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This study aims to develop chitosan-coated PLGA nanoparticles intended for nose-to-brain delivery of carmustine. Formulations were prepared by the double emulsion solvent evaporation method and optimized by using Box-Behnken Design. The optimized nanoparticles were obtained to satisfactory levels in terms of particle size, PDI, entrapment efficiency, and drug loading. In vitro drug release and ex-vivo permeation showed sustained release and enhanced permeability (approx. 2 fold) of carmustine compared to drug suspension. The AUC 0-t of brain obtained with carmustine-loaded nanoparticles via nasal administration in Albino Wistar rats was 2.8 and 14.7 times that of intranasal carmustine suspension and intravenous carmustine, respectively. The MTT assay on U87 MG cell line showed a significant decrease (P < 0.05) in the IC50 value of the formulation (71.23 μg ml−1) as compared to drug suspension (90.02 μg ml−1).These findings suggest chitosan coated nanoparticles could be used to deliver carmustine via intranasal administration to treat Glioblastoma multiforme. [ABSTRACT FROM AUTHOR]

As a clinical anti-glioma agent, the therapeutic effect of carmustine (BCNU) was largely decreased because of the drug resistance mediated by O 6-alkylguanine-DNA alkyltransferase (AGT) and the blood-brain barrier (BBB). To overcome these obstacles, we synthesized a BCNU-loaded hypoxia/esterase dual stimulus-activated nanomicelle, abbreviated as T80-HACB/BCNU NPs. In this nano-system, Tween 80 acts as the functional coating on the surface of the micelle to facilitate transport across the BBB. Hyaluronic acid (HA) with active tumor-targeting capability was linked with the hypoxia-sensitive AGT inhibitors (O 6-azobenzyloxycarbonyl group) via an esterase-activated ester bond. The obtained T80-HACB/BCNU NPs had an average particle size of 232.10 ± 10.66 nm, the zeta potential of −18.13 ± 0.91 mV, and it showed high drug loading capacity, eximious biocompatibility and dual activation of hypoxia/esterase drug release behavior. The obtained T80-HACB/BCNU NPs showed enhanced cytotoxicity against hypoxic T98G and SF763 cells with IC 50 at 132.2 μM and 133.1 μM, respectively. T80 modification improved the transportation of the micelle across an in vitro BBB model. The transport rate of the T80-HACB/Cou6 NPs group was 12.37 %, which was 7.6-fold (p <0.001) higher than the micelle without T80 modification. T80-HACB/BCNU NPs will contribute to the development of novel CENUs chemotherapies with high efficacy. [ABSTRACT FROM AUTHOR]

[Display omitted] • Strong interactions occur between HBC and BCNU.adsorption process and electronic. • The electronic properties of HBC are not sensitive to the presence of BCNU Detection. • The geometry of the nanographenes remains unchanged after the drug molecule. • BNHBC seems to be a suitable option for carrying and revealing BCNU drug. We conducted research on the adsorption of carmustine (BCNU) on the surface of pristine, N-doped, and BN-doped Hexa- peri -hexabenzocoronene (HBC) nanographene using density functional theory calculations. We used the B3LYP functional in conjunction with 6-31+G(d) and 6-311+G(d,p) basis sets to perform geometrical optimization calculations, vibrational frequencies, and natural bond orbitals (NBO) analysis. The dispersion correction term of Grimme-D3 was incorporated to account for the dispersion interactions. We found that the geometry of the nanographenes remains unchanged after the drug molecule adsorption. The calculated adsorption energies (E ads) were −17.1 kcal.mol−1 for HBC-BCNU, −17.0 kcal.mol−1 for NHBC-BCNU, and −17.9 kcal.mol−1 for BNHBC-BCNU when using the 6-31+G(d) basis set. The corresponding values calculated employing the 6-311+G(d,p) basis set were −17.9, −17.3, and −19.1 kcal.mol−1, respectively. Analysis of frontier molecular orbitals (HOMO and LUMO) showed that the electronic properties of NHBC were significantly affected by the presence of BCNU. We used NBO analysis to investigate the distribution of partial atomic charges in different systems. Finally, using the transition state equation and the smaller basis set, we found that the required time for BCNU to release from HBC, NHBC, and BNHBC is approximately 3.3, 1.8, and 13.0 s, respectively. The obtained values are 13.0, 4.6, and 96.0 s, respectively, for the higher level of calculations. The recovery time for all nanographenes is within a reasonable range, while NHBC exhibits the highest sensitivity for drug detection. [ABSTRACT FROM AUTHOR]

[Display omitted] • This study explores how nanoclusters, such as C 4 B 32 and Li@C 4 B 32 , interact with a cancer drug called carmustine with a method called density functional theory. • The surface analysis was carried out on the basis of the covalent bonds in order to present the ELF (electron-localization-function) map. • The study shows that Li@C 4 B 32 can be used to deliver drugs effectively. Nowadays, scientists are working on creating better drug delivery systems. We got inspired by the discovery of a modern kind of nanoparticles (Phys. Chem. Chem. Phys., 21 (2019) 15541). These particles, called heteroborospherenes, were created by adding four carbon atoms to a B 36 4- cluster (C 4 B 32). Both the regular and lithium-doped versions of C 4 B 32 (Li @C 4 B 32) could be useful in delivering drugs. This study explores how nanoclusters, such as C 4 B 32 and Li@C 4 B 32 , interact with a cancer drug called carmustine with a method called density functional theory. This study found that adding a Li atom to the C 4 B 32 nanocluster greatly improved its ability to attract the carmustine drug. Our UV–visible results reveal that when the drug combines with nanoclusters, the electronic spectra shift towards longer wavelengths (lower energies), showing a redshift. It was found that carmustine /Li@C 4 B 32 has strong chemical reactivity and it is important for the drug to attach to the target site effectively. This study used atoms in Molecule analysis to better understand how the analyzed systems interact with the carmustine. The research results demonstrate how carmustine and Li@C 4 B 32 bond through electrostatic features. Hence, the study showed that Li@C 4 B 32 could be a good way to deliver the carmustine drug. [ABSTRACT FROM AUTHOR]

Patients with a low micro-RNA-181d (miRNA-181d) level in glioblastoma tissue benefit most of carmustine wafer use. The study compares preoperative miRNA-181d plasma and tumor expression. This may form the base to decide, from a preoperative blood test, if carmustine wafer implantation is recommendable. A total of 60 patients suffering from glioblastoma treated between 2018 and 2020 were enrolled prospectively. Preoperatively, blood was drawn and the plasma was isolated. Tumor specimens were collected. Blood samples from 30 healthy individuals served as a reference. MiRNA-181d expression in plasma and tumor were acquired as fold change, using quantitative reverse transcription-polymerase chain reaction. Results were correlated with relevant demographic, clinical, and histopathologic aspects of the cohort. Further factors like tumor volume as well as blood panel results were considered. The Cancer Genome Atlas analysis was performed to investigate specific miRNA-181d-protein interactions to elude how miRNA-181 impact therapy response to carmustine. Patients with glioblastoma showed a significant overexpression of miRNA-181d compared with healthy individuals (P = 0.029). There was a significant correlation between miRNA-181d expression in tumor tissue and plasma (P = 0.001, R = 0.51). The sensitivity of low miRNA-181d expression in plasma predicting low miRNA-181d tumor expression was 76.6%. Tumor volume, preoperative medication, and items of blood panel analysis did not influence the prognostic value of plasma miRNA-181d expression. The Cancer Genome Atlas analysis revealed 8 potential protein targets to be regulated by miRNA-181d. miRNA-181d seems to be a potential molecular marker that can reliably be detected in blood samples of patients with glioblastoma. It should therefore prospectively be evaluated as a potential preoperative prognostic marker regarding carmustine wafer implantation. [ABSTRACT FROM AUTHOR]

• Polyethyleneimine-poly(lactic-co-glycolic acid) nanoparticles anchored with tamoxifen (TAM) and sialic acid (SA) (SA-TAM-PEI-PLGA NPs) are fabricated. • SA-TAM-PEI-PLGA NPs carried carmustine (BCNU) across the BBB. • High TAM concentrations induced apoptosis of human U87 through internalization. Management of glioblastoma multiforme (GBM), a cerebral glioma with highest-grade malignancy, is a crucial challenge to current anticancer treatment because the lack of GBM-targeting capability of antitumor drug, such as carmustine (BCNU) with a short half-life, along with low blood-brain barrier (BBB) permeability to achieve the clinical efficacy. Hence, polyethyleneimine-poly(lactic-co-glycolic acid) nanoparticles comprising stable core-shell structure with tamoxifen were crosslinked with sialic acid (SA-TAM-PEI-PLGA NPs) as nanocarriers to improve bioavailability of BCNU for pharmacotherapy. The brain-targeted experiments revealed that an increasing SA level improved BBB permeability for BCNU, and was associated with a reduction in transendothelial electrical resistance and an increase in propidium iodide penetration of endothelial monolayer. Immunocytochemical staining images evidenced that surface SA was critical in triggering transcytosis through N-acetylglucosamine on human cerebral microvessel endothelia, and surface crosslinking restrained macrophage phagocytosis. A high TAM level on the carrier surface reduced the survival rate of human U87, and western blots showed that conjugated TAM induced apoptosis of the cancer cells. The use of SA-TAM-PEI-PLGA NPs carrying BCNU as a pharmaceutical preparation is an effective strategy to overcome the BBB restriction and activate apoptosis of tumor cells to prevent the proliferation of GBM. [ABSTRACT FROM AUTHOR]

