Enhancing Pt(IV) Complexes' Anticancer Activity upon Encapsulation in Stimuli‐Responsive Nanocages

Abstract

Platinum-based chemotherapy is the first-line treatment for different cancer types and in particular for malignant pleural mesothelioma patients (a tumor histotype with urgent medical needs). Herein we present a strategy to stabilize, transport and intracellular release of a platinum IV (Pt IV ) prodrug using a breakable nanocarrier. Its reduction, and therefore activation as anticancer drug, is promoted by the presence of glutathione in neoplastic cells that also causes the destruction of the carrier. The nanocage presents a single internal cavity in which the hydrophobic complex (Pt(dach)Cl2(OH)2), (dach= R,R-diaminocyclohexane) has been encapsulated. We have evaluated the in vitro uptake and the internalization kinetics in cancer model cells and using flow cytometry analysis, demonstrated the successful release and activation of the Pt based drug inside cancer cells. The in vitro findings were confirmed by the in vivo experiments on a mice model obtained by xenografting MPM487, a patientderived malignant pleural mesothelioma. MPM487 confirmed the well-known resistance of malignant pleural mesothelioma to cisplatin treatment while an interesting 50% reduction of tumor growth was observed when mice were treated with the Pt IV , entrapped in the nanocages, at an equivalent dose of platinum complex.Received: ((will be filled in by the editorial staff))Revised: ((will be filled in by the editorial staff))

Supramolecular Nucleic Acid-Based Organosilica Nanoparticles Responsive to Physical and Biological Inputs

“…Representative images from 4T1.2 cells after treatment with Apta-OSPs for 4 and 24 h are shown in Figure S15 and Video S1. The analysis of the red fluorescent signal and the Z-stack sections of the images confirmed the intracellular localization of the Apta-OSPs at the shortest time point (4 h). The punctate emission observed for Apta-OSPs is consistent with an endosomal uptake pathway that we have also previously observed and studied in detail for other organosilica nanoparticles …”

“…The punctate emission observed for Apta-OSPs is consistent with an endosomal uptake pathway that we have also previously observed and studied in detail for other organosilica nanoparticles. 58 After the demonstration that Apta-OSPs were successfully localized in the cell, a live/dead test was carried out to evaluate the viability of Apta-OSP-treated cells. In this assay, ethidium homodimer-1 (EthD-1) is employed for labeling damaged membranes.…”

Cytotoxic Pt(ii) complexes containing alizarin: a selective carrier for DNA metalation

“…With the aim to improve cancer therapy, including receptor targeting, selective drug delivery and design of prodrugs, a wide range of functional Pt (IV) and Pt(II)-based drugs have been studied by applying different synthetic strategies. [9][10][11][12][13][14][15][16][17][18] Based on our long experience in the development of synthetic routes to afford both neutral and ionic complexes of the platinum group, [19][20][21][22] we recently synthesized and studied novel charged platinum complexes exhibiting comparable cytotoxicity to cisplatin in particular against the triple negative breast cancer cell line (MDA-MB-231). [23][24][25] Thus, we focused our attention on MDA-MB-231 known for being a highly aggressive, invasive and poorly differentiated triple-negative breast cancer (TNBC) cell line as it lacks estrogen receptor (ER) and progesterone receptor (PR) expression, as well as HER2 (human epidermal growth factor receptor 2) amplification.…”

Cargo-loaded lipid-shielded breakable organosilica nanocages for enhanced drug delivery

“…Drug delivery was also demonstrated for malignant mesothelioma and the reported in vivo experiments on the reduction of the tumor growth corroborate the possible use of such particles. 16…”

“…Drug delivery was also demonstrated for malignant mesothelioma and the reported in vivo experiments on the reduction of the tumor growth corroborate the possible use of such particles. 16 The silica surface, rich in hydroxyl groups, offers not only a highly-hydrophilic nature, but also efficacious chemical anchoring sites for functional molecules, 17 such as targeting ligands, 18 polymers 19 and lipid bilayers 20 able to improve the biodistribution and colloidal stability of the porous silica nanoparticles. In fact, the colloidal stability of a generic nanoparticle in biological media has to be strictly preserved to avoid the aggregation and degradation phenomenon, 21 as it can negatively affect the biodistribution, the endocytosis process and the delivery of the entrapped active molecules to the target tissue.…”