Oral delivery of brain-targeted miltefosine-loaded alginate nanoparticles functionalized with polysorbate 80 for the treatment of cryptococcal meningitis.

OBJECTIVES: To develop alginate nanoparticles functionalized with polysorbate 80 (P80) as miltefosine carriers for brain targeting in the oral treatment of cryptococcal meningitis. METHODS: Miltefosine-loaded alginate nanoparticles functionalized or not with P80 were produced by an emulsification/external gelation method and the physicochemical characteristics were determined. The haemolytic activity and cytotoxic and antifungal effects of nanoparticles were assessed in an in vitro model of the blood-brain barrier (BBB). A murine model of disseminated cryptococcosis was used for testing the efficacy of oral treatment with the nanoparticles. In addition, serum biomarkers were measured for toxicity evaluation and the nanoparticle biodistribution was analysed. RESULTS: P80-functionalized nanoparticles had a mean size of ∼300 nm, a polydispersity index of ∼0.4 and zeta potential around -50 mV, and they promoted a sustained drug release. Both nanoparticles were effective in decreasing the infection process across the BBB model and reduced drug cytotoxicity and haemolysis. In in vivo cryptococcosis, the oral treatment with two doses of P80 nanoparticles reduced the fungal burden in the brain and lungs, while the non-functionalized nanoparticles reduced fungal amount only in the lungs, and the free miltefosine was not effective. In addition, the P80-functionalization improved the nanoparticle distribution in several organs, especially in the brain. Finally, treatment with nanoparticles did not cause any toxicity in animals. CONCLUSIONS: These results support the potential use of P80-functionalized alginate nanoparticles as miltefosine carriers for non-toxic and effective alternative oral treatment, enabling BBB translocation and reduction of fungal infection in the brain.

A Lipid-Based In Situ-Forming Hexagonal Phase for Prolonged Retention and Drug Release in the Breast Tissue.

In this study, the addition of monoolein to phosphatidylcholine (PC), tricaprylin, and propylene glycol (PG) mixtures was studied to produce fluid precursor formulations (FIPs) that could transform into hexagonal phase (resistant to aqueous dilution) in vitro and in vivo. The overall goal was to obtain FIPs that could incorporate chemopreventive drugs for subcutaneous administration in the mammary tissue to inhibit the development and/or recurrence of breast cancer. Increasing PG content reduced FIP viscosity up to ~ 2.5-fold, while increases in PC (over monoolein) increased the formation of emulsified systems. The hexagonal phase was observed at 20% of water and higher, with the minimum amount of water necessary for this formation increasing with PG content. The selected FIP formed a depot in vivo after ~ 24 h of administration; its structure was compatible with the hexagonal phase and it remained in the mammary tissue for at least 30 days, prolonging the permanence of a fluorescent probe. In vitro, the release of the synthetic retinoid fenretinide was slow, with ~ 9% of the drug released in 72 h. Consistent with this slow release, fenretinide IC50 in breast cancer cells was ~ 100-fold higher in the selected FIP compared to its solution. The FIP reduced cell migration and presented higher cytotoxicity towards tumor compared to non-tumor cells. Given the limited number of options for pharmacological prevention of breast cancer development and recurrences, this formulation could potentially find applicability to reduce the frequency of administration and improve local concentrations of chemopreventive drugs.

Microemulsion for Prolonged Release of Fenretinide in the Mammary Tissue and Prevention of Breast Cancer Development.

