Citation: Persano, F.; Nobile, C.; Piccirillo, C.; Gigli, G.; Leporatti, S. Monodisperse and Nanometric-Sized Calcium Carbonate Particles Synthesis Optimization. Nanomaterials 2022, 12, 1494. https:// doi.org/10.3390/nano12091494 Received: 1 April 2022 Accepted: 26 April 2022 Published: 28 April 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/). nanomaterials Article Monodisperse and Nanometric-Sized Calcium Carbonate Particles Synthesis Optimization Francesca Persano 1,2, *, Concetta Nobile 2 , Clara Piccirillo 2 , Giuseppe Gigli 1,2 and Stefano Leporatti 2, * 1 Department of Mathematics and Physics, University of Salento, 73100 Lecce, Italy; giuseppe.gigli@unisalento.it 2 CNR Nanotec—Institute of Nanotechnology, 73100 Lecce, Italy; concetta.nobile@nanotec.cnr.it (C.N.); clara.piccirillo@nanotec.cnr.it (C.P.) * Correspondence: francesca.persano@unisalento.it(F.P.); stefano.leporatti@nanotec.cnr.it (S.L.); Tel.: +39-0832-3198-29 (S.L.) Abstract: Calcium carbonate (CaCO 3 ) particles represent an appealing choice as a drug delivery system due to their biocompatibility, biodegradability, simplicity and cost-effectiveness of manufac- turing, and stimulus-responsiveness. Despite this, the synthesis of CaCO 3 particles with controlled size in the nanometer range via a scalable manufacturing method remains a major challenge. Here, by using a co-precipitation technique, we investigated the impact on the particle size of different synthesis parameters, such as the salt concentration, reaction time, stirring speed, and temperature. Among them, the salt concentration and temperature resulted in having a remarkable effect on the particle size, enabling the preparation of well-dispersed spherical nanoparticles with a size below 200 nm. Upon identification of optimized synthesis conditions, the encapsulation of the antitumoral agent resveratrol into CaCO 3 nanoparticles, without significantly impacting the overall size and morphology, has been successfully achieved. Keywords: calcium carbonate nanoparticles; vaterite; nanomedicine; drug delivery; resveratrol 1. Introduction Drug delivery systems have been widely explored in a range of biomedical applica- tions and, particularly, for cancer therapy. These anti-cancer drugs tend frequently to be insoluble in water or biological media, and do not possess a target-specific effect, thus exert- ing their cytotoxic effect not only on tumor cells but also on healthy cells, leading to several collateral effects [1–3]. To overcome these issues, research over the past decades has focused on the development of new delivery systems that can improve the solubility, biodistribution, and tumor targeting-ability of anti-cancer drugs [4,5]. Nanotechnology has the potential to enhance the therapeutic efficacy of conventional anticancer drugs by increasing their stability and solubility and enabling the precise delivery of therapeutics within a specific tissue or organ [6]. Although a wide number of nanomaterials have been explored in pre- clinical models, biodegradable materials are often preferred over non-biodegradable ones for biomedical applications since they generally exhibit an improved toxicity profile [7,8]. Among these biodegradable nanomaterials, calcium carbonate (CaCO 3 ) is particularly attractive for the development of nanocarriers due to its unique properties, including high biocompatibility and pH-responsiveness, along with the simplicity and low cost of pro- duction [9,10]. The pH-responsiveness of CaCO 3 nanoparticles (CaCO 3 NPs) makes them particularly appealing for cancer treatment since acidosis is a hallmark of the tumor mi- croenvironment [11]. Importantly, to fully exploit the potential of CaCO 3 -based platforms for therapeutic applications, the particle size must be kept in the nanoscale range. Particle size is indeed one of the major parameters affecting biodistribution and consequently determining the therapeutic outcome of nano-formulated drugs [12–14]. This is valid even Nanomaterials 2022, 12, 1494. https://doi.org/10.3390/nano12091494 https://www.mdpi.com/journal/nanomaterials