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Journal of Materials Chemistry. B Mar 2023Nitrogen mustard (NM), a kind of alkylating agent similar to sulfur mustard, remains a threat to public health. However, there is nearly no satisfactory antidote for...
Nitrogen mustard (NM), a kind of alkylating agent similar to sulfur mustard, remains a threat to public health. However, there is nearly no satisfactory antidote for nitrogen mustard. Herein, we developed a supramolecular antidote to nitrogen mustard through efficient complexation of NM by carboxylatopillar[5]arene potassium salts (CP[5]AK). The cavity of methoxy pillar[5]arene (P5A) is sufficient to encapsulate NM with an association constant of 1.27 × 10 M, which was investigated by H NMR titration, density functional theory studies and independent gradient model studies. NM degrades to the reactive aziridinium salt (2) in the aqueous phase which irreversibly alkylates DNA and proteins, causing severe tissue damage. Considering the size/charge matching with toxic intermediate 2, water-soluble CP[5]AK was selected to encapsulate the toxic aziridinium salt (2), resulting in a high association constant of 4.10 × 10 M. The results of protection experiments of guanosine 5'-monophosphate (GMP) by CP[5]AK indicated that the formation of a complex could effectively inhibit the alkylation of DNA. Besides, and experiments also indicated that the toxicity of the aziridinium salt (2) is inhibited with the formation of a stable host-guest complex, and CP[5]AK has a good therapeutic effect on the damage caused by NM. This study provides a new mechanism and strategy for the treatment of NM exposure-induced skin injuries.
Topics: Mechlorethamine; Antidotes; DNA
PubMed: 36876404
DOI: 10.1039/d2tb02211g -
Animal Models and Experimental Medicine Feb 2023Sulfur mustard (SM) is a chemical warfare vesicant that severely injures exposed eyes, lungs, and skin. Mechlorethamine hydrochloride (NM) is widely used as an SM...
BACKGROUND
Sulfur mustard (SM) is a chemical warfare vesicant that severely injures exposed eyes, lungs, and skin. Mechlorethamine hydrochloride (NM) is widely used as an SM surrogate. This study aimed to develop a depilatory double-disc (DDD) NM skin burn model for investigating vesicant pharmacotherapy countermeasures.
METHODS
Hair removal method (clipping only versus clipping followed by a depilatory), the effect of acetone in the vesicant administration vehicle, NM dose (0.5-20 μmol), vehicle volume (5-20 μl), and time course (0.5-21 days) were investigated using male and female CD-1 mice. Edema, an indicator of burn response, was assessed by biopsy skin weight. The ideal NM dose to induce partial-thickness burns was assessed by edema and histopathologic evaluation. The optimized DDD model was validated using an established reagent, NDH-4338, a cyclooxygenase, inducible nitric oxide synthase, and acetylcholinesterase inhibitor prodrug.
RESULTS
Clipping/depilatory resulted in a 5-fold higher skin edematous response and was highly reproducible (18-fold lower %CV) compared to clipping alone. Acetone did not affect edema formation. Peak edema occurred 24-48 h after NM administration using optimized dosing methods and volume. Ideal partial-thickness burns were achieved with 5 μmol of NM and responded to treatment with NDH-4338. No differences in burn edematous responses were observed between males and females.
CONCLUSION
A highly reproducible and sensitive partial-thickness skin burn model was developed for assessing vesicant pharmacotherapy countermeasures. This model provides clinically relevant wound severity and eliminates the need for organic solvents that induce changes to the skin barrier function.
Topics: Female; Male; Animals; Mice; Irritants; Acetone; Acetylcholinesterase; Mechlorethamine; Skin; Disease Models, Animal
PubMed: 36872306
DOI: 10.1002/ame2.12304 -
Journal of Photochemistry and... Apr 2023Cancer treatment modalities have gradually shifted from monotherapies to multimodal therapies. It is still a challenge to develop a synergistic chemo-phototherapy system...
Cancer treatment modalities have gradually shifted from monotherapies to multimodal therapies. It is still a challenge to develop a synergistic chemo-phototherapy system with relieving tumor hypoxia, specific targeting, and real-time fluorescence tracking. In this study, we designed a multifunctional BODIPY derivative, FBD-M, for synergistic chemo-phototherapy against hypoxic tumors. FBD-M was composed of four parts: 1) The BODIPY fluorophore selected as a theranostic core, 2) A pentafluorobenzene group modified on meso-BODIPY to carry oxygen, 3) A morpholine group hooked to one side of BODIPY served as a lysosome-targeting unit for enhancing antitumor effect, and 4) An aromatic nitrogen mustard group introduced on other side of BODIPY to achieve chemotherapy. After introducing the morpholine and aromatic nitrogen mustard in BODIPY, the conjugate system of BODIPY was also expanded to realize near-infrared (NIR) phototherapy. Finally, FBD-M was obtained by a rational design, which possessed with NIR absorbance and emission, photosensitive activity, oxygen-carrying capability for relieving tumor hypoxia, high photothermal conversion efficiency, good photostability, lysosome targeting, low toxicity, and synergistic chemo-phototherapy against hypoxic tumors. FBD-M had been successfully applied for anticancer in vitro and in vivo. Our study demonstrates that FBD-M can serve as an ideal multifunctional theranostic agents.
