Periodontal evaluation after maxillary expansion with a tooth-bone-borne expander in growing patients : A randomized clinical trial.

PURPOSE: This two-arm parallel randomized controlled trial aimed to evaluate and compare periodontal changes due to rapid maxillary expansion (RME) using tooth-bone-borne and tooth-borne devices in growing patients via clinical examinations and cone-beam computed tomography (CBCT). MATERIALS AND METHODS: Forty-two eligible patients (aged 11-14 years; transverse maxillary deficiency, posterior crossbite) were screened and divided into two groups based on the treatment received (randomization was performed using computer-generated numeric sequences): hybrid hyrax tooth-bone-borne group (TBB) and hyrax tooth-borne group (TB). The primary outcome was the change in cortical bone thickness (by CBCT). In addition, the clinical attachment level (CAL), gingival recession, and bleeding were assessed. Both examinations were performed before and 3 months after the activation phase. Intergroup comparisons were performed using analysis of covariance (ANCOVA; P < 0.05). RESULTS: Twenty-one patients (12 girls and 9 boys; mean initial age, 13.3 years) were included in the TBB group and 21 (5 girls and 16 boys; mean initial age, 13.2 years) were included in the TB group. The TB group exhibited a decrease in buccal bone thickness in the first premolars and first molars at all three evaluated levels. Specifically, tooth 14 at 3 mm from the enamel-cement junction showed a significant width reduction (0.7 mm; p < 0.001), accompanied by a notable increase in palatal cortical thickness at 6 mm of enamel-cement junction (1.13 mm; p < 0.001). CONCLUSIONS: RME resulted in buccal bone thickness reduction at the first premolar with hyrax treatment. In the molar region, both devices resulted in cortical bone alterations that were less pronounced in the TBB group.

Hybrid Nanosystem Formed by DOX-Loaded Liposomes and Extracellular Vesicles from MDA-MB-231 Is Effective against Breast Cancer Cells with Different Molecular Profiles.

Drug delivery selectivity is a challenge for cancer treatment. A hybrid pegylated pH-sensitive liposome-extracellular vesicle isolated from human breast cancer cell MDA-MB-231 was developed to investigate its in vitro activity against breast cancer cells of different molecular profiles to overcome this inconvenience. The hybrid nanosystem was produced by film hydration, and doxorubicin (DOX) was encapsulated in this system using the ammonium sulfate gradient method. The characterization of this hybrid nanosystem revealed a mean diameter of 140.20 ± 2.70 nm, a polydispersity index of 0.102 ± 0.033, an encapsulation efficiency of doxorubicin of 88.9% ± 2.4, and a great storage stability for 90 days at 4 °C. The fusion of extracellular vesicles with liposomes was confirmed by nanoflow cytometry using PE-conjugated human anti-CD63. This hybrid nanosystem demonstrated cytotoxicity against human breast cancer cell lines with different molecular subtypes, enhanced anti-migration properties, and exhibited similar cellular uptake to the free DOX treatment. Preliminary acute toxicity assessments using Balb/C female mice indicated a median lethal dose of 15-17.5 mg/kg, with no evidence of splenic, liver, heart, bone marrow, and renal damage at a dose of 15 mg/kg. These findings suggest the hybrid formulation as a versatile nanocarrier for the treatment of various breast cancer subtypes.

Occurrence of antibiotics, hormones and PFAs in surface water from a Nile tilapia aquaculture facility in a Brazilian hydroelectric reservoir.

