Modulation of Colorectal Tumor Behavior via lncRNA TP53TG1-Lipidic Nanosystem.

Long non-coding RNAs (lncRNAs) are an emerging group of RNAs with a crucial role in cancer pathogenesis. In gastrointestinal cancers, TP53 target 1 (TP53TG1) is an epigenetically regulated lncRNA that represents a promising therapeutic target due to its tumor suppressor properties regulating the p53-mediated DNA damage and the intracellular localization of the oncogenic YBX1 protein. However, to translate this finding into the clinic as a gene therapy, it is important to develop effective carriers able to deliver exogenous lncRNAs to the targeted cancer cells. Here, we propose the use of biocompatible sphingomyelin nanosystems comprising DOTAP (DSNs) to carry and deliver a plasmid vector encoding for TP53TG1 (pc(TP53TG1)-DSNs) to a colorectal cancer cell line (HCT-116). DSNs presented a high association capacity and convenient physicochemical properties. In addition, pc(TP53TG1)-DSNs showed anti-tumor activities in vitro, specifically a decrease in the proliferation rate, a diminished colony-forming capacity, and hampered migration and invasiveness of the treated cancer cells. Consequently, the proposed strategy displays a high potential as a therapeutic approach for colorectal cancer.

Sphingomyelin nanosystems loaded with uroguanylin and etoposide for treating metastatic colorectal cancer.

Colorectal cancer is the third most frequently diagnosed cancer malignancy and the second leading cause of cancer-related deaths worldwide. Therefore, it is of utmost importance to provide new therapeutic options that can improve survival. Sphingomyelin nanosystems (SNs) are a promising type of nanocarriers with potential for association of different types of drugs and, thus, for the development of combination treatments. In this work we propose the chemical modification of uroguanylin, a natural ligand for the Guanylyl Cyclase (GCC) receptor, expressed in metastatic colorectal cancer tumors, to favour its anchoring to SNs (UroGm-SNs). The anti-cancer drug etoposide (Etp) was additionally encapsulated for the development of a combination strategy (UroGm-Etp-SNs). Results from in vitro studies showed that UroGm-Etp-SNs can interact with colorectal cancer cells that express the GCC receptor and mediate an antiproliferative response, which is more remarkable for the drugs in combination. The potential of UroGm-Etp-SNs to treat metastatic colorectal cancer cells was complemented with an in vivo experiment in a xenograft mice model.

Edelfosine nanoemulsions inhibit tumor growth of triple negative breast cancer in zebrafish xenograft model.

Triple negative breast cancer (TNBC) is known for being very aggressive, heterogeneous and highly metastatic. The standard of care treatment is still chemotherapy, with adjacent toxicity and low efficacy, highlighting the need for alternative and more effective therapeutic strategies. Edelfosine, an alkyl-lysophospholipid, has proved to be a promising therapy for several cancer types, upon delivery in lipid nanoparticles. Therefore, the objective of this work was to explore the potential of edelfosine for the treatment of TNBC. Edelfosine nanoemulsions (ET-NEs) composed by edelfosine, Miglyol 812 and phosphatidylcholine as excipients, due to their good safety profile, presented an average size of about 120 nm and a neutral zeta potential, and were stable in biorelevant media. The ability of ET-NEs to interrupt tumor growth in TNBC was demonstrated both in vitro, using a highly aggressive and invasive TNBC cell line, and in vivo, using zebrafish embryos. Importantly, ET-NEs were able to penetrate through the skin barrier of MDA-MB 231 xenografted zebrafish embryos, into the yolk sac, leading to an effective decrease of highly aggressive and invasive tumoral cells' proliferation. Altogether the results demonstrate the potential of ET-NEs for the development of new therapeutic approaches for TNBC.

In Vitro-In Silico Modeling Approach to Rationally Designed Simple and Versatile Drug Delivery Systems.

