[99mTc]Tc-labeled HYNIC conjugated chlorambucil as a tumor targeting Agent: Synthesis, characterization and ex-vivo evaluation.

Chlorambucil is an alkylating drug that finds application towards chemotherapy of different types of cancers. In order to explore the possibility of utilization of this drug as an imaging agent for early diagnosis of solid tumors, attempt was made to synthesize a 99mTc complex of chlorambucil and evaluate its potential in tumor bearing small animal model. HYNIC-chlorambucil was synthesized by conjugation of HYNIC with chlorambucil via an ethylenediamine linker. All the intermediates and final product were purified and characterized by standard spectroscopic techniques viz. FT-IR, 1H/13C-NMR as well as by mass spectrometry. HYNIC-chlorambucil conjugate was radiolabeled with [99mTc]Tc and found to be formed with > 95 % radiochemical purity via RP-HPLC studies. The partition coefficient (Log10Po/w) of the synthesized complex was found to be -0.78 ± 0.25 which indicated the moderate hydrophilic nature for the complex. Biological behaviour of [99mTc]Tc-HYNIC-chlorambucil, studied in fibrosarcoma bearing Swiss mice, revealed a tumor uptake of about 4.16 ± 1.52 %IA/g at 30 min post-administration, which declined to 1.91 ± 0.13 % IA/g and 1.42 ± 0.14 %IA/g at 1 h and 2 h post-administration, respectively. A comparison of different [99mTc]Tc-chlorambucil derivatives (reported in the contemporary literature) formulated using different methodologies revealed that tumor uptake and pharmacokinetics exhibited by these agents strongly depend on the lipophilicity/hydrophilicity of such agents, which in turn is dependent on the bifunctional chelators used for formulating the radiolabeled chlorambucils.

Tazarotene is as effective and well-tolerated as imiquimod in the treatment of verruca plana: a comparative randomized controlled trial.

BACKGROUND: Plane warts, when multiple and recurrent, present a therapeutic challenge acting as a source of reinfection, causing frustration and affecting a patient's quality of life. For large numbers of lesions in cosmetically significant sites, topical treatment is preferred to avoid potential sequelae. OBJECTIVES: To evaluate and compare the efficacy and tolerability of tazarotene 0.1% gel vs. imiquimod 5% cream for the treatment of plane warts. METHODS: In a parallel three-arm randomized controlled trial, 60 patients were randomized to imiquimod, tazarotene or placebo groups. Patients applied the corresponding treatment once daily at night for a maximum of 12 weeks. Primary outcomes were the percentage of respondents with complete clearance in the three studied groups, and the type and frequency of side-effects in each group. RESULTS: Both active treatments resulted in significant improvement compared with baseline and the placebo group (P = 0.001). The imiquimod 5% treated group showed complete clearance in 50% (10/20) of patients, partial response in 15% (3/20), and no response in 35% (7/20). Tazarotene 0.1% gel showed complete clearance in 40% (8/20) of patients, partial response in 40% (8/20), and no response in 20% (4/20). No significant difference was detected between the imiquimod and tazarotene groups (P = 0.19). CONCLUSIONS: Compared with imiquimod, tazarotene 0.1% gel for the treatment of plane warts seems to offer an equivalent treatment response, it maintained efficacy without recurrence and had a safer profile regarding dyspigmentation with an advantageous cheaper cost.

Halobetasol Propionate 0.01% and Tazarotene 0.045% Lotion With a Ceramide-Containing Moisturizer in Adults With Psoriasis.

