Pharmaceutics, Volume 12, Issue 11 (November 2020) – 130 articles

This work presents the development of multifunctional therapeutic membranes based on a high-performance block copolymer scaffold formed by polyether (PE) and polyamide (PA) units (known as PEBA) and layered double hydroxide (LDH) biomaterials, with the aim to study their uses as wound dressings. Two LDH layer compositions were employed containing Mg²⁺ or Zn²⁺, Fe³⁺ and Al³⁺ cations, intercalated with chloride anions, abbreviated as Mg-Cl or Zn-Cl, or intercalated with naproxenate (NAP) anions, abbreviated as Mg-NAP or Zn-NAP. Membranes were structurally and physically characterized, and the in vitro drug release kinetics and cytotoxicity assessed. PEBA-loading NaNAP salt particles were also prepared for comparison. Intercalated NAP anions improved LDH–polymer interaction, resulting in membranes with greater mechanical performance compared to the polymer only or to the membranes containing the Cl-LDHs. Drug release (in saline solution) was sustained for at least 8 h for all samples and release kinetics could be modulated: a slower, an intermediate and a faster NAP release were observed from membranes containing Zn-NAP, NaNAP and Mg-NAP particles, respectively. In general, cell viability was higher in the presence of Mg-LDH and the membranes presented improved performance in comparison with the powdered samples. PEBA containing Mg-NAP sample stood out among all membranes in all the evaluated aspects, thus being considered a great candidate for application as multifunctional therapeutic dressings. Full article

The compound 1α,25-Dihydroxyvitamin D₃ (1,25(OH)₂D₃) is the active form of vitamin D₃ and a representative ligand of the vitamin D receptor (VDR). Previous studies have described the impacts of 1,25(OH)₂D₃ on a small number of cytochrome P450 (CYP) and uridine diphosphate-glucuronyltransferase (UGT) enzymes, but comparatively little is known about interactions between several important CYP and UGT isoforms and 1,25(OH)₂D₃ in vitro and/or in vivo. Thus, we investigated the effects of 1,25(OH)₂D₃ on the gene and protein expressions and functional activities of selected CYPs and UGTs and their impacts on drug pharmacokinetics in rats. The mRNA/protein expressions of Cyp2b1 and Cyp2c11 were downregulated in rat liver by 1,25(OH)₂D₃. Consistently, the in vitro metabolic kinetics (V_max and CL_int) of BUP (bupropion; a Cyp2b1 substrate) and TOL (tolbutamide; a Cyp2c11 substrate) were significantly changed by 1,25(OH)₂D₃ treatment in liver microsomes, but the kinetics of acetaminophen (an Ugt1a6/1a7/1a8 substrate) remained unaffected, consistent with Western blotting data for Ugt1a6. In rat pharmacokinetic studies, the total body clearance (CL) and nonrenal clearance (CL_NR) of BUP were significantly reduced by 1,25(OH)₂D₃, but unexpectedly, the total area under the plasma concentration versus time curve from time zero to infinity (AUC) of hydroxybupropion (HBUP) was increased probably due to a marked reduction in the renal clearance (CL_R) of HBUP. Additionally, the AUC, CL, and CL_NR for TOL and the AUC for 4-hydroxytolbutamide (HTOL) were unaffected by 1,25(OH)₂D₃ in vivo. Discrepancies between observed in vitro metabolic activity and in vivo pharmacokinetics of TOL were possibly due to a greater apparent distribution volume at the steady-state (V_ss) and lower plasma protein binding in 1,25(OH)₂D₃-treated rats. Our results suggest possible drug-drug and drug-nutrient interactions and provide additional information concerning safe drug combinations and dosing regimens for patients taking VDR ligand drugs including 1,25(OH)₂D₃. Full article

Recent findings indicate that (a) mitochondria in proliferating cancer cells are functional, (b) cancer cells use more oxygen than normal cells for oxidative phosphorylation, and (c) cancer cells critically rely on cytosolic NADH transported into mitochondria via the malate-aspartate shuttle (MAS) for ATP production. In a spontaneous lung cancer model, tumor growth was reduced by 50% in heterozygous oxoglutarate carrier (OGC) knock-out mice compared with wild-type counterparts. To determine the mechanism through which OGC promotes tumor growth, the effects of the OGC inhibitor N-phenylmaleimide (NPM) on mitochondrial activity, oxygen consumption, and ATP production were evaluated in melanoma cell lines. NPM suppressed oxygen consumption and decreased ATP production in melanoma cells in a dose-dependent manner. NPM also reduced the proliferation of melanoma cells. To test the effects of NPM on tumor growth and metastasis in vivo, NPM was administered in a human melanoma xenograft model. NPM reduced tumor growth by approximately 50% and reduced melanoma invasion by 70% at a dose of 20 mg/kg. Therefore, blocking OGC activity may be a useful approach for cancer therapy. Full article

