**5. Conclusions**

The goal of this study was to evaluate the metastasis inhibition activity of DOXloaded SLPs. The results show that these particles synthesized with natural compounds efficiently target lung tissue after only 2 h of intravenous administration. Furthermore, these particles stably release the drug during a long period of over 40 days. This translates into an important reduction in the number of metastases in the lungs compared with unformulated DOX, triggering no detectable toxic effect. The observed antitumor activity in melanoma models [29], together with the metastatic reduction upon treatment with SLPs-DOX, suggest that these particles are an excellent alternative as adjuvant or coadjuvant treatments for numerous systemic cancers.

**Supplementary Materials:** The following are available online at https://www.mdpi.com/1999-4 923/13/1/93/s1, Figure S1. Scheme of the synthesis procedure followed to obtain magnetic DOXloaded SLPs. Figure S2. Characterization of SLPs. (a) Size distribution of SLP control (left) and SLPs-DOX (right). (b) Transmission electron microscopy image of SLPs. Figure S3. SLPs reach lung tissue. (a) Fluorescent confocal microscopy images in cryostat lungs sections after 3 and 8 h of intravenous administration. The SLPs (green channel) appear close to cell nuclei (stained with Hoechst, blue channel). (b). Inductively coupled plasma spectroscopy (ICP) quantification of Fe in tissues indicative of the biodistribution of the two types of SLPs after 20 days postinjection (*n* = 56). The plot shows the amount of Fe (µg/g) in the liver (L), heart (H), kidneys (K), intestines (I), spleen (S), lungs (Lu), and brain (B). The results were normalized with respect to control tissues (saline serum). Figure S4. Calibration curve of DOX at 597 nm using fluorimetry. Figure S5. Plot of survival rate of mice after 20 days of the experiment; *n* = 167. The results show that SLPs with DOX did not

have toxicity at the time of the experiment with respect to untreated mice. Figure S6. Loss of weight mice after 20 days of the experiment; *n* = 13.

**Author Contributions:** Conceptualization, J.G. and M.L.F.; methodology, L.V., L.G.-H. and M.L.F.; software, L.V.; validation, L.V. and L.G.-H.; formal analysis, L.V. and L.G.-H.; investigation, L.V., J.G. and L.G.-H.; resources, M.B.-L. and M.L.F.; data curation, L.V. and L.G.-H.; writing/original draft preparation, L.V., L.G.-H. and M.L.F.; writing/review and editing, J.G., M.B.-L. and R.V.; visualization, L.V. and L.G.-H.; supervision, M.L.F.; project administration, M.L.F.; funding acquisition, M.B.-L. and M.L.F. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the European Regional Development Fund (ERDF) and the Spanish MINECO Refs. PI16/00496 (AES 2016), PI19/00349 (AES 2019), and DTS19/00033; IDIVAL Refs. INNVAL17/11 and INNVAL19/12. J.G. and M.B.-L. also acknowledge financial support from the Fundação para a Ciência e a Tecnologia and the ERDF through NORTE2020 (2014–2020 North Portugal Regional Operational Program) through the projects UTAP-EXPL/NTec/0038/2017 (NANOTHER) and NORTE-01-0145-FEDER-031142 (MAGTARGETON). Nano2clinics COST Action CA17140.

**Institutional Review Board Statement:** The study was carried out in accordance with the guidelines of the Declaration of Helsinki and was approved by the Ethics Committee of the University of Cantabria (protocol code 2013-21 and acceptance date 24 January 2013).

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Acknowledgments:** We thank Débora Muñoz Guerra and Begoña Ubilla for their technical assistance. We also want to thank Koster Keunen Holland BV (Raambrug 3, 5531 AG Bladel, The Netherlands) for providing us with T1 pharmaceutical grade *Carnauba wax*. Schematic representations were generated in BioRender software.

**Conflicts of Interest:** The authors declare no conflict of interest.
