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

Our plain-English summary of Enhancing Pt(IV) Complexes' Anticancer Activity upon Encapsulation in Stimuli-Responsive Nanocages, by M. Sancho-Albero, G. Facchetti, N. Panini, et al (Advanced Healthcare Materials, 2023).

The study

• Authors: M. Sancho-Albero, G. Facchetti, N. Panini, M. Meroni, E. Bello, I. Rimoldi, M. Zucchetti, R. Frapolli, L. De Cola
• Journal: Advanced Healthcare Materials
• Published: 2023;12(17):e2202932
• Cited by: 15 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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, a strategy is presented to stabilize, transport, and intracellularly release a platinumIV (PtIV ) prodrug using a breakable nanocarrier. Its reduction, and therefore activation as an 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) is encapsulated. The in vitro uptake and the internalization kinetics in cancer model cells are evaluated and, using flow cytometry analysis, the successful release and activation of the Pt-based drug inside cancer cells are demonstrated. The in vitro findings are confirmed by the in vivo experiments on a mice model obtained by xenografting MPM487, a patient-derived malignant pleural mesothelioma. MPM487 confirms the well-known resistance of malignant pleural mesothelioma to cisplatin treatment while an interesting 50% reduction of tumor growth is observed when mice are treated with the PtIV , entrapped in the nanocages, at an equivalent dose of the platinum complex.

© 2023 The Authors. Advanced Healthcare Materials published by Wiley-VCH GmbH.

In plain English

This cell and mouse study, not involving asbestos, tested an experimental drug delivery method for malignant pleural mesothelioma. The authors packed a platinum(IV) compound, meant to become an active platinum(II) drug inside cells, into silica 'nanocages' that break apart in the presence of glutathione, highly overexpressed in cancer cells. Measured loading was 0.12 mg of platinum per mg of cages.

In HeLa cancer cells, 10 μg per mL of loaded cages raised dead cells by 50% after 24 and 48 hours. After 48 hours at 5 μg per mL, 47.7% of treated cells were in the G1 phase, versus 74.54% untreated. Empty cages caused no toxicity in cells at any concentration or time tested.

In mice bearing tumor from a patient with stage III biphasic pleural mesothelioma (four per group), cisplatin was completely ineffective. Loaded cages at an equivalent platinum dose significantly delayed growth: on day 26, treated tumors averaged 54.6% of control tumor weight (p less than 0.05). Weight loss stayed below 10% with both treatments.

The authors concluded that all the drugs worked in cell culture, but only the nanocages worked in mice.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory study with three parts: chemical preparation of drug-loaded nanoparticles, cell-culture experiments, and an animal experiment in mice carrying a patient-derived mesothelioma xenograft
• Who was studied: HeLa cancer cells and MPM487 human malignant mesothelioma cells in culture, plus 7-week-old female athymic nude mice (four per group) implanted under the skin with MPM487 tumor (Milan, Italy). The MPM487 tumor came from cells in the pleural effusion of a patient with stage III biphasic pleural mesothelioma.
• Exposure: No asbestos exposure was studied. The main treatment was a platinum(IV) prodrug, Pt(dach)Cl2(OH)2, encapsulated in breakable organosilica nanocages (ssOSCs@Pt). It was compared with cisplatin and with saline. In mice, cisplatin was given intravenously at 2.5 mg/kg twice a week, and the nanocages at the equivalent platinum content on the same schedule.
• Main results:
  • In mice with MPM487 mesothelioma, the nanocage treatment gave a T/C of 54.6% on day 26, meaning mean tumor weight in treated mice was 54.6% of that in control mice. This tumor growth delay was statistically significant (p less than 0.05).
  • In the same mouse model, cisplatin was completely ineffective.
  • With both treatments in mice, body weight loss was always below 10%. The authors took this to suggest good tolerability.
  • In HeLa cells, dead cells increased by 50% after 24 and 48 hours of incubation with 10 μg/mL of drug-loaded nanocages.
  • Cell-cycle distribution was measured 48 hours after treatment. In HeLa cells treated with 5 μg/mL of loaded nanocages, 47.7% of cells were in the G1 phase of the cell cycle, compared with 74.54% of untreated cells.
  • In MPM487 mesothelioma cells, empty nanocages caused no toxicity at any time point or concentration tested. In HeLa cells, empty nanocages showed no cytotoxic effects at any dose or time point tested.
  • MP-AES measured 0.12 (plus or minus 0.01) mg of atomic platinum per mg of nanocages, which the authors called 12% loading. Thermogravimetric analysis separately estimated the loading of the platinum compound at about 20 wt%.
• The authors' conclusion: The authors concluded that antitumor activity was present for all the drugs in cell culture but only for the drug-loaded nanocages in mice. They described the nanocages as effective in a platinum-resistant xenograft model of malignant mesothelioma.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Encapsulation, Chemotherapy, Pleural Mesothelioma, Glutathione (GSH), Cisplatin.

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