The need of pharmacological strategies to preclude breast cancer development motivated us to develop a non-aqueous microemulsion (ME) capable of forming a depot after administration in the mammary tissue and uptake of interstitial fluids for prolonged release of the retinoid fenretinide. The selected ME was composed of phosphatidylcholine/tricaprylin/propylene glycol (45:5:50, w/w/w) and presented a droplet diameter of 175.3 ± 8.9 nm. Upon water uptake, the ME transformed successively into a lamellar phase, gel, and a lamellar phase-containing emulsion in vitro as the water content increased and released 30% of fenretinide in vitro after 9 days. Consistent with the slow release, the ME formed a depot in cell cultures and increased fenretinide IC50 values by 68.3- and 13.2-fold in MCF-7 and T-47D cells compared to a solution, respectively. At non-cytotoxic concentrations, the ME reduced T-47D cell migration by 75.9% and spheroid growth, resulting in ∼30% smaller structures. The depot formed in vivo prolonged a fluorochrome release for 30 days without producing any sings of local irritation. In a preclinical model of chemically induced carcinogenesis, ME administration every 3 weeks for 3 months significantly reduced (4.7-fold) the incidence of breast tumors and increased type II collagen expression, which might contribute to limit spreading. These promising results support the potential ME applicability as a preventive therapy of breast cancer.

Development of a method for quantitative determination of the cytotoxic agent piplartine (piperlongumine) in multiple skin layers.

This study reports the development of a simple and reproducible method, with high rates of recovery, to extract the cytotoxic agent piplartine from skin layers, and a sensitive and rapid UV-HPLC method for its quantification. Considering the potential of piplartine for topical treatment of skin cancer, this method may find application for formulation development and pharmacokinetics studies to assess cutaneous bioavailability. Porcine skin was employed as a model for human tissue. Piplartine was extracted from the stratum corneum (SC) and remaining viable skin layers (VS) using methanol, vortex homogenization and bath sonication, and subsequently assayed by HPLC using a C18 column, and 1:1 (v/v) acetonitrile-water (adjusted to pH 4.0 with acetic acid 0.1%) as mobile phase. The quantification limit of piplartine was 0.2 µg/mL (0.6 µm), and the assay was linear up to 5 µg/mL (15.8 µm), with within-day and between-days assay coefficients of variation and relative errors <15%. Piplartine recovery from SC and VS varied from 86 to 96%. The method was suitable to assay samples from skin penetration studies, enabling detection of differences in cutaneous delivery in different skin compartments resulting from treatment with various formulations and time periods.

Potential of Non-aqueous Microemulsions to Improve the Delivery of Lipophilic Drugs to the Skin.

In this study, non-aqueous microemulsions were developed because of the challenges associated with finding pharmaceutically acceptable solvents for topical delivery of drugs sparingly soluble in water. The formulation irritation potential and ability to modulate the penetration of lipophilic compounds (progesterone, α-tocopherol, and lycopene) of interest for topical treatment/prevention of skin disorders were evaluated and compared to solutions and aqueous microemulsions of similar composition. The microemulsions (ME) were developed with BRIJ, vitamin E-TPGS, and ethanol as surfactant-co-surfactant blend and tributyrin, isopropyl myristate, and oleic acid as oil phase. As polar phase, propylene glycol (MEPG) or water (MEW) was used (26% w/w). The microemulsions were isotropic and based on viscosity and conductivity assessment, bicontinuous. Compared to drug solutions in lipophilic vehicles, MEPG improved drug delivery into viable skin layers by 2.5-38-fold; the magnitude of penetration enhancement mediated by MEPG into viable skin increased with drug lipophilicity, even though the absolute amount of drug delivered decreased. Delivery of progesterone and tocopherol, but not lycopene (the most lipophilic compound), increased up to 2.5-fold with MEW, and higher amounts of these two drugs were released from MEW (2-2.5-fold). Both microemulsions were considered safe for topical application, but MEPG-mediated decrease in the viability of reconstructed epidermis was more pronounced, suggesting its higher potential for irritation. We conclude that MEPG is a safe and suitable nanocarrier to deliver a variety of lipophilic drugs into viable skin layers, but the use of MEW might be more advantageous for drugs in the lower range of lipophilicity.

Nanostructured lipid carriers loaded into in situ gels for breast cancer local treatment.

