Nanotechnology applications in medical diagnosis, imaging, and therapy

Tremendous advances in molecular and personalized medicine also present challenges for translation of innovative experimental approaches into clinically relevant strategies. To overcome some of these challenges, nanotechnology offers interesting solutions for disease prevention, diagnosis, and treatment. For many systemic diseases, overcoming biological barriers and target specific delivery are the key challenges. Additionally, newer generation of molecular therapies, such as gene therapy, oligonucleotides, and RNA interference (RNAi) require robust and highly specific intracellular delivery strategies for effective and clinically meaningful therapeutic outcomes. In this presentation, I will cover several of our approaches for development of multifunctional engineered nano-systems for targeted therapies in the treatment of cancer, pain, and inflammatory diseases. Specific examples will include: (1) use of combinatorial-designed engineered nano-systems for RNA interference therapy in treatment of tumor multidrug resistance and genetic modulation of macrophage phenotype to promote anti-inflammatory effect in the treatment of autoimmune disorders. In each of the above examples, we focus on challenging medical problems with innovative solutions that use safe materials and scalable fabrication methods in order to facilitate clinical translation and improve patient outcomes

MDR1 siRNA loaded hyaluronic acid-based CD44 targeted nanoparticle systems circumvent paclitaxel resistance in ovarian cancer.

Development of multidrug resistance (MDR) is an almost universal phenomenon in patients with ovarian cancer, and this severely limits the ultimate success of chemotherapy in the clinic. Overexpression of the MDR1 gene and corresponding P-glycoprotein (Pgp) is one of the best known MDR mechanisms. MDR1 siRNA based strategies were proposed to circumvent MDR, however, systemic, safe, and effective targeted delivery is still a major challenge. Cluster of differentiation 44 (CD44) targeted hyaluronic acid (HA) based nanoparticle has been shown to successfully deliver chemotherapy agents or siRNAs into tumor cells. The goal of this study is to evaluate the ability of HA-PEI/HA-PEG to deliver MDR1 siRNA and the efficacy of the combination of HA-PEI/HA-PEG/MDR1 siRNA with paclitaxel to suppress growth of ovarian cancer. We observed that HA-PEI/HA-PEG nanoparticles can efficiently deliver MDR1 siRNA into MDR ovarian cancer cells, resulting in down-regulation of MDR1 and Pgp expression. Administration of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles followed by paclitaxel treatment induced a significant inhibitory effect on the tumor growth, decreased Pgp expression and increased apoptosis in MDR ovarian cancer mice model. Our findings suggest that CD44 targeted HA-PEI/HA-PEG/MDR1 siRNA nanoparticles can serve as a therapeutic tool with great potentials to circumvent MDR in ovarian cancer

The Effect of Magnetized Saline Water on Yield and Yield Components of Strawberry (Fragaria ananassa cv. Silva)

Introduction Considering the value of water in agriculture and the limitation of this important and vital resource and the existence of intermittent droughts in the country, saving in consumption and optimal use of available water seems necessary. Today, utilizing saltwater is considered one of the practical and effective approaches to minimize water consumption while achieving acceptable economic performance. Given the scarcity of freshwater sources, the utilization of unconventional water for strawberry cultivation holds significant economic importance. Through the application of innovative technologies, such as magnetic technology, the modification of these water sources can lead to increased quantitative and qualitative yields of agricultural products. Salinity stress, which alters the water and nutrient absorption patterns, directly impacts the plant's yield in terms of both quantity and quality. Strawberry is an important commercial product, and the quantitative and qualitative increase of its yield is emphasized from different aspects. The purpose of this research is to the effect of salinity stress under the influence of a magnetic field on the yield and yield components of the strawberry plant. Materials and Methods The purpose of this research was to investigate the effect of salinity stress under the influence of magnetic fields on the yield and yield components of strawberry plants. The factorial experiment was conducted in the form of a randomized complete block design with three replications in 2021 and 2022 in Neka city. The control treatment included full irrigation in all stages of plant growth with normal water (non-magnetic). The treatments include the type of irrigation water at two levels (Non-Magnetic Water (W1) and Magnetic Water (W2)), and water salinity was at three levels (0.86 dS/m (S1), 20 mM sodium chloride (S2), and 40 mM sodium chloride (S3). The strawberry plant of the Silva cultivar was cultivated in 3 x 4-meter plots with a row spacing of 40 cm and a between the spacing of 40 cm. Magnetization of irrigation water was created by passing water through a permanent magnet with a magnetic field intensity of 0.3 Tesla. The salt used for salinity stress was laboratory sodium chloride. The used irrigation method was drip (tape), and the amount of irrigation water and irrigation cycle was done according to the needs of the plant. Soil moisture monitoring was used to calculate the amount of applied water. Results and Discussion The results of analysis of variance showed that the effect of the irrigation water type and different levels of water salinity on the length, diameter, number of fruits per plant, fruit weight, biomass and plant yield was significant at the 1% probability level. The effect of water salinity on the number of fruits per plant was significant at the 1% probability level and on the fruit length and fruit diameter at the 5% probability level. The interaction effect of irrigation water type and water salinity was also significant at the probability level of 1%. On average, during two years of strawberry cultivation with the application of a magnetic field, the length, diameter, number of fruits per plant, fruit weight, biomass, and plant yield were increased by 9.76, 14.14, 23.05, 27.60, 27.08, and 28.36% respectively. The introduction of 20 and 40 mM sodium chloride resulted in a decrease in the physical characteristics of strawberry fruit and overall yield. The most significant reduction was observed in the number of fruits per plant at the salinity level of 40 mM sodium chloride, exhibiting a 56.69% decrease compared to the control treatment. Conclusion The growth of population and expansion of agriculture on one hand and the demand for more harvesting from limited water resources on the other hand, make it necessary to increase water productivity. Lack of water and competition for water resources has caused research to be done in order to reduce water consumption and preserve its resources. Therefore, searching for ways to reduce consumption and preserve water resources is of great importance. One of these methods is using magnetic water. The results of the research showed that the use of magnetic water technology caused a significant increase in the yield and yield components of strawberries compared to the control treatment. In addition, the salinity level of irrigation water had a significant impact on the yield and yield components of strawberries, with the highest yield observed in the treatment without salinity stress when using magnetic water technology. The findings of this study indicate that the application of magnetic water technology can enable the use of low salinity levels and lead to improved strawberry yield

