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Nanoparticle-Mediated Small RNA Deliveries for Molecular Therapies
Published in D. Sakthi Kumar, Aswathy Ravindran Girija, Bionanotechnology in Cancer, 2023
Ramasamy Paulmurugan, Uday Kumar Sukumar, Tarik F. Massoud
PLGA nanoparticles prepared using the double emulsion-solvent evaporation method and loaded with a plasmid expressing shRNA targeting VEGF were able to regress corneal neovascularization in a more sustained and vigorous manner than naked plasmids alone, making them a good in vivo non-viral gene therapy tool for sustainable, non-immunogenic, and efficient regression of murine CNV [106]. Similarly, a construct expressing shRNA targeting androgen receptor (AR) and delivered by PLGA nanoparticle has shown an antiproliferative effect in prostate cancer. AR-shRNA construct-loaded and prostate-specific membrane antigen (PSMA) A10 aptamer-conjugated PLGA nanoparticles strongly improved cellular uptake of nanoparticles in both cell culture and xenograft-based models, and considerably enhanced tumor regression compared to non-conjugated nanoparticles in various prostate cancer cell lines (22RV1, LAPC-4, and LNCaP). The tissue-specific delivery of AR-shRNA using PLGA nanoparticles indicated an effective therapy for prostate cancer [107]. VEGF is a key driving force and regulator in tumor-associated angiogenesis and tumor development in HCC and many other cancers [108]. RNAi-based therapeutics have been shown to block this angiogenesis stimulator [109]. Due to low cellular uptake and poor stability of small RNAs, the clinically suitable, safe, and effective delivery systems are required for RNAi-based therapeutics [110]. Low molecular weight chitosan-shRNA (LMWC-shRNA) nanocomplexes directed against VEGF considerably inhibited VEGF expression of HCC cells and liver tumor tissues. Intravenous injection of LMWC-shRNA nanocomplexes displayed greater and prolonged deposition of shRNA at the tumor site in orthotopic allograft liver tumor-bearing mice [111].
Obesity-Modified CD4+ T-Cells Promote an Epithelial-Mesenchymal Transition Phenotype in Prostate Cancer Cells
Published in Nutrition and Cancer, 2022
Alejandra De Angulo, Peyton Travis, Gloria Cecilia Galvan, Christopher Jolly, Linda deGraffenried
To determine whether the obesity-associated induction of EMT could result in phenotypical changes in prostate cancer epithelial cells, we assessed the impact of CM from obesity-modified CD4+ T-cells on prostate cancer epithelial cell migration (Figure 4) and prostate cancer epithelial cell invasion (Figure 5). After 24-hour exposure to the different conditions, we observed that obese-CM significantly increased LNCaP cell migration when compared to non-obese-CM (Figure 4A). Similarly, cell migration was significantly higher in LAPC-4 cells exposed to CM from obesity-modified CD4+ T-cells when compared to non-obese-CM (Figure 4B). Depleting IL-6 from the obese-CM significantly decreased migration of LNCaP cells (Figure 4A). Adding IL-6 to the non-obese condition media moderately increased invasion of LNCaP and LAPC-4 cells. Cell invasion was also significantly higher in LNCaP cells exposed to obese CM vs. those exposed to non-obese conditions (Figure 5A). Cell invasion was slightly higher in the LAPC-4 exposed to obese conditions compared to those cells exposed the non-obese conditions (Figure 5B). Depleting IL-6 from obese CM decreased migration ability in both prostate cancer cell lines. Adding IL-6 to the non-obese CM media significantly increased invasion of LNCaP prostate cells and moderately increased invasion of LAPC-4 prostate cell lines. Our results suggest that IL-6 secreted from obesity-modified T-cells induces migration and invasion of prostate cancer epithelial cells.
A patent review of BRD4 inhibitors (2013-2019)
Published in Expert Opinion on Therapeutic Patents, 2020
Tian Lu, Wenchao Lu, Cheng Luo
Bayer Pharma published a series of patents on exploring new BRD4 inhibitors between 2013 and 2019. In 2013–2014, BRD4 inhibitors with thienodiazepines scaffold were reported [40]. The t-butyl ester moiety of JQ1 is substituted with an amide of a bicyclic amine. These compounds show significant inhibitory effects against BRD4 BD1 in vitro and also have promising anti-proliferation effects on human cancer cell lines such as MOLM-13, LAPC-4, MCF-7, MOLP-8. Through following structural optimization based on GSK inhibitors, Bayer has also issued a patent for a benzodiazepine compound, replacing the five-position nitrogen atom with a carbon atom, and replacing the four-position side chain substituent with a heterocyclic ring. Table 2 summarizes the markush structures of the scaffolds and the most representative compounds in these patents, which show potent inhibitory effects on various leukemia, myeloma, and breast cancer cell lines [45–56].
Evaluation of combined effect of hyperthermia and ionizing radiation on cytotoxic damages induced by IUdR-loaded PCL-PEG-coated magnetic nanoparticles in spheroid culture of U87MG glioblastoma cell line
Published in International Journal of Radiation Biology, 2018
Parisa Rezaie, Samideh Khoei, Sepideh Khoee, Sakine Shirvalilou, Seied Rabi Mahdavi
Hyperthermia is another treatment method which has been used in the therapy of malignant brain tumors for many years. According to the previous studies, hyperthermia by damaging cell membranes, proteins and structures within cells, leads to cell death. Zhou et al. showed that thermal treatment of CaSKi human cervical cancer cells at 43 °C for 40 min indicated an inhibitory effect on cell viability (Zhou et al. 2011). Also, Attaluri et al. revealed the effects of hyperthermia on human prostate cancer cell lines, PC3 and LAPC-4, with 60-min exposure at 43 °C (Attaluri et al. 2015). At this dose, the measured surviving fraction is reduced 100-fold relative to untreated controls in LAPC-4 cells, whereas PC3 cell survival is reduced only modestly (30–40% relative to controls). One of the major challenges in hyperthermia is the accurate temperature control of the tumor, without causing overheating and damage in surrounding healthy tissues. Nanoparticle-based hyperthermia is a novel method that enables controlled heating of tumor tissue. Compared to more recent studies involving PCL-PEG diblock-based nanoparticles (Shalaby et al. 2016), we used structurally desirable nanoparticles that could enter the cells for treating GBM. Therefore, the cellular uptake efficiency of IUdR-loaded nanoparticles was determined using TEM imaging. Black grains represent nanoparticles existing in the spheroid cultures of U87MG cells. This procedure was also used by Klein et al. (2014).