Molecular Dynamics simulation has been performed to study the effect of temperature on anti-cancer drug, carmustine, mediated by a graphene sheet. Root mean square deviation has been analysed at various temperatures, which is suggestive of the stability of the drug-graphene conjugate even at higher temperatures, although elevated diffusion of the drug at higher temperature has been observed as expected. Density functional theory is instrumental in determining the energetics of the drug action– from the generation of the active reacting species to the alkylation of DNA. By the energy profile, based on DFT, it is confirmed that it is the N7 site in guanine of the DNA major groove where the drug binds preferentially. The results provide a definitive insight into the release process as well as the effects of the chemotherapeutic carmustine drug and targets at generating a wholistic approach of drug-action. Image 1 • Molecular Dynamics (MD) simulation study of anti-cancer drug mediated by graphene. • Effect of temperature on carmustine drug release process. • DFT study of reaction of drug with guanine. • Energy profile and reaction energies are reported. [ABSTRACT FROM AUTHOR]

• The conversion mechanism of anti-cancer medicine carmustine has been investigated. • The activation energy barrier for conversion is investigated. • The cis isomer is more stable thermodynamically. The conversion mechanism of cis and trans isomeric forms of anti-cancer medicine carmustine have been investigated. The density functional theory calculations were carried out utilizing the double-hybrid method of Grimme's B2PLYP combined with Grimme's D3BJ dispersion and with the basis set of def2-QZVP. According to the obtained results, the trans carmustine in the gas phase by acquiring 21.00 kcal mol−1 can overcome the nitrosyl rotation activation barrier and convert to the cis isomer. The resulting cis form by releases 2.77 kcal mol−1 of energy for gas phase is more stable than the trans carmustine. Moreover, by applying water as a solvent field, it is clear that water molecules by forming hydrogen bonds with the drug would stabilize the trans form by about 1.30 kcal mol−1. In this situation, the conversion activation barrier reaches to 17.22 kcal mol−1 which is 3.77 kcal mol−1 lower than this value for the gaseous state. [ABSTRACT FROM AUTHOR]

Abstract Wheat germ agglutinin (WGA) and folic acid (FA)-grafted methoxy poly(ethylene glycol) (MPEG)‑poly(ε‑caprolactone) (PCL) nanoparticles (WFNPs) were applied to transport anticancer drugs across the blood–brain barrier and treat glioblastoma multiforme (GBM). PCL was copolymerized with MPEG, and MPEG-PCL NPs were stabilized with pluronic F127 using a microemulsion-solvent evaporation technique and crosslinked with WGA and FA. The targeting ability of WFNPs loaded with etoposide (ETO), carmustine (BCNU) and doxorubicin (DOX) was investigated via the binding affinity of drug-loaded NP formulations to N ‑acetylglucosamine expressed in human brain microvascular endothelial cells and to folate receptor in malignant U87MG cells. We found that a shorter PCL chain in drug-loaded MPEG-PCL NPs yielded a smaller average size of the particles. An increase in PCL chain length (stronger hydrophobicity) enhanced drug entrapment efficiencies in MPEG-PCL NPs, and reduced drug-releasing rates from NP formulations. In addition, anti-proliferative activity against U87MG cells for the 3 drugs followed the order of WFNPs > FA-grafted NPs > WGA-grafted NPs > MPEG-PCL NPs. Immunofluorescence staining revealed that the ligands of drug-loaded WFNPs connected to N ‑acetylglucosamine and folate receptor with the help of surface WGA and FA. WFNPs carrying ETO, BCNU and DOX acted as dual-targeting nanocarriers, and their use can be a promising approach to inhibiting GBM growth in the brain. Highlights • Wheat germ agglutinin (WGA) and folic acid (FA)-grafted MPEG-PCL nanoparticles (WFNPs) are fabricated. • WFNPs assisted in delivering three anticancer drugs to glioblastoma multiforme (GBM). • Surface modified with WGA promoted the BBB permeation and with FA facilitated target site on U87MG cells. • Anti-proliferation against U87MG cells followed the order of WFNPs > FA-grafted NPs > WGA-grafted NPs > MPEG-PCL NPs. [ABSTRACT FROM AUTHOR]

Abstract In the present work, we apply density functional theory (DFT) calculations to investigate the drug delivery performance of the boron nitride nanotube (BNNT) having hydroxyl functional groups (-OH) for Carmustine (BCNU) agent in the gas phase and water environment. Based on the DFT results, it is found that the interaction between BCNU molecule and functionalized boron nitride nanotube (f-BNNT) is weak; so that, the adsorption of the BCNU drug on the nanotube surface is typically physisorption. Based on the structural characteristics, the stability of the BCNU/f-BNNT complexes contributed to the formation of the intermolecular hydrogen bonds (HBs) between the BCNU drug and hydroxyl groups of BNNT which confirmed by Bader theory of atoms in molecules (QTAIM) results. Our theoretical results show that the structural properties of BCNU molecule doesn't significantly change upon adsorption of drug molecule on f-BNNT. Moreover, the natural bond orbital (NBO) analysis show in BCNU/f-BNNT complexes, the charge transfers from f-BNNT to Carmustine drug and the electronic properties of BCNU drug are not affected during the adsorption process on the nanotube surface. Finally, the effects of drug concentration and temperature on the adsorption mechanism of BCNU molecules are investigated by molecular dynamics (MD) simulation. Such results provide valuable information on the potential applications of functionalized boron nitride nanotubes in the fields of drug delivery within biological systems. Highlights • The physical nature of drug adsorption on the f-BNNT. • BCNU can be formed intermolecular HBs with hydroxyl groups of BNNT. • By increasing drug concentration, the stabilities of complexes increase. [ABSTRACT FROM AUTHOR]

Introduction: Anaplastic astrocytoma has a dismal prognosis with conventional treatment. Multidisciplinary treatment is needed to control the disease; however, side effects of the treatment reduce a patient's quality of life (QOL). Carmustine-impregnated wafers (Gliadel®, Eisai Co., Ltd., Tokyo, Japan), one of the treatment modalities for anaplastic astrocytoma, has been reported to have drug-induced fever as a side effect.Case Report: A 36-year-old man underwent excision for a recurrent brain tumor. Histopathological examination established a diagnosis of anaplastic astrocytoma and an intracranial carmustine implant was placed for local chemotherapy. Postoperatively, the patient developed high fever, which could not be controlled using antipyretics. The high fever ameliorated dramatically after the administration of Kampo medicines, specifically orengedokuto and shosaikoto, and the patient could continue chemotherapy.Conclusion: To the best of our knowledge, this is the first report of successful treatment of intractable carmustine implant-induced fever using Kampo medicine. In this case, Kampo medicine led to an improvement of QOL. [ABSTRACT FROM AUTHOR]

Glioma is extremely difficult to be completely excised by surgery due to its invasive nature. Thus, chemotherapy still is the mainstay in the treatment of glioma after surgery. However, the natural blood-brain barrier (BBB) greatly restricts the penetration of chemotherapeutic agents into the central nervous system. As a front-line anti-glioma agent in clinical, carmustine (BCNU) exerts antitumor effect by inducing DNA damage at the O 6 position of guanine. However, the therapeutic effect of BCNU was largely decreased because of the drug resistance mediated by O 6-alkylguanine-DNA alkyltransferase (AGT) and insufficient local drug concentrations. To overcome these obstacles, we synthesized a BCNU-loaded hypoxia-responsive nano-micelle with BBB penetrating capacity and AGT inhibitory activity, named as T80-HA-AZO-BG/BCNU NPs. In this nano-system, Tween 80 (T80) serves as a functional coating on the surface of the micelle, promoting transportation across the BBB. Hyaluronic acid (HA) with active tumor-targeting capability was linked with the hydrophobic O 6-benzylguanine (BG) analog via a hypoxia-sensitive azo bond. Under hypoxic tumor microenvironment, the azo bond selectively breaks to release O 6-BG as AGT inhibitor and BCNU as DNA alkylating agent. The synthesized T80-HA-AZO-BG/BCNU NPs showed good stability, favorable biocompatibility and hypoxia-responsive drug-releasing ability. T80 modification improved the transportation of the micelle across an in vitro BBB model. Moreover, T80-HA-AZO-BG/BCNU NPs exhibited significantly enhanced cytotoxicity against glioma cell lines with high AGT expression compared with traditional combined medication of BCNU plus O 6-BG. We expect that the tumor-targeting nano-micelle designed for chloroethylnitrosourea will provide new tools for the development of effective glioma therapy. [Display omitted] • A multifunctional tumor targeting nanocarrier was synthesized for delivery of BCNU. • The nanocarrier disintegrates under tumor hypoxia and releases the loaded drug. • Hyaluronic acid was linked to the nanocarrier for targeting CD44 in tumor cells. • Tween 80 was coated on the surface of nanocarrier to facilitate transport across BBB. • Tumor targeting and drug resistance reversal can be achieved for CENU therapy. [ABSTRACT FROM AUTHOR]