Role of MicroRNA in Inflammatory Bowel Disease: Clinical Evidence and the Development of Preclinical Animal Models.

The dysregulation of microRNA (miRNA) is implicated in cancer, inflammation, cardiovascular disorders, drug resistance, and aging. While most researchers study miRNA\u27s role as a biomarker, for example, to distinguish between various sub-forms or stages of a given disease of interest, research is also ongoing to utilize these small nucleic acids as therapeutics. An example of a common pleiotropic disease that could benefit from miRNA-based therapeutics is inflammatory bowel disease (IBD), which is characterized by chronic inflammation of the small and large intestines. Due to complex interactions between multiple factors in the etiology of IBD, development of therapies that effectively maintain remission for this disease is a significant challenge. In this review, we discuss the role of dysregulated miRNA expression in the context of clinical ulcerative colitis (UC) and Crohn\u27s disease (CD)-the two main forms of IBD-and the various preclinical mouse models of IBD utilized to validate the therapeutic potential of targeting these miRNA. Additionally, we highlight advances in the development of genetically engineered animal models that recapitulate clinical miRNA expression and provide powerful preclinical models to assess the diagnostic and therapeutic promise of miRNA in IBD

\u3cem\u3eMDR1\u3c/em\u3e siRNA Loaded Hyaluronic Acid-Based CD44 Targeted Nanoparticle Systems Circumvent Paclitaxel Resistance in Ovarian Cancer

Development of multidrug resistance (MDR) is an almost universal phenomenon in patients with ovarian cancer, and this severely limits the ultimate success of chemotherapy in the clinic. Overexpression of the MDR1 gene and corresponding P-glycoprotein (Pgp) is one of the best known MDR mechanisms. MDR1 siRNA based strategies were proposed to circumvent MDR, however, systemic, safe, and effective targeted delivery is still a major challenge. Cluster of differentiation 44 (CD44) targeted hyaluronic acid (HA) based nanoparticle has been shown to successfully deliver chemotherapy agents or siRNAs into tumor cells. The goal of this study is to evaluate the ability of HA-PEI/HA-PEG to deliver MDR1 siRNA and the efficacy of the combination of HA-PEI/HA-PEG/MDR1 siRNA with paclitaxel to suppress growth of ovarian cancer. We observed that HA-PEI/HA-PEG nanoparticles can efficiently deliver MDR1 siRNA into MDR ovarian cancer cells, resulting in down-regulation of MDR1 and Pgp expression. Administration of HA-PEI/HA-PEG/MDR1 siRNA nanoparticles followed by paclitaxel treatment induced a significant inhibitory effect on the tumor growth, decreased Pgp expression and increased apoptosis in MDR ovarian cancer mice model. Our findings suggest that CD44 targeted HA-PEI/HA-PEG/MDR1 siRNA nanoparticles can serve as a therapeutic tool with great potentials to circumvent MDR in ovarian cancer

Local Immunomodulation Using an Adhesive Hydrogel Loaded with miRNA-Laden Nanoparticles Promotes Wound Healing.

