Combinatorial Therapy: Targeting CD133+ Glioma Stem-like Cells with a Polysaccharide-Prodrug Complex Functionalised Gold Nanocages.

Cancer treatments are advancing to harness the body's immune system against tumours, aiming for lasting effects. This progress involves combining potent chemotherapy drugs with immunogens to kill cancer cells and trigger lasting immunity. Developing new prodrugs that integrate both chemotherapy and immune-boosting elements could significantly improve anticancer outcomes by activating multiple mechanisms to kill cancer cells. While bacterial polysaccharides are typically not used in therapy due to their immune-stimulating properties, we propose a safe application of an extremophilic bacterial polysaccharide, Mauran (MR), modified with the anticancer drug 5-fluorouracil (5FU) to create a novel prodrug. This obtained prodrug, chloracetyl-MR-5FU, is specifically targeted using gold nanocages to CD133+ glioma cells. Test results have shown a high encapsulation efficiency of the drug during the polysaccharide modification process; its anticancer activity was demonstrated in vitro and the release of the prodrug was demonstrated in ex vivo studies.

Efficacy of oleylphosphocholine in experimental cutaneous leishmaniasis.

OBJECTIVES: Cutaneous leishmaniasis (CL) is a neglected tropical disease causing a range of skin lesions for which safe and efficacious drugs are lacking. Oleylphosphocholine (OLPC) is structurally similar to miltefosine and has previously demonstrated potent activity against visceral leishmaniasis. We here present the in vitro and in vivo efficacy of OLPC against CL-causing Leishmania species. METHODS: The antileishmanial activities of OLPC were evaluated and compared with miltefosine in vitro against intracellular amastigotes of seven CL-causing species. Following the confirmation of significant in vitro activity, the performance of the maximum tolerated dose of OLPC was evaluated in an experimental murine model of CL followed by a dose-response titration and the efficacy evaluation of four OLPC formulations (two with a fast-release and two with a slow-release profile) using bioluminescent Leishmania major parasites. RESULTS: OLPC demonstrated potent in vitro activity of the same order as miltefosine in the intracellular macrophage model against a range of CL-causing species. A dose of 35 mg of OLPC/kg/day administered orally for 10 days was well-tolerated and able to reduce the parasite load in the skin of L. major-infected mice to a similar extent as the positive control paromomycin (50 mg/kg/day, intraperitoneally) in both in vivo studies. Reducing the dose of OLPC resulted in inactivity and modifying the release profile using mesoporous silica nanoparticles led to a decrease in activity when solvent-based loading was used in contrast to extrusion-based loading, which had no impact on its antileishmanial efficacy. CONCLUSIONS: Together, these data suggest that OLPC could be a promising alternative to miltefosine treatment for CL. Further investigations exploring experimental models with additional Leishmania species and skin pharmacokinetic and dynamic analyses are required.

Can we Succeed in the Fight Against SARS-CoV-2 with its Emerging New Variants?

In 2019, the whole world came together to confront a life-threatening virus named SARS-CoV-2, causing COVID-19 illness. The virus infected the human host by attaching to the ACE2 and CD147 receptors in some human cells, resulting in cytokine storm and death. The new variants of the virus that caused concern are Alpha, Beta, Gamma, Delta, and Epsilon, according to the WHO label. However, Pango lineages designated them as B.1.1.7, B.1.351, P.1, B.1.617.2, and B.1.429. Variants may be progressively formed in one chronic COVID-19 patient and transmitted to others. They show some differences in cellular and molecular mechanisms. Mutations in the receptor-binding domain (RBD) and N-terminal domain (NTD) lead to alterations in the host's physiological responses. They show significantly higher transmissibility rates and viral load while evading neutralizing antibodies at different rates. These effects are through mutations, deletion, and conformational alterations in the virus, resulting in the enhanced affinity of RBD to PD of ACE2 protein, virus entry, and spike conformational change. In the clinical laboratory, new variants may diagnose from other variants using specific primers for RBD or NTD. There are some controversial findings regarding the efficacy of the developed vaccines against the new variants. This research aimed to discuss the cellular and molecular mechanisms beyond COVID-19 pathogenesis, focusing on the new variants. We glanced at why the mutations and the ability to transmit the virus increase and how likely the available vaccines will be effective against these variants.

