Selective targeting of chemically modified miR-34a to prostate cancer using a small molecule ligand and an endosomal escape agent.

Use of tumor-suppressive microRNAs (miRNAs) as anti-cancer agents is hindered by the lack of effective delivery vehicles, entrapment of the miRNA within endocytic compartments, and rapid degradation of miRNA by nucleases. To address these issues, we developed a miRNA delivery strategy that includes (1) a targeting ligand, (2) an endosomal escape agent, nigericin and (3) a chemically modified miRNA. The delivery ligand, DUPA (2-[3-(1,3-dicarboxy propyl) ureido] pentanedioic acid), was selected based on its specificity for prostate-specific membrane antigen (PSMA), a receptor routinely upregulated in prostate cancer-one of the leading causes of cancer death among men. DUPA was conjugated to the tumor suppressive miRNA, miR-34a (DUPA-miR-34a) based on the ability of miR-34a to inhibit prostate cancer cell proliferation. To mediate endosomal escape, nigericin was incorporated into the complex, resulting in DUPA-nigericin-miR-34a. Both DUPA-miR-34a and DUPA-nigericin-miR-34a specifically bound to, and were taken up by, PSMA-expressing cells in vitro and in vivo. And while both DUPA-miR-34a and DUPA-nigericin-miR-34a downregulated miR-34a target genes, only DUPA-nigericin-miR-34a decreased cell proliferation in vitro and delayed tumor growth in vivo. Tumor growth was further reduced using a fully modified version of miR-34a that has significantly increased stability.

A first-in-class fully modified version of miR-34a with outstanding stability, activity, and anti-tumor efficacy.

Altered by defects in p53, epigenetic silencing, and genomic loss, the microRNA miR-34a represents one of the most clinically relevant tumor-suppressive microRNAs. Without question, a striking number of patients with cancer would benefit from miR-34a replacement, if poor miR-34a stability, non-specific delivery, and delivery-associated toxicity could be overcome. Here, we highlight a fully modified version of miR-34a (FM-miR-34a) that overcomes these hurdles when conjugated to a synthetically simplistic ligand. FM-miR-34a is orders of magnitude more stable than a partially modified version, without compromising its activity, leading to stronger repression of a greater number of miR-34a targets. FM-miR-34a potently inhibited proliferation and invasion, and induced sustained downregulation of endogenous target genes for >120 h following in vivo delivery. In vivo targeting was achieved through conjugating FM-miR-34a to folate (FM-FolamiR-34a), which inhibited tumor growth leading to complete cures in some mice. These results have the ability to revitalize miR-34a as an anti-cancer agent, providing a strong rationale for clinical testing.

Emerging diversity in extracellular vesicles and their roles in cancer.

Extracellular vesicles have undergone a paradigm shift from being considered as 'waste bags' to being central mediators of cell-to-cell signaling in homeostasis and several pathologies including cancer. Their ubiquitous nature, ability to cross biological barriers, and dynamic regulation during changes in pathophysiological state of an individual not only makes them excellent biomarkers but also critical mediators of cancer progression. This review highlights the heterogeneity in extracellular vesicles by discussing emerging subtypes, such as migrasomes, mitovesicles, and exophers, as well as evolving components of extracellular vesicles such as the surface protein corona. The review provides a comprehensive overview of our current understanding of the role of extracellular vesicles during different stages of cancer including cancer initiation, metabolic reprogramming, extracellular matrix remodeling, angiogenesis, immune modulation, therapy resistance, and metastasis, and highlights gaps in our current knowledge of extracellular vesicle biology in cancer. We further provide a perspective on extracellular vesicle-based cancer therapeutics and challenges associated with bringing them to the clinic.

Additive Impairment of Synaptic Signaling in Cultured Cortical Neurons by Exogenously-Applied Oligomerized Amyloid-ß and Airborne Nanoparticles Generated during Photocopying.

Photocopying in offices and printing centers releases nanoparticles that can reach the brain following inhalation. We examined whether subcytotoxic levels of airborne photocopy-emitted nanoparticles could potentiate perturbation of synaptic signaling in cultured neurons following exposure to amyloid-ß (Aß). Signaling was only transiently inhibited by Aß or nanoparticles individually, but remained statistically reduced in cultures receiving both after 24 h. In vitro and in vivo studies with copier emitted nanoparticles have consistently demonstrated inflammation, oxidative stress, and cytotoxicity. Since Aß can accumulate years before cognitive decline, subcytotoxic levels of nanoparticles are one factor that could potentiate Aß-induced impairment of synaptic activity during these early stages.