INTRODUCTION: Moisturizers are often used as adjuvant therapy for psoriasis to assist with rehydration and skin barrier restoration. Fixed-combination halobetasol propionate 0.01% and tazarotene 0.045% lotion (HP/TAZ) is indicated for the topical treatment of plaque psoriasis in adults, with a demonstrated clinical profile in two phase 3 trials. However, the effect of application order with HP/TAZ has yet to be explored. This study evaluated the clinical profile of HP/TAZ applied before versus after a ceramide-containing moisturizer in adults with mild-to-moderate plaque psoriasis. METHODS: Sixteen participants were randomized to apply HP/TAZ followed by moisturizer on one side and moisturizer followed by HP/TAZ on the other side once daily for 12 weeks. Tolerability, safety, efficacy, and quality of life endpoints were assessed.  Results: Significant Investigator's Global Assessment improvement was observed across all time points (P≤0.003) regardless of application order. Total Dermatology Life Quality Index scores significantly improved at all time points (P≤0.003), and visual analog scale for itch significantly improved at weeks 4, 8, and 12 (P<0.008). Four moderate adverse events were experienced by 3 participants. Two participants reported itching/irritation, which was worse when HP/TAZ was applied first. CONCLUSIONS: The application order of moisturizer did not decrease therapeutic efficacy of HP/TAZ. Moisturizer application before HP/TAZ may reduce incidence of application site adverse events, ultimately increasing tolerability and supporting the real-world recommendation that applying a ceramide-containing moisturizer before HP/TAZ, versus after, results in a safe and effective therapeutic option for plaque psoriasis. J Drugs Dermatol. 2024;23(2):50-53.     doi:10.36849/JDD.7928.

3D structure of acetolactate synthase explains why the Asp-376-Glu point mutation does not give the same resistance level to different imidazolinone herbicides.

Resistance to ALS-inhibiting herbicides has dramatically increased worldwide due to the persisting evolution of target site mutations that reduce the affinity between the herbicide and the target. We evaluated the effect of the well-known ALS Asp-376-Glu target site mutation on different imidazolinone herbicides, including imazamox and imazethapyr. Greenhouse dose response experiments indicate that the Amaranthus retroflexus biotype carrying Asp-376-Glu was fully controlled by applying the field recommended dose of imazamox, whereas it displayed high level of resistance to imazethapyr. Likewise, Sorghum halepense, carrying Asp-376-Glu showed resistance to field recommended doses of imazethapyr but not of imazamox. Biochemical inhibition and kinetic characterization of the Asp-376-Glu mutant enzyme heterologously expressed using different plant sequence backbones, indicate that the Asp-376-Glu shows high level of insensitivity to imazethapyr but not to imazamox, corroborating the greenhouse results. Docking simulations revealed that imazamox can still inhibit the Asp-376-Glu mutant enzyme through a chalcogen interaction between the oxygen of the ligand and the sulfur atom of the ALS Met200, while imazethapyr does not create such interaction. These results explain the different sensitivity of the Asp-376-Glu mutation towards imidazolinone herbicides, thus providing novel information that can be exploited for defining stewardship guidelines to manage fields infested by weeds harboring the Asp-376-Glu mutation.

Exploring the influence of invasive weed biochar on the sorption and dissipation dynamics of imazethapyr in sandy loam soil.

The management of invasive weeds on both arable and non-arable land is a vast challenge. Converting these invasive weeds into biochar and using them to control the fate of herbicides in soil could be an effective strategy within the concept of turning waste into a wealth product. In this study, the fate of imazethapyr (IMZ), a commonly used herbicide in various crops, was investigated by introducing such weeds as biochar, i.e., Parthenium hysterophorus (PB) and Lantana camara (LB) in sandy loam soil. In terms of kinetics, the pseudo-second order (PSO) model provided the best fit for both biochar-mixed soils. More IMZ was sorbed onto LB-mixed soil compared to PB-mixed soil. When compared to the control (no biochar), both PB and LB biochars (at concentrations of 0.2% and 0.5%) increased IMZ adsorption, although the extent of this effect varied depending on the dosage and type of biochar. The Freundlich adsorption isotherm provided a satisfactory explanation for IMZ adsorption in soil/soil mixed with biochar, with the adsorption process exhibiting high nonlinearity. The values of Gibb's free energy change (ΔG) were negative for both adsorption and desorption in soil/soil mixed with biochar, indicating that sorption was exothermic and spontaneous. Both types of biochar significantly affect IMZ dissipation, with higher degradation observed in LB-amended soil compared to PB-amended soil. Hence, the findings suggest that the preparation of biochar from invasive weeds and its utilization for managing the fate of herbicides can effectively reduce the residual toxicity of IMZ in treated agroecosystems in tropical and subtropical regions.