Graphical abstract Abstract O 6-Methylguanine-DNA methyltransferase (MGMT) is a DNA repair enzyme that removes the alkyl groups from the O 6 position of guanine and is then degraded via ubiquitin-mediated degradation. Previous studies indicated that 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) facilitates the ubiquitination and degradation of MGMT in several types of cancer cells. However, the underlying mechanism of MGMT ubiquitination remains unclear. In this study, we demonstrated for the first time that ubiquitin-conjugating enzyme E2 B (UBE2B) is a novel regulator of MGMT ubiquitination mediated by BCNU in nasopharyngeal carcinoma (NPC) cells. The E3 ubiquitin ligase RAD18, a partner of UBE2B, is also involved in BCNU-mediated MGMT ubiquitination. Overexpression/knockdown of UBE2B enhanced/reduced BCNU-mediated MGMT ubiquitination. Surprisingly, UBE2B knockdown significantly increased BCNU cytotoxicity in NPC cells. Therefore, loss of UBE2B seems to disrupt ubiquitin-mediated degradation of alkylated MGMT. We found that UBE2B knockdown reduced MGMT activity, suggesting that loss of UBE2B leads to the accumulation of deactivated MGMT and suppresses MGMT protein turnover in BCNU-treated cells. These findings indicate that UBE2B modulates sensitivity to BCNU in NPC cells by regulating MGMT ubiquitination. [ABSTRACT FROM AUTHOR]

Highlights • We studied the effects of fotemustine substitution in BEAM, prompted by BCNU shortage. • BEAM and FEAM did not appear different in terms of survival and disease control. • FEAM resulted in higher rates of gastrointestinal and infectious toxicities. • Mortality from infection was higher with FEAM, due to more sepsis from Gram-negative bacteria. • FEAM is an acceptable alternative to BEAM but is not justified when BCNU is available. Graphical Abstract Unlabelled image Abstract BEAM (carmustine [bis-chloroethylnitrosourea (BCNU)]-etoposide-cytarabine-melphalan) chemotherapy is the standard conditioning regimen for autologous stem cell transplantation (ASCT) in lymphomas. Owing to BCNU shortages, many centers switched to fotemustine-substituted BEAM (FEAM), lacking proof of equivalence. We conducted a retrospective cohort study in 18 Italian centers to compare the safety and efficacy of BEAM and FEAM regimens for ASCT in lymphomas performed from 2008 to 2015. We enrolled 1038 patients (BEAM = 607, FEAM = 431), of which 27% had Hodgkin lymphoma (HL), 14% indolent non-Hodgkin lymphoma (NHL), and 59% aggressive NHL. Baseline characteristics including age, sex, stage, B-symptoms, extranodal involvement, previous treatments, response before ASCT, and overall conditioning intensity were well balanced between BEAM and FEAM; notable exceptions were median ASCT year (BEAM = 2011 versus FEAM = 2013, P <.001), Sorror score ≥3 (BEAM = 15% versus FEAM = 10%, P =.017), and radiotherapy use (BEAM = 18% versus FEAM = 10%, P <.001). FEAM conditioning resulted in higher rates of gastrointestinal and infectious toxicities, including severe oral mucositis grade ≥3 (BEAM = 31% versus FEAM = 44%, P <.001), and sepsis from Gram-negative bacteria (mean isolates/patient: BEAM =.1 versus FEAM =.19, P <.001). Response status at day 100 post-ASCT (overall response: BEAM = 91% versus FEAM = 88%, P =.42), 2-year overall survival (83.9%; 95% confidence interval [CI], 81.5% to 86.1%) and progression-free survival (70.3%; 95% CI, 67.4% to 73.1%) were not different in the two groups. Mortality from infection was higher in the FEAM group (subhazard ratio, 1.99; 95% CI, 1.02 to 3.88; P =.04). BEAM and FEAM do not appear different in terms of survival and disease control. However, due to concerns of higher toxicity, fotemustine substitution in BEAM does not seem justified, if not for easier supply. [ABSTRACT FROM AUTHOR]

Highlights • TBC-ASCT patients have a higher risk of DNA virus infections compared with BEAM-ASCT. • Fungal and parasitic infections appear more common after TBC-ASCT. • Clinicians should be aware of the differences in infections between BEAM- and TBC-ASCT patients. Abstract We investigated the incidence of viral, fungal, bacterial, and parasitic infections observed in 57 patients with central nervous system lymphoma after thiotepa, busulfan, and cyclophosphamide-conditioned autologous stem cell transplantation (TBC-ASCT) and 79 patients with systemic non-Hodgkin lymphoma after traditional carmustine, etoposide, cytarabine, and melphalan–conditioned ASCT (BEAM-ASCT). Twenty of 57 (35%) TBC-ASCT patients had detectable viremia with human herpesvirus 6, cytomegalovirus, adenovirus, or BK virus, versus 9 of 79 (11%) BEAM-ASCT patients. Eight TBC-ASCT patients had clinically relevant viral infections (4 human herpesvirus 6, 2 cytomegalovirus, 1 adenovirus, 2 BK virus), versus 0 in the BEAM-ASCT group. Four TBC-ASCT patients suffered infections from either a fungal or parasitic pathogen versus 1 BEAM-ASCT patient. TBC was associated with greater risk of viral reactivation compared with BEAM, independent of other factors (hazard ratio, 4.42; 95% confidence interval, 1.9 to 11.3; P <.001). Prolonged lymphopenia and steroid use in the peri- and post-ASCT period did not explain these observed differences. The pathogenesis of these unusual infections in TBC-ASCT patients remains incompletely understood, and may involve more potent immune suppression with TBC conditioning. Clinicians should be aware of these differences in infection risk in TBC-ASCT patients, which more closely parallel those seen in allogenic hematopoietic cell transplantation recipients. New prophylactic approaches to help minimize these infections should be considered in this population. [ABSTRACT FROM AUTHOR]

This study delves into the fascinating realm of molybdenum-doped graphene (Mo@GP) complexes, featuring captivating adsorption sites for oxygen (O) and chlorine (Cl), adorned with the mesmerizing presence of silver (Ag), gold (Au), and copper (Cu). These alluring metal-doped compounds have been proposed as potential biosensor materials, with a particular focus on their prowess in the adsorption of carmustine (cmt). Employing the formidable density functional theory (DFT) at the B3LYP-GD3BJ/def2-SVP computational approach. Enveloped by the intrigue of two distinct adsorption sites—O and Cl—we stumbled upon a remarkable revelation. Among the contenders, Cl_cmt@Ag_Mo@GP emerged triumphant with the lowest energy gap at the Cl site of carmustine adsorption, an astonishingly meager value of 0.082 eV. Following closely behind, Cl_cmt@Au_Mo@GP boasted a respectable energy gap of 0.852 eV. However, Cl_cmt@Cu_Mo@GP and Cl_cmt@Mo@GP took the stage with their grandiose energy gaps, exhibiting values of 1.128 eV and 1.843 eV, respectively. Substantially, the captivating saga unfolds, presenting the distribution of adsorption energies as follows: Cl_cmt@Mo@GP > O_cmt@Mo@GP > Cl_cmt@Au_Mo@GP > Cl_cmt@Cu_Mo@GP > O_cmt@Cu_Mo@GP > Cl_cmt@Ag_Mo@GP. In a captivating interplay of energies, the system Ag_Mo@GP unveils its preferences: the O site reigns supreme with an Eads of -0.59 eV, while the Cl site humbly follows with an Eads of -0.03. Meanwhile, within the realm of the Au_Mo@GP system, the Chlorine site claims dominance, boasting an Eads of -1.30eV, while the Oxygen site asserts its presence with an Eads of -0.21 eV. As for the Cu_Mo@GP system, the Chlorine site emerges as the epitome of favorability, commanding an Eads of -0.83 eV, while the Oxygen site modestly exhibits an Eads of -0.29 eV. Through meticulous exploration, the results unequivocally demonstrate the remarkable qualities of the investigated complexes, positioning them as promising nanomaterials for the realm of drug delivery. • DFT study of carmustine sensing on Mo@GP-X (X = Ag, Au and Cu) surfaces. • The adsorption studies showed a general favorability in the adsorption of carmustine. • Studied complexes support the adsorption of the drugs to varying degrees. • Energy gap showed Cl_Cmt@Ag_Mo@GP as the most credible for the adsorption of carmustine. • Results suggested studied complexes to possess attributes of a good nanomaterial for drug delivery. [ABSTRACT FROM AUTHOR]