Topics: Humans; Mechlorethamine; Nanoparticles; Neoplasms; Phototherapy; Oxygen; Theranostic Nanomedicine; Cell Line, Tumor
PubMed: 36842340
DOI: 10.1016/j.jphotobiol.2023.112666 -
Acta Dermato-venereologica Feb 2023
Clinical Trial
Topics: Humans; Bexarotene; Mechlorethamine; Phototherapy; Skin Neoplasms
PubMed: 36748332
DOI: 10.2340/actadv.v103.4881 -
Toxicology Mar 2023Mechlorethamine (HN2) is a derivative of the chemical warfare agent sulfur mustard (SM) and cutaneous exposure to HN2 is associated with dermal-epidermal junction (DEJ)...
Mechlorethamine (HN2) is a derivative of the chemical warfare agent sulfur mustard (SM) and cutaneous exposure to HN2 is associated with dermal-epidermal junction (DEJ) disruption (vesication). The primary purpose of the present study was to investigate the effect of HN2 on the mammalian target of rapamycin (mTOR) signaling pathway using an in vivo mouse ear vesicant model (MEVM). To this end, the ears of male C57BL/ 6 J mice were exposed to a single topical dose of HN2 (100 mM) or vehicle control (DMSO). Mice were then euthanized 30 min, 1 h or 24 h following exposure. Mouse ear skin exposed to HN2 and biopsied 24 h thereafter exhibited increased tissue expression of Raptor, an important member of the mTORC1 complex, relative to vehicle treated samples. HN2 reduced the downstream effectors phospho S6 (Ser 240/244) ribosomal protein and phospho 4E-BP1 (Thr 37/46) of the mTOR pathway in the epidermis at 30 min, 1 h and 24 h following HN2 exposure but not in the dermis. These results support the hypothesis that HN2-mediated cutaneous toxicity involves dysregulation of the mTOR signaling pathway in the epidermis.
Topics: Male; Mice; Animals; Mechlorethamine; Sirolimus; Mice, Inbred C57BL; Skin; TOR Serine-Threonine Kinases; Mammals
PubMed: 36708981
DOI: 10.1016/j.tox.2023.153434 -
European Journal of Medicinal Chemistry Mar 2023Alkylating agents are potent anticancer compounds that exert their anticancer properties through the inhibition of cell replication and transcription leading to cell...
Alkylating agents are potent anticancer compounds that exert their anticancer properties through the inhibition of cell replication and transcription leading to cell death. Despite the numerous benefits, these agents also have serious drawbacks such as their high toxicity and low specificity towards cancer cells. As previously reported by our group, conjugation of alkylating agents with azasteroids can reduce their systemic toxicity and enhance their anticancer activity. In this work, novel steroidal alkylating agents bearing POPAM-OH were synthesized and their anticancer efficacy was evaluated in vitro and in vivo. All the novel hybrids demonstrated high antiproliferative effects against 5 different cancer cell lines in the low micromolar range. Treatment of SCID mice bearing SKOV-3 or PC-3 tumor xenografts with the most potent hybrid 19 led to significant reduction of tumor size (tumor inhibition TI = 95% in SKOV3 models and TI = 85.2% in PC3 models). Importantly, the acute toxicity of hybrid 19 (LD = 36 μΜ, LD = 62 μΜ) in CB17 SCID mice exhibited three-fold decrease compared to the acute toxicity of previously reported hybrids of POPAM-NH. This is an important finding since systemic cytotoxicity is a critical limitation of alkylating agents. Collectively, the steroidal conjugates of POPAM-OH displayed significant anticancer efficacy and reduced toxicity in vitro and in vivo rendering them as good candidates for cancer therapy.
Topics: Animals; Mice; Humans; Mechlorethamine; Lactams; Mice, SCID; Steroids; Neoplasms; Alkylating Agents; Antineoplastic Agents; Cell Line, Tumor; Drug Screening Assays, Antitumor; Structure-Activity Relationship
PubMed: 36696765
DOI: 10.1016/j.ejmech.2023.115133 -
Advances in Therapy Mar 2023
Publisher Correction to: Chlormethine Gel for Patients with Mycosis Fungoides Cutaneous T Cell Lymphoma: A Review of Efficacy and Safety in Clinical Trial and Real-World Settings.