Dissipation Kinetics and Residue Distribution of Imazethapyr in Urdbean (Vigna mungo (L.) Hepper) and Urdbean Field soil and its Effect on soil Microbial Population.

Imazethapyr is the most common herbicide used for weed management in pulses. A field trial was carried out with imazethapyr 10% SL formulation at 100 and 150 g a.i./ha application rates, as pre-and post-emergence, to study dissipation of imazethapyr in soil, persistence in urdbean plant, terminal residues in urdbean grains and effect on soil microbes. An acetate buffered- quick, easy, cheap, effective, rugged, and safe (QuEChERS) method in combination with high-performance liquid chromatography (HPLC) was validated for imazethapyr residue analysis. The half-life of imazethapyr in soil ranged from 15.12 to 18.02 days. The residues of imazethapyr persist up to 60 days in soil and up to 7-15 days in urdbean plant. Residues were not detected in grains at the time of harvest. Persistence of imazethapyr residues in soil significantly impact soil microbial populations depending on herbicide application rates and timing.

Development of a chemically defined medium for Paenibacillus polymyxa by parallel online monitoring of the respiration activity in microtiter plates.

BACKGROUND: One critical parameter in microbial cultivations is the composition of the cultivation medium. Nowadays, the application of chemically defined media increases, due to a more defined and reproducible fermentation performance than in complex media. In order, to improve cost-effectiveness of fermentation processes using chemically defined media, the media should not contain nutrients in large excess. Additionally, to obtain high product yields, the nutrient concentrations should not be limiting. Therefore, efficient medium optimization techniques are required which adapt medium compositions to the specific nutrient requirements of microorganisms. RESULTS: Since most Paenibacillus cultivation protocols so far described in literature are based on complex ingredients, in this study, a chemically defined medium for an industrially relevant Paenibacillus polymyxa strain was developed. A recently reported method, which combines a systematic experimental procedure in combination with online monitoring of the respiration activity, was applied and extended to identify growth limitations for Paenibacillus polymyxa. All cultivations were performed in microtiter plates. By systematically increasing the concentrations of different nutrient groups, nicotinic acid was identified as a growth-limiting component. Additionally, an insufficient buffer capacity was observed. After optimizing the growth in the chemically defined medium, the medium components were systematically reduced to contain only nutrients relevant for growth. Vitamins were reduced to nicotinic acid and biotin, and amino acids to methionine, histidine, proline, arginine, and glutamate. Nucleobases/-sides could be completely left out of the medium. Finally, the cultivation in the reduced medium was reproduced in a laboratory fermenter. CONCLUSION: In this study, a reliable and time-efficient high-throughput methodology was extended to investigate limitations in chemically defined media. The interpretation of online measured respiration activities agreed well with the growth performance of samples measured in parallel via offline analyses. Furthermore, the cultivation in microtiter plates was validated in a laboratory fermenter. The results underline the benefits of online monitoring of the respiration activity already in the early stages of process development, to avoid limitations of medium components, oxygen limitation and pH inhibition during the scale-up.

An Investigator-Initiated Trial of a Polymeric Emulsion of Halobetasol Propionate and Tazarotene in the Treatment of Palmoplantar Psoriasis.

