Citation: Ornelas, C.; Astruc, D. Ferrocene-Based Drugs, Delivery Nanomaterials and Fenton Mechanism: State of the Art, Recent Developments and Prospects. Pharmaceutics 2023, 15, 2044. https://doi.org/10.3390/ pharmaceutics15082044 Academic Editors: Zofia Urbanczyk-Lipkowska and Anne-Marie Caminade Received: 1 July 2023 Revised: 24 July 2023 Accepted: 26 July 2023 Published: 29 July 2023 Copyright: © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). pharmaceutics Review Ferrocene-Based Drugs, Delivery Nanomaterials and Fenton Mechanism: State of the Art, Recent Developments and Prospects † Catia Ornelas 1, * and Didier Astruc 2, * 1 ChemistryX, R&D Department, R&D and Consulting Company, 9000-160 Funchal, Portugal 2 University of Bordeaux, ISM, UMR CNRS, No. 5255, 351 Cours de la Libération, CEDEX, 33405 Talence, France * Correspondence: catiaornelas@catiaornelaslab.com (C.O.); didier.astruc@u-bordeaux.fr (D.A.) † This article is dedicated to our distinguished colleague Professor Donald A. Tomalia on the occasion of his 85th birthday. Abstract: Ferrocene has been the most used organometallic moiety introduced in organic and bioinor- ganic drugs to cure cancers and various other diseases. Following several pioneering studies, two real breakthroughs occurred in 1996 and 1997. In 1996, Jaouen et al. reported ferrocifens, ferrocene analogs of tamoxifen, the chemotherapeutic for hormone-dependent breast cancer. Several ferrocifens are now in preclinical evaluation. Independently, in 1997, ferroquine, an analog of the antimalar- ial drug chloroquine upon the introduction of a ferrocenyl substituent in the carbon chain, was reported by the Biot-Brocard group and found to be active against both chloroquine-sensitive and chloroquine-resistant strains of Plasmodium falciparum. Ferroquine, in combination with artefenomel, completed phase IIb clinical evaluation in 2019. More than 1000 studies have been published on ferrocenyl-containing pharmacophores against infectious diseases, including parasitic, bacterial, fungal, and viral infections, but the relationship between structure and biological activity has been scarcely demonstrated, unlike for ferrocifens and ferroquines. In a majority of ferrocene-containing drugs, however, the production of reactive oxygen species (ROS), in particular the OH. radical, produced by Fenton catalysis, plays a key role and is scrutinized in this mini-review, together with the supramolecular approach utilizing drug delivery nanosystems, such as micelles, metal–organic frameworks (MOFs), polymers, and dendrimers. Keywords: ferrocene; metallodrug; anticancer drug; cancer; parasitic; bacterial; fungal and viral diseases; drug delivery; Fenton reaction; hydroxyl radical 1. Introduction The International Agency for Research on Cancer estimated that the number of cancer cases worldwide reached almost 20 million in 2020, with 10 million deaths [1]. Since con- ventional treatments, including surgery, radiotherapy, and chemotherapy, cannot cure all categories of cancer, a timely approach to treating solid tumors is the use of tumor-targeting drugs [2]. Likewise, there is an urgent need for environment purification and localized antibacterial treatment because bacterial infections represent the third cause of death world- wide (just after cardiovascular diseases), with an estimated 13.7 million of infectious origin in 2019 [3]. More generally, infectious diseases, in which microorganisms mature or propa- gate in or on hosts, can be divided into four categories: parasitic (with malaria as the biggest group), bacterial, fungal, and viral. The history of infectious diseases is covered with entire populations being periodically decimated, mostly with pathogenic bacteria or viruses as main infectious agents, as dramatically illustrated by the Black Death epidemic in the 14th century that decimated between a third and half of the European population and by the recent coronavirus COVID-19 that killed around 15 million people in two years, according Pharmaceutics 2023, 15, 2044. https://doi.org/10.3390/pharmaceutics15082044 https://www.mdpi.com/journal/pharmaceutics