Optimizing adjuvant inhaled chemotherapy: Synergistic enhancement in paclitaxel cytotoxicity by flubendazole nanocrystals in a cycle model approach.

Lung cancer is the leading cause of cancer-related death. In addition to new innovative approaches, practical strategies that improve the efficacy of already available drugs are urgently needed. In this study, an inhalable dry powder formulation is used to repurpose flubendazole, a poorly soluble anthelmintic drug with potential against a variety of cancer lineages. Flubendazole nanocrystals were obtained through nanoprecipitation, and dry powder was produced by spray drying. Through fractional factorial design, the spray drying parameters were optimized and the impact of formulation on aerolization properties was clarified. The loading limitations were clarified through response surface methodology, and a 15% flubendazole loading was feasible through the addition of 20% L-leucine, leading to a flubendazole particle size of 388.6 nm, median mass aerodynamic diameter of 2.9 µm, 50.3% FPF, emitted dose of 83.2% and triple the initial solubility. Although the cytotoxicity of this formulation in A549 cells was limited, the formulation showed a synergistic effect when associated with paclitaxel, leading to a surprising 1000-fold reduction in the IC50. Compared to 3 cycles of paclitaxel alone, a 3-cycle model combined treatment increased the threshold of cytotoxicity by 25% for the same dose. Our study suggests, for the first time, that orally inhaled flubendazole nanocrystals show high potential as adjuvants to increase cytotoxic agents' potency and reduce adverse effects.

Biphasic dissolution combined with modified cylinder method-A new promising method for dissolution test in drug-loaded nanoemulsions.

Dissolution testing is important in assessing the in vitro drug release performance for oral administration dosage forms. However, currently, a simple and efficient in vitro test to investigate critical factors that may impact the drug release and bioavailability at the development stage of a drug-loaded nanoemulsion (NE) is lacking. Thus, in this study, we developed a new combined biphasic and modified cylinder (BP + MC) method to evaluate the dissolution profile of NEs. Flubendazole (FLZ), a Biopharmaceutical Classification System (BCS) Class II drug, offers a new prospective for drug repositioning for treating lung cancer and cryptococcal meningitis. We compared the drug release profiles of three different FLZ formulations (micronized as a suspension, loaded in NE, and solubilized in oil) by using three different methods (dialysis bag, modified cylinder method, and a new BP + MC method). The results showed potential higher drug release of FLZ from the suspension compared to FLZ-loaded NE at pH 1.2, and higher drug release from FLZ-loaded NE compared to other forms in octanol phase. These results correlate well with the in vivo test performed in mice carried out in our previous works. Furthermore, the partition mechanism of the drug released from the NE is discussed in-depth in this article, as well as the advantage of drug-loaded NEs over other preparations in creating supersaturable conditions. Based on the results, we provide new insights into how dissolution methods for a poorly water-solubility drug can be designed. Therefore, we present this new combined BP + MC method as a potential new discriminative dissolution test for future studies when developing drug-loaded NE and comparing with other dosage forms.

Describing the Influence of Ball-milling on the Amorphization of Flubendazole Using the PDF and RMC Methods with X-ray Powder Diffraction Data.

Flubendazole (FBZ) is a poorly water-soluble drug, and different methodologies have been proposed to improve its oral bioavailability. Obtaining the amorphous drug phase is an alternative to improve its water solubility. Several techniques for drug amorphization, such as spray drying, lyophilization, melt quenching, solvent-evaporation, and ball milling, can yield various types of structural disorder and possibly render variations in physicochemical properties. Herein, we focus on evaluating the influence of the ball-milling process on the amorphization of FBZ. The characterization of the average global and local structures before, during, and after the milling process is described by sequential Rietveld refinements, pair distribution function analysis, and the Reverse Monte Carlo method. We show that preserving the local structure (nearest molecules) can be responsible for avoiding the fast structure recrystallization commonly observed when using the solvent-evaporation process for the studied drug.

Oral administration of buparvaquone nanostructured lipid carrier enables in vivo activity against Leishmania infantum.

Leishmaniasis, a neglected tropical disease, is prevalent in 98 countries with the occurrence of 1.3 million new cases annually. The conventional therapy for visceral leishmaniasis requires hospitalization due to the severe adverse effects of the drugs, which are administered parenterally. Buparvaquone (BPQ) showed in vitro activity against leishmania parasites; nevertheless, it has failed in vivo tests due to its low aqueous solubility. Though, lipid nanoparticles can overcome this holdback. In this study we tested the hypothesis whether BPQ-NLC shows in vivo activity against L. infantum. Two optimized formulations were prepared (V1: 173.9 ± 1.6 nm, 0.5 mg of BPQ/mL; V2: 232.4 ± 1.6 nm, 1.3 mg of BPQ/mL), both showed increased solubility up to 73.00-fold, and dissolution up to 83.29%, while for the free drug it was only 2.89%. Cytotoxicity test showed their biocompatibility (CC50 >554.4 µM). Besides, the V1 dose of 0.3 mg/kg/day for 10 days reduced the parasite burden in 83.4% ±18.2% (p <0.05) in the liver. BPQ-NLC showed similar leishmanicidal activity compared to miltefosine. Therefore, BPQ-NLC is a promising addition to the limited therapeutic arsenal suitable for leishmaniasis oral administration treatment.