In this study, nanostructured lipid carriers (NLC) were developed and employed to obtain in situ thermosensitive formulations for the ductal administration and prolonged retention of drugs as a new strategy for breast cancer local treatment. NLC size was influenced by the type and concentration of the oil phase, surfactants, and drug incorporation, ranging from 221.6 to 467.5 nm. The type of liquid lipid influenced paclitaxel and 5-fluorouracil cytotoxicity, with tributyrin-containing NLC reducing IC50 values by 2.0-7.0-fold compared to tricaprylin NLC in MCF-7, T-47D and MDA-MB-231 cells. In spheroids, the NLCs reduced IC50 compared to either drug solution (3.2-6.2-fold). Although a significant reduction (1.26 points, p < 0.001) on the health index of Galleria mellonella larvae was observed 5 days after NLC administration, survival was not significantly reduced. To produce thermosensitive gels, the NLCs were incorporated in a poloxamer (11 %, w/w) dispersion, which gained viscosity (2-fold) at 37 °C. After 24 h, ∼53 % of paclitaxel and 83 % of 5-fluorouracil were released from the NLC; incorporation in the poloxamer gel further prolonged release. Intraductal administration of NLC-loaded gel increased the permanence of hydrophilic (2.2-3.0-fold) and lipophilic (2.1-2.3-fold) fluorescent markers in the mammary tissue compared to the NLC (as dispersion) and the markers solutions. In conclusion, these results contribute to improving our understanding of nanocarrier design with increased cytotoxicity and prolonged retention for the intraductal route. Tributyrin incorporation increased the cytotoxicity of paclitaxel and 5-fluorouracil in monolayer and spheroids, while NLC incorporation in thermosensitive gels prolonged tissue retention of both hydrophilic and hydrophobic compounds.

Thermosensitive Polymeric Nanoparticles for Drug Co-Encapsulation and Breast Cancer Treatment.

Despite advances in breast cancer treatment, there remains a need for local management of noninvasive, low-grade ductal carcinoma in situ (DCIS). These focal lesions are well suited for local intraductal treatment. Intraductal administration supported target site drug retention, improved efficacy, and reduced systemic exposure. Here, we used a poly(N-isopropyl acrylamide, pNIPAM) nanoparticle delivery system loaded with cytotoxic piplartine and an MAPKAP Kinase 2 inhibitor (YARA) for this purpose. For tumor environment targeting, a collagen-binding peptide SILY (RRANAALKAGELYKSILYGSG-hydrazide) was attached to pNIPAM nanoparticles, and the nanoparticle diameter, zeta potential, drug loading, and release were assessed. The system was evaluated for cytotoxicity in a 2D cell culture and 3D spheroids. In vivo efficacy was evaluated using a chemical carcinogenesis model in female Sprague-Dawley rats. Nanoparticle delivery significantly reduced the IC50 of piplartine (4.9 times) compared to the drug in solution. The combination of piplartine and YARA in nanoparticles further reduced the piplartine IC50 (~15 times). Treatment with these nanoparticles decreased the in vivo tumor incidence (5.2 times). Notably, the concentration of piplartine in mammary glands treated with nanoparticles (35.3 ± 22.4 µg/mL) was substantially higher than in plasma (0.7 ± 0.05 µg/mL), demonstrating targeted drug retention. These results indicate that our nanocarrier system effectively reduced tumor development with low systemic exposure.

Topical delivery of seriniquinone for treatment of skin cancer and fungal infections is enabled by a liquid crystalline lamellar phase.

Seriniquinone (SQ) was initially described by our group as an antimelanoma drug candidate and now also as an antifungal drug candidate. Despite its promising in vitro effects, SQ translation has been hindered by poor water-solubility. In this paper, we described the challenging nanoformulation process of SQ, which culminated in the selection of a phosphatidylcholine-based lamellar phase (PLP1). Liposomes and nanostructured lipid carriers were also evaluated but failed to encapsulate the compound. SQ-loaded PLP1 (PLP1-SQ) was characterized for the presence of sedimented or non-dissolved SQ, rheological and thermal behavior, and irritation potential with hen's egg test on the chorioallantoic membrane (HET-CAM). PLP1 influence on transepidermal water loss (TEWL) and skin penetration of SQ was assessed in a porcine ear skin model, while biological activity was evaluated against melanoma cell lines (SK-MEL-28 and SK-MEL-147) and C. albicans SC5314. Despite the presence of few particles of non-dissolved SQ (observed under the microscope 2 days after formulation obtainment), PLP1 tripled SQ retention in viable skin layers compared to SQ solution at 12 h. This effect did not seem to relate to formulation-induced changes on the barrier function, as no increases in TEWL were observed. No sign of vascular toxicity in the HET-CAM model was observed after cutaneous treatment with PLP1. SQ activity was maintained on melanoma cells after 48 h-treatment (IC50 values of 0.59-0.98 µM) whereas the minimum inhibitory concentration (MIC) against C. albicans after 24 h-treatment was 32-fold higher. These results suggest that a safe formulation for SQ topical administration was developed, enabling further in vivo studies.