The topical administration of active compounds represents an advantageous strategy to reach the various skin components as well as its appendages. Pilosebaceous follicles are skin appendages originating in the deeper skin layers. They are very difficult to target, and hence higher active dosages are generally required to achieve effective biological responses, thus favoring the rise of side effects. The aim of this work was to design a supramolecular colloidal carrier, i.e., a liquid crystal nanocarrier, for the selective delivery of active compounds into the pilosebaceous follicle. This nanocarrier showed mean sizes of ~80 nm, a good stability, a negative surface charge, and great safety properties. In vitro studies highlighted its ability to contain and release different substances and to successfully permeate the skin. Minoxidil was encapsulated in the nanocarriers and the in vivo biological effect was compared with a conventional dosage form. Minoxidil-loaded liquid crystal nanocarrier was able to selectively reach the pilosebaceous follicle, thus allowing an increased biological effectiveness of the delivered active in terms of biological response, duration of the biological effects, and reduction of collaterals. Our investigation showed that liquid crystal nanocarriers represent a promising device for the treatment of different pilosebaceous follicular impairments/diseases. Full article

In recent times, many approaches have been developed against drug resistant Gram-negative bacteria. However, low-cost high effective materials which could broaden the spectrum of antibiotics are still needed. In this study, enhancement of linezolid spectrum, normally active against Gram-positive bacteria, was aimed for Gram-negative bacteria growth inhibition. For this purpose, a silica xerogel prepared from a low-cost precursor is used as a drug carrier owing to the advantages of its mesoporous structure, suitable pore and particle size and ultralow density. The silica xerogel is loaded with linezolid and capped with ε-poly-l-lysine. The developed nano-formulation shows a marked antibacterial activity against to Escherichia coli, Pseudomonas aeruginosa and Staphylococcus aureus. In comparison to free linezolid and ε-poly-l-lysine, the material demonstrates a synergistic effect on killing for the three tested bacteria. The results show that silica xerogels can be used as a potential drug carrier and activity enhancer. This strategy could provide the improvement of antibacterial activity spectrum of antibacterial agents like linezolid and could represent a powerful alternative to overcome antibiotic resistance in a near future. Full article

The blood-brain barrier is the primary obstacle to efficient intracerebral drug delivery. Focused ultrasound, in conjunction with microbubbles, is a targeted and non-invasive way to disrupt the blood-brain barrier. Many commercially available ultrasound contrast agents and agents specifically designed for therapeutic purposes have been investigated in ultrasound-mediated blood-brain barrier opening studies. The new generation of sono-sensitive agents, such as liquid-core droplets, can also potentially disrupt the blood-brain barrier after their ultrasound-induced vaporization. In this review, we describe the different compositions of agents used for ultrasound-mediated blood-brain barrier opening in recent studies, and we discuss the challenges of the past five years related to the optimal formulation of agents. Full article

Sildenafil citrate is a drug used throughout the world primarily to treat erectile dysfunction. Several problems with the commercially available product decrease its efficacy, such as limited solubility, delayed onset of action, and low bioavailability with a large variability in the absorption profile. This study aimed to develop an optimized self-nanoemulsifying lyophilized tablet for the drug to conquer the foresaid problems. Sildenafil solubility in various surfactants, oils, and cosurfactants was attempted. An optimized formulation of a loaded self-nanoemulsion with a small droplet size was developed by applying a special cubic model of the mixture design. Sixteen formulations were prepared and characterized for droplet size. On the basis of solubility studies, a clove oil/oleic acid mixture, polysorbate 20 (Tween 20), and propylene glycol were selected as the proposed oil, surfactant, and cosurfactant, respectively. On the basis of desirability, an optimized sildenafil citrate-loaded self-nanoemulsifying delivery system containing 10% of the oil mixture, 60% of the surfactant, and 30% of the cosurfactant had a droplet size of 65 nm. Subsequently, the tablet form was fabricated with optimum ratios of 0.4% fumed silica, 0.1% hydroxypropyl methylcellulose, and 0.4% sodium starch glycolate. This formula showed satisfactory results in both disintegration and dissolution studies. In vivo pharmacokinetic studies indicated a higher bioavailability (1.44 times) and rapid absorption profile for the study’s tablets compared with commercially available tablets. In conclusion, highly bioavailable oral lyophilized flash tablets of sildenafil were successfully prepared. They will be a good alternative to the conventional solid-dosage form. Full article

