The landscape of nanoparticle-based siRNA delivery and therapeutic development.

Five small interfering RNA (siRNA)-based therapeutics have been approved by the Food and Drug Administration (FDA), namely patisiran, givosiran, lumasiran, inclisiran, and vutrisiran. Besides, siRNA delivery to the target site without toxicity is a big challenge for researchers, and naked-siRNA delivery possesses several challenges, including membrane impermeability, enzymatic degradation, mononuclear phagocyte system (MPS) entrapment, fast renal excretion, endosomal escape, and off-target effects. The siRNA therapeutics can silence any disease-specific gene, but their intracellular and extracellular barriers limit their clinical applications. For this purpose, several modifications have been employed to siRNA for better transfection efficiency. Still, there is a quest for better delivery systems for siRNA delivery to the target site. In recent years, nanoparticles have shown promising results in siRNA delivery with minimum toxicity and off-target effects. Patisiran is a lipid nanoparticle (LNP)-based siRNA formulation for treating hereditary transthyretin-mediated amyloidosis that ultimately warrants the use of nanoparticles from different classes, especially lipid-based nanoparticles. These nanoparticles may belong to different categories, including lipid-based, polymer-based, and inorganic nanoparticles. This review briefly discusses the lipid, polymer, and inorganic nanoparticles and their sub-types for siRNA delivery. Finally, several clinical trials related to siRNA therapeutics are addressed, followed by the future prospects and conclusions.

siRNA Therapeutics for the Therapy of COVID-19 and Other Coronaviruses.

The ongoing pandemic of global concern has killed about three million humans and affected around 151 million people worldwide, as of April 30, 2021. Although recently approved vaccines for COVID-19 are engendering hope, finding new ways to cure the viral pandemic is still a quest for researchers worldwide. Major pandemics in history have been of viral origin, such as SARS, MERS, H1NI, Spanish flu, and so on. A larger emphasis has been on discovering potential vaccines, novel antiviral drugs, and agents that can mitigate the viral infection symptoms; however, a relatively new area, RNA interference (RNAi), has proven effective as an antiviral agent. The RNAi phenomenon has been largely exploited to cure cancer, neurodegenerative diseases, and some rare diseases. The U.S. Food and Drug Administration has recently approved three siRNA products for human use that garner significant hope in siRNA therapeutics for coronaviruses. There have been some commentaries and communications addressing this area. We have summarized and illustrated the significance and the potential of the siRNA therapeutics available as of April 30, 2021 to combat the ongoing viral pandemic and the emerging new variants such as B.1.1.7 and B.1.351. Numerous successful in vitro studies and several investigations to address the clinical application of siRNA therapeutics provide great hope in this field. This seminal Review describes the significance of siRNA-based therapy to treat diverse viral infections in addition to the current coronavirus challenge. In addition, we have thoroughly reviewed the patents approved for coronaviruses, the major challenges in siRNA therapy, and the potential approaches to address them, followed by innovation and prospects.

Applications of amphipathic and cationic cyclic cell-penetrating peptides: Significant therapeutic delivery tool.

A new class of peptides, cyclic cell-penetrating peptides (CPPs), has great potential for delivering a vast variety of therapeutics intracellularly for treating diverse ailments. CPPs have been used previously; however, their further use is limited due to instability, toxicity, endosomal degradation, and insufficient cellular penetration. Cyclic CPPs are being investigated in delivering therapeutics to treat various ailments, including multi-drug resistant microbial infections, HIV, and cancer. They can act as a carrier for a variety of cargos and target intracellularly. Approximately 40 cyclic peptides-based therapeutics are available in the market, and annually one cyclic peptide-based drug enters the market. Numerous research and review articles have been published in the last decade about linear and cyclic peptides separately. This review is the first to provide a comprehensive deliberation about cationic and amphipathic cyclic CPPs. Herein, we highlights their structures, significant advantages, translocation mechanisms, and delivery application in the area of biomedical sciences.

Knockdown of WAVE3 impairs HGF induced migration and invasion of prostate cancer cells.