This study assessed the occurrence of five antibiotics, three hormones, caffeine, and long and short-chain perfluoroalkyl and polyfluoroalkyl substances (PFASs) in surface water and feedstuff samples obtained from aquaculture cages in Três Marias reservoir in Brazil. This is the first work to evaluate the presence of PFAS in surface water used for aquaculture in Brazil. Solid-phase extraction and low temperature partitioning extraction followed by liquid chromatography coupled to mass spectrometry (LC-MS) were performed to process and analyze surface water samples and feedstuff, respectively. The ecotoxicological risk quotient was calculated for target compounds detected in water. Ciprofloxacin and caffeine were detected in all surface water samples. Pharmaceutical drugs ranged from 0.7 ng L-1 (trimethoprim) to 389.2 ng L -1 (ß-estradiol). Estrone (10.24 ng g-1) and ß-estradiol (66.20 ng g-1) were also found in feedstuff. Four PFASs (PFOA, PFDoA, PFTeDA, and PFBS) were detected (9.40-15.2 µg L-1) at levels higher than reported in studies conducted worldwide. Ecotoxicological risk assessment indicated high risks for caffeine and PFOA, PFDoA, and PFTeDA with RQ values from 10 to 103. These findings reveal risks to biodiversity, ecosystem integrity and human health considering possible intake of these contaminants by fish consumption due to potential bioaccumulation of these substances. Hence, it is critical to conduct more studies in this direction in Brazil and other low and middle-low-income countries.

The absence of eosinophils is associated with early metastatic lesions in Leishmania amazonensis-infected mice.

BACKGROUND: Eosinophils are granulocytes that rapidly increase frequency in the bloodstream during helminthic infections and allergic responses. They are found in tissue infected by Leishmania during early disease, but their role during infection is not entirely understood. OBJECTIVES: We aim to compare the disease due to Leishmania amazonensis in BALB/c and Δdbl-GATA1 mice, which lack eosinophils. METHODS: BALB/c and Δdbl-GATA1 mice infected with L. amazonensis were observed for several weeks. The parasite load and dissemination pattern were assessed. FINDINGS: The Δdbl-GATA1 mice developed an anticipated dissemination of L. amazonensis and a worsening disease. No differences were found in the lesion development or the parasite load in the footpad among Δdbl-GATA1 mice and BALB/c eight weeks after infection. However, nine weeks after infection, massive growth of metastatic lesions appeared in several parts of the skin in Δdbl-GATA1 mice, weeks earlier than BALB/c. We observed increased parasites in the bloodstream, probably an essential dissemination route. Thirteen weeks after infection, metastatic lesions were found in all Δdbl-GATA1 mice. MAIN CONCLUSION: These results suggest a protective role of eosinophils in delaying the disease caused by L. amazonensis, although several limitations of this mice strain must be considered.

Preclinical evaluation of L-fucoside from lapachol-loaded nanoemulsion as a strategy to breast cancer treatment.

Breast cancer prevails as the most common cancer in women, underscoring an urgent need for more effective therapies. This study explores the potential of our newly developed nanoemulsion containing a novel fucoside derivative of lapachol (NE-F-LapA) as an intravenous treatment strategy. We sought to overcome the solubility issues associated with fucoside with this improved drug delivery strategy that enhances tumor delivery and mitigates other dose-limiting toxicities. Nanoemulsion was prepared and characterized by DLS, zeta potential, encapsulation efficiency, and storage stability. Cytotoxicity against breast cancer cell lines (4T1 and MDA-MB-231) and non-tumor human fibroblasts (NTHF) were evaluated. In vivo assays included antitumoral activity performance and acute systemic toxicity in mice models. NE-F-LapA was synthesized and optimized to 200 nm size, - 20 mV zeta potential, and near-complete (>98%) drug encapsulation. Stability exceeded 6 months, and biological fluid exposure maintained suitable properties for administration. In vitro, NE-F-LapA showed high toxicity (3 µM) against 4T1 and MDA-MB-231, enhanced five times the breast cancer cell uptake and three times the selectivity when compared to normal cells. Systemic toxicity assessment in mice revealed no concerning hematological or biochemical changes. Finally, in a 4T1 breast tumor model, NE-F-LapA significantly inhibited growth by 50% of the subcutaneous 4T1 tumor and reduced lung metastases 5-fold versus control. Overall, tailored nanoemulsification of the lapachol derivative enabled effective intravenous administration and improved efficacy over the free drug, indicating promise for enhanced breast cancer therapy pending further optimization.