The distribution of drugs and dietary phenolic compounds in the systemic circulation de-pends on, among other factors, unspecific/specific reversible binding to plasma proteins such as human serum albumin (HSA). Phenolic substances, present in plant-derived feeds, foods, beverages, herbal medicines, and dietary supplements, are of great interest due to their biological activity. Recently, considerable research has been directed at the formation of phenol–HSA complexes, focusing above all on structure–affinity relationships. The nucleophilicity and planarity of molecules can be altered by the number and position of hydroxyl groups on the aromatic ring and by hydrogenation. Binding affinities towards HSA may also differ between phenolic compounds in their native form and conjugates derived from phase II reactions. On the other hand, food–drug interactions may increase the concentration of free drugs in the blood, affecting their transport and/or disposition and in some cases provoking adverse or toxic effects. This is caused mainly by a decrease in drug binding affinities for HSA in the presence of flavonoids. Accordingly, to avoid the side effects arising from changes in plasma protein binding, the intake of flavonoid-rich food and beverages should be taken into consideration when treating certain pathologies. Full article

Cardiovascular disease (CVD) represents a major threat for human health. The available preventive and treatment interventions are insufficient to revert the underlying pathological processes, which underscores the urgency of alternative approaches. Mitochondria dysfunction plays a key role in the etiopathogenesis of CVD and is regarded as an intriguing target for the development of innovative therapies. Oxidative stress, mitochondrial permeability transition pore opening, and excessive fission are major noxious pathways amenable to drug therapy. Thanks to the advancements of nanotechnology research, several mitochondria-targeted drug delivery systems (DDS) have been optimized with improved pharmacokinetic and biocompatibility, and lower toxicity and antigenicity for application in the cardiovascular field. This review summarizes the recent progress and remaining obstacles in targeting mitochondria as a novel therapeutic option for CVD. The advantages of nanoparticle delivery over un-targeted strategies are also discussed. Full article

Therapeutic deep eutectic systems (THEDES) have dramatically expanded their popularity in the pharmaceutical field due to their ability to increase active pharmaceutical ingredients (APIs) bioavailability. However, their biological performance has not yet been carefully scrutinized. Herein, THEDES based on the binary mixture of perillyl alcohol (POH) and ibuprofen (IBU) were prepared using different molar ratios. Our comprehensive strategy includes the characterization of their thermal and structural behavior to identify the molar ratios that successfully form deep eutectic systems. The in vitro solubility of the different systems prepared has demonstrated that, unlike other reported examples, the presence of the terpene did not affect the solubility of the anti-inflammatory agent in a physiological simulated media. The biological performance of the systems was studied in terms of their antimicrobial activity against a wide panel of microorganisms. The examined THEDES showed relevant antimicrobial activity against all tested microbial strains, with the exception of P. aeruginosa. A synergistic effect from the combination of POH and IBU as a eutectic system was verified. Furthermore, the cytotoxic profile of these eutectic systems towards colorectal cancer (CRC) in vitro cell models was also evaluated. The results provide the indication that the cell viability varies in a dose-dependent manner, with a selective THEDES action towards CRC cells. With tunable bioactivities in a ratio-dependent manner, THEDES enhanced the antimicrobial and anticancer properties, representing a possible alternative to conventional therapies. Therefore, this study provides foreseeable indications about the utility of THEDES based on POH and IBU as strong candidates for novel active pharmaceutical systems. Full article

This review highlights the pre-clinical and clinical work performed to use intranasal delivery of various compounds from growth factors to stem cells to reduce neuroimmune interactions. We introduce the concept of intranasal (IN) delivery and the variations of this delivery method based on the model used (i.e., rodents, non-human primates, and humans). We summarize the literature available on IN delivery of growth factors, vitamins and metabolites, cytokines, immunosuppressants, exosomes, and lastly stem cells. We focus on the improvement of neuroimmune interactions, such as the activation of resident central nervous system (CNS) immune cells, expression or release of cytokines, and detrimental effects of signaling processes. We highlight common diseases that are linked to dysregulations in neuroimmune interactions, such as Alzheimer’s disease, Parkinson’s disease, stroke, multiple sclerosis, and traumatic brain injury. Full article

