Abstract
Doxorubicin (DOX) is a chemotherapeutic agent broadly used in the treatment of a range of solid tumors. In spite of its high potency, as is the case for many other chemotherapeutic drugs, there are many challenges associated with the use of DOX in clinical oncology. This is particularly true for DOX in the treatment of lung cancer where in vitro potency is shown to be very high, but low lung distribution and off-target toxicity (particularly cardiotoxicity) restricts its use. Nanocarrier-based drug delivery systems (nanoDDS) have been shown to help alter biodistribution and alleviate off-target toxicity associated with DOX. While significant understanding exists regarding the design parameters to achieve those clinical benefits, much less is known regarding the design of nanoDDS capable of enhancing tumor penetration of DOX (and other drugs), which is another major factor leading to DOX's reduced efficacy. The purpose of this study was to design a dendrimer-based nanoDDS capable of enhancing the penetration of DOX as measured in an in vitro 3D lung tumor model and to correlate those results with its efficacy. Spheroids formed with A549 human lung adenocarcinoma cells/murine fibroblasts cell line (NIH/3T3 cell line) are shown to produce the essential components of the extracellular matrix (ECM), which is known as a physical barrier that hinder the transport of DOX. DOX was conjugated to generation 4, succinamic acid-terminated poly (amido-amine) (PAMAM) dendrimers (G4SA) through an enzyme-liable tetrapeptide (G4SA-GFLG-DOX) resulting in a nanoDDS with ~5.5 DOX, -17 mV surface (zeta) potential, and 10 nm in hydrodynamic diameter (HD). Penetration of DOX to the core of the spheroid in term of DOX fluorescence's was determined to be 3.1-fold greater compared to free DOX, which positively correlated with enhanced efficacy as measured by Caspase 3/7 assay. This improved penetration happens as the interactions between the G4SA-GFLG-DOX and the highly negatively charged ECM are minimized by shielding the protonatable amine of DOX upon conjugation, and the HD of the conjugate is kept smaller than the estimated mesh size of the ECM. Interestingly, the conjugate provide has more specificity for DOX to tumor cells compared to fibroblasts, while free DOX is equally distributed in both tumor and fibroblasts as assessed in the co-culture spheroids. Growth inhibition studies show that the released DOX maintains its activity, and leads to tumor reduction to the same extent as free DOX. The results obtained here are of relevance for the design of dendrimer-based nanoDDS for the treatment of solid tumors as they provide critical information regarding desirable surface characteristics and sizes for efficient tumor penetration.
PMID: 32227969 [PubMed - as supplied by publisher]
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Myocarditis in the Setting of Cancer Therapeutics: Proposed Case Definitions for Emerging Clinical Syndromes in Cardio-Oncology
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Myocarditis in the Setting of Cancer Therapeutics: Proposed Case Definitions for Emerging Clinical Syndromes in Cardio-Oncology
Circulation. 2019 07 02;140(2):80-91
Authors: Bonaca MP, Olenchock BA, Salem JE, Wiviott SD, Ederhy S, Cohen A, Stewart GC, Choueiri TK, Di Carli M, Allenbach Y, Kumbhani DJ, Heinzerling L, Amiri-Kordestani L, Lyon AR, Thavendiranathan P, Padera R, Lichtman A, Liu PP, Johnson DB, Moslehi J
Abstract
Recent developments in cancer therapeutics have improved outcomes but have also been associated with cardiovascular complications. Therapies harnessing the immune system have been associated with an immune-mediated myocardial injury described as myocarditis. Immune checkpoint inhibitors are one such therapy with an increasing number of case and cohort reports describing a clinical syndrome of immune checkpoint inhibitor–associated myocarditis. Although the full spectrum of immune checkpoint inhibitor–associated cardiovascular disease still needs to be fully defined, described cases of myocarditis range from syndromes with mild signs and symptoms to fatal events. These observations in the clinical setting stand in contrast to outcomes from randomized clinical trials in which myocarditis is a rare event that is investigator reported and lacking in a specific case definition. The complexities associated with diagnosis, as well as the heterogeneous clinical presentation of immune checkpoint inhibitor–associated myocarditis, have made ascertainment and identification of myocarditis with high specificity challenging in clinical trials and other data sets, limiting the ability to better understand the incidence, outcomes, and predictors of these rare events. Therefore, establishing a uniform definition of myocarditis for application in clinical trials of cancer immunotherapies will enable greater understanding of these events. We propose an operational definition of cancer therapy-associated myocarditis that may facilitate case ascertainment and report and therefore may enhance the understanding of the incidence, outcomes, and risk factors of this novel clinical syndrome.