Copy: Palmoplantar psoriasis is a chronic, difficult-to-treat localized variant of psoriasis that affects the palms and soles, significantly affecting patient's quality of life. OBJECTIVE: To evaluate the synergistic effect of a fixed-combination topical lotion composed of halobetasol propionate 0.01% and tazarotene 0.045% in the treatment of palmoplantar psoriasis. METHODS: This was an open-label investigator-initiated trial involving 21 patients with moderate-to-severe palmoplantar plaque-type psoriasis who underwent treatment with halobetasol propionate 0.01% and tazarotene 0.045%. Subjects were assessed for disease severity using the palmoplantar Physician Global Assessment and the mean difference over time was compared using the Wilcoxon signed-rank test. RESULTS: 5 patients (24%) achieved a palmoplantar Physician Global Assessment of 0 or 1 after week 24 or last observation carried forward. The mean palmoplantar Physician Global Assessment significantly decreased from baseline (3.57) to week 24/last observation carried forward (2.38) (P<0.001). DISCUSSION: Halobetasol propionate 0.01% and tazarotene 0.045% lotion demonstrated efficacy in adult patients with moderate-to-severe palmoplantar plaque-type psoriasis through significant improvement in palmoplantar Physician Global Assessment. The complementary mechanisms of action of the corticosteroid and tazarotene may be of benefit compared to monotherapeutic agents. J Drugs Dermatol. 2023;22(2): 223-225. doi:10.36849/JDD.7067.

Meeting Patient Expectations of Topical Psoriasis Treatment: Evidence Supporting the Use of Fixed-Combination Halobetasol/Tazarotene Lotion.

Discordance between patient and clinician treatment goals and expectations can present a challenge to implementation of effective therapeutic plans. Because topical treatments are commonly used for plaque psoriasis, both as monotherapy and adjuncts to other treatment modalities, providers need to understand the concerns of patients with psoriasis regarding use of topical products. Psoriasis is a complex and chronic disease with treatment needs that may change over time, influencing patient treatment goals and expectations of efficacy. When these expectations are not met and patient concerns are unaddressed, dissatisfaction may lead to nonadherence, which in turn can prevent patients from achieving relief from the signs and symptoms of psoriasis that affect their quality of life. Here, we detail how current topical treatments meet patient expectations and needs, with particular attention given to combination regimens using corticosteroids. This review shows that once-daily application of halobetasol propionate (0.01%) and tazarotene (0.045%) lotion (HP/TAZ) not only has a rapid onset of treatment effect and proven efficacy, but also has a remittive effect. In addition, HP/TAZ has a favorable safety profile, with low rates of irritation and local skin reactions in clinical studies. The dual mechanisms of action related to 2 active ingredients, once-daily use, and the favorable clinical findings suggest that HP/TAZ may address patient concerns and promote treatment adherence.J Drugs Dermatol. 2023;22(2):132-138. doi:10.36849/JDD.7367.

Supplement Individual Article: A Reappraisal of Fixed-Combination Halobetasol Propionate and Tazarotene for the Treatment of Psoriasis: Biological Underpinnings, Therapeutic Mechanisms, and Economic Considerations.

Psoriasis is a complex inflammatory disease, which can be triggered by the interplay among keratinocytes, various immune cells, and even dermal vascular endothelial cells. Understanding of the key players and cytokine/chemokine messengers involved in the initiation and maintenance of psoriasis has significantly evolved and led to numerous systemic biologic therapies targeting those specific components. These therapies, despite their successes, do not ubiquitously affect all pathogenic cellular pathways. They also carry their risks and may be contraindicated in certain patient populations. Therefore, other therapeutics are still necessary. Tazarotene, a decades-old topical retinoid, has been successfully used for treating cutaneous psoriasis. Its retinoid effect via binding to retinoic acid receptors (RAR)/retinoic X receptors (RXR) alters cellular gene expression of numerous pathogenic cells and leads to a long-standing maintenance effect despite discontinuation - a phenomenon known as remittance. Concurrent use of tazarotene with topical corticosteroids results in reduced incidence of treatment-related adverse events. A fixed-combination lotion containing halobetasol propionate (HP) and tazarotene (HP 0.01%/TAZ 0.045%, Duobrii, Ortho Dermatologics) was developed implementing polymeric emulsion technology that demonstrates efficacy in psoriasis while mitigating adverse events associated with each component alone as monotherapy. In this paper, we review the pathogenesis of psoriasis and illuminate the effect of tazarotene and HP on key cellular pathways. In addition, we review the clinical efficacy of fixed-combination HP 0.01%/TAZ 0.045% lotion in psoriasis as well as its long-term treatment maintenance, applicability in skin of color, and beneficial economic impact for patients and healthcare stakeholders. As HP 0.01%/TAZ 0.045% lotion is safe and exhibits excellent efficacy, it should be within the therapeutic toolbox for every psoriasis patient.J Drugs Dermatol. 2023;22:1(Suppl 1):s3-10.

