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.
In the present study, we report the delivery of anti-cancer drug curcumin to cancer cells using mesoporous silica materials. A series of mesoporous silica material based drug delivery systems (S2, S4 and S6) were first designed and developed through the amine functionalization of KIT-6, MSU-2 and MCM-41 followed by the loading of curcumin. The curcumin loaded materials were characterized with several physico-chemical techniques and thoroughly screened on cancer cells to evaluate their in vitro drug delivery efficacy. All the curcumin loaded silica materials exhibited higher cellular uptake and inhibition of cancer cell viability compared to pristine curcumin. The effective internalization of curcumin in cancer cells through the mesoporous silica materials initiated the generation of intracellular reactive oxygen species and the down regulation of poly ADP ribose polymerase (PARP) enzyme levels compared to free curcumin leading to the activation of apoptosis. This study shows that the anti-cancer activity of curcumin can be potentiated by loading onto mesoporous silica materials. Therefore, we strongly believe that mesoporous silica based curcumin loaded drug delivery systems may have future potential applications for the treatment of cancers.
Dehydroxylated MCM-41 and SBA-15 surfaces were modified by the grafting of two different titanocene complexes ([Ti(eta(5)-C(5)H(4)Me)(2)Cl(2)] and [Ti{Me(2)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)]) to give new materials, which have been characterized by powder X-ray diffraction, X-ray fluorescence, nitrogen gas sorption, MAS-NMR spectroscopy, thermogravimetry, SEM, and TEM. The toxicity of the resulting materials toward human adenocarcinoma HeLa, human myelogenous leukemia K562, human malignant melanoma Fem-x, and normal immunocompetent cells, such as peripheral blood mononuclear cells PBMC has been studied. Estimation of the number of particles per gram of material led to the calculation of Q(50) values for these samples, which is the number of particles required to inhibit normal cell growth by 50%. In addition, M(50) values (quantity of material needed to inhibit normal cell growth by 50%) of the studied surfaces is also reported. Nonfunctionalized MCM-41 and SBA-15 did not show notable antiproliferative activity, whereas functionalization of these materials with different titanocene based anticancer drugs led to very promising antitumoral activity. The best Q(50) values correspond to titanocene functionalized MCM-41 surfaces (MCM-41/[Ti(eta(5)-C(5)H(4)Me)(2)Cl(2)] (1) and MCM-41/[Ti{Me(2)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] (2)) with Q(50) values between 3.8+/-0.6x10(8) and 24.5+/-3.0x10(8) particles. Titanocene functionalized SBA-15 surfaces (SBA-15/[Ti(eta(5)-C(5)H(4)Me)(2)Cl(2)] (3) and SBA-15/[Ti{Me(2)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] (4)) gave higher Q(50) values, showing lower activity from 73.2+/-9.9x10(8) to 362+/-7x10(8) particles. The best response of the studied materials in terms of M(50) values was observed against Fem-x (309+/-42 microg for 4) and K562 (338+/-18 microg for 2), whereas moderate activities were observed in HeLa cells (from 508+/-63 microg of 2 to 912+/-10 microg of 1). In addition, the analyzed surfaces presented only marginal activity against unstimulated and stimulated PBMC, showing a slight selectivity on human cancer cells. Comparison of the in vitro cytotoxicity in solution of the titanocene complexes [Ti(eta(5)-C(5)H(4)Me)(2)Cl(2)] and [Ti{Me(2)Si(eta(5)-C(5)Me(4))(eta(5)-C(5)H(4))}Cl(2)] and the corresponding titanocene functionalized materials is also described.
Abstract:For more than 100 years metal complexes have been extensively used in therapy and since the discovery of cisplatin the research in this field has expanded exponentially. The scientific community is always in search of new alternatives to platinum compounds and a wide variety of metallodrugs based on other metals have been reported with excellent therapeutic results. This short review focuses on the work that our research group has carried out since 2007 in collaboration with others and centers on the preparation of organogallium(III) compounds, organotin(IV) derivatives, and titanocene(IV) complexes together with the study of their cytotoxic anticancer properties.
A series of nanomaterials based on mesoporous silica have been synthesised and functionalised with a photoactive polypyridyl ruthenium(ii) complex, namely [Ru(bipy)2-dppz-7-hydroxymethyl][PF6]2 (bipy = 2,2'-bipyridine, dppz = dipyrido[3,2-a:2',3'-c]phenazine), by various methods. The functionalisation reactions were based on the covalent binding to different ligands attached to the pores of the mesoporous nanoparticles and a simple physisorption using polyamino-functionalised mesoporous silica nanoparticles. The resulting nanostructured systems have been characterised by XRD, XRF, BET, SEM and TEM, observing the incorporation of the metallodrug onto the nanostructured silica in a different way depending on the synthetic method used in the loading reactions. In our studies, we have also observed that functionalisation with the metallodrug causes changes in the structural and textural features of the materials. The phototherapeutic activity of the ruthenium-functionalised materials in HeLa cervical cancer cells has been tested and the preliminary results are presented herein.
A series of alkenyl-substituted titanocene compounds have been supported on the mesoporous silica-based material KIT-6. The corresponding functionalised materials were completely characterised by different techniques (solid-state multinuclear NMR spectroscopy, IR spectroscopy, N2 adsorption-desorption isotherms, X-ray fluorescence and diffraction, SEM and TEM) to observe the incorporation of the titanocene derivatives on the external surface of the material KIT-6. Both the titanocene compounds and the materials were tested in vitro against a wide variety of human cancer and normal cell lines. A very high cytotoxicity of the synthesised titanocene derivatives (IC50 values in the range of those described in the literature for the most active cytotoxic titanocene compounds), with selectivity towards cancer cell lines was observed. The cytotoxic activity of the materials is the highest reported to date for titanocene-functionalised materials. In addition, higher Ti uptake (from 4 to 23% of the initial amount of Ti) of the cells treated with materials was observed with respect to those treated with "free" titanocene derivatives (which gave Ti uptake values from 0.4 to 4.6% of the initial amount of Ti). Additional experiments with the titanocene derivatives and the functionalised materials revealed that changes to the morphological and functional dynamics of apoptosis occurred when the active titanocene species were incorporated into mesoporous materials. In addition, the materials could induce programmed cell death in tumour cell populations by impairing the damaged DNA repair mechanisms and by upregulation of intrinsic and extrinsic apoptotic signalling pathways.
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