Rational design and development of a nanosystem usually relies on empirical approaches as well as a fair degree of serendipity. Understanding how nanosystems behave at the molecular level is of great importance for potential biomedical applications. In this work, we describe a nanosystem composed of two natural compounds, vitamin E and sphingomyelin, prepared by spontaneous emulsification (vitamin E-sphingomyelin nanosystems (VSNs)). Extensive characterization revealed suitable physicochemical properties, very high biocompatibility in vitro and in vivo, and colloidal stability during storage and in biological media, all relevant properties for clinical translation. We have additionally pursued a computational approach to gain an improved understanding of the assembling, structure, dynamics, and drug-loading capacity of VSNs, using both small molecules and biomolecules (resveratrol, curcumin, gemcitabine, and two peptides). The spontaneous formation of compartmentalized VSNs starting from completely disassembled molecules, observed here for the first time, was accurately assessed from the computational molecular dynamics trajectories. We describe here a synergistic in silico/in vitro approach showing the predictive power of computational simulations for VSNs' structural characterization and description of internal interaction mechanisms responsible for the association of bioactive molecules, representing a paradigm shift in the rational design of nanotechnologies as drug delivery systems for advanced personalized medicine.

Exosome-mimetic nanoplatforms for targeted cancer drug delivery.

BACKGROUND: Lack of effective tumor-specific delivery systems remains an unmet clinical challenge for successful translation of innovative therapies, such as, therapeutic oligonucleotides. In the past decade, exosomes have been suggested to be ideal drug delivery systems with application in a broad range of pathologies including cancer, due to their organotropic properties. Tumor-derived exosomes, having tumor-homing properties, can efficiently reach cancer cells and therefore behave as carriers for improved drug delivery to the primary tumor and metastases. However, due to their complex composition, and still undefined biological functions, safety concerns arise hampering their translation to the clinics. RESULTS: We propose here the development of exosome-mimetic nanosystems (EMNs) that simulate natural tumor-derived exosomes with respect to their structure and functionality, but with a controlled composition, for the targeted delivery of therapeutic oligonucleotides to lung adenocarcinoma cells (microRNA-145 mimics). Making use of the well-known liposome technology, EMNs can be engineered, loaded with the therapeutic compounds, and tailored with specific proteins (integrin α6ß4) providing them organotropic properties. EMNs show great similarities to natural exosomes with respect to their physicochemical properties, drug loading capacity, and ability to interact with the cancer target cells in vitro and in vivo, but are easier to manufacture, can be produced at high yields, and are safer by definition. CONCLUSIONS: We have designed a multifunctional nanoplatform mimicking exosomes, EMNs, and proved their potential to reach cancer cells with a similar efficient that tumor-derived exosomes but providing important advantages in terms of production methodology and regulations. Additionally, EMNs are highly versatile systems that can be tunable for a broader range of applications.

Engineering polymeric nanocapsules for an efficient drainage and biodistribution in the lymphatic system.

Polymer-based nanocarriers have shown potential for enhancing the immunological response of antigens. However, the key drivers for this response have not been fully elucidated. The objective of this work was to evaluate the influence of particle size (≈100 versus 200 nm) and surface composition of polymeric nanocapsules (chitosan, polyarginine and carboxymethyl-ß-glucan) on their ability to target specific immune cells in the lymphatics. For this purpose, we used a powerful imaging technique, two-photon intravital microscopy, which minimises tissue damage in the visualisation of biological processes at cellular/subcellular levels. As expected, particle size was critical in the distribution and lymph node accumulation of all nanocapsules. Chitosan particles with a mean size below 100 nm accumulated significantly more in the popliteal lymph node than those with a larger size. Additionally, a comparative analysis of 100 nm nanocapsules with different polymeric shells indicated that cationic nanocapsules (chitosan and polyarginine) show higher accumulation in the popliteal lymph node than the anionic ones (carboxymethyl-ß-glucan). In contrast, these anionic nanocapsules showed significant accumulation in the lumbar lymph node. In conclusion, tuning the physicochemical properties and composition of the nanocapsules allows the modulation of their lymphatic uptake and biodistribution, which may have important implications in the immune response.