Mesenchyme-derived IGF2 is a major paracrine regulator of pancreatic growth and function.

The genetic mechanisms that determine the size of the adult pancreas are poorly understood. Imprinted genes, which are expressed in a parent-of-origin-specific manner, are known to have important roles in development, growth and metabolism. However, our knowledge regarding their roles in the control of pancreatic growth and function remains limited. Here we show that many imprinted genes are highly expressed in pancreatic mesenchyme-derived cells and explore the role of the paternally-expressed insulin-like growth factor 2 (Igf2) gene in mesenchymal and epithelial pancreatic lineages using a newly developed conditional Igf2 mouse model. Mesenchyme-specific Igf2 deletion results in acinar and beta-cell hypoplasia, postnatal whole-body growth restriction and maternal glucose intolerance during pregnancy, suggesting that the mesenchyme is a developmental reservoir of IGF2 used for paracrine signalling. The unique actions of mesenchymal IGF2 are demonstrated by the absence of any discernible growth or functional phenotypes upon Igf2 deletion in the developing pancreatic epithelium. Additionally, increased IGF2 levels specifically in the mesenchyme, through conditional Igf2 loss-of-imprinting or Igf2r deletion, leads to pancreatic acinar overgrowth. Furthermore, ex-vivo exposure of primary acinar cells to exogenous IGF2 activates AKT, a key signalling node, and increases their number and amylase production. Based on these findings, we propose that mesenchymal Igf2, and perhaps other imprinted genes, are key developmental regulators of adult pancreas size and function.

Improvement of multicatalytic properties of nitrilase from Paraburkholderia graminis for efficient biosynthesis of 2-chloronicotinic acid.

Nitrilases are promising biocatalysts to produce high-value-added carboxylic acids through hydrolysis of nitriles. However, since the enzymes always show low activity and sometimes with poor reaction specificity toward 2-chloronicotinonitrile (2-CN), very few robust nitrilases have been reported for efficient production of 2-chloronicotinic acid (2-CA) from 2-CN. Herein, a nitrilase from Paraburkholderia graminis (PgNIT) was engineered to improve its catalytic properties. We identified the beneficial residues via computational analysis and constructed the mutant library. The positive mutants were obtained and the activity of the "best" mutant F164G/I130L/N167Y/A55S/Q260C/T133I/R199Q toward 2-CN was increased from 0.14 × 10-3  to 4.22 U/mg. Its reaction specificity was improved with elimination of hydration activity. Molecular docking and molecular dynamics simulation revealed that the conformational flexibility, the nucleophilic attack distance, as well as the interaction forces between the enzyme and substrate were the main reason alternating the catalytic properties of PgNIT. With the best mutant as biocatalyst, 150 g/L 2-CN was completely converted, resulting in 2-CA accumulated to 169.7 g/L. When the substrate concentration was increased to 200 g/L, 203.1 g/L 2-CA was obtained with yield of 85.7%. The results laid the foundation for industrial production of 2-CA with the nitrilase-catalyzed route.

Ligand release from silicon phthalocyanine dyes triggered by X-ray irradiation.

Ligand release from silicon phthalocyanine (SiPc) dyes triggered by near-infrared (NIR) light is a key photochemical reaction involving caged compounds based on SiPc. Although NIR light is relatively permeable compared with visible light, this light can be attenuated by tissue absorption and scattering; therefore, using light to induce photochemical reactions deep inside the body is difficult. Herein, because X-rays are highly permeable and can produce radicals through the radiolysis of water, we investigated whether the axial ligands of SiPcs can be cleaved using X-ray irradiation. SiPcs with different axial ligands (alkoxy, siloxy, oxycarbonyl, and phenoxy groups) were irradiated with X-rays under hypoxic conditions. We found that the axial ligands were cleaved via reactions with hydrated electrons (e-aq), not OH radicals, generated from water in response to X-ray irradiation, and SiPc with alkoxy groups exhibited the highest cleavage efficiency. A quantitative investigation revealed that X-ray-induced axial ligand cleavage proceeds via a radical chain reaction. The reaction is expected to be applicable to the molecular design of X-ray-activatable functional molecules in the future.

