Dicationic Acridinium/Carbene Hybrids as Strongly Oxidizing Photocatalysts.

A new design concept for organic, strongly oxidizing photocatalysts is described based upon dicationic acridinium/carbene hybrids. A highly modular synthesis of such hybrids is presented, and the dications are utilized as novel, tailor-made photoredox catalysts in the direct oxidative C-N coupling. Under optimized conditions, benzene and even electron-deficient arenes can be oxidized and coupled with a range of N-heterocycles in high to excellent yields with a single low-energy photon per catalytic turnover, while commonly used acridinium photocatalysts are not able to perform the challenging oxidation step. In contrast to traditional photocatalysts, the hybrid photocatalysts reported here feature a reversible two-electron redox system with regular or inverted redox potentials for the two-electron transfer. The different oxidation states could be isolated and structurally characterized supported by NMR, EPR, and X-ray analysis. Mechanistic experiments employing time-resolved emission and transient absorption spectroscopy unambiguously reveal the outstanding excited-state potential of our best-performing catalyst (+2.5 V vs SCE), and they provide evidence for mechanistic key steps and intermediates.

Visualizing the 4D Impact of Gold Nanoparticles on DNA.

The genotoxicity of AuNPs has sparked a scientific debate, with one perspective attributing it to direct DNA damage and another to oxidative damage through reactive oxygen species (ROS) activation. This controversy poses challenges for the widespread use of AuNPs in biomedical applications. To address this debate, we employed four-dimensional atomic force microscopy (4DAFM) to examine the ability of AuNPs to damage DNA in vitro in the absence of ROS. To further examine whether the size and chemical coupling of these AuNPs are properties that control their toxicity, we exposed individual DNA molecules to three different types of AuNPs: small (average diameter = 10 nm), large (average diameter = 22 nm), and large conjugated (average diameter = 39 nm) AuNPs. We found that all types of AuNPs caused rapid (within minutes) and direct damage to the DNA molecules without the involvement of ROS. This research holds significant promise for advancing nanomedicines in diverse areas like viral therapy (including COVID-19), cancer treatment, and biosensor development for detecting DNA damage or mutations by resolving the ongoing debate regarding the genotoxicity mechanism. Moreover, it actively contributes to the continuous endeavors aimed at fully harnessing the capabilities of AuNPs across diverse biomedical fields, promising transformative healthcare solutions.

Nanomedicine for overcoming therapeutic and diagnostic challenges associated with pancreatic cancer.

Pancreatic cancer is the second leading cause of cancer-related death in the USA. The 5-year survival rate for pancreatic cancer is as low as 10%, making it one of the most deadly cancers. This dismal prognosis is caused, in part, by the lack of early detection and screening options, leading to late-stage detection of the disease, at a point at which chemotherapy is no longer effective. However, nanoparticle (NP) drug delivery systems have increased the efficacy of chemotherapeutics by improving the targeting ability of drugs to the tumor site, while also decreasing the risk of local and systemic toxicity. Such efforts can contribute to the development of early diagnosis and routine screening tests, which will drastically improve the survival rates and prognosis of patients with pancreatic cancer.

Multiple strategies for the treatment of invasive breast carcinoma: A comprehensive prospective.

In this review, we emphasize on evolving therapeutic strategies and advances in the treatment of breast cancer (BC). This includes small-molecule inhibitors under preclinical and clinical investigation, phytoconstituents with antiproliferative potential, targeted therapies as antibodies and antibody-drug conjugates (ADCs), vaccines as immunotherapeutic agents and peptides as a novel approach inhibiting the interaction of oncogenic proteins. We provide an update of molecules under different phases of clinical investigation which aid in the identification of loopholes or shortcomings that can be overcomed with future breast cancer research.

Nano-therapeutic strategies to target coronavirus.

The coronaviruses have caused severe acute respiratory syndrome (SARS), the Middle East respiratory syndrome (MERS), and the more recent coronavirus pneumonia (COVID-19). The global COVID-19 pandemic requires urgent action to develop anti-virals, new therapeutics, and vaccines. In this review, we discuss potential therapeutics including human recombinant ACE2 soluble, inflammatory cytokine inhibitors, and direct anti-viral agents such as remdesivir and favipiravir, to limit their fatality. We also discuss the structure of the SARS-CoV-2, which is crucial to the timely development of therapeutics, and previous attempts to generate vaccines against SARS-CoV and MERS-CoV. Finally, we provide an overview of the role of nanotechnology in the development of therapeutics as well as in the diagnosis of the infection. This information is key for computational modeling and nanomedicine-based new therapeutics by counteracting the variable proteins in the virus. Further, we also try to effectively share the latest information about many different aspects of COVID-19 vaccine developments and possible management to further scientific endeavors.