PubMed: 36658455
DOI: 10.1007/s12325-022-02403-y -
Topical Mechlorethamine for the Treatment of Psoriasis: A Report of Two Cases and Literature Review.Dermatology and Therapy Feb 2023Psoriasis is a common inflammatory skin disease that significantly impacts patients' psychosocial wellbeing. Despite increasingly effective treatment options, the...
INTRODUCTION
Psoriasis is a common inflammatory skin disease that significantly impacts patients' psychosocial wellbeing. Despite increasingly effective treatment options, the recurrence of plaques after discontinuation of therapy in many patients highlights the need for additional therapies.
METHODS
We report two cases of patients with concurrent psoriasis and mycosis fungoides who were treated with topical mechlorethamine (MCH). A literature review was performed by searching PubMed using the keywords psoriasis, mechlorethamine, chlormethine, and nitrogen mustard.
RESULTS
Both patients had significant improvement in their psoriasis following treatment with topical MCH gel, which was well tolerated and maintained clearance after 1 and 3 years of follow-up. Seven prospective cohort studies investigating the use of topical MCH were identified through literature review. Out of five studies reporting clinical outcomes by patient, 68 of 77 patients (88%) experienced an improvement in their psoriasis, with 47 of 77 (61%) achieving complete or near-complete clearance. The remaining two studies reported clinical outcomes by lesion, demonstrating improvement in 40 of 45 lesions (88%) and complete or near-complete clearance in 32 of 42 lesions (76%). Contact dermatitis was the most frequent adverse effect, observed in 56 of 125 patients (45%).
CONCLUSIONS
Topical MCH may be an option for patients with psoriasis who fail or have incomplete responses to other treatments. Published studies are limited by lack of standardized treatment regimens and well-defined outcome measures, highlighting the need for prospective clinical trials to better understand the utility of this topical agent in psoriasis.
PubMed: 36543971
DOI: 10.1007/s13555-022-00871-2 -
Cancer Management and Research 2022Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL) and often has an indolent course, particularly for patients presenting with... (Review)
Review
Mycosis fungoides (MF) is the most common type of cutaneous T-cell lymphoma (CTCL) and often has an indolent course, particularly for patients presenting with early-stage (patch/plaque) disease. Early-stage MF is primarily managed with skin-directed therapies. Topical mechlorethamine hydrochloride (nitrogen mustard [NM]) gel has increased tolerability compared to prior NM formulations, though contact dermatitis remains a common side effect. The addition of topical steroids can improve tolerability while maintaining the efficacy of NM gel. Real-world experience supports that NM gel also has a role in combination therapy and as adjunctive therapy in advanced-stage disease. Here we review factors that may influence patient selection for use of NM gel, including MF variants, special patient populations, cost effectiveness, and impact on quality of life for patients with MF.
PubMed: 36444357
DOI: 10.2147/CMAR.S351420 -
Pharmaceuticals (Basel, Switzerland) Sep 2022The efficacy of pure and aluminum (Al)-doped boron nitride nanocarriers (BN and AlBN) in adsorbing Chlormethine (CM), an anti-cancer drug, was comparatively dissected by...
The efficacy of pure and aluminum (Al)-doped boron nitride nanocarriers (BN and AlBN) in adsorbing Chlormethine (CM), an anti-cancer drug, was comparatively dissected by means of the density functional theory method. The CM∙∙∙BN and ∙∙∙AlBN complexes were studied within two configurations, A and B, in which the adsorption process occurred via N∙∙∙ and Cl∙∙∙B/Al interactions, respectively. The electrostatic potential affirmations confirmed the opulent ability of the studied nanocarriers to engage in delivering CM via two prominent electrophilic sites (B and Al). Furthermore, the adsorption process within the CM∙∙∙AlBN complexes was noticed to be more favorable compared to that within the CM∙∙∙BN analog and showed interaction and adsorption energy values up to -59.68 and -52.40 kcal/mol, respectively, for configuration A. Symmetry-adapted perturbation theory results indicated that electrostatic forces were dominant in the adsorption process. Notably, the adsorption of CM over BN and AlBN nanocarriers exhibited predominant changes in their electronic properties. An elemental alteration was also revealed for the softness and hardness of BN and AlBN nanocarriers before and following the CM adsorption. Spontaneity and exothermic nature were obviously observed for the studied complexes and confirmed by the negative values of thermodynamic parameters. In line with energetic manifestation, Gibbs free energy and enthalpy change were drastically increased by the Al doping process, with values raised to -37.15 and -50.14 kcal/mol, respectively, for configuration A of the CM∙∙∙AlBN complex. Conspicuous enhancement was noticed for the adsorption process in the water phase more than that in the gas phase and confirmed by the negative values of the solvation energy up to -53.50 kcal/mol for configuration A of the CM∙∙∙AlBN complex. The obtained outcomes would be the linchpin for the future utilization of boron nitride as a nanocarrier.
PubMed: 36297293
DOI: 10.3390/ph15101181