Novel lipid nanovesicle-loaded dissolving microarray patches for fenretinide in breast cancer chemoprevention.

The retinoid fenretinide (FENR) is a promising compound for preventing breast cancer recurrence but faces challenges due to poor solubility and low bioavailability. This study explores the development of dissolving microneedles (MNs) containing FENR-loaded ethosomes for minimally invasive breast cancer chemoprevention, aiming to enhance local drug distribution. Ethosomes were formulated using ethanol, propylene glycol, soya lecithin, water, and polysorbate 80 micelles. MNs were created from poly(vinyl alcohol) and poly(vinylpyrrolidone) hydrogels by adding polymer powder directly into ethosomes suspensions, reducing manufacturing time and cost. Two methods were used to load ethosomes into high-density moulds: 1) only in the needle area, and 2) in both the needle area and baseplate. Dynamic light scattering confirmed nanostructures in the hydrogels and MNs. Micelle-based ethosomes dissolved MNs in 15 min, compared to 30 min for other MNs. Skin deposition studies showed greater drug deposition (up to 10 µg/patch) and enhanced skin permeation of FENR (up to 40 µg) with Method 2. In-vivo studies in rats demonstrated that oral administration resulted in plasma FENR levels below 10 ng/g in the first three hours, whereas MN administration delayed delivery, reaching a maximum plasma concentration of 52 ng/g at 48 h. Skin deposition of FENR from MNs decreased from 3 µg/g on day 1 to <0.3 µg/g by the last day. This study indicates that MNs are a potential minimally invasive dosage form for delivering FENR, offering a new approach for breast cancer chemoprevention.

Lamellar liquid crystalline phases for cutaneous delivery of Paclitaxel: impact of the monoglyceride.

PURPOSE: To develop liquid crystalline phases with monoglycerides, and assess whether the monoglyceride type favors cutaneous over transdermal paclitaxel delivery. METHODS: BRIJ-based lamellar phases were prepared with 0.5% paclitaxel and 20% of either monocaprylin (LP-MC), monomyristolein (LP-MM) or monoolein (LP-MO). Skin electrical resistance, drug release and cutaneous delivery in vitro and in vivo were assessed. Viability of skin equivalents and release of IL-1α were assessed as indexes of irritation potential. RESULTS: An inverse relationship between monoglyceride acyl chain length and amount of paclitaxel delivered was observed. Although the largest paclitaxel amounts were delivered by LP-MC, all formulations delivered higher levels of drug in the skin (56-64-fold) than across the tissue. The superiority of LP-MC seems related to a stronger decrease in skin resistance (as an index of permeability), and not to increased drug release. LP-MC displayed similar penetration-enhancing ability in vivo, and a much lower irritation potential than Triton-X100 (a moderate irritant), leading to 3-fold higher skin equivalent viability and release of 60-fold less IL-1α. CONCLUSIONS: Even though LP-MC delivered the largest amounts of paclitaxel, all formulations provided similar cutaneous/transdermal delivery ratios, suggesting that changing the monoglyceride acyl chain length did not affect the balance between cutaneous and transdermal delivery.

Collagen-Binding Nanoparticles for Paclitaxel Encapsulation and Breast Cancer Treatment.