Carmustine (BCNU) is a typical chemotherapy used for treatment of cerebroma and other solid tumors, which exerts antitumor effect by inducing DNA damage at O 6 position of guanine. However, the clinical application of BCNU was extremely limited due to the drug resistance mainly mediated by O 6-alkylguanine-DNA alkyltransferase (AGT) and absence of tumor-targeting ability. To overcome these limitations, we developed a hypoxia-responsive nanomicelle with AGT inhibitory activity, which was successfully loaded with BCNU. In this nano-system, hyaluronic acid (HA) acts as an active tumor-targeting ligand to bind the overexpressing CD44 receptors on the surface of tumor cells. An azo bond selectively breaks in hypoxic tumor microenvironment to release O 6-benzylguanine (BG) as AGT inhibitor and BCNU as DNA alkylating agent. The obtained HA-AZO-BG NPs with shell core structure had an average particle size of 176.98 ± 11.19 nm and exhibited good stability. Meanwhile, HA-AZO-BG NPs possessed a hypoxia-responsive drug release profile. After immobilizing BCNU into HA-AZO-BG NPs, the obtained HA-AZO-BG/BCNU NPs exhibited obvious hypoxia-selectivity and superior cytotoxicity in T98G, A549, MCF-7 and SMMC-7721 cells with IC 50 at 189.0, 183.2, 90.1 and 100.1 μm, respectively, under hypoxic condition. Near-infrared imaging in HeLa tumor xenograft models showed that HA-AZO-BG/DiR NPs could effectively accumulate in tumor site at 4 h of post-injection, suggesting its good tumor-targetability. In addition, in vivo anti-tumor efficacy and toxicity evaluation indicated that HA-AZO-BG/BCNU NPs was more effective and less harmful compared to the other groups. After treatment, the tumor weight of HA-AZO-BG/BCNU NPs group was 58.46 % and 63.33 % of the control group and BCNU group, respectively. Overall, HA-AZO-BG/BCNU NPs was expected to be a promising candidate for targeted delivery of BCNU and elimination of chemoresistance. • Poor selectivity and AGT-induced drug resistance limit the clinical application of carmustine (BCNU) as a chemotherapy. • A hypoxia and CD44 receptors dual-targeted nano-micelle with AGT inhibitor as a skeleton is developed for delivery of BCNU. • The nano-micelle showed good stability, favorable biocompatibility and high sensitivity in responding to tumor hypoxia. • BCNU-loaded nano-micelle showed high therapeutic efficacy, providing an optimized strategy for clinical application of CENUs. [ABSTRACT FROM AUTHOR]

The adsorption behavior of Carmustine drug on the surface of (5, 5) pristine single-walled carbon nanotube and the functionalized single-walled carbon nanotube with a carboxylic acid group is studied by density functional theory calculation. For both studied nanotubes, the effect of the molecular orientation on the adsorption energies, molecular structure, equilibrium distances and the quantum molecular descriptors are studied. According to the obtained results, the process of the Carmustine adsorption on the external surface of the functionalized nanotube is exothermic and all of the functionalized configurations are stable, while the process of drug adsorption on the external surface of the pristine carbon nanotube is endothermic and the adsorbed structures are unstable. It is found that the intermolecular hydrogen bonds between Carmustine and the functionalized nanotube play the significant role in the stability of the physisorption configurations. Furthermore, the negative stability energy represented by a polarizable continuum model shows the significant increase in the solubility of the nanotubes after drug adsorption on their surfaces in the presence of water solvent. The intermolecular interactions have been explored by calculation of electron densities and their Laplacian at the bond critical point using Atoms-in-Molecule method. The natural bond orbital analysis indicated that the Carmustine molecule can be adsorbed on the nanotube surface with a charge transfer from the nanotubes to drug molecule. [ABSTRACT FROM AUTHOR]

The impact of age at diagnosis on outcomes of patients with Hodgkin lymphoma (HL) undergoing autologous hematopoietic transplantation (auto-HCT) is unclear. We retrospectively evaluated the impact of age on outcomes of 310 consecutive patients with relapsed/refractory HL who underwent auto-HCT between January 1996 and December 2010 with carmustine, etoposide, cytarabine, and melphalan conditioning therapy. Patients were stratified into ≤ 55 and >55-year-age groups based on age at diagnosis. At a median follow-up of 80 (range, 1 to 180) months, progression-free survival was similar between both age groups. However, age older than 55 years at diagnosis was associated with significantly poor overall survival with a hazard ratio [HR] of  2.3 ( P  = .003) from higher rate of second malignancies (HR, 3.8; P  = .015) compared with patients 55 years or younger. In conclusion age > 55 years at diagnosis increases risk of second malignancies after auto-HCT. [ABSTRACT FROM AUTHOR]

The lyophilized formulation of melphalan has several limitations based on its marginal solubility, limited stability after reconstitution, and the requirement to reconstitute it in propylene glycol (PG). PG-free melphalan (Evomela; Spectrum Pharmaceuticals, Irvine CA) overcomes these limitations by using the solubilizing agent Captisol (Ligand Pharmaceuticals, Inc., LaJolla CA) to improve the stability of the reconstituted melphalan and avoid the potential toxicities of PG. This phase II study investigated the safety and efficacy of high-dose PG-free melphalan when included in the carmustine, etoposide, and cytarabine (BEAM) regimen for adult patients with non-Hodgkin lymphoma (NHL) or Hodgkin lymphoma (HL). Carmustine, etoposide, and cytarabine were given at standard doses on day –6 through day –3. PG-free melphalan, 140 mg/m 2 , was infused over 30 minutes on day –2. The primary endpoint was toxicity. Fifty patients (33 NHL/17 HL) completed BEAM with PG-free melphalan and stem cell infusion. The most common grades 3 to 4 nonhematologic toxicities were neutropenic fever (68%), infections (36%), and electrolyte abnormalities. Forty-one patients (82%) had oral mucositis, which was mostly grades 1 to 2 (6% grade 3). Moderate or severe gastrointestinal toxicities were uncommon. There were no treatment-related deaths. Forty-nine patients (98%) had neutrophil and platelet engraftment at a median of 10 and 19 days, respectively. At response assessment at 60 to 100 days after autologous stem cell transplantation, 42 patients (82%) were in complete remission, 2 in partial remission, and 6 had progressive disease. Progression-free survival at 1 year was 70%. These results demonstrate that PG-free melphalan can be used in place of the standard, lyophilized formulation of melphalan in the BEAM regimen for lymphoma patients undergoing autologous stem cell transplantation. It has a safety profile that compares favorably with standard lyophilized melphalan, and the engraftment rate and response rates were consistent with expectations. [ABSTRACT FROM AUTHOR]

Targeted delivery of carmustine (BCNU), an efficient brain tumor therapeutic, has been challenged with bioavailability issues due to the Blood Brain Barrier (BBB). The currently effective delivery approach is by implants at the site of the tumor, but this is highly invasive. The intranasal route, which is non-invasive and bypasses the BBB, may be alternative route for delivering BCNU to the brain. In this work, polyvinyl alcohol/polyethyleneimine/fIuorecein isothiocyanate complex (Polyplex) coated iron-oxide nanoparticles (Magnetite) were synthesized employing co-precipitation, epoxidation and EDC/NHS coupling reactions. The Polyplex coated magnetite (Nano-co-Plex) was loaded with BCNU for potential magnetically targeted delivery to the brain following intranasal administration. The Nano-co-Plex was characterized employing Thermogravimetric analysis (TGA), Superconducting Quantum Interference Device (SQUID) magnetometry, Fourier Transform Infrared Spectroscopy (FTIR), Nuclear Magnetic Resonance (NMR), X-ray Diffractometry (XRD), Transmission Electron Microscopy (TEM) and Zetasize analysis. Results revealed superparamagnetic hexagonally shaped “core-shell” nanoparticles with cell labeling attributes, of size ranging between 30–50 nm, and a zeta potential value of +32 ± 2 mV. The Nano-co-Plex synthesized was found to possess high degree of crystallinity with 32% Polyplex coating. The loading and release studies indicated a time-dependent loading with maximum loading capacity of 176.82 μg BCNU/mg of the carrier and maximum release of 75.8% of the loaded BCNU. Cytotoxicity of the BCNU-loaded Nano-co-Plex displayed superiority over the conventional BCNU towards human glioblastoma (HG) cells. Cell studies revealed enhanced uptake and internalization of BCNU-loaded Nano-co-plex in HG cells in the presence of an external magnetic field. These Nano-co-Plexes may be ideal as an intranasal magnetic drug targeting device for BCNU delivery. [ABSTRACT FROM AUTHOR]

Solid lipid nanoparticles (SLNs) conjugated with tamoxifen (TX) and lactoferrin (Lf) were applied to carry anticancer carmustine (BCNU) across the blood–brain barrier (BBB) for enhanced antiproliferation against glioblastoma multiforme (GBM). BCNU-loaded SLNs with modified TX and Lf (TX-Lf-BCNU-SLNs) were used to penetrate a monolayer of human brain-microvascular endothelial cells (HBMECs) and human astrocytes and to target malignant U87MG cells. The surface TX and Lf on TX-Lf-BCNU-SLNs improved the characteristics of sustained release for BCNU. When compared with BCNU-loaded SLNs, TX-Lf-BCNU-SLNs increased the BBB permeability coefficient for BCNU about ten times. In addition, TX-BCNU-SLNs considerably promoted the fluorescent intensity of intracellular acetomethoxy derivative of calcein (calcein-AM) in HBMECs via endocytosis. However, the conjugated Lf could only slightly increase the fluorescence of calcein-AM. Moreover, the order of formulation in the inhibition to U87MG cells was TX-Lf-BCNU-SLNs > TX-BCNU-SLNs > Lf-BCNU-SLNs > BCNU-SLNs. TX-Lf-BCNU-SLNs can be effective in infiltrating the BBB and delivering BCNU to GBM for future chemotherapy application. [ABSTRACT FROM AUTHOR]