Tazarotene 0.045% Lotion: A Novel Retinoid Formulation.

OBJECTIVE: The aim of this study is to review the available data on efficacy and tolerability of tazarotene 0.045% lotion. DATA SOURCES: A literature search of MEDLINE (PubMed) and EMBASE databases was completed in November 2021. STUDY SELECTION AND DATA EXTRACTION: Articles that discussed efficacy, tolerability, and pharmacology of tazarotene 0.045% lotion, written in English and published before mid-November 2021, were assessed. DATA SYNTHESIS: In two, 12-week phase III clinical trials, tazarotene 0.045% lotion had higher rates of treatment success (study 1: 25.5% and study 2: 29.6%) than individuals who received the vehicle (study 1: 13.0% and study 2: 17.3%) (both Ps < 0.001). Participants treated with tazarotene 0.045% lotion had greater least squares mean reduction in inflammatory (study 1: 55.5% and study 2: 59.5%) and noninflammatory (study 1: 51.4% and study 2: 60%) acne lesions when compared with vehicle (inflammatory acne lesions, study 1: 45.7% and study 2:49%; noninflammatory acne lesions, study 1: 41.5% and study 2: 41.6%) (P < 0.001 for studies 1 and 2). Tazarotene 0.045% lotion was well tolerated. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE: Retinoids are first-line therapy in the treatment of acne vulgaris. However, many patients experience cutaneous irritation, which can decrease patient adherence and efficacy. Tazarotene 0.045% lotion is the first retinoid to utilize polymeric emulsion technology (PET) to efficiently distribute the medication across the skin, decreasing adverse effects while maintaining efficacy. CONCLUSIONS: Tazarotene 0.045% lotion is an effective and well-tolerated retinoid recently approved by the US Food and Drug Administration (FDA) for treating acne vulgaris in individuals 9 years of age and older.

Crystal structures of the M1 and M4 muscarinic acetylcholine receptors.

Muscarinic M1-M5 acetylcholine receptors are G-protein-coupled receptors that regulate many vital functions of the central and peripheral nervous systems. In particular, the M1 and M4 receptor subtypes have emerged as attractive drug targets for treatments of neurological disorders, such as Alzheimer's disease and schizophrenia, but the high conservation of the acetylcholine-binding pocket has spurred current research into targeting allosteric sites on these receptors. Here we report the crystal structures of the M1 and M4 muscarinic receptors bound to the inverse agonist, tiotropium. Comparison of these structures with each other, as well as with the previously reported M2 and M3 receptor structures, reveals differences in the orthosteric and allosteric binding sites that contribute to a role in drug selectivity at this important receptor family. We also report identification of a cluster of residues that form a network linking the orthosteric and allosteric sites of the M4 receptor, which provides new insight into how allosteric modulation may be transmitted between the two spatially distinct domains.

GelMA/PEGDA microneedles patch loaded with HUVECs-derived exosomes and Tazarotene promote diabetic wound healing.

Clinical work and research on diabetic wound repair remain challenging globally. Although various conventional wound dressings have been continuously developed, the efficacy is unsatisfactory. The effect of drug delivery is limited by the depth of penetration. The sustained release of biomolecules from biological wound dressings is a promising treatment approach to wound healing. An assortment of cell-derived exosomes (exos) have been proved to be instrumental in tissue regeneration, and researchers are dedicated to developing biomolecules carriers with unique properties. Herein, we reported a methacrylate gelatin (GelMA) microneedles (MNs) patch to achieve transdermal and controlled release of exos and tazarotene. Our MNs patch comprising GelMA/PEGDA hydrogel has distinctive biological features that maintain the biological activity of exos and drugs in vitro. Additionally, its unique physical structure prevents it from being tightly attached to the skin of the wound, it promotes cell migration, angiogenesis by slowly releasing exos and tazarotene in the deep layer of the skin. The full-thickness cutaneous wound on a diabetic mouse model was carried out to demonstrate the therapeutic effects of GelMA/PEGDA@T + exos MNs patch. As a result, our GelMA/PEGDA@T + exos MNs patch presents a potentially valuable method for repairing diabetic wound in clinical applications.