In this study, we developed a novel hybrid collagen-binding nanocarrier for potential intraductal administration and local breast cancer treatment. The particles were formed by the encapsulation of nanostructured lipid carriers (NLCs) containing the cytotoxic drug paclitaxel within a shell of poly(N-isopropylacrylamide) (pNIPAM), and were functionalized with SILY, a peptide that binds to collagen type I (which is overexpressed in the mammary tumor microenvironment) to improve local retention and selectivity. The encapsulation of the NLCs in the pNIPAM shell increased nanoparticle size by approximately 140 nm, and after purification, a homogeneous system of hybrid nanoparticles (∼96%) was obtained. The nanoparticles exhibited high loading efficiency (<76%) and were capable of prolonging paclitaxel release for up to 120 h. SILY-modified nanoparticles showed the ability to bind to collagen-coated surfaces and naturally elaborated collagen. Hybrid nanoparticles presented cytotoxicity up to 3.7-fold higher than pNIPAM-only nanoparticles on mammary tumor cells cultured in monolayers. In spheroids, the increase in cytotoxicity was up to 1.8-fold. Compared to lipid nanoparticles, the hybrid nanoparticle modified with SILY increased the viability of nontumor breast cells by up to 1.59-fold in a coculture model, suggesting the effectiveness and safety of the system.

Development and cytotoxicity evaluation of multiple nanoemulsions for oral co-delivery of 5-fluorouracil and short chain triglycerides for colorectal cancer.

Colorectal cancer (CRC) is the third most common cancer in the world, but current chemotherapy options are limited due to adverse effects and low oral bioavailability of drugs. In this study, we investigated the obtainment parameters and composition of new multiple nanoemulsions (MN) based on microemulsions for oral co-delivery of 5-fluorouracil (5FU) and short-chain triglycerides (SCT, either tributyrin or tripropionin). The area of microemulsion formation was increased from 14% to 38% when monocaprylin was mixed with tricaprylin as oil phase. Addition of SCT reduced this value to 24-26%. Using sodium alginate aqueous dispersion as internal aqueous phase (to avoid phase inversion) did not further affected the area but increased microemulsion viscosity by 1.5-fold. To obtain the MN, selected microemulsions were diluted in an external aqueous phase; droplet size was 500 nm and stability improved using polyoxyethylene oleyl ether at 1-2.5% as surfactant in the external phase and a dilution ratio of 1:1 (v/v). 5FU in vitro release could be better described by the Korsmeyer-Peppas model. No pronounced changes in droplet size were observed when selected MNs were incubated in buffers mimicking gastrointestinal fluids. The 5FU cytotoxicity in monolayer cell lines presenting various mutations was influenced by its incorporation in the nanocarrier, presence of SCT and cell mutation status. The MNs selected reduced the viability of tumor spheroids (employed as 3D tumor models) by 2.2-fold compared to 5FU solution and did not affect the survival of the G. mellonella, suggesting effectiveness and safety.

Using a Kirschner Wire as a Stylet for the Management of a Difficult Neonatal Airway: A Case Report.

We report the successful management of a difficult airway in an extremely low birth weight neonate (700 g) using a Kirschner wire as a substitute for an endotracheal tube stylet. Several intubation attempts were unsuccessful because of the difficulty in guiding a very small and malleable tube under the epiglottis. This study highlights that every maternity hospital should be prepared to manage airways in unexpected extremely low birth weight neonates. Appropriate size equipment and protocols should be readily available.

Contributions of nanotechnology to the intraductal drug delivery for local treatment and prevention of breast cancer.

Breast cancer is a major public health problem, affecting millions of people. It is a very heterogeneous disease, with localized and invasive forms, and treatment generally consists of a combination of surgery and radiotherapy followed by administration of estrogen receptor modulators or aromatase inhibitors. Given its heterogeneity, management strategies that take into consideration the type of disease and biological markers and can provide more personalized and local treatment are required. More recently, the intraductal administration (i.e., into the breast ducts) of drugs has attracted significant attention due to its ability of providing drug distribution through the ductal tree in a minimally invasive manner. Although promising, intraductal administration is not trivial, and difficulties in duct identification and cannulation are important challenges to the further development of this route. New drug delivery strategies such as nanostructured systems can help to achieve the full benefits of the route due to the possibility of prolonging tissue retention, improving targeting and selectivity, increasing cytotoxicity and reducing the frequency of administration. This review aims at discussing the potential benefits and challenges of intraductal administration, focusing on the design and use of nanocarriers as innovative and feasible strategies for local breast cancer therapy and prevention.