Folate Functionalized Lipid Nanoparticles for Targeted Therapy of Methicillin-Resistant Staphylococcus aureus.

Methicillin-resistant Staphylococcus aureus (MRSA), commonly called a superbug, is a highly alarming antibiotic-resistant population of Staphylococcus aureus (S. aureus) bacteria. Vancomycin (VAN) was first approved by the FDA in 1988, and it is still regarded as the treatment of choice for MRSA. The efficacy of VAN treatment has become less effective due to the development of VAN resistance in MRSA and the potential for nephrotoxicity. This study aims to improve the efficacy of VAN treatment by identifying the folate receptor for MRSA infected tissues and developing folate decorated lipid nanoparticles containing VAN (LVAN). In comparison to conventional VAN, LVAN showed a higher bactericidal effect and a superior ability to inhibit biofilm in MRSA with an enhanced accumulation in MRSA infected thigh tissues and a reduced accumulation in kidney. The results suggested that LVAN is a promising candidate to overcome the current limitations of bacterial resistance and adverse side effects in kidneys found in VAN.

Overcoming the Tumor Microenvironmental Barriers of Pancreatic Ductal Adenocarcinomas for Achieving Better Treatment Outcomes.

Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with the lowest survival rate among all solid tumors. The lethality of PDAC arises from late detection and propensity of the tumor to metastasize and develop resistance against chemo and radiation therapy. A highly complex tumor microenvironment composed of dense stroma, immune cells, fibroblast, and disorganized blood vessels, is the main obstacle to current PDAC therapy. Despite the tremendous success of immune checkpoint inhibitors (ICIs) in cancers, PDAC remains one of the poorest responders of ICIs therapy. The immunologically "cold" phenotype of PDAC is attributed to the low mutational burden, high infiltration of myeloid-derived suppressor cells and T-regs, contributing to a significant immunotherapy resistance mechanism. Thus, the development of innovative strategies for turning immunologically "cold" tumor into "hot" ones is an unmet need to improve the outcome of PDAC ICIs therapies. Other smart strategies, such as nanomedicines, sonic Hedgehog inhibitor, or smoothened inhibitor, are discussed to enhance chemotherapeutic agents' efficiency by disrupting the PDAC stroma. This review highlights the current challenges and various preclinical and clinical strategies to overcome current PDAC therapy difficulties, thus significantly advancing PDAC research knowledge.

Transferrin: Biology and Use in Receptor-Targeted Nanotherapy of Gliomas.

Gliomas constitute 80% of malignant brain tumors. The survival rate of patients diagnosed with malignant gliomas is only 34.4%, as seen in both adults as well as children. The biggest challenge in treatment of gliomas is the impenetrable blood-brain barrier. With the availability of only a very few choices of chemotherapeutics in the treatment of gliomas, it is imperative that a novel strategy to effectively deliver drugs into the brain is researched and applied. The most popular strategy that is gaining importance is the receptor-mediated uptake of targeted nanoparticles comprising of ligands specific to the receptors. This review discusses briefly one such receptor called the transferrin receptor that is highly expressed in the brain and can be applied effectively for targeted nanoparticle delivery systems in gliomas.

Recent advances in nano delivery systems for blood-brain barrier (BBB) penetration and targeting of brain tumors.

Gliomas constitute about 80% of brain tumors and have a meager two-year survival rate. The treatment options available are very few because of poor prognosis and a lack of targeted nanodelivery systems that can cross the blood-brain barrier (BBB) and the blood-tumor barrier. This short review attempts to clarify the challenges for delivery systems designed to cross the BBB, and provides a brief description of the different types of targeted nanodelivery system that have shown potential for success in delivering drugs to the brain. Further, this review describes the most recent studies that have developed nanoparticles for brain delivery in the past five years. We also provide an insight into the most recent clinical trials designed to assess the efficacy of these nanodelivery systems for glioma.

CD44 Targeted Nanomaterials for Treatment of Triple-Negative Breast Cancer.

