Translation of killing based into differentiation based therapy of malignant diseases using nanotechnology: Getting out of the vicious circle
2021
Тип документа:
Конференцијски прилог (Објављена верзија)
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© 2021 by the Microscopy Conference
Метаподаци
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There is growing evidence about tumor promoting features of dying cells in advanced tumor tissue. Crosstalk between
dying and surrounding cells often leads to tumor repopulation, local immuno-suppression and metastasis.
Consequently, resistance to chemotherapy is rather connected to proliferative response to cell death induced by the
therapy than to development of apoptotic resistant phenotype of individual cell. As an alternative approach that will
avoid chemotherapy induced tumor repopulation, induction of cell differentiation emerges. Until today, different
naturally/synthetic compounds able to convert non/low differentiated malignant cell into less invasive or normal cell
like phenotype have been discovered. It was also found that not just the type of the drug, but also dynamic of drug
delivery, can define its action and replace cell death induction with non-aggressive tumor suppression.
Objectives: This lecture will give insight into usage of SBA-15 mesoporous silica nanomaterial as a biocompatible drug
carrier of metal based chemotherapeutics in terms of improved stability, drug efficacy, and conversion of killing-based
to differentiation-inducing property.
Material and methods: Antitumor effect of SBA-15 mesoporous silica nanoparticles loaded with organotin(IV)
compound has been evaluated on two melanoma cell lines - less invasive B16 mouse and highly aggressive,
anaplastic human melanoma cell line - A375 and singeneic model of melanoma in C57BL6 mice. Cell viability has
been determined by MTT and CV. Cell death, proliferation, senescence and production of reactive oxygen/nitrogen
species have been estimated by Flow cytometry. Biochemical assays, light microscopy and TEM were used for
detection of melanoma cell differentiation. The protein expression relevant for stem maintenance has been assessed
by WB.
Results: Melanoma cells internalized drug loaded nanoparticles after 2 h of incubation through passive fluid-phase
uptake and macropinocytosis, thus leading to later phenotype changes and loss of malignant potential in both- B16
and A375 cells. In contrast to free immobilized compound induced cell differentiation, an effect previously unknown for
metal-based drugs and nanomaterial alone. The strong therapeutic potential was achieved in lower dose range than
in the case of the free drug, reflected on morphological, biochemical and ultra-structural features of treated melanoma
cells. While anaplastic A375 cells lost stemness and became senescent, B16 cells differentiated into more mature,
melanocyte like phenotype. Abolished tumor growth observed in syngeneic model in vivo confirmed in vitro obtained
data, showing that applied treatment was safe and highly efficient.
Conclusion: In opposite to free drug, organotin(IV) compound loaded into mesoporous silica SBA-15 nanocarriers
induced melanoma cell reprograming. In this form agent prevented tumor repopulation as a tissue reactive response
to cell damage, opening the interest for nanotechnology application in nonaggressive treatments of advanced solid
tumors.
У:
- Proceedings: Joint Meeting of Dreiländertagung & Multinational Congress on Microscopy: MC 2021 goes digital; 2021 Aug 22-26; Online. 2021. p. 363.