Integrated aerobic exercise with LDE-docetaxel treatment: a novel approach to combat prostate cancer progression.

The variability in response to conventional prostate cancer (PC) therapies, coupled with the emergent issue of drug resistance, underscores the critical need for innovative treatment strategies. Aerobic physical exercise reduced incidence of several cancers, but the mechanism underlying these effects associated the nanoemulsion not fully understood. The application of a lipid nanoemulsion (LDE) delivery system for docetaxel (DTX), showing marked enhancement in therapeutic efficacy when combined with aerobic physical exercise. This novel intervention potentiates the antitumor activity of LDE-delivered DTX by augmenting nanoparticle internalization and inducing cell cycle arrest. Our findings reveal that this synergistic treatment not only significantly reduces prostate weight and mitigates adenocarcinoma proliferation but also attenuates anti-apoptotic BCL-2 protein expression. Concurrently, it elevates pro-apoptotic proteins and diminishes inflammatory markers. Metabolic profiling of the combined therapy group disclosed additional benefits, such as reduced lipid and plasma glucose levels. Collectively, our data illuminate the profound impact of integrating LDE-mediated DTX delivery with structured physical exercise, which together spearhead a dual-front assault on PC. This multimodal approach heralds a new paradigm in PC management, accentuating the promise of combined pharmacological and non-pharmacological interventions to elevate tumor suppressor protein activity and refine patient outcomes.

Treatment With Methotrexate Associated With Lipid Core Nanoparticles Prevents Aortic Dilation in a Murine Model of Marfan Syndrome.

In Marfan syndrome (MFS), dilation, dissection, and rupture of the aorta occur. Inflammation can be involved in the pathogenicity of aortic defects and can thus be a therapeutic target for MFS. Previously, we showed that the formulation of methotrexate (MTX) associated with lipid nanoparticles (LDE) has potent anti-inflammatory effects without toxicity. To investigate whether LDEMTX treatment can prevent the development of aortic lesions in the MFS murine model. MgΔloxPneo MFS (n = 40) and wild-type (WT, n = 60) mice were allocated to 6 groups weekly injected with IP solutions of: (1) only LDE; (2) commercial MTX; (3) LDEMTX (dose = 1mg/kg) between 3rd and 6th months of life. After 12 weeks of treatments, animals were examined by echocardiography and euthanatized for morphometric and molecular studies. MFS mice treated with LDEMTX showed narrower lumens in the aortic arch, as well as in the ascending and descending aorta. LDEMTX reduced fibrosis and the number of dissections in MFS but not the number of elastic fiber disruptions. In MFS mice, LDEMTX treatment lowered protein expression of pro-inflammatory factors macrophages (CD68), T-lymphocytes (CD3), tumor necrosis factor-α (TNF-α), apoptotic factor cleaved-caspase 3, and type 1 collagen and lowered the protein expression of the transforming growth factor-ß (TGF-ß), extracellular signal-regulated kinases ½ (ERK1/2), and SMAD3. Protein expression of CD68 and CD3 had a positive correlation with an area of aortic lumen (r 2 = 0.36; p < 0.001), suggesting the importance of inflammation in the causative mechanisms of aortic dilation. Enhanced adenosine availability by LDEMTX was suggested by higher aortic expression of an anti-adenosine A2a receptor (A2a) and lower adenosine deaminase expression. Commercial MTX had negligible effects. LDEMTX prevented the development of MFS-associated aortic defects and can thus be a candidate for testing in clinical studies.

Uptake of lipid core nanoparticles by fragments of tissues collected during cerebral tumor excision surgeries: hypotheses for use in drug targeting therapy.

PURPOSE: Malignant cerebral tumors have poor prognosis and the blood-brain barrier is a major hindrance for most drugs to reach those tumors. Lipid nanoparticles (LDE) that bind to lipoprotein receptors may carry anticancer drugs and penetrate the cells through those receptors that are overexpressed in gliomas. The aim was to investigate the in vivo uptake of LDE by human cerebral tumors. METHODS: Twelve consecutive patients (4 with glioblastomas, 1 meduloblastoma, 1 primary lymphoma, 2 with non-cerebral metastases and 4 with benign tumors) scheduled for tumor excision surgery were injected intravenously, 12 h before surgery, with LDE labeled 14C-cholesterol oleate. Fragments of tumors and of normal head tissues (muscle, periosteum, dura mater) discarded by the surgeon were submitted to lipid extraction and radioactive counting. RESULTS: Tumor LDE uptake (range: 10-283 d.p.m./g of tissue) was not lower than that of normal tissues (range: 20-263 d.p.m./g). Malignant tumor uptake was threefold greater than benign tumor uptake (140 ± 93 vs 46 ± 18 d.p.m./g, p < 0.05). Results show that LDE can concentrate in brain malignant tumors and may be used to carry drugs directed against those tumors. CONCLUSION: As LDE was previously shown to markedly decrease drug toxicity this new therapeutic strategy should be tested in future trials.

Lipid nanoparticles for amphotericin delivery in the treatment of American tegumentary leishmaniasis.

