Effect of chain length on the cytotoxic activity of (alkyl-ω-ol)triphenyltin(IV) loaded into SBA-15 nanostructured silica and in vivo study of SBA-15~Cl|Ph3Sn(CH2)8OH.

A series of nanostructured SBA-15-based materials functionalized with the tetraorganotin(IV) metallodrugs Ph3Sn(CH2)nOH (n = 3, 4, 6, 8 and 11) are synthesized and structurally characterized by different techniques used in solid-state chemistry. The cytotoxicity of both the organotin(IV) compounds and the tin-functionalized SBA-15 materials are studied against different cancer cell lines observing that the materials have similar cytotoxic activity in comparison with the free organotin compounds in terms of mass. However, considering that the percentage of active metal compound loaded into material is low, the utilization of mesoporous silica as drug vehicle clearly improves the cytotoxic effectiveness of metal-based drugs against cancer cells. One of the most potent between all tested systems is material SBA-15~Cl|Ph3Sn(CH2)8OH. Its cytotoxicity seems to come from additional mechanisms apart from apoptosis provoking cell reprogram in B16 melanoma into more mature and less aggressive phenotype. Moderated production of ROS/RNS is probably in the background of observed phenomenon. Obtained results are further confirmed in syngeneic mouse model of melanoma in C57BL6 mice. The in vivo results show that SBA-15 do not disturb tumor growth, while both Ph3Sn(CH2)8OH and SBA-15~Cl|Ph3Sn(CH2)8OH significantly decreases tumor volume with an enhancement of the antitumor potential of the tetraorganotin(IV) compound upon immobilization in SBA-15.

The interaction between SBA-15 derivative loaded with Ph3Sn(CH2)6OH and human melanoma A375 cell line: uptake and stem phenotype loss.

Extraordinary progress in medicinal inorganic chemistry in the past few years led to the rational design of novel platinum compounds, as well as nonplatinum metal-based antitumor agents, including organotin compounds, whose activity is not based on unrepairable interaction with DNA. To overcome poor solubility and toxicity problems that limited the application of these compounds numerous delivering systems were used (Lila et al. in Biol Pharm Bull 37:206-211, 2014; Yue and Cao in Curr Cancer Drug Targets 16:480-488, 2016; Duan et al. in WIREs Nanomed Nanobiotechnol 8:776-791, 2016). Regarding high drug loading capacity, mesoporous silica nanoparticles like SBA-15 became more important for targeted drug delivery. In this study, cellular uptake and biological activities responsible for organotin(IV) compound Ph3Sn(CH2)6OH (Sn6) grafted into (3-chloropropyl)triethoxysilane functionalized SBA-15 (SBA-15p → SBA-15p|Sn6) were evaluated in human melanoma A375 cell line. Moreover, the influence of SBA-15p grafted with organotin(IV) compound on the stemness of A375 cell was tested. Given the fact that SBA-15p|Sn6 nanoparticles are nonspherical and relatively large, their internalization efficiently started even after 15 min with stable adhesion to the cell membrane. After only 2 h of incubation of A375 cells with SBA-15p|Sn6 passive fluid-phase uptake and macropinocytosis were observed. Inside of the cell, treatment with SBA-15p loaded with Sn6 promoted caspase-dependent apoptosis in parallel with senescence development. The subpopulation of cells expressing Schwann-like phenotype arose upon the treatment, while the signaling pathway responsible for maintenance of pluripotency and invasiveness, Wnt, Notch1, and Oct3/4 were modulated towards less aggressive signature. In summary, SBA-15p enhances the efficacy of free Sn6 compound through efficient uptake and well profiled intracellular response followed with decreased stem characteristics of highly invasive A375 melanoma cells.

Evaluation of functionalized mesoporous silica SBA-15 as a carrier system for Ph3Sn(CH2)3OH against the A2780 ovarian carcinoma cell line.

SBA-15|Sn3, a mesoporous silica-based material (derivative of SBA-15) loaded with an organotin compound Ph3Sn(CH2)3OH (Sn3), possesses improved antitumor potential against the A2780 high-grade serous ovarian carcinoma cell line in comparison to Sn3. It is demonstrated that both the compound and the nanostructured material are internalized by the A2780 cells. A similar mode of action of Sn3 and SBA-15|Sn3 against the A2780 cell line was found. Explicitly, induction of apoptosis, caspase 2, 3, 8 and 9 activation, accumulation of cells in the hypodiploid phase as well as accumulation of ROS were observed. Interestingly, Sn3 loaded in the mesoporous silica-based material needed to reach a concentration 3.5 times lower than the IC50 value of the Sn3 compound, pointing out a higher effect of the SBA-15|Sn3 than Sn3 alone. Clonogenic potential, growth in 3D culture as well as mobility of cells were disturbed in the presence of SBA-15|Sn3. Such behavior could be associated with the suppression of p-38 MAPK. Less profound effect of Sn3 compared to SBA-15|Sn3 could be attributed to a different regulation of p-38 and STAT-3, which are mainly responsible for an appropriate cellular response to diverse stimuli or metastatic properties.

Organotin(IV)-loaded mesoporous silica as a biocompatible strategy in cancer treatment.

The strong therapeutic potential of an organotin(IV) compound loaded in nanostructured silica (SBA-15pSn) is demonstrated: B16 melanoma tumor growth in syngeneic C57BL/6 mice is almost completely abolished. In contrast to apoptosis as the basic mechanism of the anticancer action of numerous chemotherapeutics, the important advantage of this SBA-15pSn mesoporous material is the induction of cell differentiation, an effect unknown for metal-based drugs and nanomaterials alone. This non-aggressive mode of drug action is highly efficient against cancer cells but is in the concentration range used nontoxic for normal tissue. JNK (Jun-amino-terminal kinase)-independent apoptosis accompanied by the development of the melanocyte-like nonproliferative phenotype of survived cells indicates the extraordinary potential of SBA-15pSn to suppress tumor growth without undesirable compensatory proliferation of malignant cells in response to neighboring cell death.