Identified as the second leading cause of cancer-related deaths among American women after lung cancer, breast cancer of all types has been the focus of numerous research studies. Even though triple-negative breast cancer (TNBC) represents 15-20% of the number of breast cancer cases worldwide, its existing therapeutic options are fairly limited. Due to the pivotal role of the presence/absence of specific receptors to luminal A, luminal B, HER-2+, and TNBC in the molecular classification of breast cancer, the lack of these receptors has accounted for the aforementioned limitation. Thereupon, in an attempt to participate in the ongoing research endeavors to overcome such a limitation, the conducted study adopts a combination strategy as a therapeutic paradigm for TNBC, which has proven notable results with respect to both: improving patient outcomes and survivability rates. The study hinges upon an investigation of a promising NPs platform for CD44 mediated theranostic that can be combined with JAK/STAT inhibitors for the treatment of TNBC. The ability of momelotinib (MMB), which is a JAK/STAT inhibitor, to sensitize the TNBC to apoptosis inducer (CFM-4.16) has been evaluated in MDA-MB-231 and MDA-MB-468. MMB + CFM-4.16 combination with a combination index (CI) ≤0.5, has been selected for in vitro and in vivo studies. MMB has been combined with CD44 directed polymeric nanoparticles (PNPs) loaded with CFM-4.16, namely CD44-T-PNPs, which selectively delivered the payload to CD44 overexpressing TNBC with a significant decrease in cell viability associated with a high dose reduction index (DRI). The mechanism underlying their synergism is based on the simultaneous downregulation of P-STAT3 and the up-regulation of CARP-1, which has induced ROS-dependent apoptosis leading to caspase 3/7 elevation, cell shrinkage, DNA damage, and suppressed migration. CD44-T-PNPs showed a remarkable cellular internalization, demonstrated by uptake of a Rhodamine B dye in vitro and S0456 (NIR dye) in vivo. S0456 was conjugated to PNPs to form CD44-T-PNPs/S0456 that simultaneously delivered CFM-4.16 and S0456 parenterally with selective tumor targeting, prolonged circulation, minimized off-target distribution.

LDL receptors and their role in targeted therapy for glioma: a review.

Gliomas are highly lethal forms of cancers occurring in the brain. Delivering the drugs into the brain is a major challenge to the treatment of gliomas because of the highly selectively permeable blood-brain barrier (BBB). Tapping the potential of receptor-mediated drug delivery systems using targeted nanoparticles (NPs) is a sought-after step forward toward successful glioma treatment. Several receptors are the focus of research for application in drug delivery. Low-density lipoprotein receptors (LDLR) are abundantly expressed in both healthy brains and diseased brains with a disrupted BBB. In this review, we discuss the LDLR and the types of NPs that have been used to target the brain via this receptor.

Folate Receptors' Expression in Gliomas May Possess Potential Nanoparticle-Based Drug Delivery Opportunities.

Brain cancer effected around estimated 23 890 adults and 3540 children under the age of 15 in 2020. The chemotherapeutic agents that are already approved by the FDA for brain cancer are proving to be not highly effective because of the interference from the tumor microenvironment as well as their own toxicities. Added to this is the impedance presented by the extremely restrictive permeability of the blood brain barrier (BBB). Targeted nanoparticulate drug delivery systems offer a good opportunity to traverse the BBB and selectively target the tumor cells. Folate receptors are found to be one of the most useful targets for drug delivery to the brain. Hence, this Mini-Review discusses the folate receptors and their application in the treatment of brain cancers using targeted nanoparticles.

Novel approaches for the treatment of methicillin-resistant Staphylococcus aureus: Using nanoparticles to overcome multidrug resistance.

Methicillin-resistant Staphylococcus aureus (MRSA) causes serious infections in both community and hospital settings, with high mortality rates. Treatment of MRSA infections is challenging because of the rapidly evolving resistance mechanisms combined with the protective biofilms of S. aureus. Together, these characteristic resistance mechanisms continue to render conventional treatment modalities ineffective. The use of nanoformulations with unique modes of transport across bacterial membranes could be a useful strategy for disease-specific delivery. In this review, we summarize treatment approaches for MRSA, including novel techniques in nanoparticulate designing for better therapeutic outcomes; and facilitate an understanding that nanoparticulate delivery systems could be a robust approach in the successful treatment of MRSA.

Progress in Clinical Trials of Photodynamic Therapy for Solid Tumors and the Role of Nanomedicine.

