Pharmaceutics 2022, 14, 405. https://doi.org/10.3390/pharmaceutics14020405 www.mdpi.com/journal/pharmaceutics Article Photosensitive EGFR-Targeted Nanocarriers for Combined Photodynamic and Local Chemotherapy Elena de las Heras 1 , M. Lluïsa Sagristá 2 , Montserrat Agut 1 and Santi Nonell 1, * 1 Institut Químic de Sarrià, Universitat Ramon Llull, 08017 Barcelona, Spain; elenaherasg@iqs.url.edu (E.d.l.H.); montserrat.agut@iqs.url.edu (M.A.) 2 Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, 08028 Barcelona, Spain; mlsagrista@ub.edu * Correspondence: santi.nonell@iqs.url.edu Abstract: The major limitation of any cancer therapy lies in the difficulty of precisely controlling the localization of the drug in the tumor cells. To improve this drawback, our study explores the use of actively-targeted chemo-photo-nanocarriers that recognize and bind to epidermal growth factor re- ceptor-overexpressing cells and promote the local on-demand release of the chemotherapeutic agent doxorubicin triggered by light. Our results show that the attachment of high concentrations of dox- orubicin to cetuximab-IRDye700DX-mesoporous silica nanoparticles yields efficient and selective photokilling of EGFR-expressing cells mainly through singlet oxygen-induced release of the doxo- rubicin from the nanocarrier and without any dark toxicity. Therefore, this novel triply functional- ized nanosystem is an effective and safe nanodevice for light-triggered on-demand doxorubicin re- lease. Keywords: mesoporous silica nanoparticles; photodynamic therapy; chemotherapy; cetuximab; EGFR; singlet oxygen; drug delivery 1. Introduction The major drawback of any cancer therapy is the lack of selectivity of the treatment, leading to serious side effects for the patients. This limitation lies in the difficulties of pre- cisely delivering the drug selectively to the tumor tissue. The light-based cancer therapy photodynamic therapy (PDT) involves the admin- istration of a photosensitizing drug that is not cytotoxic per se, but upon activation with light of a specific wavelength triggers the formation of reactive oxygen species, mostly singlet oxygen ( 1 O2), which leads to irremediable damage and, consequently, tumor re- gression [1,2]. The combination of PDT with other therapeutic modalities, such as chem- otherapy and immunotherapy, can improve the effectiveness of the treatment and, more importantly, increase its selectivity and, thus, its safety [3–7]. A convenient strategy for delivering different therapies at once is by using nano-sized drug delivery systems. Among all the smart nanovehicles, mesoporous silica nanoparticles (MSNPs) are ideal nanocarriers for co-delivering different agents to the desired locations due to their various advantageous properties, including (i) the capability of co-delivering high pay- loads of multiple therapeutic agents; (ii) the easy surface functionalization; and (iii) the desired biological behavior, particularly biocompatibility. For these reasons, MSNPs are expected to be the ideal platform for combined chemo-immuno-phototherapy. Further- more, to avoid unwanted release of the anti-cancer agent from the nanocarrier and thus improve even more the selectivity of the system, the action of the chemotherapeutic agent can be modulated on-demand by the singlet oxygen generated by PDT [8–13]. In this way, PDT would also have the function of controlling drug release in this combinatorial Citation: de las Heras, E.; Sagristá, M.L.; Agut, M.; Nonell, S. Photosensitive EGFR-Targeted Nanocarriers for Combined Photodynamic and Local Chemotherapy. Pharmaceutics 2022, 14, 405. https://doi.org/10.3390/phar- maceutics14020405 Academic Editors: Francesca Moret and Greta Varchi Received: 10 December 2021 Accepted: 4 February 2022 Published: 13 February 2022 Publisher’s Note: MDPI stays neu- tral with regard to jurisdictional claims in published maps and institu- tional affiliations. Copyright: © 2022 by the authors. Li- censee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and con- ditions of the Creative Commons At- tribution (CC BY) license (https://cre- ativecommons.org/licenses/by/4.0/).