Engineering oncogene-targeted anisamide-functionalized pBAE nanoparticles as efficient lung cancer antisense therapies.

Non-small cell lung cancer (NSCLC) is one of the leading causes of worldwide death, mainly due to the lack of efficient and safe therapies. Currently, NSCLC standard of care for consist on the use of traditional chemotherapeutics, non-selectively distributed through the whole body, thus causing severe side effects while not achieving high efficacy outcomes. Consequently, the need of novel therapies, targeted to modify specific subcellular routes aberrantly expressed only in tumor cells is still urgent. In this context, the delivery of siRNAs that can know-down overexpressed oncogenes, such as mTOR, could become the promised targeted therapy. However, siRNA effective delivery remains a challenge due to its compromised stability in biological fluids and its inability to cross biological and plasmatic membranes. Therefore, polymeric nanoparticles that efficiently encapsulate siRNAs and are selectively targeted to tumor cells could play a pivotal role. Accordingly, we demonstrate in this work that oligopeptide end-modified poly(beta aminoester) (OM-pBAE) polymers can efficiently complex siRNA in small nanometric particles using very low polymer amounts, protecting siRNA from nucleases attack. These nanoparticles are stable in the presence of serum, advantageous fact in terms of in vivo use. We also demonstrated that they efficiently transfect cells in vitro, in the presence of serum and are able to knock down target gene expression. Moreover, we demonstrated their antitumor efficacy by encapsulating mTOR siRNA, as a model antisense therapy, which showed specific lung tumor cell growth inhibition in vitro and in vivo. Finally, through the addition of anisamide functionalization to the surface of the nanoparticles, we proved that they become selective to lung tumor cells, while not affecting healthy cells. Therefore, our results are a first step in the discovery of a tumor cell-targeted efficient silencing nanotherapy for NSCLC patients survival improvement.

Synthesis and Characterization of mRNA-Loaded Poly(Beta Aminoesters) Nanoparticles for Vaccination Purposes.

Vaccination has been one of the major successes of modern society and is indispensable in controlling and preventing disease. Traditional vaccines were composed of entire or fractions of the infectious agent. However, challenges remain, and new vaccine technologies are mandatory. In this context, the use of mRNA for immunizing purposes has shown an enhanced performance, as demonstrated by the speedy approval of two mRNA vaccines preventing SARS-CoV-2 infection. Beyond success in preventing viral infections, mRNA vaccines can also be used for therapeutic cancer applications. Nevertheless, the instability of mRNA and its fast clearance from the body due to the presence of nucleases makes its naked delivery not possible. In this context, nanomedicines, and specifically polymeric nanoparticles, are critical mRNA delivery systems. Thus, the aim of this article is to describe the protocol for the formulation and test of an mRNA vaccine candidate based on the proprietary polymeric nanoparticles. The synthesis and chemical characterization of the poly(beta aminoesters) polymers used, their complexation with mRNA to form nanoparticles, and their lyophilization methodology will be discussed here. This is a crucial step for decreasing storage and distribution costs. Finally, the required tests to demonstrate their capacity to in vitro transfect and mature model dendritic cells will be indicated. This protocol will benefit the scientific community working on vaccination because of its high versatility that enables these vaccines to prevent or cure a wide variety of diseases.

Cancer immunotherapies revisited: state of the art of conventional treatments and next-generation nanomedicines.

Nowadays, the landscape of cancer treatments has broadened thanks to the clinical application of immunotherapeutics. After decades of failures, cancer immunotherapy represents an exciting alternative for those patients suffering from a wide variety of cancers, especially for those skin cancers, such as the early stages of melanoma. However, those cancers affecting internal organs still face a long way to success, because of the poor biodistribution of immunotherapies. Here, nanomedicine appears as a hopeful strategy to modulate the biodistribution aiming at target organ accumulation. In this way, efficacy will be improved, while reducing the side effects at the same time. In this review, we aim to highlight the most promising cancer immunotherapeutic strategies. From monoclonal antibodies and their traditional use as targeted therapies to their current use as immune checkpoint inhibitors; as well as adoptive cell transfer therapies; oncolytic viruses, and therapeutic cancer vaccination. Then, we aim to discuss the important role of nanomedicine to improve the performance of these immunotherapeutic tools to finally review the already marketed nanomedicine-based cancer immunotherapies.

Nanomedicine in Non-Small Cell Lung Cancer: From Conventional Treatments to Immunotherapy.

Non-small cell lung cancer (NSCLC) remains the most common cause of cancer-related mortality. The heterogeneous nature of this disease hinders its diagnosis and treatment, requiring continuous advances in research aiming to understand its intricate nature. Consequently, the retrospective analysis of conventional therapies has allowed the introduction of novel tools provided by nanotechnology, leading to considerable improvements in clinical outcomes. Furthermore, the development of novel immunotherapies based on the recently understood interaction of the immune system with the tumor highlights the real possibility of definitively treating NSCLC from its early stages. Novel engineering approaches in nanomedicine will enable to overcome the intrinsic limits of conventional and emerging therapies regarding off-site cytotoxicity, specificity, resistance mechanisms, and administration issues. The convergence point of these therapies with nanotechnology lays the foundation for achieving currently unmet needs.