Current research to find effective anticancer treatments is being performed on photodynamic therapy (PDT) with increasing attention. PDT is a very promising therapeutic way to combine a photosensitive drug with visible light to manage different intense malignancies. PDT has several benefits, including better safety and lower toxicity in the treatment of malignant tumors over traditional cancer therapy. This reasonably simple approach utilizes three integral elements: a photosensitizer (PS), a source of light, and oxygen. Upon light irradiation of a particular wavelength, the PS generates reactive oxygen species (ROS), beginning a cascade of cellular death transformations. The positive therapeutic impact of PDT may be limited because several factors of this therapy include low solubilities of PSs, restricting their effective administration, blood circulation, and poor tumor specificity. Therefore, utilizing nanocarrier systems that modulate PS pharmacokinetics (PK) and pharmacodynamics (PD) is a promising approach to bypassing these challenges. In the present paper, we review the latest clinical studies and preclinical in vivo studies on the use of PDT and progress made in the use of nanotherapeutics as delivery tools for PSs to improve their cancer cellular uptake and their toxic properties and, therefore, the therapeutic impact of PDT. We also discuss the effects that photoimmunotherapy (PIT) might have on solid tumor therapeutic strategies.

Smart treatment strategies for alleviating tauopathy and neuroinflammation to improve clinical outcome in Alzheimer's disease.

Alzheimer's disease (AD) is a complex neurodegenerative disease leading to progressive loss of memory that mainly affects people above 60 years of age. It is one of the leading causes of deaths in the USA. Given its inherent heterogeneity and a still-incomplete understanding of its pathology, biomarkers, and targets available for therapy, it is a challenge to design an effective therapeutic strategy. Several hypotheses have been proposed to understand the disease and to identify reliable markers and targets for treatments. However, none have resulted in strong support from clinical trials. In this review, we objectively discuss the various therapeutic strategies and mechanistic approaches to improve the current clinical outcome of AD therapy.

Correction: Oves M, et al. Graphene Decorated Zinc Oxide and Curcumin to Disinfect the Methicillin-Resistant Staphylococcus aureus. Nanomaterials 2020, 10(5), 1004.

The authors wish to make the following corrections to this paper [...].

Carbonic Anhydrase-IX Guided Albumin Nanoparticles for Hypoxia-mediated Triple-Negative Breast Cancer Cell Killing and Imaging of Patient-derived Tumor.

Triple-Negative Breast Cancer (TNBC) is considered as the most onerous cancer subtype, lacking the estrogen, progesterone, and HER2 receptors. Evaluating new markers is an unmet need for improving targeted therapy against TNBC. TNBC depends on several factors, including hypoxia development, which contributes to therapy resistance, immune evasion, and tumor stroma formation. In this study, we studied the curcumin analogue (3,4-Difluorobenzylidene Curcumin; CDF) encapsulated bovine serum albumin (BSA) nanoparticle for tumor targeting. For tumor targeting, we conjugated Acetazolamide (ATZ) with CDF and encapsulated it in the BSA to form a nanoparticle (namely BSA-CDF-ATZ). The in vitro cytotoxicity study suggested that BSA-CDF-ATZ is more efficient when compared to free CDF. The BSA-CDF-ATZ nanoparticles showed significantly higher cell killing in hypoxic conditions compared to normoxic conditions, suggesting better internalization of the nanoparticles into cancer cells under hypoxia. Fluorescent-dye labeled BSA-CDF-ATZ revealed higher cell uptake of the nanoparticle compared to free dye indicative of better delivery, substantiated by a high rate of apoptosis-mediated cell death compared to free CDF. The significantly higher tumor accumulation and low liver and spleen uptake in TNBC patient-derived tumor xenograft models confirm the significant potential of BSA-CDF-ATZ for targeted TNBC imaging and therapy.

Graphene Decorated Zinc Oxide and Curcumin to Disinfect the Methicillin-Resistant Staphylococcus aureus.