The present paper reports a thorough continuous powder blending process design of acetylsalicylic acid (ASA) and microcrystalline cellulose (MCC) based on the Process Analytical Technology (PAT) guideline. A NIR-based method was applied using multivariate data analysis to achieve in-line process monitoring. The process dynamics were described with residence time distribution (RTD) models to achieve deep process understanding. The RTD was determined using the active pharmaceutical ingredient (API) as a tracer with multiple designs of experiment (DoE) studies to determine the effect of critical process parameters (CPPs) on the process dynamics. To achieve quality control through material diversion from feeding data, soft sensor-based process control tools were designed using the RTD model. The operation block model of the system was designed to select feasible experimental setups using the RTD model, and feeder characterizations as digital twins, therefore visualizing the output of theoretical setups. The concept significantly reduces the material and instrumental costs of process design and implementation. Full article

Supercritical carbon dioxide (SC-CO₂) can serve as solvent, anti-solvent and solute, among others, in the field of drug delivery applications, e.g., for the formulation of polymeric nanocarriers in combination with different drug molecules. With its tunable properties above critical pressure and temperature, SC-CO₂ offers control of the particle size, the particle morphology, and their drug loading. Moreover, the SC-CO₂-based techniques overcome the limitations of conventional formulation techniques e.g., post purification steps. One of the widely used polymers for drug delivery systems with excellent mechanical (T_g, crystallinity) and chemical properties (controlled drug release, biodegradability) is poly (lactic acid) (PLA), which is used either as a homopolymer or as a copolymer, such as poly(lactic-co-glycolic) acid (PLGA). Over the last 30 years, extensive research has been conducted to exploit SC-CO₂-based processes for the formulation of PLA carriers. This review provides an overview of these research studies, including a brief description of the SC-CO₂ processes that are widely exploited for the production of PLA and PLGA-based drug-loaded particles. Finally, recent work shows progress in the development of SC-CO₂ techniques for particulate drug delivery systems is discussed in detail. Additionally, future perspectives and limitations of SC-CO₂-based techniques in industrial applications are examined. Full article

Alkanediols are often used as alternative antimicrobial preservatives for dermal formulations, e.g., hydrophilic creams. These substances show an antimicrobial effect due to their amphiphilic structure. At the same time, their amphiphilic behavior enables various interactions with the cream base itself. Therefore, the effect of four different alkanediols, namely 1,2-pentanediol, 2-methyl-2,4-pentanediol (hexylene glycol), 1,2-hexanediol, and 1,2-octanediol on the physical stability of a nonionic hydrophilic cream was investigated. Further, the incorporation of the alkanediols into lamellar structures of the cream was evaluated using differential scanning calorimetry (DSC) and small-angle X-ray scattering (SAXS) measurements. The interaction with the mixed crystals of the cream was found to increase with raising alkyl chain length of the added alkanediol. As a result, consistency and stability of the cream are slightly impaired. A test for efficacy of antimicrobial preservation according to the European Pharmacopoeia (Ph.Eur.) revealed that the antimicrobial activity is directly linked to the length of the alkyl chain of the alkanediols. 2-Methyl-2,4-pentanediol differs from both findings. This compound has non-vicinal hydroxy groups which result in a reduced amphiphilicity compared to the others. Consequently, it has a smaller impact on the colloidal structure of the cream and shows a comparatively low antimicrobial activity. Full article

The aim of this study was to investigate the use of a three-fluid atomising nozzle in a lab-scale spray dryer for the production of dry powders intended for pulmonary delivery. Powders were composed of salbutamol sulphate and theophylline in different weight ratios. The three-fluid nozzle technology enabled powders containing a high theophylline content to be obtained, overcoming the problems associated with its relatively low solubility, by pumping two separate feed solutions (containing the two different active pharmaceutical ingredients (APIs)) into the spray dryer via two separate nozzle channels at different feed rates. The final spray-dried products were characterized in terms of morphology, solid-state properties and aerosolization performance, and were compared with an equivalent formulation prepared using a standard two-fluid atomising nozzle. Results confirmed that most of the powders made using the three-fluid atomising nozzle met the required standards for a dry powder inhaler formulation in terms of physical characteristics; however, aerosolization characteristics require improvement if the powders are to be considered suitable for pulmonary delivery. Full article

