ABSTRACT
Triple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells' proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.
Subject(s)
Antineoplastic Agents/administration & dosage , Nanoparticles/administration & dosage , Phospholipid Ethers/administration & dosage , Triple Negative Breast Neoplasms/drug therapy , Administration, Cutaneous , Animals , Antineoplastic Agents/pharmacokinetics , Apoptosis/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Drug Compounding/methods , Emulsions , Excipients/chemistry , Female , Humans , Nanoparticles/chemistry , Permeability , Phosphatidylcholines/chemistry , Phospholipid Ethers/pharmacokinetics , Skin/metabolism , Triglycerides/chemistry , Triple Negative Breast Neoplasms/pathology , Xenograft Model Antitumor Assays , ZebrafishABSTRACT
Macrophages are pivotal cells of the innate immune system specialized in the phagocytosis of foreign elements. Nanoparticles intentionally designed to target macrophages and modulate their response are of especial interest in the case of chronic inflammatory diseases, cancer and for vaccine development. This work aimed to understand the role of size and shell composition of polymeric nanocapsules (NCs) in their interaction with macrophages, both in vitro and in vivo. A systematic study was performed using two different sizes of inulin and chitosan NCs, negatively and positively charged, respectively, small (≈ 70â¯nm) and medium (170-250â¯nm). The in vitro results showed that small NCs interacted more efficiently with macrophages than their larger counterparts. Inulin NCs were significantly less toxic than chitosan NCs. Finally, following in vivo administration (intravenous/intramuscular) to zebrafish, small NCs, regardless of their composition, disseminated considerably faster and further than their medium size counterparts. These results emphasize how small changes in the nanometric range can lead to a remarkably different interaction with the immune cells and biodistribution profile.
Subject(s)
Chitosan/chemistry , Inulin/chemistry , Macrophages/metabolism , Nanocapsules , Animals , Mice , Particle Size , Polymers/chemistry , RAW 264.7 Cells , Tissue Distribution , ZebrafishABSTRACT
The human cancer cell xenograft in zebrafish embryos has become a very useful preclinical tool in oncology research. While many anticancer drugs have been assayed with this model, few studies regarding the toxicity limits of these drugs for the host have been addressed. Here, we evaluated the acute toxicity of five approved and routinely used human anticancer drugs embracing different mechanism action types: Carboplatin (CarboPt), Irinotecan (IT), Doxorubicin (DOX), Paclitaxel (PT) and Chloroquine (CQ). They were tested in zebrafish embryos using the Fish Embryo Acute Toxicity (FET) test at 0 and 72 hours per fertilization (hpf). Additionally, we compared those results with in vitro toxicity assays and could find notable differences between both models. Our results indicate that the toxicity data of a compound evaluated in vitro and in a FET test at 0 hpf do not guarantee a reliable toxicity determination for performing xenografts in zebrafish, being necessary additional toxicity studies using 72 hpf embryos, the starting point of drug treatment in this kind of preclinical assays.
Subject(s)
Antineoplastic Agents/toxicity , Drug Evaluation, Preclinical/methods , Embryo, Nonmammalian/drug effects , Embryonic Development/drug effects , Xenograft Model Antitumor Assays , Zebrafish , Animals , Time Factors , Toxicity Tests, AcuteABSTRACT
The zebrafish model can play a role in education because of its suitability for manipulation and attractiveness to students compared to traditional lecture-based instruction. Furthermore, zebrafish offer advantages over other model species. Seeing as fewer and fewer students are entering science degree programs, this project has been developed to encourage scientific vocations among secondary school students. To do so, an aquarium was given to 114 schools so that they could look after adult zebrafish, mate them, and visualize embryo development. For training on more sophisticated techniques, a virtual tool was developed to simulate a real genetics laboratory on a personal computer. Results based on teachers' feedback indicate that the students were fully dedicated to the project and achieved better understanding of genetic concepts and techniques. These results demonstrate the potential of alternative teaching methods for engaging students in science learning.
