12, 13 Increasing evidence has shown that infiltrated macrophages and resident microglia acquire a tumor-associated macrophages (TAMs) phenotype to facilitate tumor progression. 9 – 11 Taking into account the GBM microenvironment, it has been shown that surrounding cells act to favor tumor development and invasiveness. These processes are highly complex and depend on physicochemical characteristics of nanoparticles and microenvironment such as the cell population at the site of therapeutic action. Once within the tumor site, LNC needs to be captured by surrounding cells and deliver the loaded drug to exert its therapeutic effect.
7 The higher efficiency of MTX-LNC on GBM treatment is possibly associated with enhanced drug delivery at the tumor site our group has previously shown that LNC is a technological platform suitable to carry medicines across the BBB. 6 It is noteworthy that MTX presents a narrow safety margin and low penetration across the BBB, which limits its therapeutic use for GBM treatment.
4, 5 Based on this hypothesis, our group has previously shown that methotrexate (MTX) incorporated into poly(ε-caprolactone) lipid-core nanocapsules (LNC) and administered by the intraperitoneal route was more efficient than a conventional MTX solution for the treatment of a rat glioma model. Over the past few years, it has been proposed that the incorporation of medicines to nanoparticles can be an effective strategy to overcome physiological barriers, including the BBB. 3 Therefore, innovative pharmacological approaches are imminently needed to provide effective GBM treatments. 2 For this reason, higher doses of medicines are required to achieve therapeutic concentrations in the brain, causing severe systemic toxic adverse effects. 1 The inability of drugs to cross the blood–brain barrier (BBB) to access the tumor site is the most prominent obstacle to the effectiveness of available chemotherapy. Glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor. Data from graph ( A) were analyzed by one-way ANOVA, whereas ( B– D) were analyzed by the Student’s t-test, * P<0.05 vs control.Ībbreviations: LDL, low-density lipoprotein HBSS, Hank’s balanced salt solution SEM, standard error of the mean ANOVA, analysis of variance. The results are expressed as mean ± SEM, n=3–5 per group. In all the cases, the control group was considered as the 100% reference. For phagocytosis analyses, the number of labeled cells (presence of phagosome) was counted, whereas for clathrin- or caveolin-mediated endocytosis, the fluorescence intensity (au) within cells was determined. BV2 cells were incubated with HBSS containing choleric toxin conjugated to Alexa Fluor 488 (10 µg/mL) in the absence (control) or presence of MβC (5 mmol/L). ( D) Positive control of caveolin-mediated endocytosis. BV2 cells were incubated with HBSS containing LDL conjugated to Alexa Fluor 488 (20 µg/mL) in the absence (control) or presence of high concentration of Suc (0.5 mol/L). ( C) Positive control of clathrin-mediated endocytosis. BV2 cells were incubated with HBSS containing zymozan conjugated to Alexa Fluor 488 (500 µg/mL) in the absence (control) or presence of Cyto D (10 µmol/L). ( B) Positive control of phagocytosis-mediated endocytosis. Figure S2: ( A) Bar graphs and representative images showing fluorescence of RhoB/MTX-LNC (5,500 nmol/L) in BV2 cells after 1, 5, 20, 40, or 60 minutes of incubation.
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