  Citation: Alvear-Jiménez, A.; Zabala Gutierrez, I.; Shen, Y.; Villaverde, G.; Lozano-Chamizo, L.; Guardia, P.; Tinoco, M.; Garcia-Pinel, B.; Prados, J.; Melguizo, C.; et al. Electrospraying as a Technique for the Controlled Synthesis of Biocompatible PLGA@Ag 2 S and PLGA@Ag 2 S@SPION Nanocarriers with Drug Release Capability. Pharmaceutics 2022, 14, 214. https://doi.org/10.3390/ pharmaceutics14010214 Academic Editors: Donato Cosco and Nicolò Mauro Received: 3 December 2021 Accepted: 12 January 2022 Published: 17 January 2022 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2022 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 Article Electrospraying as a Technique for the Controlled Synthesis of Biocompatible PLGA@Ag 2 S and PLGA@Ag 2 S@SPION Nanocarriers with Drug Release Capability Alexis Alvear-Jiménez 1 , Irene Zabala Gutierrez 1 , Yingli Shen 2 , Gonzalo Villaverde 1 , Laura Lozano-Chamizo 3,4 , Pablo Guardia 5 , Miguel Tinoco 6 , Beatriz Garcia-Pinel 7,8,9 , José Prados 7,8,9 , Consolación Melguizo 7,8,9 , Manuel López-Romero 10 , Daniel Jaque 2 , Marco Filice 3,11 and Rafael Contreras-Cáceres 1, * 1 Departamento de Química en Ciencias Farmacéuticas, Universidad Complutense de Madrid, 28040 Madrid, Spain; alexial@ucm.es (A.A.-J.); irenezab@ucm.es (I.Z.G.); gonvilla@ucm.es (G.V.) 2 Fluorescence Imaging Group, Facultad de Ciencias, Universidad Autónoma de Madrid, 28049 Madrid, Spain; yingli.shen@estudiante.uam.es (Y.S.); daniel.jaque@uam.es (D.J.) 3 Nanobiotechnology for Life Sciences Group, Department of Chemistry in Pharmaceutical Sciences, Faculty of Pharmacy, Universidad Complutense de Madrid (UCM), Plaza Ramón y Cajal, 28040 Madrid, Spain; laurloza@ucm.es (L.L.-C.); mfilice@ucm.es (M.F.) 4 Atrys Health, 28001 Madrid, Spain 5 Institute of Materials Science of Barcelona (ICMAB-CSIC), Campus UAB, 08193 Bellaterra, Spain; pguardia@icmab.es 6 ICTS—Centro Nacional de Microscopía Electrónica, Universidad Complutense de Madrid, 28040 Madrid, Spain; mitinoco@ucm.es 7 Department of Anatomy and Embryology, Faculty of Medicine, University of Granada, 18071 Granada, Spain; beatrizgarnel@ugr.es (B.G.-P.); jcprados@ugr.es (J.P.); melguizo@ugr.es (C.M.) 8 Center of Biomedical Research (CIBM), Institute of Biopathology and Regenerative Medicine (IBIMER), University of Granada, 18100 Granada, Spain 9 Instituto Biosanitario de Granada (ibs.GRANADA), 18014 Granada, Spain 10 Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Málaga, 29071 Malaga, Spain; jmromero@uma.es 11 Microscopy and Dynamic Imaging Unit, Fundación Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC F.S.P.), Calle Melchor Fernández Almagro 3, 28029 Madrid, Spain * Correspondence: rafcontr@ucm.es; Tel.: +34-91-3941823 Abstract: Ag 2 S nanoparticles are near-infrared (NIR) probes providing emission in a specific spectral range (~1200 nm), and superparamagnetic iron oxide nanoparticles (SPION) are colloidal systems able to respond to an external magnetic field. A disadvantage of Ag 2 S NPs is the attenuated luminescent properties are reduced in aqueous media and human fluids. Concerning SPION, the main drawback is the generation of undesirable clusters that reduce particle stability. Here, we fabricate biocompatible hybrid nanosystems combining Ag 2 S NPs and SPION by the electrospraying technique for drug delivery purposes. These nanostructures are composed of poly(lactic-co-glycolic acid) (PLGA) as the polymeric matrix in connection with both Ag 2 S NPs and SPIONs. Initially, we fabricate a hybrid colloidal nanosystem composed of Ag 2 S NPs in connection with PLGA (PLGA@Ag 2 S) by three different routes, showing good photoluminescent (PL) properties with relatively high average decay times. Then, we incorporate SPIONs, obtaining a PLGA polymeric matrix containing both Ag 2 S NPs and SPION (PLGA@Ag 2 S@SPION). Interestingly, in this hybrid system, the location of Ag 2 S NPs and SPIONs depends on the synthesis route performed during electrospraying. After a detailed characterization, we demonstrate the encapsulation and release capabilities, obtaining the kinetic release using a model chemotherapeutic drug (maslinic acid). Finally, we perform in vitro cytotoxicity assays using drug-loaded hybrid systems against several tumor cell lines. Keywords: electrospraying; Ag 2 S nanoparticles; SPIONs; hybrid system; chemotherapeutic drug; drug release Pharmaceutics 2022, 14, 214. https://doi.org/10.3390/pharmaceutics14010214 https://www.mdpi.com/journal/pharmaceutics