PMID: 31390169 [PubMed - indexed for MEDLINE]
3 April 2020
11:48
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sFRP1 protects H9c2 cardiac myoblasts from doxorubicin-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway.
sFRP1 protects H9c2 cardiac myoblasts from doxorubicin-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway.
Acta Pharmacol Sin. 2020 Apr 01;:
Authors: Hu YH, Liu J, Lu J, Wang PX, Chen JX, Guo Y, Han FH, Wang JJ, Li W, Liu PQ
Abstract
Doxorubicin (Dox) is an effective chemotherapy drug against a wide range of cancers, including both hematological and solid tumors. However, the serious cardiotoxic effect restricted its clinical application. We previously have illuminated the protective role of canonical Wnt/β-catenin signaling in Dox-induced cardiotoxicity. Secreted frizzled-related protein 1 (sFRP1) is one of the endogenous inhibitors of both canonical and noncanonical Wnt signaling. In this study, we investigated the relationship between sFRP1 and noncanonical Wnt/PCP-JNK (Wnt/planar cell polarity-c-Jun N-terminal kinase) pathway in Dox-induced cardiotoxicity in vitro and in vivo. We showed that treatment of H9c2 cardiac myoblasts with Dox (1 μM) time-dependently suppressed cell viability accompanied by significantly decreased sFRP1 protein level and increased Wnt/PCP-JNK signaling. Pretreatment with SP600125, the Wnt/PCP-JNK signaling inhibitor, attenuated Dox-induced apoptosis of H9c2 cells. Overexpression of sFRP1 protected H9c2 cells from Dox-induced apoptosis by inhibiting the Wnt/PCP-JNK pathway. After intraperitoneal injection of a cumulative dose of 15 mg/kg Dox, rats displayed significant cardiac dysfunction; their heart showed inhibited Wnt/β-catenin signaling and activated Wnt/PCP-JNK signaling. These results suggest that sFRP1 may be a novel target for Dox-induced cardiotoxicity.
PMID: 32238888 [PubMed - as supplied by publisher]
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Comparison of outcomes in a population-based cohort of metastatic breast cancer patients receiving anti-HER2 therapy with clinical trial outcomes.
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Comparison of outcomes in a population-based cohort of metastatic breast cancer patients receiving anti-HER2 therapy with clinical trial outcomes.
Breast Cancer Res Treat. 2020 Mar 31;:
Authors: Gong IY, Yan AT, Earle CC, Trudeau ME, Eisen A, Chan KKW
Abstract
PURPOSE: Little data exist for comparing cardiac safety and survival outcomes of trastuzumab/pertuzumab or ado-T emtansine (TDM1) in metastatic breast cancer (MBC) patients enrolled in randomized clinical trial (RCT) vs the real-world.
METHODS: This was a retrospective population-based cohort of all patients with MBC treated with trastuzumab/pertuzumab or TDM1 (2012-2017) in Ontario, Canada. Outcomes were incident heart failure (HF) and overall survival (OS). RCT data were obtained from digitizing survival curves and compared with cohort data using Kaplan-Meier analysis. Age-based comparison of outcomes was conducted for patients ≥ 65 years old vs younger than 65.
RESULTS: The two cohorts composed of 833 and 397 patients treated with trastuzumab/pertuzumab and TDM1, of whom 5.5% and 7.6% had baseline HF, respectively. Incident HF following trastuzumab/pertuzumab or TDM1 was low (trastuzumab/pertuzumab 1.8 events/100 person years; TDM1 0.02 events/100 person years). The median OS was 39.2 and 56.4 months in the trastuzumab/pertuzumab population-based cohort and CLEOPATRA, respectively. The median OS was 15.4 and 30.9 months in the TDM1 population-based cohort and EMILIA, respectively. Cohort OS was significantly worse than RCT OS (trastuzumab/pertuzumab HR 1.67, 95% CI 1.37-2.03, p < 0.0001;< 0.0001).
CONCLUSION: HF incidence during trastuzumab/pertuzumab or TDM1 therapy in this real-world cohort was low. Survival in this cohort was worse compared to RCT, suggesting that recruitment of patients similar to the real-world population is required.
PMID: 32236828 [PubMed - as supplied by publisher]
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Human serum albumin-based doxorubicin prodrug nanoparticles with tumor pH-responsive aggregation-enhanced retention and reduced cardiotoxicity.