Activated Carbon/Pectin Composite Enterosorbent for Human Protection from Intoxication with Xenobiotics Pb(II) and Sodium Diclofenac.

The use of enterosorbents-materials which can be administered orally and eliminate toxic substances from the gastrointestinal tract (GIT) by sorption-offers an attractive complementary protection of humans against acute and chronic poisoning. In this study, we report the results of developing a microgranulated binary biomedical preparation for oral use. It was designed with a core-shell structure based on pectin with low degree of esterification as the core, and nanoporous activated carbon produced from rice husk, AC-RH, as the shell, designated as AC-RH@pectin. The adsorption properties of the synthesized materials were studied in aqueous solutions for the removal of lead (II) nitrate as a representative of toxic polyvalent metals and sodium diclofenac as an example of a medicinal drug. The composite enterosorbent demonstrated high adsorption capacity for both adsorbates studied. Adsorption kinetics of lead and diclofenac adsorption by AC-RH, pectin, and AC-RH@pectin, fitted well a pseudo-second-order model. According to the Langmuir adsorption isotherm model, the best fitted isotherm model, the maximum adsorption capacity, qmax, of AC-RH@pectin for diclofenac and for lead (II) was 130.9 mg/g and 227.8 mg/g, respectively. Although qmax of AC-RH for diclofenac, 537.6 mg/g, and qmax of pectin for lead (II), 245.7 mg/g, were higher, the maximum adsorption capacity of AC-RH for lead (II), 52.7 mg/g, was much lower than that of the composite AC-RH@pectin and the adsorption capacity of pectin for diclofenac was negligible. Therefore, the composite material AC-RH@pectin demonstrated substantial efficiency of removing both species which potentially defines it as a more universal enterosorbent suitable for treating poisoning caused by substances of different chemical nature.

The World Against Versatile SARS-Cov-2 Nanomachines: Mythological or Reality?

Nanomachines hold promise for the next generation of emerging technology; however, nanomachines are not a new concept. Viruses, nature's nanomachines, have already existed for thousands of years. In 2019, the whole world had to come together to confront a life-threatening nanomachine named "SARS-CoV-2", which causes COVID-19 illness. SARS-CoV-2, a smart nanomachine, attaches itself to the ACE2 and CD147 receptors present on the cell surfaces of the lungs, kidneys, heart, brain, intestines, testes, etc. and triggers pathogenesis. Cell entry triggers a cascade of inflammatory responses resulting in tissue damage, with the worst affected cases leading to death. SARS-CoV-2 influences several receptors and signalling pathways; therefore, finding a biomaterial that caps these signalling pathways and ligand sites is of interest. This research aimed to compare the similarities and differences between COVID-19 and its elderly sisters, MERS and SARS. Furthermore, we glanced at emerging therapeutics that carry potential in eliminating SARS-CoV-2, and the tissue damage it causes. Simple prophylactic and therapeutic strategies for the treatment of COVID- 19 infection have been put forward.

Film-Forming Systems for the Delivery of DNDI-0690 to Treat Cutaneous Leishmaniasis.