The absence of eosinophils is associated with early metastatic lesions in Leishmania amazonensis-infected mice

BACKGROUND Eosinophils are granulocytes that rapidly increase frequency in the bloodstream during helminthic infections and allergic responses. They are found in tissue infected by Leishmania during early disease, but their role during infection is not entirely understood. OBJECTIVES We aim to compare the disease due to Leishmania amazonensis in BALB/c and Δdbl-GATA1 mice, which lack eosinophils. METHODS BALB/c and Δdbl-GATA1 mice infected with L. amazonensis were observed for several weeks. The parasite load and dissemination pattern were assessed. FINDINGS The Δdbl-GATA1 mice developed an anticipated dissemination of L. amazonensis and a worsening disease. No differences were found in the lesion development or the parasite load in the footpad among Δdbl-GATA1 mice and BALB/c eight weeks after infection. However, nine weeks after infection, massive growth of metastatic lesions appeared in several parts of the skin in Δdbl-GATA1 mice, weeks earlier than BALB/c. We observed increased parasites in the bloodstream, probably an essential dissemination route. Thirteen weeks after infection, metastatic lesions were found in all Δdbl-GATA1 mice. MAIN CONCLUSION These results suggest a protective role of eosinophils in delaying the disease caused by L. amazonensis, although several limitations of this mice strain must be considered.

In Vitro and Preclinical Antitumor Evaluation of Doxorubicin Liposomes Coated with a Cholesterol-Based Trimeric ß-D-Glucopyranosyltriazole.

The coating of liposomes with polyethyleneglycol (PEG) has been extensively discussed over the years as a strategy for enhancing the in vivo and in vitro stability of nanostructures, including doxorubicin-loaded liposomes. However, studies have shown some important disadvantages of the PEG molecule as a long-circulation agent, including the immunogenic role of PEG, which limits its clinical use in repeated doses. In this context, hydrophilic molecules as carbohydrates have been proposed as an alternative to coating liposomes. Thus, this work studied the cytotoxicity and preclinical antitumor activity of liposomes coated with a glycosyl triazole glucose (GlcL-DOX) derivative as a potential strategy against breast cancer. The glucose-coating of liposomes enhanced the storage stability compared to PEG-coated liposomes, with the suitable retention of DOX encapsulation. The antitumor activity, using a 4T1 breast cancer mouse model, shows that GlcL-DOX controlled the tumor growth in 58.5% versus 35.3% for PEG-coated liposomes (PegL-DOX). Additionally, in the preliminary analysis of the GlcL-DOX systemic toxicity, the glucose-coating liposomes reduced the body weight loss and hepatotoxicity compared to other DOX-treated groups. Therefore, GlcL-DOX could be a promising alternative for treating breast tumors. Further studies are required to elucidate the complete GlcL-DOX safety profile.

Alpha-tocopheryl succinate and doxorubicin-loaded liposomes improve drug uptake and tumor accumulation in a murine breast tumor model.

Liposomes composed of a rigid bilayer have high plasma stability; however, they can be challenged in efficacy due to complications in releasing the encapsulated drug as well as being internalized by the tumor cell. On the other hand, fusogenic liposomes may fuse with the plasmatic membrane and release encapsulated material directly into the cytoplasm. In a previous study, fusogenic liposomes composed of alpha-tocopheryl succinate (TS) and doxorubicin (DOX) were developed (pHSL-TS-DOX). These stabilized tumor growth and reduced toxicity compared to a commercial formulation. In the present study, we investigated whether cellular uptake or DOX accumulation in the tumor could justify the better performance of the pHSL-TS-DOX formulation. Release, deformability, and DOX plasmatic concentration studies were also carried out. pHSL-TS-DOX showed an adequate release profile and demonstrated characteristics of a deformable formulation. Data from apoptosis, cell cycle, and nuclear morphology studies have shown that the induction of cell death caused by pHSL-TS-DOX occurred more quickly. Higher DOX cellular uptake and tumor accumulation were observed when pHSL-TS-DOX was administered, demonstrating better drug delivery capacity. Therefore, better DOX uptake as well as tumor accumulation explain the great antitumor activity previously demonstrated for this formulation.

Toxins from Animal Venoms as a Potential Source of Antimalarials: A Comprehensive Review.