Chronic wounds are characterized by impaired healing and uncontrolled inflammation, which compromise the protective role of the immune system and may lead to bacterial infection. Upregulation of miR-223 microRNAs (miRNAs) shows driving of the polarization of macrophages toward the anti-inflammatory (M2) phenotype, which could aid in the acceleration of wound healing. However, local-targeted delivery of microRNAs is still challenging, due to their low stability. Here, adhesive hydrogels containing miR-223 5p mimic (miR-223*) loaded hyaluronic acid nanoparticles are developed to control tissue macrophages polarization during wound healing processes. In vitro upregulation of miR-223* in J774A.1 macrophages demonstrates increased expression of the anti-inflammatory gene Arg-1 and a decrease in proinflammatory markers, including TNF-α, IL-1β, and IL-6. The therapeutic potential of miR-223* loaded adhesive hydrogels is also evaluated in vivo. The adhesive hydrogels could adhere to and cover the wounds during the healing process in an acute excisional wound model. Histological evaluation and quantitative polymerase chain reaction (qPCR) analysis show that local delivery of miR-223* efficiently promotes the formation of uniform vascularized skin at the wound site, which is mainly due to the polarization of macrophages to the M2 phenotype. Overall, this study demonstrates the potential of nanoparticle-laden hydrogels conveying miRNA-223* to accelerate wound healing

Inhibition of ABCB1 (MDR1) Expression by an siRNA Nanoparticulate Delivery System to Overcome Drug Resistance in Osteosarcoma

Background: The use of neo-adjuvant chemotherapy in treating osteosarcoma has improved patients’ average 5 year survival rate from 20% to 70% in the past 30 years. However, for patients who progress after chemotherapy, its effectiveness diminishes due to the emergence of multi-drug resistance (MDR) after prolonged therapy. Methodology/Principal Findings: In order to overcome both the dose-limiting side effects of conventional chemotherapeutic agents and the therapeutic failure resulting from MDR, we designed and evaluated a novel drug delivery system for MDR1 siRNA delivery. Novel biocompatible, lipid-modified dextran-based polymeric nanoparticles were used as the platform for MDR1 siRNA delivery; and the efficacy of combination therapy with this system was evaluated. In this study, multi-drug resistant osteosarcoma cell lines (KHOSR2 and U-2OSR2) were treated with the MDR1 siRNA nanocarriers and MDR1 protein (P-gp) expression, drug retention, and immunofluoresence were analyzed. Combination therapy of the MDR1 siRNA loaded nanocarriers with increasing concentrations of doxorubicin was also analyzed. We observed that MDR1 siRNA loaded dextran nanoparticles efficiently suppresses P-gp expression in the drug resistant osteosarcoma cell lines. The results also demonstrated that this approach may be capable of reversing drug resistance by increasing the amount of drug accumulation in MDR cell lines. Conclusions/Significance: Lipid-modified dextran-based polymeric nanoparticles are a promising platform for siRNA delivery. Nanocarriers loaded with MDR1 siRNA are a potential treatment strategy for reversing MDR in osteosarcoma

Polymeric nanoparticle-based delivery of microRNA-199a-3p inhibits proliferation and growth of osteosarcoma cells

Our prior screening of microRNAs (miRs) identified that miR-199a-3p expression is reduced in osteosarcoma cells, one of the most common types of bone tumor. miR-199a-3p exhibited functions of tumor cell growth inhibition, suggesting the potential application of miR-199a-3p as an anticancer agent. In the study reported here, we designed and developed a lipid-modified dextran-based polymeric nanoparticle platform for encapsulation of miRs, and determined the efficiency and efficacy of delivering miR-199a-3p into osteosarcoma cells. In addition, another potent miR, let-7a, which also displayed tumor suppressive ability, was selected as a candidate miR for evaluation. Fluorescence microscopy studies and real-time polymerase chain reaction results showed that dextran nanoparticles could deliver both miR-199a-3p and let-7a into osteosarcoma cell lines (KHOS and U-2OS) successfully. Western blotting analysis and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays demonstrated that dextran nanoparticles loaded with miRs could efficiently downregulate the expression of target proteins and effectively inhibit the growth and proliferation of osteosarcoma cells. These results demonstrate that a lipid-modified dextran-based polymeric nanoparticle platform may be an effective nonviral carrier for potential miR-based anticancer therapeutics

Synthesis and Evaluation of Tripodal Peptide Analogues for Cellular Delivery of Phosphopeptides

Tripodal peptide analogues were designed on the basis of the phosphotyrosine binding pocket of the Src SH2 domain and assayed for their ability to bind to fluorescein-labeled phosphopeptides. Fluorescence polarization assays showed that a number of amphipathic linear peptide analogues (LPAs), such as LPA4, bind to fluorescein-labeled GpYEEI (F-GpYEEI). LPA4 was evaluated for potential application in cellular delivery of phosphopeptides. Fluorescence microimaging cellular uptake studies with fluorescein-attached LPA4 (F-LPA4) alone or with the mixture of LPA4 and F-GpYEEI in BT-20 cells showed dramatic increase of the fluorescence intensity in cytosol of cells, indicating that LPA4 can function as a delivery tool of F-GpYEEI across the cell membrane. Fluorescent flow cytometry studies showed the cellular uptake of F-LPA4 in an energy-independent pathway and confirmed the cellular uptake of F-GpYEEI in the presence of LPA4. These studies suggest that amphipathic tripodal peptide analogues, such as LPA4, can be used for cellular delivery of phosphopeptides