In cutaneous leishmaniasis (CL), parasites reside in the dermis, creating an opportunity for local drug administration potentially reducing adverse effects and improving treatment adherence compared to current therapies. Polymeric film-forming systems (FFSs) are directly applied to the skin and form a thin film as the solvent evaporates. In contrast to conventional topical dosage forms, FFSs strongly adhere to the skin, favouring sustained drug delivery to the affected site, reducing the need for frequent applications, and enhancing patient compliance. This study reports the first investigation of the use of film-forming systems for the delivery of DNDI-0690, a nitroimidazole compound with potent activity against CL-causing Leishmania species. A total of seven polymers with or without plasticiser were evaluated for drying time, stickiness, film-flexibility, and cosmetic attributes; three FFSs yielded a positive evaluation for all test parameters. The impact of each of these FFSs on the permeation of the model skin permeant hydrocortisone (hydrocortisone, 1% (w/v) across the Strat-M membrane was evaluated, and the formulations resulting in the highest and lowest permeation flux (Klucel LF with triethyl citrate and Eudragit RS with dibutyl sebacate, respectively) were selected as the FFS vehicle for DNDI-0690. The release and skin distribution of the drug upon application to Leishmania-infected and uninfected BALB/c mouse skin were examined using Franz diffusion cells followed by an evaluation of the efficacy of both DNDI-0690 FFSs (1% (w/v)) in an experimental CL model. Whereas the Eudragit film resulted in a higher permeation of DNDI-0690, the Klucel film was able to deposit four times more drug into the skin, where the parasite resides. Of the FFSs formulations, only the Eudragit system resulted in a reduced parasite load, but not reduced lesion size, when compared to the vehicle only control. Whereas drug delivery into the skin was successfully modulated using different FFS systems, the FFS systems selected were not effective for the topical application of DNDI-0690. The convenience and aesthetic of FFS systems alongside their ability to modulate drug delivery to and into the skin merit further investigation using other promising antileishmanial drugs.

The role of nanotechnology in current COVID-19 outbreak.

COVID-19 has recently become one of the most challenging pandemics of the last century with deadly outcomes and a high rate of reproduction number. It emphasizes the critical need for the designing of efficient vaccines to prevent virus infection, early and fast diagnosis by the high sensitivity and selectivity diagnostic kits, and effective antiviral and protective therapeutics to decline and eliminate the viral load and side effects derived from tissue damages. Therefore, non-toxic antiviral nanoparticles (NPs) have been under development for clinical application to prevent and treat COVID-19. NPs showed great promise to provide nano vaccines against viral infections. Here, we discuss the potentials of NPs that may be applied as a drug itself or as a platform for the aim of drug and vaccine repurposing and development. Meanwhile, the advanced strategies based on NPs to detect viruses will be described with the goal of encouraging scientists to design effective and cost-benefit nanoplatforms for prevention, diagnosis, and treatment.

COVID-19 Vaccines in Clinical Trials and their Mode of Action for Immunity against the Virus.

For nearly two decades, coronaviruses have caused many health and economic problems, while no effective commercial vaccine has yet been developed. It is worth mentioning that despite some mutations and recombination in SARS-CoV-2, its genotype is very close to the original strain from Wuhan, China. Therefore, the development of an effective vaccine would be promising. It might be hypothesized that BCG vaccination is performed in high-risk populations before the commercialization of an effective SARS-CoV-2 vaccine. However, the development of an effective vaccine without considering the adverse immune reactions derived from antibody-dependent or cell-based immune enhancement may threaten vaccinated people's lives and long-term side effects must be considered. To this end, targeting of the receptor-binding domain (RBD) in spike and not whole spike, glycolization of FC receptors, PD-1 blockers, CPPs, etc., are promising. Therefore, the subunit vaccines or RNA vaccines that encode the RBP segment of the spike are of interest. To enhance the vaccine efficacy, its co-delivery with an adjuvant has been recommended. Nanoparticles modulate immune response with higher efficiency than the soluble form of antigens and can be functionalized with the positively charged moieties and ligands of targeted cells, such as dendritic cells, to increase cellular uptake of the antigens and their presentation on the surface of immune cells. This research aimed to discuss the COVID-19 vaccines entering the clinical trial and their mode of action effective immunity against the virus and discusses their advantages compared to each other.