Malaria is an infectious disease caused by Plasmodium spp. and it is mainly transmitted to humans by female mosquitoes of the genus Anopheles. Malaria is an important global public health problem due to its high rates of morbidity and mortality. At present, drug therapies and vector control with insecticides are respectively the most commonly used methods for the treatment and control of malaria. However, several studies have shown the resistance of Plasmodium to drugs that are recommended for the treatment of malaria. In view of this, it is necessary to carry out studies to discover new antimalarial molecules as lead compounds for the development of new medicines. In this sense, in the last few decades, animal venoms have attracted attention as a potential source for new antimalarial molecules. Therefore, the aim of this review was to summarize animal venom toxins with antimalarial activity found in the literature. From this research, 50 isolated substances, 4 venom fractions and 7 venom extracts from animals such as anurans, spiders, scorpions, snakes, and bees were identified. These toxins act as inhibitors at different key points in the biological cycle of Plasmodium and may be important in the context of the resistance of Plasmodium to currently available antimalarial drugs.

Emetic Tartar-Loaded Liposomes as a New Strategy for Leishmaniasis Treatment.

Emetic tartar (ET), was used in the treatment of leishmaniasis but its use was discontinued due to its low therapeutic index. Liposomes have been shown to be a promising strategy for delivery of bioactive substances in the region of interest, in order to reduce and/or eliminate undesirable effects. In the present study, liposomes containing ET were prepared and characterized to evaluate acute toxicity as well as their leishmanicidal action using BALB/c mice with an inoculum of Leishmania (Leishmania) infantum. Liposomes were composed of egg phosphatidylcholine and 3ß-[N-(N',N'-dimethylaminoethane)-carbamoyl]cholesterol, with an average diameter of 200 nm, zeta potential of +18 mV, and ET encapsulated into liposomes at a concentration near 2 g/L. Healthy mice were treated with ET or liposome containing ET (Lip-ET) in a single dose of 16 mg/kg of Sb3+ intravenously and observed for 14 days. The death of two animals in the ET-treated group and no deaths in the Lip-ET-treated group was observed. Higher hepatic and cardiac toxicity were observed in animals treated with ET when compared to animals treated with Lip-ET, blank liposomes (Blank-Lip) and PBS. The study of antileishmanial efficacy was conducted by intraperitoneal administration of Lip-ET, for ten consecutive days. It was observed by limiting dilution that treatments with liposomal formulations containing ET, as well as Glucantime®, led to a significant reduction in parasitic load in spleen and liver (p < 0.05) when compared to the untreated control group.

Co-Encapsulation of Simvastatin and Doxorubicin into pH-Sensitive Liposomes Enhances Antitumoral Activity in Breast Cancer Cell Lines.

Doxorubicin (DOX) is a potent chemotherapeutic drug used as the first line in breast cancer treatment; however, cardiotoxicity is the main drawback of the therapy. Preclinical studies evidenced that the association of simvastatin (SIM) with DOX leads to a better prognosis with reduced side effects and deaths. In this work, a novel pH-sensitive liposomal formulation capable of co-encapsulating DOX and SIM at different molar ratios was investigated for its potential in breast tumor treatment. Studies on physicochemical characterization of the liposomal formulations were carried out. The cytotoxic effects of DOX, SIM, and their combinations at different molar ratios (1:1; 1:2 and 2:1), free or co-encapsulated into pH-sensitive liposomes, were evaluated against three human breast cancer cell lines (MDA-MB-231, MCF-7, and SK-BR-3). Experimental protocols included cell viability, combination index, nuclear morphological changes, and migration capacity. The formulations showed a mean diameter of less than 200 nm, with a polydispersity index lower than 0.3. The encapsulation content was ~100% and ~70% for DOX and SIM, respectively. A more pronounced inhibitory effect on breast cancer cell lines was observed at a DOX:SIM molar ratio of 2:1 in both free and encapsulated drugs. Furthermore, the 2:1 ratio showed synergistic combination rates for all concentrations of cell inhibition analyzed (50, 75, and 90%). The results demonstrated the promising potential of the co-encapsulated liposome for breast tumor treatment.

Cisplatin-Loaded Thermosensitive Liposomes Functionalized with Hyaluronic Acid: Cytotoxicity and In Vivo Acute Toxicity Evaluation.

