MULTIFUNCTIONAL NANOSYSTEMS BASED ON GOLD NANOPARTICLES AND MITOCHONDRIA-TARGETED ANTIBIOTICS FOR THE TREATMENT OF MELANOMA

CAMMARATA A.; DURAN H.; GLISONI RJ.; ATIA M.; TAVERNA PORRO M.

Mar del Plata

Congreso; S A I C . S A F E . S A B . SAP 2 0 1 9 Participan AACYTAL . NANOMED-AR . HCS; 2019

SAIC-NANOMED-ar

Malignant melanoma is a tumor characterized by a very high level of heterogeneity, responsible for its malignant behavior and resistance to conventional therapies. Thus, new treatment strategies are urgently needed to help remedy this unmet clinical need. Treatment failure and disease progression has been attributed to the existence of cancer stem cells (CSCs). These have been implicated in tumor initiation, metastatic spread and poor survival in multiple tumor types, melanoma included. CSCs selectively overexpress key mitochondrial-related proteins and inhibition of mitochondrial function may represent a new potential approach for their eradication. Moreover, the combined use of radio and chemotherapy is being commonly used in cancer treatment. The side effects of the combined treatment can be minimized through the use of nanotechnology. In this regard, gold nanoparticles (AuNPs) can play a significant role since they can be used as radiation dose enhancers and anticancer drug carriers. In this context, we propose the evaluation of the radiosensitizer capacity of AuNPs functionalized with doxycycline (DOXY) and modified 9-aminoDOXY, both inhibitors of mitochondrial biogenesis, in melanoma cells. First, the in vitro metabolic activity and cytotoxic effect of the free DOXY and 9-aminoDOXY in human melanoma cell lines A375, A375-G10 and Mel-J was studied by MTT and trypan blue dye exclusion, respectively. Both compounds reduced the metabolic activity of all cell lines and diminished their viability. Then, melanoma cells pre-treated with both antibiotics for 48 h were irradiated with a 137Cs gamma source (0-5 Gy). A significant increase in radiation effect in DOXY and 9-aminoDOXY treated cells was found. These results showed that both antibiotics can be used as radiosensitizers in radiotherapy of melanoma. Finally, for their conjugation to AuNPS, polyethyleneglycol-DOXY conjugates were obtained by two different approaches: (i) a direct route of synthesis by DCC/DMAP catalyzed reaction and (ii) a two-step synthesis through the introduction of a -NO2 group in the structure of DOXY followed by a reduction and the final amidation. These polymers will be conjugated to AuNPs synthesized by the Turkevich method. Based on our preliminary results we believe in the possibility of treating melanoma resistant cells through a mitochondria-targeted therapy and the development of these nanosystems as a multifunctional theranostic platform.