Autoregulation of blood flow drives early hypotension in a rat model of systemic inflammation induced by bacterial lipopolysaccharide.

Uncontrolled vasodilation is known to account for hypotension in the advanced stages of sepsis and other systemic inflammatory conditions, but the mechanisms of hypotension in earlier stages of such conditions are not clear. By monitoring hemodynamics with the highest temporal resolution in unanesthetized rats, in combination with ex-vivo assessment of vascular function, we found that early development of hypotension following injection of bacterial lipopolysaccharide is brought about by a fall in vascular resistance when arterioles are still fully responsive to vasoactive agents. This approach further uncovered that the early development of hypotension stabilized blood flow. We thus hypothesized that prioritization of the local mechanisms of blood flow regulation (tissue autoregulation) over the brain-driven mechanisms of pressure regulation (baroreflex) underscored the early development of hypotension in this model. Consistent with this hypothesis, an assessment of squared coherence and partial-directed coherence revealed that, at the onset of hypotension, the flow-pressure relationship was strengthened at frequencies (<0.2 Hz) known to be associated with autoregulation. The autoregulatory escape to phenylephrine-induced vasoconstriction, another proxy of autoregulation, was also strengthened in this phase. The competitive demand that drives prioritization of flow over pressure regulation could be edema-associated hypovolemia, as this became detectable at the onset of hypotension. Accordingly, blood transfusion aimed at preventing hypovolemia brought the autoregulation proxies back to normal and prevented the fall in vascular resistance. This novel hypothesis opens a new avenue of investigation into the mechanisms that can drive hypotension in systemic inflammation.

Phosphatidylcholine-Based Nanoemulsions for Paclitaxel and a P-Glycoprotein Inhibitor Delivery and Breast Cancer Intraductal Treatment.

In this study, incorporation of the cytotoxic agent paclitaxel and the P-glycoprotein inhibitor elacridar in hyaluronic acid (HA)-modified nanoemulsions was studied for intraductal delivery and breast cancer localized treatment. To improve cytotoxicity, we investigated the incorporation of perillyl alcohol or tributyrin as components of the nanoemulsion oil phase. The nanoemulsions presented size <180 nm and negative zeta potential. Both tributyrin and perillyl alcohol increased nanoemulsion cytotoxicity in MCF-7 cells, but not in MDA-MB-231. However, perillyl alcohol reduced nanoemulsion stability in the presence of the drugs. Concomitant incorporation of paclitaxel and elacridar in HA- and tributyrin-containing nanoemulsions (PE-NETri) increased cytotoxicity and reduced IC50 by 1.6 to 3-fold in MCF-7 and MDA-MB-231 cells compared to the nanoemulsion containing only paclitaxel (P-NE). This nanoemulsion also produced a 3.3-fold reduction in the viability of MDA-MB-231 spheroids. Elacridar incorporated in the nanoemulsion was capable of inhibiting P-glycoprotein in membranes. In vivo intraductal administration of the NE containing HA resulted in a three-fold higher retention of a fluorescent marker compared to a solution or nanoemulsion without HA, demonstrating the importance of HA. The nanoemulsion produced no histological changes in the mammary tissue. These results support the potential applicability of the nanoemulsion for local breast cancer management.

Beyond Formulation: Contributions of Nanotechnology for Translation of Anticancer Natural Products into New Drugs.

