Abstract
Sarcomas are aggressive tumors which often show a poor response to current treatments. As a promising therapeutic alternative, we focused on mithramycin (MTM), a natural antibiotic with a promising anti-tumor activity but also a relevant systemic toxicity. Therefore, the encapsulation of MTM in nano-delivery systems may represent a way to increase its therapeutic window. Here, we designed novel transfersomes and PLGA polymeric micelles by combining different membrane components (phosphatidylcholine, Span 60, Tween 20 and cholesterol) to optimize the nanoparticle size, polydispersity index (PDI) and encapsulation efficiency (EE). Using both thin film hydration and the ethanol injection methods we obtained MTM-loaded transferosomes displaying an optimal hydrodynamic diameter of 100–130 nm and EE values higher than 50%. Additionally, we used the emulsion/solvent evaporation method to synthesize polymeric micelles with a mean size of 228 nm and a narrow PDI, capable of encapsulating MTM with EE values up to 87%. These MTM nano-delivery systems mimicked the potent anti-tumor activity of free MTM, both in adherent and cancer stem cell-enriched tumorsphere cultures of myxoid liposarcoma and chondrosarcoma models. Similarly to free MTM, nanocarrier-delivered MTM efficiently inhibits the signaling mediated by the pro-oncogenic factor SP1. In summary, we provide new formulations for the efficient encapsulation of MTM which may constitute a safer delivering alternative to be explored in future clinical uses.
Highlights
Sarcomas comprise a heterogeneous group of malignant neoplasms that arise from mesenchymal stem/progenitor cells (MSCs) and affect mesodermal tissues such as bones, muscles, cartilage or fat
The sizes obtained by DLS were in the range of 210–267 nm for the PLGA polymeric micelles, which is an indication that all formulations present an appropriate size with a narrow polydispersity index (PDI) between 0.083 and 0.137
The sizes obtained by DLS were in the range of 97–133 nm, with similar sizes observed in TFS–thin film hydration (TFH) and TFS–ethanol injection method (EIM)
Summary
Sarcomas comprise a heterogeneous group of malignant neoplasms that arise from mesenchymal stem/progenitor cells (MSCs) and affect mesodermal tissues such as bones, muscles, cartilage or fat. These tumors involve only 1% of global cancer diagnoses, this value rises to 12%–15% in terms of pediatric malignancies [1]. The treatment of localized sarcomas involves the surgical resection of tumor mass supported by radiotherapy or neoadjuvant chemotherapy [2,3]. The overall survival of these patients has remained unchanged for the last 30 years and below 20% in the case of metastatic osteosarcomas and soft tissue sarcomas [2,3], highlighting the need for more efficient therapies. Mithramycin A (MTM), known as Plicamycin, is a natural aureolic acid-type polyketide that was originally isolated from Streptomyces agrillaceus [4]
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