Cisplatin (CDDP) is a potent antitumor drug used in first-line chemotherapy against several solid tumors, including breast cancer. However, toxicities and drug resistance limit its clinical application. Thermosensitive liposome (TSL) functionalized with hyaluronic acid (HA) containing cisplatin (TSL-CDDP-HA) was developed by our research group aiming to promote the release of CDDP in the tumor region under hyperthermia conditions, as well as to decrease toxicity. Thus, this study aimed to evaluate this new formulation (HA-coated TSL-CDDP) concerning in vitro behavior and in vivo toxicity compared to non-coated TSL-CDDP and free CDDP. Cytotoxicity assays and nuclear morphology were carried out against triple-negative breast cancer cells (MDA-MB-231), while an in vivo toxicity study was performed using healthy Swiss mice. The results showed an increase (around 3-fold) in cytotoxicity of the cationic formulation (non-coated TSL-CDDP) compared to free CDDP. On the other hand, TSL-CDDP treatment induced the appearance of 2.5-fold more senescent cells with alteration of nuclear morphology than the free drug after hyperthermia condition. Furthermore, the association of liposomal formulations treatment with hyperthermia increased the percentage of apoptotic cells compared to those without heating. The percentage of apoptotic cells was 1.7-fold higher for TSL-CDDP-HA than for TSL-CDDP. For the in vivo toxicity data, the TSL-CDDP treatment was also toxic to healthy cells, inducing nephrotoxicity with a significant increase in urea levels compared to the saline control group (73.1 ± 2.4 vs. 49.2 ± 2.8 mg/mL). On the other hand, the HA-coated TSL-CDDP eliminated the damages related to the use of CDDP since the animals did not show changes in hematological and biochemical examinations and histological analyses. Thus, data suggest that this new formulation is a potential candidate for the intravenous therapy of solid tumors.

Clinical acute presentation of lumbar facet joint ganglia with bilateral sciatica / Apresentação clínica aguda de quistos facetários lombares com ciatalgia bilateral / Presentación clinica aguda de quistes facetarios lumbares con dolor ciático bilateral

ABSTRACT Facet joint ganglia are benign cystic lesions located adjacent to a facet joint. The majority is asymptomatic. However, can cause important low-back pain and radiculopathy. Neurogenic deficit, claudication, and cauda equina syndrome have also been reported. The authors report two cases of acute low back pain with bilateral sciatica, dorsal foot dysesthesia, and hallux dorsiflexion/extension deficit, due to the presence of encapsulated cysts adjacent to the facet joints causing a significant reduction of the spinal canal. Urgent surgical decompression was performed in both patients with an uneventful recovery. Symptomatic facet joint ganglia is a highly unusual cause of back pain, although it can present with acute onset of bilateral sciatica and canal stenosis requiring urgent surgical decompression. This paper highlights facet joint synovial as a differential diagnosis of lumbar pain and describes two different surgical approaches with good outcomes. Level of Evidence IV; Case Series.

RESUMO: Os quistos facetários são lesões císticas benignas localizadas adjacentes a uma articulação facetária. A maioria é assintomática. No entanto, podem ser causa de importante dor lombar e radiculopatia. Estão ainda relatados casos de déficit neurogénico, claudicação e síndrome de cauda equina. Os autores apresentam dois casos de dor lombar aguda com ciatalgia bilateral, disestesia do dorso do pé e défice na dorsiflexão/extensão do hálux, causados por uma redução significativa do canal medular devido à presença de quistos encapsulados adjacentes às articulações facetarias. Os doentes foram submetidos a descompressão cirúrgica urgente com uma excelente recuperação. Os quistos facetários sintomáticas são uma causa rara de lombalgia, porém podem apresentar-se inicialmente com um quadro agudo de ciatalgia bilateral e estenose canalar com necessidade de descompressão cirúrgica urgente. Este artigo realça os quistos facetários como diagnóstico diferencial de lombalgia e descreve duas abordagens cirúrgicas diferentes com bons resultados. Nível de Evidência IV; Série de Casos.