Nature is the largest pharmacy in the world. Doxorubicin (DOX) and paclitaxel (PTX) are two examples of natural-product-derived drugs employed as first-line treatment of various cancer types due to their broad mechanisms of action. These drugs are marketed as conventional and nanotechnology-based formulations, which is quite curious since the research and development (R&D) course of nanoformulations are even more expensive and prone to failure than the conventional ones. Nonetheless, nanosystems are cost-effective and represent both novel and safer dosage forms with fewer side effects due to modification of pharmacokinetic properties and tissue targeting. In addition, nanotechnology-based drugs can contribute to dose modulation, reversion of multidrug resistance, and protection from degradation and early clearance; can influence the mechanism of action; and can enable drug administration by alternative routes and co-encapsulation of multiple active agents for combined chemotherapy. In this review, we discuss the contribution of nanotechnology as an enabling technology taking the clinical use of DOX and PTX as examples. We also present other nanoformulations approved for clinical practice containing different anticancer natural-product-derived drugs.

Hyaluronic acid nanoemulsions improve piplartine cytotoxicity in 2D and 3D breast cancer models and reduce tumor development after intraductal administration.

Nanoemulsions modified with chitosan (NE-Q) or hyaluronic acid (NE-HA), developed for intraductal administration of piplartine (piperlongumine) and local breast cancer treatment, were evaluated for cytotoxic effects in vitro in 2D and 3D breast cancer models and in vivo in a chemically induced carcinogenesis model. Droplet size was lower than 100 nm, and zeta potential varied from +17.9 to -25.5 mV for NE-Q and NE-HA, respectively. Piplartine nanoencapsulation reduced its IC50 up to 3.6-fold in T-47D and MCF-7 monolayers without differences between NE-Q and NE-HA, and up to 6.6-fold in cancer spheroids. Cytotoxicity improvement may result from a more efficient NE-mediated delivery, as suggested by stronger fluorescent staining of cells and spheroids. In 1-methyl-1-nitrosourea -induced breast cancer models, intraductal administration of piplartine-loaded NE-HA inhibited breast tumor development and histological alterations. These results support the potential applicability of piplartine-loaded NE-HA for intraductal treatment of breast cancer.

In vivo synergism of free miltefosine or in alginate-based nanocarrier combined with voriconazole on aspergillosis.

Aim: To evaluate the activity of miltefosine (MFS), in its free form or loaded-alginate nanoparticles (MFS-AN), alone or combined with voriconazole (VRC) on Aspergillus fumigatus and Aspergillus flavus. Materials & methods: A broth microdilution assay was used for the susceptibility testing of Aspergillus isolates, and the antifungal efficacy was assessed using the aspergillosis model in Galleria mellonella larvae. Results: The in vitro synergistic effect of MFS with VRC was observed only against A. fumigatus, whereas both combined therapies (MFS + VRC and MFS-AN + VRC) showed synergism in reducing the larval mortality rate and fungal burden in the larvae infected by A. fumigatus and A. flavus. Conclusions: MFS and MFS-AN combined with VRC may be an important strategy for improving antifungal therapy against aspergillosis.

Nanostructured lipid carriers containing chitosan or sodium alginate for co-encapsulation of antioxidants and an antimicrobial agent for potential application in wound healing.

The high incidence and costs of chronic wounds in the elderly have motivated the search for innovations to improve product performance and the healing process while reducing costs. In this study, bioadhesive nanostructured lipid carriers (NLC) were developed for the co-encapsulation of compounds with antioxidant (α-tocopherol and quercetin) and antimicrobial (tea tree oil) activity for management of wounds. The NLC was produced with shea butter and argan oil, and modified with sodium alginate or chitosan to confer bioadhesive properties. Spherical nanoparticles of ~307-330 nm and zeta potential varying from -21.2 to +11.8 mV were obtained. Thermal analysis demonstrated that the lipid matrix reduced tea tree oil thermal loss (~1.8-fold). Regardless of the type of polysaccharide employed, the NLCs promoted cutaneous localization of antioxidants in damaged (subjected to incision) skin, with a ~74 to 180-fold higher delivery into the skin compared to percutaneous delivery. This result is consistent with the similar bioadhesive properties of chitosan or sodium alginate-modified NLC. Nanoencapsulation of tea tree oil did not preclude its antimicrobial effects against susceptible and resistant strains of S. aureus and P. aeruginosa, while co-encapsulation of antioxidants increased the NLC-induced fibroblasts migration, supporting their potential usefulness for management of wounds.