Biomaterials science is one of the most rapidly evolving fields in biomedicine. However, although novel biomaterials have achieved well-defined goals, such as the production of devices with improved biocompatibility and mechanical properties, their development could be more ambitious. Indeed, the integration of active targeting strategies has been shown to allow spatiotemporal control of cell–material interactions, thus leading to more specific and better-performing devices. This manuscript reviews recent advances that have led to enhanced biomaterials resulting from the use of natural structural macromolecules. In this regard, several structural macromolecules have been adapted or modified using biohybrid approaches for use in both regenerative medicine and therapeutic delivery. The integration of structural and functional features and aptamer targeting, although still incipient, has already shown its ability and wide-reaching potential. In this review, we discuss aptamer-functionalized hybrid protein-based or polymeric biomaterials derived from structural macromolecules, with a focus on bioresponsive/bioactive systems. Full article

Oral nanomedicines are being investigated as an innovative strategy for targeted drug delivery to treat inflammatory bowel diseases. Preclinical studies have shown that nanoparticles (NPs) can preferentially penetrate inflamed intestinal tissues, allowing for targeted drug delivery. NP size is a critical factor affecting their interaction with the inflamed intestinal barrier and this remains poorly defined. In this study we aimed to assess the impact of NP particle size (PS) and polydispersity (PDI) on cell interaction and uptake in an inflamed epithelial cell model. Using 10, 55 and 100 mg/mL poly(lactic-co-glycolic acid)-polyethylene glycol (PLGA-PEG), NPs of 131, 312 and 630 nm PS, respectively, were formulated by solvent dispersion. NP recovery was optimised by differential centrifugation to yield NPs of decreased and unimodal size distribution. NP-cell interaction was assessed in healthy and inflamed caco-2 cell monolayers. Results show that NP interaction with caco-2 cells increased with increasing PS and PDI and was significantly enhanced in inflamed cells. Trypan blue quenching revealed that a significant proportion of multimodal NPs were primarily membrane bound, while monomodal NPs were internalized within cells. These results are interesting as the PS and PDI of NPs can be optimised to allow targeting of therapeutic agents to the epithelial membrane and/or intracellular targets in the inflamed intestinal epithelium. Full article

In recent years, a number of clinical trials have been published on the efficacy and safety of drug delivery using microneedles (MNs). This review aims to systematically summarize and analyze the current evidence including the clinical effect and safety of MNs. Three electronic databases, including PubMed, were used to search the literature for randomized controlled trials (RCTs) and clinical controlled trials (CCTs) that evaluated the therapeutic efficacy of MNs from their inception to 28 June 2018. Data were extracted according to the characteristics of study subjects; disorder, types, and details of the intervention (MNs) and control groups; outcome measurements; effectiveness; and incidence of adverse events (AEs). Overall, 31 RCTs and seven CCTs met the inclusion criteria. Although MNs were commonly used in skin-related studies, evaluating the effects of MNs was difficult because many studies did not provide adequate comparison values between groups. For osteoporosis treatment, vaccine, and insulin delivery studies, MNs were comparable to or more effective than the gold standard. Regarding the safety of MNs, most AEs reported in each study were minor (grade 1 or 2). A well-designed RCT is necessary to clearly evaluate the effectiveness of MNs in the future. Full article

Detection and characterization of particles in the visible and subvisible size range is critical in many fields of industrial research. Commercial particle analysis systems have proliferated over the last decade. Despite that growth, most systems continue to be based on well-established principles, and only a handful of new approaches have emerged. Identifying the right particle-analysis approach remains a challenge in research and development. The choice depends on each individual application, the sample, and the information the operator needs to obtain. In biopharmaceutical applications, particle analysis decisions must take product safety, product quality, and regulatory requirements into account. Biopharmaceutical process samples and formulations are dynamic, polydisperse, and very susceptible to chemical and physical degradation: improperly handled product can degrade, becoming inactive or in specific cases immunogenic. This article reviews current methods for detecting, analyzing, and characterizing particles in the biopharmaceutical context. The first part of our article represents an overview about current particle detection and characterization principles, which are in part the base of the emerging techniques. It is very important to understand the measuring principle, in order to be adequately able to judge the outcome of the used assay. Typical principles used in all application fields, including particle–light interactions, the Coulter principle, suspended microchannel resonators, sedimentation processes, and further separation principles, are summarized to illustrate their potentials and limitations considering the investigated samples. In the second part, we describe potential technical approaches for biopharmaceutical particle analysis as some promising techniques, such as nanoparticle tracking analysis (NTA), micro flow imaging (MFI), tunable resistive pulse sensing (TRPS), flow cytometry, and the space- and time-resolved extinction profile (STEP^®) technology. Full article