Ciprofibrate-Loaded Nanoparticles Prepared by Nanoprecipitation: Synthesis, Characterization, and Drug Release.

Ciprofibrate (CIP) is a highly lipophilic and poorly water-soluble drug, typically used for dyslipidemia treatment. Although it is already commercialized in capsules, no previous studies report its solid-state structure; thus, information about the correlation with its physicochemical properties is lacking. In parallel, recent studies have led to the improvement of drug administration, including encapsulation in polymeric nanoparticles (NPs). Here, we present CIP's crystal structure determined by PXRD data. We also propose an encapsulation method for CIP in micelles produced from Pluronic P123/F127 and PEO-b-PCL, aiming to improve its solubility, hydrophilicity, and delivery. We determined the NPs' physicochemical properties by DLS, SLS, ELS, SAXS and the loaded drug amount by UV-Vis spectroscopy. Micelles showed sizes around 10-20 nm for Pluronic and 35-45 nm for the PEO-b-PCL NPs with slightly negative surface charge and successful CIP loading, especially for the latter; a substantial reduction in ζ-potential may be evidenced. For Pluronic nanoparticles, we scanned different conditions for the CIP loading, and its encapsulation efficiency was reduced while the drug content increased in the nanoprecipitation protocol. We also performed in vitro release experiments; results demonstrate that probe release is driven by Fickian diffusion for the Pluronic NPs and a zero-order model for PEO-b-PCL NPs.

Cancer treatment in the lymphatic system: A prospective targeting employing nanostructured systems.

Cancer related to lymphangiogenesis has gained a great deal of attention in recent decades ever since specific markers of this intriguing system were discovered. Unlike the blood system, the lymphatic system has unique features that can advance cancer in future metastasis, or, conversely, can provide an opportunity to prevent or treat this disease that affects people worldwide. The aim of this review is to show the recent research of cancer treatment associated with the lymphatic system, considered one of the main gateways for disseminating metastatic cells to distant organs. Nanostructured systems based on theranostics and immunotherapies can offer several options for this complex disease. Precision targeting and accumulation of nanomaterials into the tumor sites and their elimination, or targeting the specific immune defense cells to promote optimal regression of cancer cells are highlighted in this paper. Moreover, therapies based on nanostructured systems through lymphatic systems may reduce the side effects and toxicity, avoid first pass hepatic metabolism, and improve patient recovery. We emphasize the general understanding of the association between the immune and lymphatic systems, their interaction with tumor cells, the mechanisms involved and the recent developments in several nanotechnology treatments related to this disease.

Impact of acid straightener's pH value in the hair fiber properties.

BACKGROUND: Acid straightener products are widely used, and it can cause changes in the hair shaft properties. The pH value of these products established by ANVISA (Brazil's National Health Surveillance Agency) as secure is above 2.0. However, the industries are interested in working at lower pH values in order to increase the straightening effect. Unfortunately, there are a lot of products in the market with pH value under the permitted. OBJECTIVE: Analyze two different pH values (1.0 and 2.0) of acid straightener formulation and the influence of this difference in the hair shaft properties. In order to provide information to professionals as cosmetologists, dermatologists, and hairdressers. METHODS: Combing and colorimetric analyses, tensile strength, differential scanning calorimetry (DSC), environmental scanning electron microscope (ESEM), and tryptophan content. RESULTS: The tresses treated at pH 1.0 had a better result in the straightening capacity, improving the combing test in 59.4%, while those at pH 2.0, only in 33.0% compared with virgin hair. However, the tensile strength, at pH 1.0 decreased by 16.0% and 9.0% to the pH 2.0. In addition, the tryptophan content was lower in the tresses treated with formulation at pH 1.0. The DSC analysis showed impairment in the straightened tresses. The images by ESEM, indicated a possible formation of a film around the fiber. CONCLUSIONS: It was possible to conclude that the pH value interferes in the hair shaft properties. Tresses treated with pH 1.0 had more modifications than tresses treated with pH 2.0.

Co-delivery of buparvaquone and polymyxin B in a nanostructured lipid carrier for leishmaniasis treatment.

