We report potent radiosensitization of prostate cancers in vitro and in vivo using goserelin-conjugated gold nanorods. Progressive receptor-mediated internalization of conjugated nanorods over time increases the radiation interaction cross-section of cells and contributes to the effects observed in vitro. The low concentrations of gold required, the long interval between injection of nanoparticles and radiation, and the use of megavoltage radiation to generate radiosensitization in vivo foretell the possibility of eventual clinical translation of this approach.

The microRNA (miR)-200s and their negative regulator ZEB1 have been extensively studied in the context of the epithelial-mesenchymal transition. Loss of miR-200s has been shown to enhance cancer aggressiveness and metastasis, whereas replacement of miR-200 miRNAs has been shown to inhibit cell growth in several types of tumors, including lung cancer. Here, we reveal a novel function of miR-200c, a member of the miR-200 family, in regulating intracellular reactive oxygen species signaling and explore a potential application for its use in combination with therapies known to increase oxidative stress such as radiation. We found that miR-200c overexpression increased cellular radiosensitivity by direct regulation of the oxidative stress response genes PRDX2, GAPB/Nrf2, and SESN1 in ways that inhibits DNA double-strand breaks repair, increase levels of reactive oxygen species, and upregulate p21. We used a lung cancer xenograft model to further demonstrate the therapeutic potential of systemic delivery of miR-200c to enhance radiosensitivity in lung cancer. Our findings suggest that the antitumor effects of miR-200c result partially from its regulation of the oxidative stress response; they further suggest that miR-200c, in combination with radiation, could represent a therapeutic strategy in the future.

No abstract

Summary To repair neural circuitry following spinal cord injury (SCI), neural stem cell (NSC) transplantation has held a primary focus; however, stochastic outcomes generate challenges driven in part by NSC differentiation and tumor formation. The recent ability to generate regionally specific neurons and their support cells now allows consideration of directed therapeutic approaches with pre-differentiated and networked spinal neural cells. Here, we form encapsulated, transplantable neuronal networks of regionally matched cervical spinal motor neurons, interneurons, and oligodendrocyte progenitor cells derived through trunk-biased neuromesodermal progenitors. We direct neurite formation in alginate-based neural ribbons to generate electrically active, synaptically connected networks, characterized by electrophysiology and calcium imaging before transplantation into rodent models of contused SCI for evaluation at 10-day and 6-week timepoints. The in vivo analyses demonstrate viability and retention of interconnected synaptic networks that readily integrate with the host parenchyma to advance goals of transplantable neural circuitry for SCI treatment.

In this work, we aim to experimentally assess increments of dose due to nanoparticle-radiation interactions via electron spin resonance (ESR) dosimetry performed with a biological-equivalent sensitive material.We employed 2-Methyl-Alanine (2MA) in powder form to compose the radiation sensitive medium embedding gold nanoparticles (AuNPs) 5 nm in diameter. Dosimeters manufactured with 0.1% w/w of AuNPs or no nanoparticles were irradiated with clinically utilized 250 kVp orthovoltage or 6 MV linac x-rays in dosimetric conditions. Amplitude peak-to-peak (App) at the central ESR spectral line was used for dosimetry. Dose-response curves were obtained for samples with or without nanoparticles and each energy beam. Dose increments due to nanoparticles were analyzed in terms of absolute dose enhancements (DEs), calculated as App ratios for each dose/beam condition, or relative dose enhancement factors (DEFs) calculated as the slopes of the dose-response curves.Dose enhancements were observed to present an amplified behavior for small doses (between 0.1-0.5 Gy), with this effect being more prominent with the kV beam. For doses between 0.5-5 Gy, dose-independent trends were observed for both beams, stable around (2.1   ±   0.7) and (1.3   ±   0.4) for kV and MV beams, respectively. We found DEFs of (1.62   ±   0.04) or (1.27   ±   0.03) for the same beams. Additionally, we measured no interference between AuNPs and the ESR apparatus, including the excitation microwaves, the magnetic fields and the paramagnetic radicals.2MA was demonstrated to be a feasible paramagnetic radiation-sensitive material for dosimetry in the presence of AuNPs, and ESR dosimetry a powerful experimental method for further verifications of increments in nanoparticle-mediated doses of biological interest. Ultimately, gold nanoparticles can cause significant and detectable dose enhancements in biological-like samples irradiated at both kilo or megavoltage beams.