RESUMEN: Los quistes facetarios son lesiones quísticas benignas situadas junto a una articulación facetaria. La mayoría es asintomática. Pero pueden causar dolor lumbar y radiculopatía importantes. También se han descrito déficit neurogénico, claudicación y síndrome de cauda equina. Los autores presentan dos casos de lumbalgia aguda con dolor ciático bilateral, disestesia del dorso del pie y déficit en la dorsiflexión/extensión del hallux, causados por una reducción significativa del canal medular debido a la presencia de quistes encapsulados adyacentes a las articulaciones facetarias. Los pacientes fueron sometidos a descompresión quirúrgica urgente con una excelente recuperación. Los quistes facetarios sintomáticos son una causa poco frecuente de lumbalgia, aunque pueden presentarse inicialmente con un cuadro agudo de dolor ciático bilateral y estenosis del canal que requiere descompresión quirúrgica urgente. Este artículo destaca los quistes facetarios como diagnóstico diferencial de la lumbalgia y describe dos abordajes quirúrgicos diferentes con buenos resultados. Nivel de Evidencia IV; Serie de Casos.

Intoxicação de cães por venenos de anuros: prevalência, danos aos animais e protocolos clínicos / Dog poisoning by anuran poisons: prevalence, animal damage and clinical protocols

Indivíduos da família Bufonidae são comumente associados a casos de intoxicação de cães após contato com o veneno secretado nas glândulas presentes no tegumento, reforçando a importância de tratamentos efetivos após esta interação. Neste trabalho apresentamos uma revisão sobre casos de intoxicação de cães por venenos de anuros, relacionando os principais sintomas nos cães e os protocolos clínicos utilizados. Realizamos uma busca por artigos que relatem casos de intoxicação de cães por anuros nos repositórios Google Scholar, Scielo e PubMed. Utilizamos palavras-chave nos idiomas português e inglês. Um total de 430 artigos foram encontrados, sendo apenas 17 de acordo com a proposta da pesquisa. Os registros encontrados foram para o Brasil, Austrália e Estados Unidos. As espécies de anuros reportadas na literatura foram exclusivamente as do gênero Rhinella. O maior número dos casos registrados no Brasil ocorreu em ambiente urbano. Os principais sintomas descritos após intoxicação de cães foram salivação em excesso, convulsão e vômito. Óbitos também foram encontrados durante a busca. Principais protocolos para o tratamento após envenenamento foram lavagem da cavidade oral do cão, e administração de atropina, diazepam e fluidoterapia. Foi observado que há influência do tamanho dos cães na severidade após intoxicação, sendo os de pequeno porte mais suscetíveis a quadros letais. Sugerimos, por conta do baixo número de registros, que possivelmente a quantidade de casos acerca desta temática seja subestimado. Neste estudo evidenciamos que os protocolos utilizados para o cuidado dos cães intoxicados não são realizados de forma padrão, alterando de acordo com o quadro clínico apresentado.

Individuals of the Bufonidae family are commonly associated with cases of poisoning in dogs after contact with the venom secreted in glands present in the tegument, reinforcing the importance of effective treatments after this interaction. In this paper, we present a review of cases of poisoning in dogs by anuran venom, relating the main symptoms in dogs and the clinical protocols used. We performed a search for articles reporting cases of anuran poisoning in dogs in the Google Scholar, Scielo, and PubMed repositories. We used keywords in Portuguese and English. A total of 430 articles were found and only 17 of which were in accordance with the research proposal. The records found were for Brazil, Australia, and the United States. The species of anurans reported in the literature were exclusively those of the genus Rhinella. The greatest number of cases registered in Brazil occurred in an urban environment. The main symptoms described after intoxication in dogs were excessive salivation, convulsion, and vomiting. Deaths were also found during the search. The main protocols for treatment after poisoning were washing the dog's oral cavity, and administration of atropine, diazepam, and fluid therapy. It was observed that the size of the dogs influences the severity after intoxication, with small dogs being more susceptible to lethal conditions. Due to the low number of records, we suggest that the number of cases on this topic is possibly underestimated. In this study, we showed that the protocols used for the care of intoxicated dogs are not performed in a standard way, changing according to the clinical picture presented.