Pharmaco-resistant epilepsies, and also some neuropsychiatric disorders, are often associated with malformations in hippocampal and neocortical structures. The mechanisms leading to these cortical malformations causing an imbalance between the excitatory and inhibitory system are largely unknown. Animal models using chemical or physical manipulations reproduce different human pathologies by interfering with cell generation and neuronal migration. The model of in utero injection of methylazoxymethanol (MAM) acetate mimics periventricular nodular heterotopia. The freeze lesion model reproduces (poly)microgyria, focal heterotopia and schizencephaly. The in utero irradiation model causes microgyria and heterotopia. Intraperitoneal injections of carmustine 1-3-bis-chloroethyl-nitrosurea (BCNU) to pregnant rats produces laminar disorganization, heterotopias and cytomegalic neurons. The ibotenic acid model induces focal cortical malformations, which resemble human microgyria and ulegyria. Cortical dysplasia can be also observed following prenatal exposure to ethanol, cocaine or antiepileptic drugs. All these models of cortical malformations are characterized by a pronounced hyperexcitability, few of them also produce spontaneous epileptic seizures. This dysfunction results from an impairment in GABAergic inhibition and/or an increase in glutamatergic synaptic transmission. The cortical region initiating or contributing to this hyperexcitability may not necessarily correspond to the site of the focal malformation. In some models wide-spread molecular and functional changes can be observed in remote regions of the brain, where they cause pathophysiological activities. This paper gives an overview on different animal models of cortical malformations, which are mostly used in rodents and which mimic the pathology and to some extent the pathophysiology of neuronal migration disorders associated with epilepsy in humans. [ABSTRACT FROM AUTHOR]

In this survey, the effectiveness of the carbon nitride in the form of graphitic structure (CN) as a drug delivery system for hydroxyurea (HU) and carmustine (BCN) anticancer drugs was evaluated through density functional theory (DFT) in both aqueous and vacuum phase. Moreover, a type of possible carrier based on functionalization graphitic-carbon nitride with chitosan is established with the goal of improving therapeutic efficacy and boosting designed deliverer for anticancer drugs. To explore the effectiveness of CN and functionalized CN, some important characteristics of HU and BCN drugs, CN carriers, and drug/CN complexes were calculated. Optimized geometries show that the best appropriate site for the adsorption of selected drugs on the nanosheets surface is the parallel orientation. The calculated adsorption energy in all studied complexes is negative, indicating that all of the analyzed structures are reliable and the interaction of the drug molecules with the examined nanosheets is a spontaneous process. Also, it turned out that the adsorption of BCN on the CN and f-CN is greater than HU. In accordance with the findings of the NBO, in the HU/CN and HU/f-CN complexes, the charges transfer positions on the direction of the HU molecule to the nanosheet, while in the BCN/CN and BCN/f-CN structures, charge transfer happens from the nanosheet to the BCN drug. The values of solvation energy exhibited a remarkable enhancement in the stability of f-CN after adsorption of the drug in the presence of water solvent. Functionalized nanosheets have a high sensitivity according to their electrical characteristics, implying their potential for drug release. Thus, HU/f-CN and BCN/f-CN complexes are favorable systems and functionalized nanosheet is a better carrier in comparison to pristine nanosheet for the HU and BCN drug delivery system. Generally, the results imply that g-C3N4 might be utilized as an effective drug-deliverer design for the HU and BCN drugs to treat diverse kinds of cancer. • The g-C3N4 is used as a drug carrier. • Chitosan not only improves therapeutic efficacy, but it also makes drug adsorption more effective. • The f-CN sheet has more interaction energy with BCN and HU drug than CN sheet. • BCN molecule has a stronger interaction with CN and f-CN than HU. • Results show g-C3N4 sheet has therapeutic potential as a drug delivery vehicle. [ABSTRACT FROM AUTHOR]

High-dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) improves outcomes in relapsed lymphoma, but the relative efficacy of different preparative regimens is not well defined. We included patients undergoing autologous HCT using BEAM (carmustine, 300 mg/m 2 , etoposide, cytarabine, and melphalan) or BEP (carmustine 600 mg/m 2 , etoposide, and cisplatin) between January 2004 and December 2013; 65 patients received BEP and 64 patients BEAM. Both cohorts were similar for advanced-stage disease, extranodal and bulky disease, and prior therapies. Median neutrophil and platelet engraftment was 10 and 20 days for both regimens, respectively. Febrile neutropenia, serum creatinine concentration increase, and electrolyte abnormalities were more frequent with BEP. Incidence of carmustine pneumonitis was not higher with BEP, likely the result of corticosteroid prophylaxis, although 2 cases of fatal pneumonitis were observed after BEP. One-year nonrelapse mortality was 6.8% after BEP and 0% after BEAM ( P = .379). After a median follow-up of 39.4 months (range, 1 to 128), 4-year rates of overall survival (OS) after BEP and BEAM were 80.4% and 72.3%, respectively ( P = .611). Diffuse large B cell lymphoma patients transplanted after early relapse post-rituximab-based first-line therapy presented 3-year rates of OS and progression-free survival (PFS) of 73.8% and 65%, respectively. There were no statistically significant differences in the OS and PFS of follicular lymphoma, mantle cell lymphoma, or Hodgkin lymphoma. BEP is a valid alternative to BEAM in autologous HCT. Although associated with more renal and electrolytic toxicities, BEP results in similar disease control and long-term survival as BEAM. Prospective studies are needed to confirm whether intensification of conditioning regimens for autologous HCT can improve disease control in high-risk relapsed lymphoma patients. [ABSTRACT FROM AUTHOR]

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor, and the prognosis of patients afflicted with GBM has been dismal, exhibiting progressive neurologic impairment and imminent death. Even with the most active regimens currently available, chemotherapy achieves only modest improvement in the overall survival. New chemotherapeutic agents and novel approaches to therapy are required for improving clinical outcomes. In this study, we used an electrospinning technique and developed biodegradable poly[(d,l)-lactide- co -glycolide] nanofibrous membranes that facilitated a sustained release of carmustine (or bis-chloroethylnitrosourea, BCNU), irinotecan, and cisplatin. An elution method and a high-performance liquid chromatography assay were employed to characterize the in vitro and in vivo release behaviors of pharmaceuticals from the nanofibrous membranes. The experimental results showed that the biodegradable, nanofibrous membranes released high concentrations of BCNU, irinotecan, and cisplatin for more than 8 weeks in the cerebral cavity of rats. A histological examination revealed progressive atrophy of the brain tissues without inflammatory reactions. Biodegradable drug-eluting nanofibrous membranes may facilitate sustained delivery of various and concurrent chemotherapeutic agents in the cerebral cavity, enhancing the therapeutic efficacy of GBM treatment and preventing toxic effects resulting from the systemic administration of chemotherapeutic agents. [ABSTRACT FROM AUTHOR]

Administration of the alkylating agent carmustine to pregnant mice induces hyperlocomotion in the offspring. Motor performance was evaluated by the rotarod task, which revealed that these animals have diminished Grab Frequency and a higher Performance Index, whereas Error of Latency and Latency to Fall were unaffected. Considering the recently revealed role of Bergmann cells of cerebellum in the control of motor activity, we used the transgenic mice GFAP-GFP to explore the impact of carmustine on the organization of these glial cells. Multiple examples of cell layer disorganization were detected; many soma of Bergmann cells were displaced to the external cell layer, and their processes were not well defined until young adulthood. In addition, the roof of the fourth ventricle was convoluted. These observations suggest that the exacerbated locomotion induced by carmustine may be due, in part, to the altered organization of the cell layers of cerebellum. [ABSTRACT FROM AUTHOR]

The role of allogeneic stem cell transplantation (SCT) in the management of aggressive non-Hodgkin lymphoma (NHL) remains to be defined, but the number of procedures performed continues to increase. We report here the outcomes of allogeneic SCT using carmustine, etoposide, cytarabine, and melphalan (BEAM)-Campath (Genzyme Corporation, Cambridge, MA) conditioning for aggressive NHL as reported to the British Society of Blood and Marrow Transplantation (BSBMT). This retrospective study identified 46 patients who reported to the BSBMT registry as having undergone BEAM-Campath conditioned allogeneic SCT for aggressive NHL between 1999 and 2010. Disease histology was diffuse large B cell lymphoma (DLBCL, n = 25), DLBCL/Burkitt lymphoma (n = 5), and T cell lymphoma (n = 16). At diagnosis, the median age was 42.5 (range, 17 to 59), 37 had advanced stage disease (Ann Arbor III/IV), 28 had 2 or more extra-nodal sites of disease, and 23 had elevated lactate dehydrogenase. International prognostic index was high or high/intermediate in 58%. The median number of prior therapies was 3 (range, 1 to 5) and 5 patients had previously undergone transplantation (4 autologous, 1 allogeneic). The median age at transplantation was 44.8 (range, 18 to 59), with 34 patients demonstrating chemo-sensitive disease and 22 undergoing transplantation in first response. Performance score was good in 40 patients and all engrafted with a median of 14 days (range, 11 to 27) to neutrophil recovery. At latest follow-up, 20 patients were alive with 17 in complete remission. Acute graft-versus-host disease (GVHD) developed in 7 patients and chronic GVHD developed in 13 (7 limited, 6 extensive). Five patients died from nonrelapse causes, with a cumulative incidence of nonrelapse mortality of 7% at 100 days and 11% at 3 and 5 years. Twenty-one patients died after lymphoma relapse, with a cumulative incidence of relapse/progression of 51% at 1 year and 53% at 5 years. Disease status at transplantation had no impact on relapse rate. Progression-free survival was 41% at 1 year and 36% at 5 years. Overall survival was 54% at 1 year and 42% at 5 years. Overall, BEAM-Campath–conditioned allogeneic SCT is well tolerated and able to deliver durable disease-free survival to a subset of patients with aggressive NHL. However, the high relapse rates indicate further investigation is needed to identify those patients most likely to benefit. [ABSTRACT FROM AUTHOR]