OBJECTIVES: This study aimed to describe the preparation and in vitro evaluation of a surface-modified nanostructured lipid carrier (NLC) using chitosan and dextran for co-delivery of buparvaquone (BPQ) and polymyxin B (PB) against leishmaniasis. METHODS: The NLC was prepared using high-pressure homogenisation. Polymyxin B binding and surface modification with biopolymers were achieved by electrostatic interaction. In vitro cytotoxicity was assessed in mouse peritoneal macrophages, and leishmanicidal activity in amastigotes of Leishmania infantum. RESULTS: The performance attributes of BPQ-NLC, BPQ-NLC-PB[A-] (anionic) and BPQ-NLC-PB[C+] (cationic) were respectively: Z-average 173.9 ± 1.6, 183.8 ± 4.5 and 208.8 ± 2.6 nm; zeta potential -19.6 ± 1.5, -20.1 ± 1.1 and 31.1 ± 0.8 mV; CC50 583.4 ± 0.10, 203.1 ± 0.04 and 5.7 ± 0.06 µM; IC50 229.0 ± 0.04, 145.7 ± 0.04 and 150.5 ± 0.02 nM. The NLC in vitro leishmanicidal activity showed up to 3.1-fold increase when compared with free BPQ (P < 0.05, α = 0.05). CONCLUSIONS: The developed NLC proved to be a promising formulation with which to overcome the drawbacks of current leishmaniasis treatment by the co-delivery of two alternative drugs and a macrophage targeting modified surface.

Niclosamide repositioning for treating cancer: Challenges and nano-based drug delivery opportunities.

Drug repositioning may be defined as a process when new biological effects for known drugs are identified, leading to recommendations for new therapeutic applications. Niclosamide, present in the Model List of Essential Medicines, from the World Health Organization, has been used since the 1960s for tapeworm infection. Several preclinical studies have been shown its impressive anticancer effects, which led to clinical trials for colon and prostate cancer. Despite high expectations, proof of efficacy and safety are still required, which are associated with diverse biopharmaceutical challenges, such as the physicochemical properties of the drug and its oral absorption, and their relationship with clinical outcomes. Nanostructured systems are innovative drug delivery strategies, which may provide interesting pharmaceutical advantages for this candidate. The aim of this review is to discuss challenges involving niclosamide repositioning for cancer diseases, and the opportunities of therapeutic benefits from nanosctrutured system formulations containing this compound.

A new solvate of afatinib, a specific inhibitor of the ErbB family of tyrosine kinases.

Afatinib (systematic name: N-{4-(3-chloro-4-fluoro-anilino)-7-[(tetra-hydro-furan-3-yl)-oxy]quinazolin-6-yl}-4-(di-methyl-amino)-but-2-enamide), is a specific in-hibitor of the ErbB family of tyrosine kinases. The free base form crystallizes from aceto-nitrile as a mixed water-aceto-nitrile solvent, C24H25ClFN5O3·0.25C2H3N·2H2O. It crystallizes with two independent mol-ecules (A and B) in the asymmetric unit of the chiral space group P4212, but exhibits close to perfect pseudo-inversion symmetry, emulating P4/ncc that relates the two mol-ecules to each other. Exact inversion symmetry is however broken by swapping of oxygen and CH2 moieties of the outer tetra-hydro-furanyl substituents of the two independent mol-ecules. This can, in turn, be traced back to C-H⋯N and C-H⋯O inter-actions of the aceto-nitrile solvent mol-ecules with the tetra-hydro-furan oxygen and CH2 units. In the crystal, neighboring mol-ecules are connected via N-H⋯O hydrogen bonds between the secondary amine and the amide keto O atom. Additional hydrogen bonds are formed through the water solvent mol-ecules, which are engaged in O-H⋯O and O-H⋯N hydrogen bonds connecting to the di-methyl-amino N atom, the amide keto O atom, and one of the quinazoline N atoms of a neighboring mol-ecule, leading to an intricate three-dimensional hydrogen-bonded superstructure. There are two types of channels stretching along the direction of the c axis; one along the fourfold rotational axis, occupied by aceto-nitrile solvent mol-ecules situated on that axis, and parallel channels which are not occupied by any solvent.

Ozone Gas as a Benign Sterilization Treatment for PLGA Nanofiber Scaffolds.

The use of electrospun nanofibers for tissue engineering and regenerative medicine applications is a growing trend as they provide improved support for cell proliferation and survival due, in part, to their morphology mimicking that of the extracellular matrix. Sterilization is a critical step in the fabrication process of implantable biomaterial scaffolds for clinical use, but many of the existing methods used to date can negatively affect scaffold properties and performance. Poly(lactic-co-glycolic acid) (PLGA) has been widely used as a biodegradable polymer for 3D scaffolds and can be significantly affected by current sterilization techniques. The aim of this study was to investigate pulsed ozone gas as an alternative method for sterilizing PLGA nanofibers. The morphology, mechanical properties, physicochemical properties, and response of cells to PLGA nanofiber scaffolds were assessed following different degrees of ozone gas sterilization. This treatment killed Geobacillus stearothermophilus spores, the most common biological indicator used for validation of sterilization processes. In addition, the method preserved all of the characteristics of nonsterilized PLGA nanofibers at all degrees of sterilization tested. These findings suggest that ozone gas can be applied as an alternative method for sterilizing electrospun PLGA nanofiber scaffolds without detrimental effects.