The usage of insects as a sustainable and functional natural products resource is a new promise in complementary and alternative medicine. The present study aimed to investigate the ability of Musca domestica (housefly) larval hemolymph (insect blood) to display the enhanced in vitro antioxidant and cytotoxic effects. The oxidative stress (OS) was elicited by inducing lipopolysaccharides (LPS) treatment as an exogenous stressor. Determination of superoxide dismutase 1 (SOD1), glutathione (GSH), malondialdehyde (MDA) and total antioxidant capacity (TAC), and mRNA and protein expressions of SOD1, was investigated as confirmatory markers of oxidative stress induction. Cytotoxicity on cancerous MCF-7 and normal Vero cells were also evaluated using an MTT assay at 24 h post-injection. The injection of LPS induced a significant (p < 0.05) increase in SOD, GSH and TAC, whereas, the MDA was diminished. Hemolymph was collected from normal and treated larvae after 6, 12 and 24 h. The M. domestica superoxide dismutase (MdSOD1) transcripts were significantly (p < 0.05) upregulated 6 and 12 h post-treatment, while a significant downregulation was observed after 24 h. Western blot analysis showed that MdSOD1 was expressed in the hemolymph of the treated larvae with an increase of 1.2 folds at 6 and 12 h and 1.6 folds at 24 h relative to the control group. LPS-treated larval hemolymphs exhibited significant cytotoxicity with respect to the untreated ones against MCF-7 while Vero cells showed no cytotoxicity for both hemolymphs. The DPPH free radical scavenging activity was examined and a significant antioxidant potential potency was observed at 6 h (50% maximal inhibitory concentration (IC₅₀): 63.3 ± 3.51 µg/mL) when compared to the control M. domestica larval hemolymph (IC₅₀: 611.7 ± 10.41 µg/mL). Taken together, M. domestica larval hemolymph exhibited enhanced antioxidant and consequently increased cytotoxic capacities under stressed conditions. Full article

Bisindolylmaleimide I (BIM-I) is a competitive pan protein kinase C inhibitor with anti-inflammatory and anti-metastatic properties, suggested to treat inflammatory diseases and various cancer entities. However, despite its therapeutic potential, BIM-I has two major drawbacks, i.e., it has a poor water solubility, and it binds the human ether-à-go-go-related gene (hERG) ion channels, potentially causing deadly arrhythmias. In this case, a targeted delivery of BIM-I is imperative to minimize peripheral side effects. To circumvent these drawbacks BIM-I was encapsulated into nanoparticles prepared from poly(lactic-co-glycolic acid) (PLGA) functionalized by the near-infrared dye DY-635. DY-635 served as an active targeting moiety since it selectively binds the OATP1B1 and OATP1B3 transporters that are highly expressed in liver and cancer cells. PLGA-DY-635 (BIM-I) nanoparticles were produced by nanoprecipitation and characterized using dynamic light scattering, analytical ultracentrifugation, and cryogenic transmission electron microscopy. Particle sizes were found to be in the range of 20 to 70 nm, while a difference in sizes between the drug-loaded and unloaded particles was observed by all analytical techniques. In vitro studies demonstrated that PLGA-DY-635 (BIM-I) NPs prevent the PKC activation efficiently, proving the efficacy of the inhibitor after its encapsulation, and suggesting that BIM-I is released from the PLGA-NPs. Ultimately, our results present a feasible formulation strategy that improved the cytotoxicity profile of BIM-I and showed a high cellular uptake in the liver as demonstrated in vivo by intravital microscopy investigations. Full article

In this study, we developed γ-cyclodextrin-based multifunctional nanoparticles (NPs) for tumor-targeted therapy. The NPs were self-assembled using a γ-cyclodextrin (γCD) coupled with phenylacetic acid (PA), 2,3-dimethylmaleic anhydride (DMA), poly(ethylene glycol) (PEG), and transferrin (Tf), termed γCDP-(DMA/PEG-Tf) NPs. These γCDP-(DMA/PEG-Tf) NPs are effective in entrapping topotecan (TPT, as a model antitumor drug) resulting from the ionic interaction between pH-responsive DMA and TPT or the host–guest interaction between γCDP and TPT. More importantly, the γCDP-(DMA/PEG-Tf) NPs can induce ionic repulsion at an endosomal pH (~6.0) resulting from the chemical detachment of DMA from γCDP, which is followed by extensive TPT release. We demonstrated that γCDP-(DMA/PEG-Tf) NPs led to a significant increase in cellular uptake and MDA-MB-231 tumor cell death. In vivo animal studies using an MDA-MB-231 tumor xenografted mice model supported the finding that γCDP-(DMA/PEG-Tf) NPs are effective carriers of TPT to Tf receptor-positive MDA-MB-231 tumor cells, promoting drug uptake into the tumors through the Tf ligand-mediated endocytic pathway and increasing their toxicity due to DMA-mediated cytosolic TPT delivery. Full article

