Mechanisms of the effectiveness of poly(ε-caprolactone) lipid-core nanocapsules loaded with methotrexate on glioblastoma multiforme treatment

Abstract

PurposeThe low penetration of drugs across the blood–brain barrier (BBB) compromises the delivery of chemotherapeutic agents to the brain parenchyma and contributes to the poor prognosis of glioblastoma multiforme (GBM). We investigated the efficacy of methotrexate-loaded lipid-core nanocapsules (MTX-LNC) administered by the oral route to treat murine GBM, its ability to cross the BBB, and the mechanisms of MTX-LNC uptake by cultured GL261 glioma and BV2 microglia cells.Materials and methodsFemale C57B/6 mice were used in intravital microscopy assays to investigate the penetrance of rhodamine B-label MTX-LNC (RhoB/MTX-LNC) in the brain after oral or IV administration, and to evaluate the BBB integrity. Intracranial implantation of GL261 cells was undertaken to induce a murine GBM model, and the effectiveness of oral MTX or MTX-LNC treatments (started on Day 10 of GBM, every 2 days for 12 days) was quantified by tumor size, body weight, and leukogram. Pharmacological blockade of endocytic pathways was done to investigate the mechanisms of MTX-LNC uptake by cultured GL261 and microglia BV2 cells by using fluorescence microscopy. The effect of MTX-LNC or MTX on GL261 and BV2 proliferation was evaluated to compare the cytotoxicity of such compounds.ResultsRhoB/MTX-LNC was detected in brain parenchyma of mice after IV or oral administration, without any damage on BBB. Oral treatment with MTX-LNC reduced tumor volume and prevented weight loss and leukopenia in comparison to MTX-treated mice. MTX-LNC uptake by GL261 is caveolae-dependent, whereas endocytosis of MTX-LNC by BV2 occurs via phagocytosis and macropinocytosis. Both MTX-LNC and MTX reduced GL261 and BV2 proliferation; however, MTX-LNC showed higher efficacy in the inhibition of glioma proliferation.ConclusionTogether, we infer that the higher ability of MTX-LNC to cross the BBB and be captured by cancer and immune brain cells by different mechanisms is responsible for the higher efficacy of oral MTX-LNC treatment in GBM.

Direct Effects of poly(ε-caprolactone) lipid-core Nanocapsules on Human Immune Cells

“…Corroborating our previous studies [12,21], we here confirmed that LNCs prompted penetrated into cytoplasm of human PMBCs and PMNs without causing cell death. The LNCs concentrations employed in the present study exhibited a therapeutic efficacy in experimental models of melanoma and glioma in mice when daily administered by oral or intravenous routes for seven or 21 days [15,21,38].…”

“…PCL-LNCs present biodegradability and biocompatibility, which turn it into a promising drug carrier with a high potential for therapeutic applications [10,11]. In this way, it has been shown there is a therapeutic benefit of PCL-LNCs loaded with different molecules for treatment of cancer [12][13][14][15][16], inflammatory conditions [17][18][19] and neurodegenerative diseases [20]. Beyond its potential use as a drug carrier, we had previously shown that drug-free LNCs display in vitro and in vivo beneficial effects.…”

<p>Biomedical Applications of Multifunctional Polymeric Nanocarriers: A Review of Current Literature</p>

“… Tumor-bearing C57Bl6 mice after subcutaneous injection of B16F10 (murine melanoma) cells Passive PEGylated lipid squalene nanocarriers 135 Gemcitabine Convection-enhanced delivery (the infusion of therapeutic molecules directly into the brain) Healthy Sprague- Dawley or tumor-bearing Fischer 344 rats after intracranial implantation of RG2 (rat glioma) cells Passive PEGylated PLGA nanoca r riers 136 Glabrescione b i.v. Tumor-bearing SCID/Beige mice after subcutaneous injection of PANC-1 (human pancreas carcinoma) cells Passive PCLnanocarriers 137 Methotrexate Orally or i.v. Healthy or tumor-bearing C57Bl/6 mice after intracranial implantation of GL261 (murine glioma) cells Passive Chitosan and Eudragit S100 nanocarriers 138 Psoralidin Orally Healthy Sprague-Dawley rats Passive PCL nanocarriers 139 Resveratrol i.p.…”

Tailoring the Nanoparticles Surface for Efficient Cancer Therapeutics Delivery

“…Polymeric NPs are one of the most studied across all aspects of the field, including biomedical applications due to their facile synthesis [45,[67][68][69][70]. Polymeric NPs consist of the polymeric membrane, such as a hydrophilic and lipophilic surfactant.…”