Multiple Sclerosis: LIFNano-CD4 for Trojan Horse Delivery of the Neuro-Protective Biologic "LIF" Into the Brain: Preclinical Proof of Concept.

Multiple sclerosis (MS) is a demyelinating autoimmune disease that attacks the brain, with year-on-year loss of brain volume, starting late teens and becoming manifest late twenties. There is no cure, and current therapies are immunosuppressive only. LIF is a vital stem cell growth factor active throughout life-and essential for health of the central nervous system (CNS), being tolerogenic, myelinogenic, and neuroprotective. Nano-formulation of LIF (LIFNano) using FDA-approved PLGA captures LIF's compound therapeutic properties, increasing potency 1,000-fold when targeted to CD4 (LIFNano-CD4). Moreover, circulating CD4+ lymphocytes are themselves regulated by LIF to express the Treg phenotype, known to release T cell-derived LIF upon engagement with cognate antigen, perpetuating antigen-specific self-tolerance. With the longer-term aim of treating inflammatory lesions of MS, we asked, does LIFNano-CD4 cross the blood-brain barrier (BBB)? We measure pK and pD using novel methodologies, demonstrate crossing of the BBB, show LIF-cargo-specific anti-inflammatory efficacy in the frontal cortex of the brain, and show safety of intravenous delivery of LIFNano-CD4 at doses known to provide efficacious concentrations of LIF cargo behind the BBB.

Pharmacokinetics and Pharmacodynamics of the Nitroimidazole DNDI-0690 in Mouse Models of Cutaneous Leishmaniasis.

The nitroimidazole DNDI-0690 is a clinical drug candidate for visceral leishmaniasis (VL) that also shows potent in vitro and in vivo activity against cutaneous leishmaniasis (CL). To support further development of this compound into a patient-friendly oral or topical formulation for the treatment of CL, we investigated the free drug exposure at the dermal site of infection and subsequent elimination of the causative Leishmania pathogen. This study evaluates the pharmacokinetics (PK) and pharmacodynamics (PD) of DNDI-0690 in mouse models of CL. Skin microdialysis and Franz diffusion cell permeation studies revealed that DNDI-0690 permeated poorly (<1%) into the skin lesion upon topical drug application (0.063% [wt/vol], 30 µl). In contrast, a single oral dose of 50 mg/kg of body weight resulted in the rapid and nearly complete distribution of protein-unbound DNDI-0690 from the plasma into the infected dermis (ratio of the area under the curve [0 to 6 h] of the free DNDI-0690 concentration in skin tissue to blood [fAUC0-6 h, skin tissue/fAUC0-6 h, blood] is greater than 80%). Based on in vivo bioluminescence imaging, two doses of 50 mg/kg DNDI-0690 were sufficient to reduce the Leishmania mexicana parasite load by 100-fold, while 6 such doses were needed to achieve similar killing of L. major; this was confirmed by quantitative PCR. The combination of rapid accumulation and potent activity in the Leishmania-infected dermis indicates the potential of DNDI-0690 as a novel oral treatment for CL.

The role of mouse tumour models in the discovery and development of anticancer drugs.

Our understanding of cancer biology has increased substantially over the past 30 years. Despite this, and an increasing pharmaceutical company expenditure on research and development, the approval of novel oncology drugs during the past decade continues to be modest. In addition, the attrition of agents during clinical development remains high. This attrition can be attributed, at least in part, to the clinical development being underpinned by the demonstration of predictable efficacy in experimental models of human tumours. This review will focus on the range of models available for the discovery and development of anticancer drugs, from traditional subcutaneous injection of tumour cell lines to mice genetically engineered to spontaneously give rise to tumours. It will consider the best time to use the models, along with practical applications and shortcomings. Finally, and most importantly, it will describe how these models reflect the underlying cancer biology and how well they predict efficacy in the clinic. Developing a line of sight to the clinic early in a drug discovery project provides clear benefit, as it helps to guide the selection of appropriate preclinical models and facilitates the investigation of relevant biomarkers.