Nectin-4-targeted immunoSPECT/CT imaging and photothermal therapy of triple-negative breast cancer.

BACKGROUND: Triple-negative breast cancer (TNBC) is more prone to distant metastasis and visceral recurrence in comparison to other breast cancer subtypes, and is related to dismal prognosis. Nevertheless, TNBC has an undesirable response to targeted therapies. Therefore, to tackle the huge challenges in the diagnosis and treatment of TNBC, Nectin-4 was selected as a theranostic target because it was recently found to be highly expressed in TNBC. We developed anti-Nectin-4 monoclonal antibody (mAbNectin-4)-based theranostic pair, 99mTc-HYNIC-mAbNectin-4 and mAbNectin-4-ICG. 99mTc-HYNIC-mAbNectin-4 was applied to conduct immuno-single photon emission computed tomography (SPECT) for TNBC diagnosis and classification, and mAbNectin-4-ICG to mediate photothermal therapy (PTT) for relieving TNBC tumor growth. METHODS: Nectin-4 expression levels of breast cancer cells (MDA-MB-468: TNBC cells; and MCF-7, non-TNBC cells) were proved by western blot, flow cytometry, and immunofluorescence imagning. Cell uptake assays, SPECT imaging, and biodistribution were performed to evaluate Nectin-4 targeting of 99mTc-HYNIC-mAbNectin-4. A photothermal agent (PTA) mAbNectin-4-ICG was generated and characterized. In vitro photothermal therapy (PTT) mediated by mAbNectin-4-ICG was conducted under an 808 nm laser. Fluorescence (FL) imaging was performed for mAbNectin-4-ICG mapping in vivo. In vivo PTT treatment effects on TNBC tumors and corresponding systematic toxicity were evaluated. RESULTS: Nectin-4 is overexpressed in MDA-MB-468 TNBC cells, which could specifically uptake 99mTc-HYNIC-mAbNectin-4 with high targeting in vitro. The corresponding immunoSPECT imaging demonstrated exceptional performance in TNBC diagnosis and molecular classification. mAbNectin-4-ICG exhibited favourable biocompatibility, photothermal effects, and Nectin-4 targeting. FL imaging mapped biodistribution of mAbNectin-4-ICG with excellent tumor-targeting and retention in vivo. Moreover, mAbNectin-4-ICG-mediated PTT provided advanced TNBC tumor destruction efficiency with low systematic toxicity. CONCLUSION: mAbNectin-4-based radioimmunoimaging provides visualization tools for the stratification and diagnosis for TNBC, and the corresponding mAbNectin-4-mediated PTT shows a powerful anti-tumor effect. Our findings demonstrate that this Nectin-4 targeting strategy offers a simple theranostic platform for TNBC.

In vitro and in vivo cytotoxicity assessment of glyphosate and imazethapyr-based herbicides and their association.