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Human serum albumin-based doxorubicin prodrug nanoparticles with tumor pH-responsive aggregation-enhanced retention and reduced cardiotoxicity.
J Mater Chem B. 2020 Apr 01;:
Authors: Zhang B, Wan S, Peng X, Zhao M, Li S, Pu Y, He B
Abstract
Doxorubicin (DOX) is a widely-used anticancer drug, but its cardiotoxicity severely hampers its potency in chemotherapy. Herein, human serum albumin (HSA) is engaged as a biocompatible nanocarrier to load a pH-sensitive DOX prodrug, DMDOX, generating HSA-DMDOX nanoparticles via self-assembly driven by hydrophobic interactions. HSA-DMDOX disperses well in a physiological environment (∼40 nm) but aggregates in a tumor acidic microenvironment (pH 6.5, ∼140 nm) owing to the hydrophobicity increase of DMDOX by protonation of carboxylic groups. In vitro anticancer study showed that HSA-DMDOX exhibited enhanced cellular uptake by 4T1 cells and superior cytotoxicity in comparison to HSA-DOX nanoparticles. In vivo study suggested that HSA-DMDOX achieved long blood circulation, aggregation enhanced tumor retention, comparable antitumor efficacy and reduced cardiotoxicity relative to free DOX. Our work presents a facile and effective approach to delivering anthracyclines by HSA-based tumor pH-responsive nanoparticles with aggregation-enhanced tumor retention and reduced toxicity.
PMID: 32236239 [PubMed - as supplied by publisher]
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Combined treatment of melatonin and sodium tanshinone IIA sulfonate reduced the neurological and cardiovascular toxicity induced by deltamethrin in zebrafish.
//www.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--linkinghub.elsevier.com-ihub-images-PubMedLink.gif Related Articles
Combined treatment of melatonin and sodium tanshinone IIA sulfonate reduced the neurological and cardiovascular toxicity induced by deltamethrin in zebrafish.
Chemosphere. 2020 Mar;243:125373
Authors: Li M, Zhang T, Jia Y, Sun Y, Zhang S, Mi P, Feng Z, Zhao X, Chen D, Feng X
Abstract
The pyrethroid insecticide deltamethrin has been reported to have an effect on vertebrate development and cardiovascular disease. Sodium tanshinone IIA sulfonate (STS) is considered to have cardioprotective effects and melatonin is known to regulate sleep-waking cycles. In this experiment, we used transgenic zebrafish Tg (kdrl:mCherry) and Tg (myl7:GFP) to investigate whether STS and melatonin could reverse the cardiovascular toxicity and neurotoxicity induced by deltamethrin. Zebrafish embryos were exposed to 25 μg/L deltamethrin at 10 hpf and treated with 100 mmol/L STS and 1 μmol/L melatonin showed that deltamethrin treatment affected normal cardiovascular development. In situ hybridization and qRT-PCR results showed that deltamethrin could interfere with the normal expression of cardiovascular development-related genes vegfr2, shh, gata4, nkx2.5, causing functional defects in the cardiovascular system. In addition, deltamethrin could affect the sleep-waking behavior of larvae, increasing the activity of larvae, decreasing the rest behavior and the expression of hcrt, hcrtr, aanat2 were down-regulated. The addition of melatonin and STS can significantly alleviate cardiovascular toxicity and sleep-waking induced by deltamethrin, while restoring the expression of related genes to normal levels. Our study demonstrates the role of STS and melatonin in protecting cardiovascular and sleep-waking behavior caused by deltamethrin.
PMID: 31765895 [PubMed - indexed for MEDLINE]
4 April 2020
13:06
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Tumor Microenvironment Stimuli-responsive Nanoparticles for Programmed Anticancer Drug Delivery.
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Tumor Microenvironment Stimuli-responsive Nanoparticles for Programmed Anticancer Drug Delivery.