Solid lipid nanoparticles (SLNs) stabilized with catanionic surfactants and grafted with serotonergic 1B receptor subtype antagonist (S1BRSA) were employed to encapsulate carmustine (BCNU) (denoted as S1BRSA/BCNU–CASLNs) for brain-targeted delivery. BCNU–CASLNs were fabricated by microemulsion method and the monolayer of human brain-microvascular endothelial cells (HBMECs) regulated by human astrocytes were treated with S1BRSA/BCNU–CASLNs to evaluate the BCNU permeability across the blood–brain barrier. An increase in the catanionic surfactant concentration promoted the surface charge and toxicity to HBMECs and U87MG cells of glioblastoma multiforme (GBM). The catanionic surfactant concentration at 1 mM yielded the smallest particle size and highest entrapment efficiency of BCNU. An increase in the weight percentage of Compritol 888 ATO (CA) reduced the particle size and surface charge and enhanced the grafting efficiency of S1BRSA, viability of HBMECs, and BCNU permeability. A maximal entrapment efficiency of BCNU emerged at 50% (w/w) CA. An increase in the S1BRSA concentration reduced the grafting efficiency of S1BRSA and improved the BCNU permeability. The developed S1BRSA/BCNU–CASLNs, showing an anticancer efficacy against the growth of malignant GBM U87MG cells, were efficacious carriers in delivering BCNU to HBMECs and could be administered by intravenous injection in clinical application. [ABSTRACT FROM AUTHOR]

Background Systemic delivery of therapeutic agents remains ineffective against diffuse intrinsic pontine glioma (DIPG), possibly due to an intact blood–brain-barrier (BBB) and to dose-limiting toxicity of systemic chemotherapeutic agents. Convection-enhanced delivery (CED) into the brainstem may provide an effective local delivery alternative for DIPG patients. New method The aim of this study is to develop a method to perform CED into the murine brainstem and to test this method using the chemotherapeutic agent carmustine (BiCNU). To this end, a newly designed murine CED catheter was tested in vitro and in vivo. After determination of safety and distribution, mice bearing VUMC-DIPG-3 and E98FM-DIPG brainstem tumors were treated with carmustine dissolved in DW 5% or carmustine dissolved in 10% ethanol. Results Our results show that CED into the murine brainstem is feasible and well tolerated by mice with and without brainstem tumors. CED of carmustine dissolved in 5% DW increased median survival of mice with VUMC-DIPG-3 and E98FM-DIPG tumors with 35% and 25% respectively. Dissolving carmustine in 10% ethanol further improved survival to 45% in mice with E98FM-DIPG tumors. Comparison with existing methods Since genetically engineered and primary DIPG models are currently only available in mice, murine CED studies have clear advantages over CED studies in other animals. Conclusion CED in the murine brainstem can be performed safely, is well tolerated and can be used to study efficacy of chemotherapeutic agents orthotopically. These results set the foundation for more CED studies in murine DIPG models. [ABSTRACT FROM AUTHOR]

This study shows on a large sample that in patients with follicular lymphoma who received total body irradiation-based autologous stem-cell transplantation after 1995 increased non-relapse mortality and treatment-related myelodysplastic syndromes/acute myelogenous leukaemia risks did not emerge compared with carmustin, etoposide, cytarabine and melphalan (BEAM) while disease control was at least equivalent.Background The aim of this study was to investigate the impact of the high-dose regimen on the outcome of patients with follicular lymphoma (FL) having had autologous stem-cell transplantation (ASCT) in a recent time period. Patients Between 1995 and 2007, 2233 patients with FL had their first ASCT with either a total body irradiation (TBI)-containing regimen or carmustin, etoposide, cytarabine and melphalan (BEAM), of which 47% were autografted in first remission. Results After a median observation time of 73 months (interquartile range 30–107), 5- and 10-year non-relapse mortality (NRM) was similar (6% and 10% in both groups). No significant NRM differences became evident after multivariate adjustment for confounders. Secondary malignancies were observed in 9.7% and 7.9% of the patients after TBI and BEAM (P = 0.19), which were treatment-related myelodysplastic syndromes/acute myelogenous leukaemia (t-MDS/AML) in 3.4% and 2.8% (P = 0.57). The median time to t-MDS/AML was around 50 months in both groups. Because of a lower relapse incidence, TBI was associated with better event-free survival reaching statistical significance in the patients transplanted in first remission but not in those transplanted beyond first remission. Conclusions In patients with FL who received TBI-based ASCT after 1995 increased NRM and t-MDS/AML risks did not emerge compared with BEAM while disease control was at least equivalent. [ABSTRACT FROM PUBLISHER]

Abstract: A deficiency of mitochondrial glutathione reductase (or GR2) is capable of adversely affecting the reduction of GSSG and increasing mitochondrial oxidative stress. BCNU [1,3-bis (2-chloroethyl)-1-nitrosourea] is an anticancer agent and known inhibitor of cytosolic GR ex vivo and in vivo. Here we tested the hypothesis that a BCNU-induced GR2 defect contributes to mitochondrial dysfunction and subsequent impairment of heart function. Intraperitoneal administration of BCNU (40mg/kg) specifically inhibited GR2 activity by 79.8±2.7% in the mitochondria of rat heart. However, BCNU treatment modestly enhanced the activities of mitochondrial Complex I and other ETC components. The cardiac function of BCNU-treated rats was analyzed by echocardiography, revealing a systolic dysfunction associated with decreased ejection fraction, decreased cardiac output, and an increase in left ventricular internal dimension and left ventricular volume in systole. The respiratory control index of isolated mitochondria from the myocardium was moderately decreased after BCNU treatment, whereas NADH-linked uncoupling of oxygen consumption was significantly enhanced. Extracellular flux analysis to measure the fatty acid oxidation of myocytes indicated a 20% enhancement after BCNU treatment. When the mitochondria were immunoblotted with antibodies against GSH and UCP3, both protein S-glutathionylation of Complex I and expression of UCP3 were significantly up-regulated. Overexpression of SOD2 in the myocardium significantly reversed BCNU-induced GR2 inhibition and mitochondrial impairment. In conclusion, BCNU-mediated cardiotoxicity is characterized by the GR2 deficiency that negatively regulates heart function by impairing mitochondrial integrity, increasing oxidative stress with Complex I S-glutathionylation, and enhancing uncoupling of mitochondrial respiration. [Copyright &y& Elsevier]

Cancer remains among the world's top devastating diseases, with millions of lives been affected each year. Conventional anticancer therapies are often far from ideal due to non-selective biodistribution. Therefore, the carbon nanotube (CNT) has been developed as a drug carrier for targeting specific cancer cells. In this work, we applied computer modeling approaches to investigate the interactions of single-wall carbon nanotube (SWCNT) with three different anticancer drugs: doxorubicin (DOX), Bendamustine (BEN), and Carmustine (CAR). Here we find physicochemical characteristics from the ligands that can contribute to a higher affinity towards the CNT, such as the presence of halogen substituents and the positively charged cation. On the other hand, the presence of anions groups, such as carboxylate, can decrease the interaction of the ligands and CNT. The binding free energy results indicate the SWCNT(15,15) with a diameter of 20.3 Å as the most favorable for encapsulating drugs ranging from 12 to 39 heavy atoms. The basic knowledge obtained from this study is expected to contribute to the molecular understanding of drug-loaded SWCNT for the development of a more efficiently anticancer drug carrier. [Display omitted] • Simulations were applied to investigate the single-wall carbon nanotube as a drug carrier. • Halogen substituents and charged cations contribute to a higher affinity towards the carbon nanotube. • Anions groups can decrease the interaction with carbon nanotube. • Carbon nanotube with a diameter of 20.3 Å was the most favorable for encapsulating drugs ranging from 12 to 39 heavy atoms. [ABSTRACT FROM AUTHOR]

The present study investigated the protective effect of dried white Mulberry extract (DWME) against carmustine (Crm) induced biochemical alterations and spermatological, histopathological, and fertility damage in Wistar albino rats. Male rats were divided into four groups (control, Crm, Crm + DWME, and DWME group). It was found that Crm decreased the motility. Crm decreased the concentration (not different from control group) compared to DWME groups. Total blood MDA levels were reduced during the recovery period. Also, the recovery period reduced the MDA levels in the Crm group/testicular tissue. The GSH levels in the Crm + DWME group were the highest among all groups in the testicular tissue/experiment period. In the immunohistochemical evaluation of the testicular tissue, a high level of caspase-3 was observed in the cells that underwent meiosis in the Crm group. The most pronounced DNA damage was also detected in the Crm group. The Crm + DWME group showed the highest number of offspring born during recovery period. In conclusion, dried white mulberry extract protects against the spermatological damages caused by carmustine. Moreover, recovery period played a positive effect on spermatological parameters and fertility. • Carmustine induced a toxicity in testes. • Carmustine caused DNA damage in rat spermatozoa. • Carmustine increased Caspase-3 activation in testes. • Dried White mulberry extract protected spermatological parameters and fertility from toxic effect of Carmustine. [ABSTRACT FROM AUTHOR]