Resistance to glyphosate herbicide has initiated usage of combined application of herbicides as a weed control measure. Imazethapyr-based herbicides associated with glyphosate herbicide seem to be an alternative to suppress weed resistance. The aim of this study was to examine the adverse effects of Glyphosate Atanor 48® (ATN) and Imazethapyr Plus Nortox® (IMZT) formulations in both single forms and mixtures using HepG2 cells and zebrafish early-life stages models. Data demonstrated cytotoxicity due to exposure to ATN, IMZT for both models, as follows: (1) ATN (0.5 mg/L), IMZT (5 mg/L), and M3 (0.05 mg/L ATN + 5 mg/L IMZT) increased cytotoxicity by disturbing the mitochondrial activity of HepG2 cells 24 hr after exposure; (2) ATN and IMZT (5 mg/L), and M3 (0.05 mg/L ATN + 5 mg/L IMZT) also decreased the integrity of the membrane of HepG2 cells after 24 hr incubation; (3) only ATN and IMZT (5 mg/L) in their single forms diminished the mitochondrial potential of zebrafish; (4) ATN (single form) at 0.5 mg/L induced apoptosis in zebrafish larvae. In conclusion, these herbicides in their single forms appeared to produce greater cytotoxicity to HepG2 cells and zebrafish compared to the herbicide mixtures.

In Vitro Rheology Predicts Improved Spreadability of Tazarotene 0.045% Lotion Versus Trifarotene 0.005% Cream.

BACKGROUND: Intrinsic properties of vehicles used to deliver topical therapies can profoundly impact drug penetration, efficacy, patient acceptance, and treatment adherence. Therefore, advancements in vehicle technology demand sophisticated, quantitative approaches to describe and differentiate topical formulations. The objective of these studies was to quantitatively evaluate spreadability of two topical formulations for the treatment of acne via in vitro rheological measurement (how a substance’s flow characteristics change under applied stress or force) and spreadability on living skin. METHODS: Rheological characteristics (shear-thinning, rigidity, yield stress, and yield strain) of tazarotene 0.045% lotion and trifarotene 0.045% cream were measured using 5 samples of each product. In a clinical split-body study, each formulation was applied to one side of the back of healthy volunteers, and the extent to which each formulation could be spread was measured. RESULTS: Compared to trifarotene cream, tazarotene lotion demonstrated lower mean viscosity, rigidity, and yield stress, and higher yield strain, suggesting a superior spreadability profile. This finding was confirmed in the split-body study of 30 healthy White adults, in which the average area of spread was significantly larger for tazarotene lotion than trifarotene cream (167.0 vs 130.3 cm2; P<0.001). CONCLUSIONS: Rheological assessment effectively predicted the superior spreadability of tazarotene 0.045% lotion versus trifarotene 0.005% cream on living skin. Given the importance of aesthetics of topical formulations, techniques to quantify these properties may have broad implications when developing novel vehicle formulations for dermatology. J Drugs Dermatol. 2022;21(3):250-257. doi:10.36849/JDD.6703.

Efficacy and Safety of Tazarotene Lotion, 0.045% in the Treatment of Truncal Acne Vulgaris.

BACKGROUND: Although truncal acne is thought to have the same pathophysiology as facial acne, treatment response may differ based on body area involvement. Traditionally, prescribers have relied on oral therapies for the management of truncal acne, possibly because oral therapy has been considered more convenient than topical application of medication to the chest and back. A lotion formulation may be particularly well-suited for the treatment of truncal acne. Tazarotene lotion, 0.045% is FDA approved for treatment of acne vulgaris in individuals 9 years of age or older. This pilot study was designed to investigate the efficacy and safety of Arazlo lotion for the treatment of truncal acne. STUDY FINDINGS: A total of 19 subjects ranging in age from 12 to 58 years completed the 12-week study. There were significant reductions in truncal IGA (the primary endpoint) at each of the study follow-up visits. At week 12, 89% of subjects were clear or almost clear, as assessed by truncal IGA score. There were statistically significant reductions in inflammatory, non-inflammatory, and total lesion counts from baseline to week 12. Treatment with tazarotene lotion 0.045% was well-tolerated, with erythema, dryness, peeling, oiliness, pruritis, and burning generally rated as trace or mild. Most subjects (64% or more) rated the lotion as “Good” or “Excellent” in general and in comparison to their prior medications. CONCLUSIONS: Tazarotene lotion, 0.045% is shown to be effective and well-tolerated for the management of truncal acne in this pilot study. Further studies with placebo control and larger populations are warranted. J Drugs Dermatol. 2022;21(7):713-716. doi:10.36849/JDD.6967.