Leishmaniasis occurs in the five continents and represents a serious public health challenge, but is still a neglected disease, and the current pharmacological weaponry is far from satisfactory. Triglyceride-rich nanoparticles mimicking chylomicrons (TGNP) behave metabolically like native chylomicrons when injected into the bloodstream. Previously we have shown that TGNP as vehicle to amphothericin B (AB) for treatment of fungi infection showed reduced renal toxicity and lower animal death rates compared to conventional AB. The aim of the current study was to test the tolerability and effectiveness of the TGNP-AB preparation in a murine model of Leishmania amazonensis infection. The in vitro assays determined the cytotoxicity of TGNP-AB, AB, and TGNP in macrophages and promastigote forms and the leishmanicidal activity in infected macrophages. The in vivo toxicity tests were performed in healthy mice with increasing doses of TGPN-AB and AB. Then, animals were treated with 2.5 mg/kg/day of AB, 17.5 mg/kg/day of TGNP-AB, or TGNP three times a week for 4 weeks. TGNP-AB formulation was less cytotoxic for macrophages than AB. TGNP-AB was more effective than AB against the promastigotes forms of the parasite and more effective in reducing the number of infected macrophages and the number of amastigotes forms per cell. TGNP-AB-treated animals showed lower hepatotoxicity. In addition, TGNP-AB group showed a marked reduction in lesion size on the paws and parasitic load. The TGNP-AB preparation attained excellent leishmanicidal activity with remarkable lower drug toxicity at very high doses that, due to the toxicity-buffering properties of the nanocarrier, become fully tolerable.

Veiculação de quimioterápicos isolados ou em combinação através de nanoemulsões lipídicas para o tratamento da aterosclerose: estudos em coelho / Vehiculation of chemotherapeutic agents isolated or in combination by lipid nanoemulsions in atherosclerosis treatment. studies in rabbit

Aterosclerose é uma doença inflamatória e proliferativa que tem início quando fatores de risco alteram o endotélio vascular. Células inflamatórias e vasculares liberam citocinas e fatores de crescimento que estimulam a proliferação e migração das células de músculo liso e a síntese de componentes da matriz extracelular. A nanoemulsão lipídica LDE se concentra em regiões onde a proliferação celular e a inflamação são maiores, tornando-se um veículo para fármacos. O etoposide, fármaco antiproliferativo, ainda não foi explorado no tratamento da aterosclerose. O paclitaxel recobre stents utilizados em angioplastia para evitar a reestenose. A associação do LDE-etoposide ao LDE-paclitaxel aumentaria o efeito antiproliferativo dos fármacos isolados, por agirem em diferentes fases do ciclo celular. Este estudo tem por objetivos avaliar a eficácia do tratamento com LDE-etoposide e com a combinação LDE-etoposide/LDE-paclitaxel da aterosclerose induzida por dieta rica em colesterol em coelhos; comparar a eficácia dos tratamentos; no grupo de tratamento mais eficaz e no grupo Controle, avalia a expressão protéica de receptores de lipoproteínas, citocinas, MMP9 e marcadores de proliferação celular. Para tanto, 27 coelhos receberam dieta rica em colesterol por 8 semanas. Depois de 4 semanas, foram divididos em 3 grupos: grupo Controle, que recebeu 6 mL de solução salina intravenosa; LDE-etoposide, que recebeu dose de 6mg/kg; e grupo Combinação, que recebeu LDE-etoposide/LDE-paclitaxel nas doses de 6mg/kg e 4mg/kg, respectivamente. Os tratamentos foram administrados uma vez por semana durante 4 semanas. Foram avaliados perfil lipídico, hematológico, ponderal e o consumo de ração. Após a eutanásia, as lesões ateroscleróticas macroscópicas foram medidas. Depois, o arco aórtico foi analisado por morfometria e por imunohistoquímica. Foi observado que não houve diferença no perfil ponderal e no consumo de ração entre os grupos de estudo. No perfil lipídico, ao final do estudo...

Atherosclerosis is an inflammatory and proliferative disease that is triggered by risk factors damaging vascular endothelium. Inflammatory and vascular cells release cytokines and growth factors, promoting the proliferation and migration of smooth muscle cells and extracellular matrix elements synthesis. LDE, an artificial nanoemulsion, concentrates in areas of greater proliferation and inflammation rates and can be used as a vehicle to direct drugs to those cells. Etoposide, an antiproliferative drug, have not been studied in atherosclerosis treatment. Paclitaxel is used in drug-eluting stents to avoid restenosis. The association of LDE-etoposide and LDE-paclitaxel would enhance the antiproliferativo effect of the isolated drugs, due to act in different cell cycle phase. The aim of this study was to evaluate the effectiveness of the treatment with LDE-etoposide and with LDE-etoposide/LDE-paclitaxel of atherosclerosis induced by a cholesterol-rich diet in rabbits; compare the effectiveness of these treatments; in the most effective treatment group and in Control group, evaluate the protein expression of lipoprotein receptors, cytokines, MMP9 and cell proliferation markers. To do so, 3 groups of 9 rabbits were fed a cholesterol-rich diet during 8 weeks then the animals were separated in 3 groups: Control, intravenously injected with 6mL of saline solution; LDE-etoposide, injected with a dose 6mg/kg; and Combination, injected with LDE-etoposide/LDE-paclitaxel in a dose of 6mg/kg and 4mg/kg, respectively. Treatments were administered once a week during 4 weeks. Lipids, blood cell count, weight and food intake were evaluated. The animals were sacrificed and the macroscopic atherosclerotic lesions were measured. Later, the aortic arch was analyzed by microscopic morphometry and by immunohistochemistry. It was seen that there was no difference in food intake and weight between study groups. Total cholesterol and triglycerides concentration increased in all...