Irinotecan-Loaded Polymeric Micelles as a Promising Alternative to Enhance Antitumor Efficacy in Colorectal Cancer Therapy.

Colorectal cancer has been considered a worldwide public health problem since current treatments are often ineffective. Irinotecan is a frontline chemotherapeutic agent that has dose-limiting side effects that compromise its therapeutic potential. Therefore, it is necessary to develop a novel, targeted drug delivery system with high therapeutic efficacy and an improved safety profile. Here, micellar formulations composed of 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethyleneglycol)-2000] (DSPE-mPEG2k) containing irinotecan were proposed as a strategy for colorectal cancer therapy. Firstly, the irinotecan-loaded micelles were prepared using the solvent evaporation method. Then, micelles were characterized in terms of size, polydispersity, zeta potential, entrapment efficiency, and release kinetics. Cytotoxicity and in vivo antitumor activity were evaluated. The micelles showed size around 13 nm, zeta potential near neutral (-0.5 mV), and encapsulation efficiency around 68.5% (irinotecan 3 mg/mL) with a sustained drug release within the first 8 h. The micelles were evaluated in a CT26 tumor animal model showing inhibition of tumor growth (89%) higher than free drug (68.7%). Body weight variation, hemolytic activity, hematological, and biochemical data showed that, at the dose of 7.5 mg/kg, the irinotecan-loaded micelles have low toxicity. In summary, our findings provide evidence that DSPE-mPEG2k micelles could be considered potential carriers for future irinotecan delivery and their possible therapeutic application against colorectal cancer.

Investigation of the Antitumor Activity and Toxicity of Tumor-Derived Exosomes Fused with Long-Circulating and pH-Sensitive Liposomes Containing Doxorubicin.

Exosome-liposome hybrid nanocarriers containing chemotherapeutic agents have been developed to enhance drug delivery, improve the efficacy of the treatment of metastatic cancer, and overcome chemoresistance in cancer therapy. Thus, the objectives of this study were to investigate the toxicological profiles of exosomes fused with long-circulating and pH-sensitive liposomes containing doxorubicin (ExoSpHL-DOX) in healthy mice and the antitumor activity of ExoSpHL-DOX in Balb/c female mice bearing 4T1 breast tumors. The acute toxicity was determined by evaluating the mortality and morbidity of the animals and conducting hematological, biochemical, and histopathological analyses after a single intravenous administration of ExoSpHL-DOX. The results of the study indicated that the ExoSpHL-DOX treatment is less toxic than the free doxorubicin (DOX) treatment. ExoSpHL-DOX showed no signs of nephrotoxicity, even at the highest dose of DOX, indicating that the hybrid nanosystem may alter the distribution of DOX and reduce the kidney damage. Regarding the antitumor activity, ExoSpHL-DOX showed an antitumor effect compared to the control group. Furthermore, the hybrid nanocarrier of tumor-derived exosomes fused with long-circulating and pH-sensitive liposomes reduced the number of metastatic foci in the lungs. These results indicate that ExoSpHL-DOX may be a promising nanocarrier for the treatment of breast cancer, reducing toxicity and inhibiting metastasis, mainly in the lungs.

Current Applications of Plant-Based Drug Delivery Nano Systems for Leishmaniasis Treatment.

Leishmania is a trypanosomatid that causes leishmaniasis. It is transmitted to vertebrate hosts during the blood meal of phlebotomine sandflies. The clinical manifestations of the disease are associated with several factors, such as the Leishmania species, virulence and pathogenicity, the host-parasite relationship, and the host's immune system. Although its causative agents have been known and studied for decades, there have been few advances in the chemotherapy of leishmaniasis. The urgency of more selective and less toxic alternatives for the treatment of leishmaniasis leads to research focused on the study of new pharmaceuticals, improvement of existing drugs, and new routes of drug administration. Natural resources of plant origin are promising sources of bioactive substances, and the use of ethnopharmacology and folk medicine leads to interest in studying new medications from phytocomplexes. However, the intrinsic low water solubility of plant derivatives is an obstacle to developing a therapeutic product. Nanotechnology could help overcome these obstacles by improving the availability of common substances in water. To contribute to this scenario, this article provides a review of nanocarriers developed for delivering plant-extracted compounds to treat clinical forms of leishmaniasis and critically analyzing them and pointing out the future perspectives for their application.

