Abstract
BackgroundSarcomas comprise a group of aggressive malignancies with very little treatment options beyond standard chemotherapy. Reposition of approved drugs represents an attractive approach to identify effective therapeutic compounds. One example is mithramycin (MTM), a natural antibiotic which has demonstrated a strong antitumour activity in several tumour types, including sarcomas. However, its widespread use in the clinic was limited by its poor toxicity profile.ResultsIn order to improve the therapeutic index of MTM, we have loaded MTM into newly developed nanocarrier formulations. First, polylactide (PLA) polymeric nanoparticles (NPs) were generated by nanoprecipitation. Also, liposomes (LIP) were prepared by ethanol injection and evaporation solvent method. Finally, MTM-loaded hydrogels (HG) were obtained by passive loading using a urea derivative non-peptidic hydrogelator. MTM-loaded NPs and LIP display optimal hydrodynamic radii between 80 and 105 nm with a very low polydispersity index (PdI) and encapsulation efficiencies (EE) of 92 and 30%, respectively. All formulations show a high stability and different release rates ranging from a fast release in HG (100% after 30 min) to more sustained release from NPs (100% after 24 h) and LIP (40% after 48 h). In vitro assays confirmed that all assayed MTM formulations retain the cytotoxic, anti-invasive and anti-stemness potential of free MTM in models of myxoid liposarcoma, undifferentiated pleomorphic sarcoma and chondrosarcoma. In addition, whole genome transcriptomic analysis evidenced the ability of MTM, both free and encapsulated, to act as a multi-repressor of several tumour-promoting pathways at once. Importantly, the treatment of mice bearing sarcoma xenografts showed that encapsulated MTM exhibited enhanced therapeutic effects and was better tolerated than free MTM.ConclusionsOverall, these novel formulations may represent an efficient and safer MTM-delivering alternative for sarcoma treatment.Graphical abstract
Highlights
Mithramycin (MTM), called plycamicin is an antitumoural antibiotic natural product approved for the treatment of hypercalcemia [1] and which has demonstrated good antitumour responses in the treatment of testicular cancer, glioblastoma or Ewing sarcoma [2,3,4]
MTM-loaded hydrogels (MTM-HG) were obtained by passive loading after slow pH change of the hydrogelator 5-(3-(4-nitrophenyl)ureido)isophthalic acid generated by the well-controlled hydrolysis of glucono-δ-lactone (GL) (Fig. 1A–B) [30]
We had previously demonstrated that this tumoursphere model was highly enriched in cancer stem cells (CSCs) as seen by their increased ability to initiate tumour growth in transplantation assays in immunocompromised mice [35]. We found that both free MTM and all assayed MTM nanocarrier systems were able to reduce the number (IC50 ≈ 40–60 nM) and the size of T-5 H-FC#1 tumourspheres, without observing any toxic effect after the treatment with empty nanoparticles (Fig. 6A–B)
Summary
Mithramycin (MTM), called plycamicin is an antitumoural antibiotic natural product approved for the treatment of hypercalcemia [1] and which has demonstrated good antitumour responses in the treatment of testicular cancer, glioblastoma or Ewing sarcoma [2,3,4]. MTM has been found to interfere with the transcription mediated by a cancer-associated fusion gene [2, 7] and to induce differentiation through specific promoter reprogramming mechanisms [8] Despite these promising antitumour properties, the appearance of severe systemic toxicities, such as a dose-related bleeding syndrome and liver toxicity, has limited its clinical use [9, 10]. Since MTM had shown promising results for the treatment of pancreatic carcinoma through the inhibition of the transcription factor Sp1, MTM were loaded into polymeric nanoparticles These nanocarriers showed highly therapeutic efficacy in in vivo models of pancreatic carcinoma [17]. Its widespread use in the clinic was limited by its poor toxicity profile
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