Sometimes, life-threatening infections are initiated by the biofilm formation facilitated at the infection site by the drug-resistant bacteria Staphylococcus aureus. The aggregation of the same type of bacteria leads to biofilm formation on the delicate tissue, dental plaque, and skin. In the present investigation, a Graphene (Gr)-based nano-formulation containing Curcumin (C.C.M.) and Zinc oxide nanoparticles (ZnO-NPs) showed a wide range of anti-microbial activity against Methicillin-resistant Staphylococcus aureus (MRSA) biofilm and demonstrated the anti-microbial mechanism of action. The anti-microbial effect of GrZnO nanocomposites, i.e., GrZnO-NCs, suggests that the integrated graphene-based nanocomposites effectively suppressed both sensitive as well as MRSA ATCC 43300 and BAA-1708 isolates. The S. aureus inhibitory effect of GrZnO-NCs improved >5-fold when combined with C.C.M., and demonstrated a M.I.C. of 31.25 µg/mL contrasting with the GrZnO-NCs or C.C.M. alone having M.I.C. value of 125 µg/mL each. The combination treatment of GrZnO-NCs or C.C.M. inhibited the M.R.S.A. topical dermatitis infection in a mice model with a significant decrease in the CFU count to ~64%. Interestingly, the combination of C.C.M. and GrZnO-NCs damaged the bacterial cell wall structure, resulting in cytoplasm spillage, thereby diminishing their metabolism. Thus, owing to the ease of synthesis and highly efficient anti-microbial properties, the present graphene-based curcumin nano-formulations can cater to a new treatment methodology against M.R.S.A.

Exploring siRNA Umpired Nanogels: A Tale of Barrier Combating Carrier.

Potential short interfering RNAs (siRNA) modulating gene expression have emerged as a novel therapeutic arsenal against a wide range of maladies and disorders containing cancer, viral infections, bacterial ailments and metabolic snags at the molecular level. Nanogel, in the current medicinal era, displayed a comprehensive range of significant drug delivery prospects. Biodegradation, swelling and de-swelling tendency, pHsensitive drug release and thermo-sensitivity are some of the renowned associated benefits of nanogel drug delivery system. Global researches have also showed that nanogel system significantly targets and delivers the biomolecules including DNAs, siRNA, protein, peptides and other biologically active molecules. Biomolecules delivery via nanogel system explored a wide range of pharmaceutical, biomedical engineering and agro-medicinal application. The siRNAs and DNAs delivery plays a vivacious role by addressing the hitches allied with chronic and contemporary therapeutic like generic possession and low constancy. They also incite release kinetics approach from slow-release while mingling to rapid release at the targets will be beneficial as interference RNAs delivery carriers. Therefore, in this research, we focused on the latest improvements in the delivery of siRNA loaded nanogels by enhancing the absorption, stability, sensitivity and combating the hindrances in cellular trafficking and release process.

Stable abnormal N-heterocyclic carbenes and their applications.

Although N-heterocyclic carbenes (NHCs) have been known as ligands for organometallic complexes since the 1960s, these carbenes did not attract considerable attention until Arduengo et al. reported the isolation of a metal-free imidazol-2-ylidene in 1991. In 2001 Crabtree et al. reported a few complexes featuring an NHC isomer, namely an imidazol-5-ylidene, also termed abnormal NHC (aNHCs). In 2009, it was shown that providing to protect the C-2 position of an imidazolium salt, the deprotonation occurred at the C-5 position, affording imidazol-5-ylidenes that could be isolated. Over the last ten years, stable aNHCs have been used for designing a range of catalysts employing Pd(ii), Cu(i), Ni(ii), Fe(0), Zn(ii), Ag(i), and Au(i/iii) metal based precursors. These catalysts were utilized for different organic transformations such as the Suzuki-Miyaura cross-coupling reaction, C-H bond activation, dehydrogenative coupling, Huisgen 1,3-dipolar cycloaddition (click reaction), hydroheteroarylation, hydrosilylation reaction and migratory insertion of carbenes. Main-group metal complexes were also synthesized, including K(i), Al(iii), Zn(ii), Sn(ii), Ge(ii), and Si(ii/iv). Among them, K(i), Al(iii), and Zn(ii) complexes were used for the polymerization of caprolactone and rac-lactide at room temperature. In addition, based on the superior nucleophilicity of aNHCs, relative to that of their nNHCs isomers, they were used for small molecules activation, such as carbon dioxide (CO2), nitrous oxide (N2O), tetrahydrofuran (THF), tetrahydrothiophene and 9-borabicyclo[3.3.1]nonane (9BBN). aNHCs have also been shown to be efficient metal-free catalysts for ring opening polymerization of different cyclic esters at room temperature; they are among the most active metal-free catalysts for ε-caprolactone polymerization. Recently, aNHCs successfully accomplished the metal-free catalytic formylation of amides using CO2 and the catalytic reduction of carbon dioxide, including atmospheric CO2, into methanol, under ambient conditions. Although other transition metal complexes featuring aNHCs as ligand have been prepared and used in catalysis, this review article summarize the results obtained with the isolated aNHCs.