Pharmaceutics 2022, 14, 2770. https://doi.org/10.3390/pharmaceutics14122770 www.mdpi.com/journal/pharmaceutics Article Co-Delivery System of Curcumin and Colchicine Using Functionalized Mesoporous Silica Nanoparticles Promotes Anticancer and Apoptosis Effects Khaled AbouAitah 1, *, Ahmed A. F. Soliman 2 , Anna Swiderska-Sroda 3 , Amr Nassrallah 4 , Julita Smalc-Koziorowska 5 , Stanislaw Gierlotka 3 and Witold Lojkowski 3, * 1 Medicinal and Aromatic Plants Research Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre (NRC), 33 El-Behouth Street, Dokki, Giza 12622, Egypt 2 Drug Bioassay-Cell Culture Laboratory, Pharmacognosy Department, Pharmaceutical and Drug Industries Research Institute, National Research Centre (NRC), 33 El-Behouth St, Dokki, Giza 12622, Egypt 3 Laboratory of Nanostructures and Nanomedicine, Institute of High Pressure Physics, Polish Academy of Sciences, Sokolowska 29/37, 01-142 Warsaw, Poland 4 Biochemistry Department, Faculty of Agriculture, Cairo University, Giza 12613, Egypt 5 Laboratory of Semiconductor Characterization, Institute of High Pressure Physics, Polish Academy of Sciences, Sokolowska 29/37, 01-142 Warsaw, Poland * Correspondence: ke.abouaitah@nrc.sci.eg (K.A.); w.lojkowski@labnano.pl (W.L.); Tel.: +20233371635 (K.A.); +48-22-888-0429 or +48-22-632-4302 (W.L.); Fax: +20233371010 (K.A.); +48-22-632-4218 (W.L.) Abstract: Purpose: Many natural agents have a high anticancer potential, and their combination may be advantageous for improved anticancer effects. Such agents, however, often are not water soluble and do not efficiently target cancer cells, and the kinetics of their action is poorly controlled. One way to overcome these barriers is to combine natural agents with nanoparticles. Our aim in the current study was to fabricate an anticancer nanoformulation for co-delivery of two natural agents, curcumin (CR) and colchicine (CL), with a core-shell structure. Using cancer cell lines, we compared the anticancer efficacy between the combination and a nanoformulation with CL alone. Methods: For the single-drug nanoformulation, we used phosphonate groups to functionalize mesoporous silica nanoparticles (MSNs) and loaded the MSNs with CL. Additional loading of this nanoformu- lation with CR achieved the co-delivery format. To create the structure with a core shell, we selected a chitosan–cellulose mixture conjugated with targeting ligands of folic acid for the coating. For eval- uating anticancer and apoptosis effects, we assessed changes in important genes and proteins in apoptosis (p53, caspase-3, Bax, Bcl-2) in several cell lines (MCF-7, breast adenocarcinoma; HCT-116, colon carcinoma; HOS, human osteosarcoma; and A-549, non–small cell lung cancer). Results: Nanoformulations were successfully synthesized and contained 10.9 wt.% for the CL single-deliv- ery version and 18.1 wt.% for the CL+CR co-delivery nanoformulation. Anticancer effects depended on treatment, cell line, and concentration. Co-delivery nanoformulations exerted anticancer effects that were significantly superior to those of single delivery or free CL or CR. Anticancer effects by cell line were in the order of HCT-116 > A549 > HOS > MCF-7. The lowest IC50 value was obtained for the nanoformulation consisting of CL and CR coated with a polymeric shell conjugated with FA (equivalent to 4.1 ± 0.05 μg/mL). With dual delivery compared with the free agents, we detected strongly increased p53, caspase-3, and Bax expression, but inhibition of Bcl-2, suggesting promotion of apoptosis. Conclusions: Our findings, although preliminary, indicate that the proposed dual de- livery nanoformulation consisting of nanocore: MSNs loaded with CL and CR and coated with a shell of chitosan–cellulose conjugated folic acid exerted strong anticancer and apoptotic effects with potent antitumor activity against HCT-116 colon cells. The effect bested CL alone. Evaluating and confirming the efficacy of co-delivery nanoformulations will require in vivo studies. Keywords: co-delivery system; natural agent; cancer cell; curcumin combined colchicine core-shell nanoformulation; functionalized mesoporous silica nanoparticle; active cancer targeting Citation: AbouAitah, K.; Soliman, A.A.F.; Swiderska-Sroda, A.; Nassrallah, A.; Smalc-Koziorowska, J.; Gierlotka, S.; Lojkowski, W. Co-Delivery System of Curcumin and Colchicine Using Functionalized Mesoporous Silica Nanoparticles Promotes Anticancer and Apoptosis Effects. Pharmaceutics 2022, 14, 2770. https://doi.org/10.3390/ pharmaceutics14122770 Academic Editors: Marek Drozdzik and Magdalena Peruzynska Received: 2 November 2022 Accepted: 6 December 2022 Published: 11 December 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/).