Mol Pharm. 2020 Apr 03;:
Authors: Jia N, Li W, Liu D, Wu S, Song B, Ma J, Chen D, Hu H
Abstract
It is well known that large size nanoparticles stay long in the circulation system, but show poor tissue penetration and low cellular uptake. In order to reconcile the conflicting needs for extended circulation time, extensive tumor tissue penetration and enhanced cellular uptake for nano-drug delivery systems, we designed DOX-containing hypersensitive nanoparticles that responded to the tumor microenvironment for programmed DOX delivery. A super-sensitive polymer material, poly (2-ethyl-2-oxazoline)-poly (methacryloyl sulfadimethoxine), was synthesized (PEOz-b-PSD, pKa=6.96). At the physiological environment, PEOz-b-PSD and polyamidoamine/DOX (PAMAM/DOX) can form nanoparticles PEOz-b-PSD/PAMAM/DOX (PEPSD/PAM/DOX) via electrostatic adsorption. The PEPSD/PAM/DOX has an intact structure, which can prolong circulation time. While in the tumor environment, the PEOz-b-PSD was rapidly protonated and showed charge reversal, leading PEOz-b-PSD to get detached from the nanoparticles, then the large size nanoparticles with a negative charge (PEPSD/PAM/DOX) instantaneously turn into positively charged ultrafine nanoparticles. The sudden inversion of size and charge can effectively improve tumor accumulation and internal penetration. After entering tumor cells, nanoparticles can release drugs quickly through the action of PAMAM proton sponge, resulting in enhanced tumor inhibition. Our results proved that the programmed nanoparticles could remarkable enhance the in vivo antitumor efficacy and reduce cardiotoxicity of DOX. This study designed ultra-sensitive nanoparticles in the tumor microenvironment, which appear to be beneficial for enhancing the treatment efficacy of DOX in solid tumors.
PMID: 32243181 [PubMed - as supplied by publisher]
5 April 2020
13:32
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Programmed Cell Death-1: Programmed Cell Death-Ligand 1 Interaction Protects Human Cardiomyocytes Against T-Cell Mediated Inflammation and Apoptosis Response In Vitro.
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Programmed Cell Death-1: Programmed Cell Death-Ligand 1 Interaction Protects Human Cardiomyocytes Against T-Cell Mediated Inflammation and Apoptosis Response In Vitro.
Int J Mol Sci. 2020 Mar 31;21(7):
Authors: Tay WT, Fang YH, Beh ST, Liu YW, Hsu LW, Yen CJ, Liu PY
Abstract
AIM: Immunological checkpoint therapy is considered a powerful method for cancer therapy and acts by re-activating autologous T cells to kill the cancer cell. Myocarditis cases have been reported in cancer patients after immunological therapy; for example, nivolumab treatment is a monoclonal antibody that blocks programmed cell death-1/programmed cell death ligand-1 ligand interaction. This project provided insight into the inflammatory response as a benchmark to investigate the potential cardiotoxic effect of T cell response to the programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis in regulating cardiomyocyte injury in vitro.
METHODS AND RESULTS: We investigated cardiomyopathy resulted from the PD-1/PD-L1 axis blockade using the anti-PD-1 antibody in Rockefeller University embryonic stem cells-derived cardiomyocytes (RUES2-CMs) and a melanoma tumor-bearing murine model. We found that nivolumab alone did not induce inflammatory-related proteins, including PD-L1 expression, and did not induce apoptosis, which was contrary to doxorubicin, a cardiotoxic chemotherapy drug. However, nivolumab was able to exacerbate the immune response by increasing cytokine and inflammatory gene expression in RUES2-CMs when co-cultured with CD4+ T lymphocytes and induced apoptosis. This effect was not observed when RUES2-CMs were co-cultured with CD8+ T lymphocytes. The in vivo model showed that the heart function of tumor-bearing mice was decreased after treatment with anti-PD-1 antibody and demonstrated a dilated left ventricle histological examination. The dilated left ventricle was associated with an infiltration of CD4+ and CD8+ T lymphocytes into the myocardium. PD-L1 and inflammatory-associated gene expression were significantly increased in anti-PD-1-treated tumor-bearing mice. Cleaved caspase-3 and mouse plasma cardiac troponin I expressions were increased significantly.
CONCLUSION: PD-L1 expression on cardiomyocytes suppressed T-cell function. Blockade of PD-1 by nivolumab enhanced cardiomyocyte inflammation and apoptosis through the enhancement of T-cell response towards cardiomyocytes.
PMID: 32244307 [PubMed - as supplied by publisher]
6 April 2020
14:28
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The Role of Cardiac MRI in Animal Models of Cardiotoxicity: Hopes and Challenges.
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The Role of Cardiac MRI in Animal Models of Cardiotoxicity: Hopes and Challenges.
J Cardiovasc Transl Res. 2020 Apr 04;:
Authors: Park CJ, Branch ME, Vasu S, Meléndez GC
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