Highlights: [•] Toxicity of chemotherapeutic agents delivered locally developed in dose- or concentration-dependent manner. [•] Toxicities of chemotherapeutic agents with high diffusibility developed in concentration-dependent manner. [•] Toxicities of chemotherapeutic agents with limited diffusibility developed in dose-dependent manner. [•] Concentration rather than dose affect the local brain toxicity after extensive delivery with convection-enhanced delivery. [ABSTRACT FROM AUTHOR]

Abstract: The application of carmustine (BCNU) for glioma treatment is limited due to its poor selectivity for tumor and tumor resistance caused by O6-methylguanine-DNA-methyl transferase (MGMT). To improve the efficacy of BCNU, we constructed chitosan surface-modified poly (lactide-co-glycolides) nanoparticles (PLGA/CS NPs) for targeting glioma, loading BCNU along with O6-benzylguanine (BG), which could directly deplete MGMT. With core–shell structure, PLGA/CS NPs in the diameter around 177 nm showed positive zeta potential. In vitro plasma stability of BCNU in NPs was improved compared with free BCNU. The cellular uptake of NPs increased with surface modification of CS and decreasing particle size. The cytotoxicity of BCNU against glioblastoma cells was enhanced after being encapsulated into NPs; furthermore, with the co-encapsulation of BCNU and BG into NPs, BCNU + BG PLGA/CS NPs showed the strongest inhibiting ability. Compared to free drugs, PLGA/CS NPs could prolong circulation time and enhance accumulation in tumor and brain. Among all treatment groups, F98 glioma-bearing rats treated with BCNU + BG PLGA/CS NPs showed the longest survival time and the smallest tumor size. The studies suggested that the co-encapsulation of BCNU and BG into PLGA/CS NPs could remarkably enhance the efficacy of BCNU, accompanied with greater convenience for therapy. [Copyright &y& Elsevier]

Abstract: Although reduced-intensity conditioning has become standard of care for patients with hematologic malignancies undergoing allogeneic hematopoietic cell transplantation (HCT), the optimum regimen has yet to be defined, and may depend on pretransplantation patient– and/or disease-specific risk factors. We report here results in 100 adults, ages 18 to 69, with high-risk hematologic malignancy who received conditioning with fludarabine, carmustine, melphalan, and rabbit antithymocyte globulin (FBM-A). Outcomes were stratified using the disease risk index (DRI) as published by Armand et al. (Blood 2012;120:905-913). Median age was 56, and patients were ineligible for standard myeloablative conditioning because of age, organ dysfunction, or prior autologous HCT. Patients underwent transplantation for myeloid (acute myelogenous leukemia, n = 40; myelodysplastic syndrome, n = 24; myelofibrosis, n = 13; other myeloid, n = 2) or lymphoid (acute lymphoblastic leukemia, n = 8; non-Hodgkin lymphoma, n = 8; Hodgkin lymphoma, n = 4, chronic lymphocytic leukemia, n = 1) malignancy. Donors were related in 26 patients (22 matched, 4 mismatched at 1 antigen) and unrelated in 74 (mismatched at 1 or 2 HLA loci in 33); grafts were peripheral blood stem cells in 97 patients, bone marrow in 2, and double cord in 1. According to the DRI, 68 patients were classified as low (n = 1) or intermediate risk (n = 67), and 32 were classified as high (n = 28) or very high risk (n = 4). With a median follow-up of surviving patients of 18 months, the Kaplan-Meier estimate of overall survival at 2 years for patients in the low/intermediate risk group is 80%, compared with 66% in the high/very high group (P = .11). Two-year cumulative incidence of relapse and nonrelapse mortality in the low/intermediate group are 9.9% and 15%, versus 25% and 19% in the high/very high group (respective P values .07 and .81). The cumulative incidence of acute graft-versus-host (GVHD) grades III to IV at 100 days was 8.1%, and the incidence of National Institutes of Health–defined moderate to severe chronic GVHD was 22% at 2 years. No deaths were attributable to chronic GVHD. Survival was not influenced by age, hematopoietic comorbidity index score, donor type, donor gender, or presence of mismatch. We conclude that FBM-A is an effective and safe conditioning regimen for adults up to age 69 with hematologic malignancies who have low-, intermediate-, or high-risk scores according to the DRI. [Copyright &y& Elsevier]

Abstract: Triple-negative breast cancer is characterized by aggressive tumours whose cells lack oestrogen and progesterone receptors and do not over-express HER2. It accounts for approximately 10–15% of breast cancer cases. We sought to generate a cellular model of chemotherapy drug resistance for this type of disease to provide the tools for the development of new therapies. Doxorubicin is a component of some chemotherapy regimes used to treat this form of cancer but resistance preventing disease eradication frequently occurs, mainly due to over-expression of drug transporters such as P-glycoprotein. CALDOX cells were generated by exposure of CAL51 to doxorubicin. Resistance to doxorubicin did not involve drug transporters, as the both parental and resistant cells accumulated doxorubicin to comparable levels. CALDOX cells had slower proliferation rate and an extended G1 cell cycle stage than the parental line, mainly due to an intrinsic activation of CDNK1 (p21), but this cell cycle block was not involved in the mechanism of resistance. CALDOX cells had reduced levels of TOP2A (topoisomerase IIα) and were cross resistant to the topoisomerase II inhibitors etoposide and mitoxantrone. CALDOX cells showed collateral sensitivity to carmustine due to the lack of O6-methylguanine-DNA-methyltransferase (MGMT) expression, related to the hypermethylation of its promoter. The collateral sensitivity of CALDOX cells to carmustine provides the rationale to evaluate MGMT promoter methylation status to design better therapeutic strategies for triple negative breast cancer. [Copyright &y& Elsevier]

Abstract: The purpose of this study was to evaluate the standard outpatient dose of 131-Iodine tositumomab (75 cGy) combined with high-dose carmustine, etoposide, cytarabine, and melphalan (BEAM) followed by autologous stem cell rescue for the treatment of chemotherapy-sensitive relapsed or refractory, or high-risk first complete remission (CR) patients with diffuse large B cell non-Hodgkin''s lymphoma (DLBCL). Forty patients with chemotherapy-sensitive persistent or relapsed or high/intermediate or high international prognostic index DLCBL were treated in a phase II trial combining 75 cGy 131-Iodine tositumomab with high-dose BEAM followed by autologous stem cell transplantation. The CR rate after transplantation was 78%, and the overall response rate was 80%. Short-term and long-term toxicities were similar to historical control patients treated with BEAM alone. With a median follow-up of 6 years (range, 3-10 years), the 5-year overall survival (OS) was 72% (95% confidence interval [CI], 55%-83%), and the 5-year progression-free survival (PFS) rate was 70% (95% CI, 53%-82%). The PFS and OS were encouraging in this group of chemotherapy-sensitive persistent, relapsed, or high-risk patients with DLBCL. A follow-up phase III trial with 131-Iodine tositumomab/BEAM vs rituximab/BEAM was planned based on this information. [Copyright &y& Elsevier]

Abstract: Purpose: For the last few years wafers of Gliadel have been inserted into the operation cavity in patients with glioblastoma multiforme. This is followed by concurrent radio-chemotherapy with temozolomide (TMZ) according to the Stupp protocol. Only a few studies have investigated this kind of treatment regimen and the impact in terms of survival and toxicity of the combination of Gliadel with TMZ and radiotherapy. Methods and materials: From November 2006 to January 2010, 24 patients with a newly diagnosed glioblastoma have undergone a tumour resection which was considered to be macroscopically complete in 12 cases and with tumour residue in another 12 cases. The mean age at the moment of diagnosis was 60.25years and the median age 63. Twenty-three patients underwent subsequently concurrent radio-chemotherapy with TMZ followed by cycles of elevated doses of TMZ as an adjuvant treatment. One patient had adjuvant radiotherapy alone followed by adjuvant chemotherapy. Thirteen were able to receive 6 or more cycles of adjuvant TMZ. Seven patients had received less than 6 cycles of TMZ as an adjuvant therapy. Two patients did not receive adjuvant TMZ at all. Results: The median overall survival of our group was 19.2months and the median progression free survival was 12.3months. Overall survival for the macroscopically complete-resection patients was 14months, and 12.85months in subtotal-resection patients. The median OS was 14.25months for patients PS 0 – 1 at the moment of diagnosis and 12.65 for PS 2 patients. Chemotherapy with TMZ had to be stopped prematurely in 10 cases due to haematotoxicity, digestive toxicity or early relapse. Conclusions: The concomitant use of surgery with implantation of BCNU wafers and radio-chemotherapy seems to be well tolerated. Despite the small number of patients treated in our group, particular attention should be paid to the potential haematological consequences of this multimodal treatment regimen. [Copyright &y& Elsevier]