BACKGROUND: The WASP (Wiskott-Aldrich syndrome protein) and WAVE (WASP Verpolin homologous) family of proteins are structurally related and responsible for regulation of actin polymerization through their interaction with actin related proteins 2&3 (ARP 2/3). WAVE-3 has exhibited an association with disease progression and poorer prognosis of certain malignancies. In the current study, we determined the role of WAVE-3 in hepatocyte growth factor induced cellular changes including cell matrix interaction, invasion and cellular motility, and pathways that may be responsible for the changes in prostate cancer cells. METHODS: We used hammer head ribozymes to knock down the expression of WAVE-3 in PC-3 prostate cancer cell line. In vitro cellular functional assays including growth, invasion, adhesion, motility and invasion, were performed to assess the effects of WAVE-3 knock down. Further experimentation was performed to investigate the role of different pathway through expression and phosphorylation status of various intermediate proteins. RESULTS: WAVE-3 knockdown reduced invasive potential and motility of prostate cancer cells. Following addition of HGF, control cells showed significantly increased invasion and motility (p value <0.5) and marked increase in cellular growth. However, WAVE-3 knockdown cell line failed to show any increase in these trends (p value <0.5) except increased growth compared with control cells. Further experiments revealed that HGF-induced activation of Paxillin was weakened by the knockdown of WAVE-3. Our study also indicated that reduced invasiveness following WAVE-3 knockdown, may be related to reduce activity of MMP-2. CONCLUSIONS: Our studies suggest a vital role of WAVE-3 in HGF induced invasion and migration in which Paxillin and MMP-2 are involved. Further study will shed light on its potential as therapeutic target to suppress local invasion and metastasis of prostate cancer cells.

Bone morphogenetic protein-10 (BMP-10) inhibits aggressiveness of breast cancer cells and correlates with poor prognosis in breast cancer.

Our recent study showed that a novel member of bone morphogenetic protein (BMP) family, BMP-10, was decreased in prostate cancer. In the present study, we investigated the implication of BMP-10 in breast cancer, particularly the relation of its expression with clinical aspects. The expression of BMP-10 was examined in a cohort of human breast cancer specimens (normal, n = 23; cancer, n = 97), using both quantitative real-time PCR and immunohistochemical staining. The full-length human BMP-10 was cloned into a mammalian expression plasmid vector and then transfected into breast cancer cells. The effect on growth, cell matrix adhesion, motility, and invasion of MDA-MB-231 cells by BMP-10 was then investigated using in vitro growth assays. Immunohistochemical staining and quantitative real-time PCR revealed a decreased expression of BMP-10 in breast cancer. Further analysis of BMP-10 transcript level against the clinical aspect demonstrated that the decreased BMP-10 expression correlated with disease progression, bone metastasis, and poor prognosis. The disease-free survival of the patients with a higher level of BMP-10 was 132.8 (95% CI, 122.0-143.5) months, significantly longer compared to 93.7 (95% CI, 60.3-127.2) months for patients with a lower level of BMP-10 expression (P = 0.043). The overexpression of BMP-10 has broad inhibitory effects on the in vitro growth, invasion, and motility of breast cancer cells. Taken together, BMP-10 can inhibit the cell growth of breast cancer cells, and decreased BMP-10 expression correlates to poor prognosis and disease progression, particularly the lymphatic and bone metastasis. Bone morphogenetic protein-10 (BMP-10) may function as a tumor suppressor in breast cancer.

Sorption of organophosphorous pesticides onto chickpea husk from aqueous solutions.

The sorption efficiency of chickpea husk of black gram variety (BGH), for the removal of organophosphorous pesticides (OPPs), i.e. triazophos (TAP) and methyl parathion (MP) from aqueous media has been investigated. Optimization of operating sorption parameters, i.e. particle size, sorbent dose, agitation time, pH, initial concentration of sorbates, and temperature has been studied. The sorption data fitted well to Freundlich, Langmuir and Dubinin-Radushkevich (D-R) sorption isotherms. The maximum sorption capacities of BGH for TAP and MP were calculated to be 3.5+/-0.45 and 10.6+/-0.83 mmol g(-1) by Freundlich, 0.0077+/-0.021 and 0.025+/-0.0094 mmol g(-1) by Langmuir and 0.48+/-0.037 and 0.15+/-0.077 mmol g(-1) by D-R isotherms respectively, employing 0.2g of sorbent, at pH 6, 90 min agitation time and at 303 K. Application of first order Lagergren and Morris-Weber equations to the kinetic data yielded correlation coefficients, close to unity and showed partial intra-particle diffusion. The negative values of thermodynamic parameters, i.e. DeltaH (kJ mol(-1)), DeltaS (J mol(-1) K(-1)) and DeltaG (kJ mol(-1)) indicate the exothermic and spontaneous nature of the sorption process. The sorbed pesticides were recovered by sonication with methanol, making the regeneration and reutilization of the sorbents promising. The investigated sorbent exhibited potential applications in water decontamination, treatments of industrial and agricultural waste waters and thus productively demonstrated viable use of agricultural waste material.