In Vitro and In Vivo Effect of pH-Sensitive PLGA-TPGS-Based Hybrid Nanoparticles Loaded with Doxorubicin for Breast Cancer Therapy.

Doxorubicin (DOX) is an antineoplastic agent clinically employed for treating breast cancer patients. Despite its effectiveness, its inherent adverse toxic side effects often limit its clinical application. To overcome these drawbacks, lipid-polymer hybrid nanoparticles (LPNP) arise as promising nanoplatforms that combine the advantages of both liposomes and polymeric nanoparticles into a single delivery system. Alpha-tocopherol succinate (TS) is a derivative of vitamin E that shows potent anticancer mechanisms, and it is an interesting approach as adjuvant. In this study, we designed a pH-sensitive PLGA-polymer-core/TPGS-lipid-shell hybrid nanoparticle, loaded with DOX and TS (LPNP_TS-DOX). Nanoparticles were physicochemically and morphologically characterized. Cytotoxicity studies, migration assay, and cellular uptake were performed in 4T1, MCF-7, and MDA-MB-231 cell lines. Antitumor activity in vivo was evaluated in 4T1 breast tumor-bearing mice. In vitro studies showed a significant reduction in cell viability, cell migration, and an increase in cellular uptake for the 4T1 cell line compared to free DOX. In vivo antitumor activity showed that LPNP-TS-DOX was more effective in controlling tumor growth than other treatments. The high cellular internalization and the pH-triggered payload release of DOX lead to the increased accumulation of the drugs in the tumor area, along with the synergic combination with TS, culminating in greater antitumor efficacy. These data support LPNP-TS-DOX as a promising drug delivery system for breast cancer treatment.

The Amazonian kambô frog Phyllomedusa bicolor (Amphibia: Phyllomedusidae): Current knowledge on biology, phylogeography, toxinology, ethnopharmacology and medical aspects.

Phyllomedusa bicolor (Phyllomedusidae), popularly known as the kambô in Brazil, is a tree frog that is widely distributed in South American countries and is known for producing a skin secretion that is rich in bioactive peptides, which are often used in indigenous rituals. The biological effects of the skin secretion were observed in the first studies with indigenous communities. Over the last six decades, researchers have been studying the chemical composition in detail, as well as the potential pharmacological applications of its constituents. For this reason, indigenous communities and health agents fear the misuse of the kambô, or the inappropriate use of the species, which can result in health complications or even death of users. This article seeks to provide a transdisciplinary review that integrates knowledge regarding the biology of P. bicolor, ethnoknowledge about the ritual of the kambô, and the chemistry and pharmacology of the skin secretion of this species, in addition to medical aspects of the indiscriminate use of the kambô. Furthermore, this review seeks to shed light on perspectives on the future of research related to the kambô.

Cholesterol improves stability of amphotericin B nanoemulsion: promising use in the treatment of cutaneous leishmaniasis.

Aim: Amphotericin B (AmB) is an antileishmanial drug with high toxicity; however, this drawback might overcome by decreasing the AmB self-aggregation state. This work aimed at evaluating the influence of cholesterol on the aggregation state of AmB loaded in a nanoemulsion (NE-AmB) for the treatment of cutaneous leishmaniasis. NE-AmB (1, 4 and 8 mg/kg/day) was administered intravenously to animals infected by Leishmania major every 2 days for a total of five injections. Results: Ultraviolet-visible spectroscopy and circular dichroism studies demonstrated that cholesterol reduced AmB aggregation state in NE. NE-AmB was stable after 180 days, and its hemolytic toxicity was lower than that observed for the conventional AmB. NE-AmB administered intravenously into animals infected by Leishmania major at 8 mg/kg was capable of stabilizing the lesion size and reducing the parasitic load. Conclusion: These findings support the NE potential as a stable nanocarrier for AmB in the treatment of cutaneous leishmaniasis.