Curcumin (CUR) is an attractive polyphenol for its anti-inflammatory, antibacterial, antioxidant, and anticancer properties. Poor solubility in water and sensitivity against sunlight are the most challenging characteristics in the development of CUR for clinical use. The aim is to develop oral lipid-based bioactive self-nanoemulsifying drug delivery systems (Bio-SNEDDSs) for curcumin as a candidate for cancer therapy. Bio-SNEDDSs containing black seed oil, medium-chain mono- and diglycerides, and surfactants were prepared as CUR delivery vehicles. The morphology, droplet size, physical stability, encapsulation efficiency, risk of precipitation, lipid digestion, antioxidant activity, and antimicrobial activity were evaluated for the representative formulations. Finally, an MTT assay was performed on MCF-7 cells to determine the cytotoxic effect of the different formulations. The results showed lower droplet size (28.53 nm) and higher drug-loading (CUR 20 mg, thymoquinone 1.2 mg) for the representative Bio-SNEDDS (black seed oil/Imwitor 988/KolliphorEL (35/15/50) % w/w), along with a transparent appearance upon aqueous dilution. The dynamic dispersion and in-vitro lipolysis data proved that the Bio-SNEDDS was able to keep the CUR in a solubilized form in the gastrointestinal tract. From the antioxidant and antimicrobial studies, it was suggested that the Bio-SNEDDS had the highest activity for disease control. The MTT assay showed that the representative Bio-SNEDDS treatment led to a reduction of cell viability of MCF-7 cells compared to pure CUR and conventional SNEDDSs. A Bio-SNEDDS with elevated entrapment efficiency, antioxidant/antimicrobial activities, and an antiproliferative effect could be the best anticancer drug candidate for potential oral delivery. Full article

(1) Background: Natural peptides supporting the innate immune system studied at the functional and mechanistic level are a rich source of innovative compounds for application in human therapy. Increasing evidence indicates that apart from antimicrobial activity, some of them exhibit selective cytotoxicity towards tumor cells. Their cationic, amphipathic structure enables interactions with the negatively-charged membranes of microbial or malignant cells. It can be modeled in 3D by application of dendrimer chemistry. (2) Methods: Here we presented design principles, synthesis and bioactivity of branched peptides constructed from ornithine (Orn) assembled as proline (Pro)- or histidine (His)-rich dendrons and dendrimers of the bola structure. The impact of the structure and amphipathic properties of dendrons/dendrimers on two glioblastoma cell lines U87 and T98G was studied with the application of proliferation, apoptosis and cell migration assays. Cell morphology/cytoskeleton architecture was visualized by immunofluorescence microscopy. (3) Results: Dimerization of dendrons into bola dendrimers enhanced their bioactivity. Pro- and His-functionalized bola dendrimers displayed cytostatic activity, even though differences in the responsiveness of U87 and T98G cells to these compounds indicate that their bioactivity depends not only on multiple positive charge and amphipathic structure but also on cellular phenotype. (4) Conclusion: Ornithine dendrons/dendrimers represent a group of promising anti-tumor agents and the potential tools to study interrelations between drug bioactivity, its chemical properties and tumor cells’ phenotype. Full article

Novel-antibiotics are urgently needed to combat an increase in morbidity and mortality due to resistant bacteria. The preclinical candidate corallopyronin A (CorA) is a potent antibiotic against Gram-positive and some Gram-negative pathogens for which a solid oral formulation was needed for further preclinical testing of the active pharmaceutical ingredient (API). The neat API CorA is poorly water-soluble and instable at room temperature, both crucial characteristics to be addressed and overcome for use as an oral antibiotic. Therefore, amorphous solid dispersion (ASD) was chosen as formulation principle. The formulations were prepared by spray-drying, comprising the water-soluble polymers povidone and copovidone. Stability (high-performance liquid chromatography, Fourier-transform-infrared spectroscopy, differential scanning calorimetry), dissolution (biphasic dissolution), and solubility (biphasic dissolution, Pion’s T3 apparatus) properties were analyzed. Pharmacokinetic evaluations after intravenous and oral administration were conducted in BALB/c mice. The results demonstrated that the ASD formulation principle is a suitable stability- and solubility-enhancing oral formulation strategy for the API CorA to be used in preclinical and clinical trials and as a potential market product. Full article

