficiency and release kinetics.

CPX-351, a Dual-Drug Liposomal Formulation, Alleviates the Cardiotoxicity of Daunorubicin and Cytarabine to Induced Human Pluripotent Stem Cell-Derived Cardiomyocytes

Introduction: CPX-351 (US: Vyxeos ®; EU: Vyxeos ® Liposomal), a dual-drug liposomal encapsulation of daunorubicin + cytarabine at a synergistic 1:5 molar ratio, is a standard of care for therapy-related acute myeloid leukemia (AML) or AML with myelodysplastic-related changes. Daunorubicin, an anthracycline, is a known cardiotoxicant. While liposomal formulations have shown promise in mitigating these effects (O'Brien, et al. Ann Oncol 2004), this potential advantage is difficult to assess clinically due to numerous confounding factors. Here, we sought to develop and employ an in vitro model to study the relative toxicity of CPX-351 versus free daunorubicin + cytarabine applied as a combination at the same concentrations. Model development: The hiPSC-derived cardiomyocytes used in this study were derived from fibroblasts obtained from a single adult Caucasian female donor with no known diseases, induced into a pluripotent state, and then reprogrammed into cardiomyocytes (CDI Datasheet 2018). They present many of the characteristics of healthy human cardiac muscle cells, including gene and protein expression and rhythmic beating. During model development, the prototypical compounds doxorubicin and liposomal doxorubicin were used as proof-of-concept to establish the translational value of the model because clinical data regarding their relative cardiotoxicity were available (O'Brien, et al. Ann Oncol 2004). The model recapitulated the cumulative toxicity of free doxorubicin and differentiated between liposomal and free drug. The in vitro model was then applied to compare the relative cardiotoxicity of CPX-351 versus the combination of free daunorubicin + cytarabine (1:5), which were applied to the cardiomyocytes for 24 hours on Days 1, 3, and 5 at concentrations ranging from 0 to 1,000 ng/mL daunorubicin (0 to 2,273 ng/mL cytarabine). Bright-field microscopy imaging, lactate dehydrogenase (LDH) release (reflects cell membrane integrity), ATP content (indicates metabolic activity), cell beat rate (indicates cardiomyocyte function), and cardiac biomarkers (FABP3, cardiac troponin I, NT-proBNP, and BNP) were evaluated on Days 2, 4, 6, and 8. Results: Qualitative review of the microscopic images suggested single dose- and cumulative dose-dependent cytotoxicity of free daunorubicin + cytarabine, especially at the highest doses on Day 8. These observations were confirmed by dose-dependent increases in single-day or cumulative LDH activity in the cell media and decreases in ATP content starting on Day 4. Specifically, after a single 24-hour exposure, LDH activity (a measure of plasma membrane damage) was comparable to that of saline-treated cardiomyocytes for both the free-drug combination and CPX-351. However, after repeated exposure to the free-drug combination, increasing drug concentration was associated with increasing LDH activity in the media, peaking at levels ~12 times the saline control on Day 8. In contrast, the LDH activity following repeated equivalent doses of CPX-351 was only ~3 times the saline control. Conversely, ATP content (a measure of cellular metabolic fitness) gradually decreased between Day 2 and Day 8. The ATP depletion (Day 8 vs Day 2) was more profound in cardiomyocytes exposed to the free-drug combination (−98.1%) than in those exposed to equivalent concentrations of CPX-351 (−38.5%). Following repeated exposure to the free-drug combination, the cell beat rate demonstrated a biphasic response consisting of an initial increase followed by a significant slowing and sometimes arrest of beating, demonstrating significant injury; this effect was not observed following repeated exposure to CPX-351. Finally, the cardiac biomarkers FABP3 and cardiac troponin I were significantly released from cardiomyocytes exposed to the free-drug combination, but not from those exposed to CPX-351, even after 3 repeated exposures. Conclusions: Overall, at equivalent concentrations administered on the same schedule, CPX-351 was considerably less toxic to hiPSC-derived cardiomyocytes than the free-drug combination of daunorubicin + cytarabine, as measured by viability (imaging, LDH release), metabolic health (ATP content), function (beating rate), and the cardiac biomarkers FABP3 and cardiac troponin I. Clinical data are needed to confirm the reduced cardiotoxicity observed with CPX-351 versus free drugs in this in vitro model. Disclosures Fortin: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. LaCroix: StemoniX: Current Employment; Jazz Pharmaceuticals: Consultancy. Wang: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cheung: Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.