Local Skin Inflammation in Cutaneous Leishmaniasis as a Source of Variable Pharmacokinetics and Therapeutic Efficacy of Liposomal Amphotericin B.

Disfiguring skin lesions caused by several species of the Leishmania parasite characterize cutaneous leishmaniasis (CL). Successful treatment of CL with intravenous (i.v.) liposomal amphotericin B (LAmB) relies on the presence of adequate antibiotic concentrations at the dermal site of infection within the inflamed skin. Here, we have investigated the impact of the local skin inflammation on the pharmacokinetics (PK) and efficacy of LAmB in two murine models of localized CL (Leishmania major and Leishmania mexicana) at three different stages of disease (papule, initial nodule, and established nodule). Twenty-four hours after the administration of one 25 mg/kg of body weight LAmB (i.v.) dose to infected BALB/c mice (n = 5), drug accumulation in the skin was found to be dependent on the causative parasite species (L. major > L. mexicana) and the disease stage (papule > initial nodule > established nodule > healthy skin). Elevated tissue drug levels were associated with increased vascular permeability (Evans blue assay) and macrophage infiltration (histomorphometry) in the infected skin, two pathophysiological parameters linked to tissue inflammation. After identical treatment of CL in the two models with 5 × 25 mg/kg LAmB (i.v.), intralesional drug concentrations and reductions in lesion size and parasite load (quantitative PCR [qPCR]) were all ≥2-fold higher for L. major than for L. mexicana In conclusion, drug penetration of LAmB into CL skin lesions could depend on the disease stage and the causative Leishmania species due to the influence of local tissue inflammation.

Comparative efficacy, toxicity and biodistribution of the liposomal amphotericin B formulations Fungisome® and AmBisome® in murine cutaneous leishmaniasis.

Fungisome® (F), a liposomal amphotericin B (AmB) product, is marketed in India as a safe and effective therapeutic for the parasitic infection visceral leishmaniasis. Its potential in the treatment of cutaneous leishmaniasis (CL), a disfiguring form of the disease affecting the skin, is currently unknown. Here, we report the evaluation of the efficacy of F in the Leishmania major BALB/c murine model of CL, including a head-to-head comparison with the standard liposomal AmB formulation AmBisome® (A). Upon intravenous administration at dose levels of 5, 10 and 15 mg/kg of body weight (on days 0, 2, 4, 6 and 8), F showed clear signs of toxicity (at 15 mg/kg), while A did not. After complete treatment (day 10), the tolerated doses of 5 and 10 mg/kg F had significant antileishmanial activity (ED50 = 4.0 and 12.8 mg/kg for qPCR-based parasite load and lesion size, respectively), although less than that of A at identical doses (ED50 = 3.0 and 8.8 mg/kg). The efficacy of F was inferior compared to A because lower levels of the active agent AmB accumulated within the infected lesion. In conclusion, despite possibly being less safe and efficacious than A at equivalent doses, the moderate in vivo activity of F could indicate a role in the systemic pharmacotherapy of CL.

Dose-dependent effect and pharmacokinetics of fexinidazole and its metabolites in a mouse model of human African trypanosomiasis.

Human African trypanosomiasis (HAT) is a neglected tropical disease, with a population of 70 million at risk. Current treatment options are limited. In the search for new therapeutics, the repurposing of the broad-spectrum antiprotozoal drug fexinidazole has completed Phase III trials with the anticipation that it will be the first oral treatment for HAT. This study used the recently validated bioluminescence imaging model to assess the dose and rate of kill effect of fexinidazole in infected mice, and the dose-dependent effect of fexinidazole on trypanosome infection. Pharmacokinetics of fexinidazole in plasma and central nervous system (CNS) compartments were similar in both infected and uninfected mice. Drug distribution within the CNS was further examined by microdialysis, showing similar levels in the cortex and hippocampus. However, high variability in drug distribution and exposure was found between mice.