**1. Introduction**

In cancer, surgery is the treatment of choice. However, it is often not an option because many cancer cells have already escaped from the primary tumor and colonized distant tissues. Most patients with advanced metastatic disease confront a terminal illness. In fact, metastasis is the greatest challenge to a cancer patient's survival. There are currently no effective treatments to stop or prevent this process, so there is an urgent need to find new diagnostic and therapeutic approaches. To inhibit metastasis, local treatment is generally complemented by radiation therapy and high doses of chemotherapy that cause numerous side effects [1,2], limiting the success of metastasis treatment [3]. However, systemically applied cytotoxic drugs are not effective in preventing the spread of metastatic cells that cause 90% of cancer deaths [4].

Melanoma is an example of a fatal malignancy with rapid systemic dissemination. The 5-year survival rate for metastatic melanoma is less than 15%, and the median survival after developing pulmonary metastasis is on average 7.3 months [5]. The high recurrence of the tumor (one-third of all patients) and the low survival rate are due to the failure of chemotherapy as a systemic treatment for metastasis [6]. Recently, hormone therapy and immunotherapy have produced effective results boosting cell-mediated innate and adaptive antitumor immunity [7,8]. Thus, while understanding the molecular mechanisms behind cancer cell invasion of distal vital organs [1,9], new treatments must be developed to prevent/reduce the rate of metastasis.

**Citation:** Valdivia, L.; García-Hevia, L.; Bañobre-López, M.; Gallo, J.; Valiente, R.; López Fanarraga, M. Solid Lipid Particles for Lung Metastasis Treatment. *Pharmaceutics* **2021**, *13* , 93 . https://doi.org/ 10.3390/pharmaceutics13010093

Received: 16 December 2020 Accepted: 6 January 2021 Published: 13 January 2021

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**Copyright:** © 2021 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/).

One possible solution to this issue could be the use of encapsulated drugs in nanosystems to reduce the systemic toxicity and improve the local effect and drug stability through a sustained and controlled drug release. In this sense, nanotechnology can greatly contribute by the development of delivery nanosystems which can inhibit primary tumors and, at the same time, prevent metastases before they sprout. Nanomedicine offers interesting opportunities to design different drug delivery systems, such as liposomes [3], carbon nanotubes [10], or gold nanoparticles [11], among others. These nanosystems can help in (i) reducing the toxicity of the treatment, (ii) preventing the premature elimination or degradation of the therapeutic compound, and (iii) significantly modifying the biodistribution of the encapsulated drug [12–15]. In this way, drugs with extraordinary pharmacological interest, but discarded due to their poor pharmacological properties or high systemic toxicity, can be reformulated into new nanocomposites showing multifunctional properties and improved therapeutic outputs [16]. Here, we have encapsulated doxorubicin (DOX) in lipidic particles. This drug has already been encapsulated in liposomes in previous studies that have been approved by the U. S. Food and Drug Administration (FDA) (Doxil® [16], Myocet® [17], and LipoDox® [18]). The advantages of these formulations are mainly to do with toxicity. They have less severe side effects than the free drug.

Numerous types of nanocarriers that allow the encapsulation of drugs to be systemically administered have been described. Among these, the most employed are liposomes [3,6], dendrimers [12–14], polymeric micelles [5–8], and silica-based materials [19–21]. Most of these nanomaterials have similar drug release patterns. In most examples, encapsulated therapeutic compounds are released at once, upon detachment, degradation, or permeabilization of the nanocarrier and/or its seal [22,23]. This "burstrelease effect" triggers a fast peak of drug activity at the local or systemic level that closely mimics the effect caused by the free drug. Unfortunately, the effect of the drug is not sustained over time, selecting surviving cells and so generating resistant clones able to travel and colonize distant tissues. Thus, the development of drug carriers providing an initial delivery together with a sustained and controlled therapeutic release for long periods to obtain a level of drug higher than the minimum effective concentration is highly desirable. This suggests that the design of two-stage-release drug delivery systems could improve the prevention of metastasis.

Here, we used solid lipid particles (SLPs), which are aqueous colloidal dispersions with a matrix composed of solid biodegradable lipids. These nanoformulations present several advantages compared with other nanovehicles. Among the advantages, they show great biocompatibility, high drug-loading capacity, improved pharmaceutic stability, and excellent reproducibility [24]. Furthermore, the natural carnauba wax chosen in this study represents one of the best options to obtain excellent drug encapsulation efficiencies while maintaining the plasma drug concentration within the therapeutic window during a prolonged period [25].

In this study, we have investigated the antimetastatic effect of carnauba wax DOXloaded SLPs. This drug is the first-line treatment for a wide range of cancers including lymphomas, leukemias, and solid tumors in the bladder, breast, stomach, lung, and ovaries, among others [26]. However, DOX use is currently decreasing due to its side effects, which include cardiotoxicity and nephrotoxicity [27,28]. This encapsulation system has already proved its efficacy in vitro in malignant melanoma cell cultures (2D and 3D melanoma models) [29] compared to the free DOX. Herein, we have studied the in vivo efficacy of the encapsulated DOX in a melanoma metastatic model.