Photosensitivity induced by drugs is a widely experienced problem, concerning both molecule design and clinical practice. Indeed, photo-induced cutaneous eruptions represent one of the most common drug adverse events and are frequently an important issue to consider in the therapeutic management of patients. Phototoxicity and photoallergy are the two different pathogenic mechanisms involved in photosensitization. Related cutaneous manifestations are heterogeneous, depending on the culprit drug and subject susceptibility. Here we report an updated review of the literature with respect to pathogenic mechanisms of photosensitivity, clinical manifestations, patient management, and prediction and evaluation of drug-induced photosensitivity. We present and discuss principal groups of photosensitizing drugs (antimicrobials, nonsteroidal anti-inflammatory drugs, anti-hypertensives, anti-arrhythmics, cholesterol, and glycemia-lowering agents, psychotropic drugs, chemotherapeutics, etc.) and their main damage mechanisms according to recent evidence. The link between the drug and the cutaneous manifestation is not always clear; more investigations would be helpful to better predict drug photosensitizing potential, prevent and manage cutaneous adverse events and find the most appropriate alternative therapeutic strategy. Full article

Photodynamic therapy (PDT) combined with upconverting nanoparticles (UCNPs) are viewed together as an effective method of ablating tumors. After absorbing highly tissue-penetrating near-infrared (NIR) light, UCNPs emit a shorter wavelength light (~660 nm) suitable for PDT. In this study, we designed and prepared highly red fluorescence-emitting silica-coated core-shell upconverting nanoparticles modified with polyethylene glycol (PEG_5k)-folic acid and tetrakis(4-carboxyphenyl)porphyrin (TCPP) ([email protected]₂-NH₂@FA/PEG/TCPP) as an efficient photodynamic agent for killing tumor cells. The UCNPs consisted of two simple lanthanides, erbium and lutetium, as the core and shell, respectively. The unique core-shell combination enabled the UCNPs to emit red light without green light. TCPP, folic acid, and PEG were conjugated to the outer silica layer of UCNPs as a photosensitizing agent, a ligand for tumor attachment, and a dispersing stabilizer, respectively. The prepared UCNPs of ~50 nm diameter and −34.5 mV surface potential absorbed 808 nm light and emitted ~660 nm red light. Most notably, these UCNPs were physically well dispersed and stable in the aqueous phase due to PEG attachment and were able to generate singlet oxygen (¹O₂) with a high efficacy. The HeLa cells were treated with each UCNP sample (0, 1, 5, 10, 20, 30 μg/mL as a free TCPP). The results showed that the combination of [email protected]₂-NH₂@FA/PEG/TCPP and the 808 nm laser was significantly cytotoxic to HeLa cells, almost to the same degree as naïve TCPP plus the 660 nm laser based on MTT and Live/Dead assays. Furthermore, the [email protected]₂-NH₂@FA/PEG/TCPP was well internalized into HeLa cells and three-dimensional HeLa spheroids, presumably due to the surface folic acid and small size in conjunction with endocytosis and the nonspecific uptake. We believe that our [email protected]₂-NH₂@FA/PEG/TCPP will serve as a new platform for highly efficient and deep-penetrating photodynamic agents suitable for various tumor treatments. Full article

Microneedles (MNs) are tiny needle like structures used in drug delivery through layers of the skin. They are non-invasive and are associated with significantly less or no pain at the site of administration to the skin. MNs are excellent in delivering both small and large molecules to the subjects in need thereof. There exist several strategies for drug delivery using MNs, wherein each strategy has its pros and cons. Research in this domain lead to product development and commercialization for clinical use. Additionally, several MN-based products are undergoing clinical trials to evaluate its safety, efficacy, and tolerability. The present review begins by providing bird’s-eye view about the general characteristics of MNs followed by providing recent updates in the treatment of cancer using MNs. Particularly, we provide an overview of various aspects namely: anti-cancerous MNs that work based on sensor technology, MNs for treatment of breast cancer, skin carcinoma, prostate cancer, and MNs fabricated by additive manufacturing or 3 dimensional printing for treatment of cancer. Further, the review also provides limitations, safety concerns, and latest updates about the clinical trials on MNs for the treatment of cancer. Furthermore, we also provide a regulatory overview from the “United States Food and Drug Administration” about MNs. Full article