Background High-dose chemotherapy followed by autologous stem-cell transplantation (HCT–ASCT) is a promising approach in eligible patients with primary central nervous system lymphoma (PCNSL). We report long-term data of patients who were treated according to HCT–ASCT containing protocols. Patients and methods We analyzed survival and relapse rates in 43 (<67 years) immunocompetent patients with newly diagnosed PCNSL being treated according to two different high-dose methotrexate-based protocols followed by high-dose carmustine/thiotepa (BCNU/TT) plus ASCT (±whole brain irradiation). Analysis was conducted for all patients (intention-to-treat) and those patients who actually received HCT–ASCT (per-protocol). Results Thirty-four patients achieved complete remission, of those 12 relapsed (35%), while 6 of them relapsed 5 years after diagnosis. After a median follow-up of 120 months, median overall survival (OS) was reached after 104 months. Two- and 5-year OS was 81% and 70% and 2- and 5-year event-free survival (EFS) was 81% and 67%, respectively. In per-protocol analysis (N = 34), 5-year OS and EFS was 82% and 79%, respectively. HCT–ASCT associated related mortality was not observed. Conclusions Sequential high-dose MTX containing chemotherapy followed by high-dose carmustine/thiotepa plus ASCT (±whole brain irradiation) is safe and leads to high survival rates in eligible patients with newly diagnosed PCNSL. [ABSTRACT FROM AUTHOR]

Total body irradiation has been the mainstay of conditioning since the inception of allogeneic hematopoietic cell transplantation, but toxicity often precludes its use. For less-fit patients with acute lymphoblastic leukemia and other hematologic malignancies frequently affecting the central nervous system, we designed a radiation-free regimen with fludarabine (25 mg/m2/day on days −6 to −4), carmustine (400 mg/m2 on day −6), and thiotepa (5 mg/kg twice daily on days −5 and −4), all of which readily penetrate the blood-brain barrier and have potent antileukemic and lymphotoxic activity. Here we present a series of 30 consecutive patients with high-risk or relapsed disease who underwent allogeneic hematopoietic cell transplantation with this protocol. The median patient age was 60 years (range, 42-70 years), and the median follow-up was 968 days (range, 58-1989 days). Graft-versus-host disease prophylaxis consisted of cyclosporine A and alemtuzumab (10-20 mg). At 2 years, overall survival was 52% (95% confidence interval [CI], 34%-71%), event-free survival was 39% (95% CI, 22%-57%), cumulative incidence of relapse/progression was 30% (95% CI, 17%-52%), and treatment-related mortality was 31% (95% CI, 18%-53%). Neurologic toxicity is a concern, especially in older and heavily pretreated patients. Our experience indicates the feasibility of this regimen as an alternative to total body irradiation and a potentially curative option for less-fit patients who need a highly central nervous system–active conditioning. [ABSTRACT FROM AUTHOR]

Abstract: Malignant glioma is a very devastating disease. Conventional surgery, radio-and chemotherapy are of limited benefit to improve the cure of patients with malignant astrocytomas. In this research, we evaluated the inhibitory effect of Pulsatilla chinensis polysaccharides (PCPS) on glioma in vivo and in vitro. PCPS had a significant anti-proliferative effect on C6 glioma in vitro assay. Meanwhile a remarkable inhibitory effect PCPS on the growth of C6 glioma and prolongation of life survival could be observed in vivo, comparable to carmustine (BCNU) administration. Moreover PCPS treatment to tumor bearing mice could not only decrease the body weight loss, but also elevate the thymus and spleen indices. In addition, PCPS administration to tumor bearing mice could relieve the liver and kidney damage with decreased levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT) and urea, and enhance superoxide dismutase (SOD) and catalase (CAT) enzyme activities with lower MDA levels in the plasma of tumor bearing mice. The above data proved that PCPS had strong antitumor activity and could be considered as a possible candidate drugs for the glioma therapy. [Copyright &y& Elsevier]

Purpose: Retrospective study of patients treated for high-grade glioma, with or without biodegradable carmustine wafers and according to the Stupp protocol. Methods and Materials: Between May 2007 and June 2008, 65 patients underwent surgery for high-grade glioma, 28 had implantation of Gliadel and 37 patients did not. Patients received radiotherapy with concomitant temozolomide followed by 5 consecutive days of temozolomide every month for 6 months. Results: Overall median follow-up was 17.1 months; the median relapse-free survival (RFS) was 14 months with a RFS of 54% at 12 months, and 38% at 24 months. For patient with and without Gliadel, median and 1-year RFS were 12.9 months and 52% vs. 14 months and 42%, respectively (p = 0.89). According to pathology, Gliadel did not influence RFS of patients with Grade III or glioblastoma. However, for all patients, in multivariate analysis, non-methylated methylguanine methyltransferase (MGMT) was the only unfavorable prognostic factor of RFS (p = 0.017; HR 2.8; CI [1.2–7]). Median overall survival (OS) was 20.8 months; the OS rate at 12 months was 78.5%, and at 24 months 35.4%. For patients treated with and without Gliadel, median and 1-year OS were 20.6 months and 78.6% vs. 20.8 months and 78.4%, respectively. According to pathology, Gliadel did not influence OS of patients with Grade III or glioblastoma. For all patients, in multivariate analysis, unfavorable prognosticators for OS were non-methylated MGMT (p = 0.001; HR: 6.5; CI [2–20]) and irradiation dose <60 Gy (p = 0.02; HR: 6.3; CI [2–20]). With carmustine wafers, before irradiation, median gross tumor volume plus edema was 84 mL (27–229), whereas it was 68 mL (10–362) without carmustine (p = nonsignificant). Four cases of Grade 3 thrombopenia occurred, all in the carmustine wafer group. Conclusion: In patients with high-grade gliomas, adding Gliadel before performing a Stupp protocol did not improve survival. [ABSTRACT FROM AUTHOR]

Abstract: Accumulation of reactive oxygen species (ROS) caused by the inhibition of glutathione reductase (GR) has been proposed as one of the mechanisms responsible for carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU)-induced cytotoxicity. Since mitogen-activated protein kinases (MAPKs) are known to mediate ROS-dependent cell death in multiple cell types, we examined whether redox-sensitive MAPK activation mediated the carmustine-induced cell death of neuronally differentiated PC12 cells. Carmustine induced a concentration- and time-dependent cell death, which was associated with increased caspase-3 activation, a reduction in GR activity accompanied by a concomitant decrease in reduced glutathione levels, and accumulation of ROS. Carmustine-induced caspase-3 activation and cell death were prevented by pretreatment with anti-oxidants or a reducing agent, indicating that carmustine-induced caspase-3 activation and cell death occur via redox-dependent processes. Carmustine induced phosphorylation of the MAPKs, such as extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. The activation of these kinases was inhibited by pretreatment with N-acetyl-l-cysteine (NAC). Although all the MAPKs were activated by carmustine, only the inhibitors of JNK and ERK prevented carmustine-induced cell death and caspase-3 activation. Our data suggest that carmustine-induced neurotoxicity is, at least in part, due to the activation of ROS-dependent JNK and ERK signaling. [Copyright &y& Elsevier]

Abstract: The possible chemopreventive role of dimethylthiourea (DMTU) against carmustine (1,3-bis(2-chloroethyl)-1-nitrosourea, BCNU)-induced myelotoxicity was assessed through evaluation of apoptosis, lipid peroxidation, glutathione (GSH) content and some antioxidant enzymes activities in bone marrow cells of rats. Thirty-six rats were randomly classified into four groups. The first group was injected i.p. with ethanol and served as a control. The second group was treated with BCNU. The third group was given DMTU, while the fourth group was co-administered with DMTU prior to BCNU administration. BCNU treatment in a single dose of 30mg/kg significantly decreased the normal counts of RBCs, WBCs and platelets as well as hemoglobin level. In addition, BCNU exhibited marked apoptotic effect associated with significant alterations in the oxidative cascade parameters. Treatment of animals with DMTU in a single dose of 500mg/kg 1h before BCNU injection, followed by 125mg/kg twice daily for 5 consecutive days significantly mitigated the induced changes in the hematological parameters. The induced alterations in the oxidant and antioxidant parameters as well as apoptosis were also improved. Conclusively, DMTU treatment exhibited marked chemopreventive effect against BCNU-induced myelotoxicity; an effect which may be partially attributed to its inherently antioxidant potential. [Copyright &y& Elsevier]

Abstract: Innovated catanionic solid lipid nanoparticles (CASLNs) carrying carmustine (BCNU) (BCNU-CASLNs) were grafted with anti-epithelial growth factor receptor (EGFR) (anti-EGFR/BCNU-CASLNs) and applied to inhibiting the propagation of human brain malignant glioblastomas cells. U87MG cells were treated with anti-EGFR/BCNU-CASLNs and stained for the expression of EGFR. The minimal average diameter of BCNU-CASLNs and maximal entrapment efficiency of BCNU emerged when the concentration of catanionic surfactants was 1 mm. An increase in the weight percentage of cacao butter (CB) reduced the zeta potential, enhanced the viability of human brain microvasscular endothelial cells (HBMECs), and decreased the expression of tumor necrosis factor-α by HBMECs. The dissolution rate of BCNU and inhibition against the multiplication of U87MG cells using anti-EGFR/BCNU-CASLNs followed the order: 100% CB > 0% CB > 50% CB. Anti-EGFR/BCNU-CASLNs demonstrated the properties including an effective delivery to U87MG cells and antiproliferative efficacy against the growth of malignant brain tumors. [Copyright &y& Elsevier]