Janus Mesoporous Silica Nanoparticles for Dual Targeting of Tumor Cells and Mitochondria Victoria Ló pez, † Maria Rocío Villegas, †,‡ Veró nica Rodríguez, † Gonzalo Villaverde, †,‡ Daniel Lozano, †,‡ Alejandro Baeza,* ,†,‡ and María Vallet-Regí* ,†,‡ † Departamento de Química Inorga ́ nica y Bioinorga ́ nica, Facultad de Farmacia, Universidad Complutense de Madrid, 28040 Madrid, Spain ‡ Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, Avenida Monforte de Lemos, 3-5, 28029 Madrid, Spain * S Supporting Information ABSTRACT: The development of targeted nanocarriers able to be selectively internalized within tumor cells, and therefore to deliver anti-tumor drugs specifically to diseased cells, constitutes one of the most important goals in nano-oncology. Herein, the development of Janus mesoporous silica particles asymmetrically decorated with two targeting moieties, one of them selective for folate membrane cell receptors (folic acid) and the other one able to bind to mitochondria membrane (triphenylphosphine, TPP), is described in order to achieve sequential cell to organelle vectorization. The asymmetric decoration of each side of the particle allows fine control in the targeting attachment process in comparison with the use of symmetric nanocarriers. The presence of folic acid induces a higher increase in particle accumulation inside tumor cells, and once there, these nanocarriers are guided close to mitochondria by the action of the TPP moiety. This strategy can be applied for improving the therapeutic efficacy of current nanomedicines. KEYWORDS: Janus nanoparticles, targeted nanosystems, nano-oncology, mesoporous silica nanoparticles, mitochondria targeting ■ INTRODUCTION The paramount discovery made in 1986 by Matsumura and Maeda 1 about the natural tendency of nanometric systems to be passively accumulated within solid tumors triggered the race to design nanocarriers able to deliver anti-tumor agents specifically into diseased tissues. 2,3 Neoplastic tissues are irrigated by blood vessels, which have been built in a chaotic way so that they usually exhibit porous regions with diameters around a few hundred of nanometers. 4 Therefore, when the nanocarrier reaches the tumor area, it is able to pass through these pores to reach the tumor tissue, whereas it cannot cross the healthy vessel walls. Additionally, the rapid expansion of tumor cells compresses the nearby located lymphatic vessels, compromising the drainage, which enhances the accumulation time of nanocarriers into the diseased zone. This phenomenon, called the EPR (enhanced permeation and retention) effect, has also been described as primary targeting, being responsible for nanocarrier accumulation in tumor tissues. However, this effect alone is not enough to achieve an improved therapeutic response over conventional therapy. Tumor masses are incredibly complex tissues that are formed by a myriad of different cells (cancerous, supportive, and immune cells and so on) 5 Therefore, the capacity to distinguish between malignant and healthy cells is necessary for improving the effectiveness of nanomedicines. In order to acquire this property, the external surface of nanocarriers can be decorated with certain moieties such as antibodies, 6 aptamers, 7 vitamins, 8 peptides, 9 or synthetic molecules, 10 which are recognized by specific membrane cell receptors overexpressed by the tumor cells. The presence of these targeting agents (called secondary targeting) enhances accumulation within the tumor cell. Additionally, two targeting moieties can be anchored on the same nanocarrier in order to enhance even more the selectivity of the nanodevice. 11-13 It is also possible to control nanoparticle trafficking within the cell by placing targeting moieties able to recognize organelles such as mitochondria or cell nucleus (tertiary targeting). 14 Therefore, different tertiary targeting agents have been attached on drug-loaded nano- particles to achieve significant improvements in the therapeutic efficacy of the transported payloads. 15 In light of these results, the possibility to design systems that combine these targeting capacities (tissue, cell, and organelle) has aroused great attention in the scientific community for improving even more the capacity to destroy tumor cells while limiting the side Received: May 16, 2017 Accepted: July 31, 2017 Published: July 31, 2017 Research Article www.acsami.org © 2017 American Chemical Society 26697 DOI: 10.1021/acsami.7b06906 ACS Appl. Mater. Interfaces 2017, 9, 26697-26706 Downloaded via UNIV COMPLUTENSE DE MADRID on September 24, 2018 at 10:29:44 (UTC). See https://pubs.acs.org/sharingguidelines for options on how to legitimately share published articles.