Mesoporous Silica Nanoparticles Enhance the Anticancer Efficacy of Platinum(IV)-Phenolate Conjugates in Breast Cancer Cell Lines

Abstract

The main reasons for the limited clinical efficacy of the platinum(II)-based agent cisplatin include drug resistance and significant side effects. Due to their better stability, as well as the possibility to introduce biologically active ligands in their axial positions constructing multifunctional prodrugs, creating platinum(IV) complexes is a tempting strategy for addressing these limitations. Another strategy for developing chemotherapeutics with lower toxicity relies on the ability of nanoparticles to accumulate in greater quantities in tumor tissues through passive targeting. To combine the two approaches, three platinum(IV) conjugates based on a cisplatin scaffold containing in the axial positions derivatives of caffeic and ferulic acid were prepared and loaded into SBA-15 to produce the corresponding mesoporous silica nanoparticles (MSNs). The free platinum(IV) conjugates demonstrated higher or comparable activity with respect to cisplatin against different human breast cancer cell lines, while upon immobilization, superior antiproliferative activity with markedly increased cytotoxicity (more than 1000-fold lower IC50 values) compared to cisplatin was observed. Mechanistic investigations with the most potent conjugate, cisplatin-diacetyl caffeate (1), and the corresponding MSNs (SBA-15|1) in a 4T1 mouse breast cancer cell line showed that these compounds induce apoptotic cell death causing strong caspase activation. In vivo, in BALB/c mice, 1 and SBA-15|1 inhibited the tumor growth while decreasing the necrotic area and lowering the mitotic rate.

Triphenyltin(IV) Carboxylates with Exceptionally High Cytotoxicity against Different Breast Cancer Cell Lines

“…This can be probed utilizing the ApoStat assay. Figure 5 A reveals that [Ph 3 Sn(IND)] and [Ph 3 Sn(FBP)] do not activate, but rather inhibit the activity of these enzymes, whereas cisplatin has no effect on the caspase activity, although previous reports link cisplatin-induced cell death with caspase-activated apoptosis [ 61 , 83 , 84 , 85 , 86 , 87 ]. These results, however, are in agreement with the ones obtained with the AnnV/PI experiments and confirm that apoptotic mechanisms in BT-474 cells could not be detected within the 48 h of treatment.…”

Recent Advances in Mesoporous Silica Nanoparticle-Mediated Drug Delivery for Breast Cancer Treatment

“…The relative extents of necrosis and mitosis were reduced in all tumor cells with 14 and 12% necrosis for SBA-15-1 and DDP. No hepatotoxicity, nephrotoxicity or inflammation was observed in the treated animals (unlike unaided DDP therapy), except the dilatation of minor venules in SBA-15-1-administered mice [ 205 ]. The study, therefore, offers significant insights, with DDP being the frontline drug; a moderation of its dosage could be important for its future reliability.…”

Ferulic Acid: A Natural Phenol That Inhibits Neoplastic Events through Modulation of Oncogenic Signaling

“…The use of adjuvants was found to be an effective tool for cancer therapy targeting ROS-modulated pathways [ 68 ]. Furthermore, a combination of caffeic and ferulic acid lipophilic derivatives also showed increased cytotoxicity toward human breast cancer cell lines, and thus could be applicable for chemopreventive and/or chemotherapeutic purposes [ 69 ]. From the above discussion, it can be determined that this bioactive natural substance has the potential to have synergistic effects on growth inhibition, apoptosis induction, and anticarcinogenic properties, and it may prove to be a promising alternative approach for boosting therapeutic potency and lowering systemic toxicity of chemotherapeutic drugs [ 70 ].…”