Minimal Cardiotoxicity Research Articles

Light-Responsive conjugated polymer nanoparticles with Spatial-Controlled camptothecin release via π − π stacking for improved Combinatorial therapy of breast cancer

The treatment of breast cancer (BC) remains a significant challenge, exemplified by the limitations of chemotherapy due to its high side effects. Light-responsive drug delivery systems (DDS) offer a promising approach to spatially and temporally release drugs, minimizing chemotherapy side effects and enhancing efficacy. However, achieving precise delivery and site-specific drug release poses complex challenges. Here, We present a novel nano-system combining light-responsive photothermal therapy (PTT) with photothermal-responsive chemotherapy via π − π Stacking. Conjugated polymer nanoparticles (cRGD-PTer N25/CPT NPs) is designed for spatiotemporal targeted PTT/chemotherapy. Research shows that the strong near-infrared absorption of PTer N25 endows cRGD-PTer N25/CPT NPs with excellent photothermal capabilities(57.4 %) and near-infrared laser-triggered drug release performance. The cRGD-PTer N25/CPT NPs enhanced BC-specific cellular accumulation, prolonged blood circulation, exhibited good biocompatibility, and improved PTT and chemotherapy efficacy in BC cell lines and mouse models while reducing systemic toxicity. The photothermal effect triggered the on-demand release of camptothecin (CPT), producing therapeutic effects and downregulating heat shock protein 70 (HSP 70), reducing cancer cell thermoresistance, and enhancing combined treatment efficacy. Under spatial and temporal control, the tumor growth inhibition rate of the cRGD-PTer N25/CPT NPs group reached 93.6 %, nearly eradicating tumor presence, whereas the control group exhibited only partial inhibition. Minimal cardiotoxicity and metastatic side effects are not observed. This work presents a viable strategy for designing novel controlled-release drug systems to improve breast cancer treatment efficiency.

Modeling doxorubicin-induced cardiotoxicity with human myocardial tissue slices: insights on genetic susceptibility and cardioprotection

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): PSIDER and HARVEY (ZonMW) Introduction Cardiotoxicity poses a significant challenge in drug development, often leading to the withdrawal of approved drugs. To address this issue, there is a critical need for improved models to predict cardiac adverse effects. In line with the imperative for animal-free preclinical testing, this study aimed to develop a novel model using human myocardial tissue slices to get a deeper understanding and potential prevention of doxorubicin-Induced cardiotoxicity. Methods Human myocardial tissue slices of 300 μm thick were derived from end-stage heart failure patients explanted hearts, including those harbouring likely or pathogenic cardiovascular mutations (class 4 and 5) (N=3) and non-genetic cardiovascular etiology (N=3). Myocardial tissue slices were cultured under physiological mechanical and electrical conditions. Slices were exposed to doxorubicin (1 µM) over a 10-day culture period, and their responses were compared to DMSO-vehicle controls, by recording contractile force and Ca2+ transients. Additionally, a subset of slices was treated with a cardioprotective agent, dexrazoxane (100 µM), 1 day prior to and during doxorubicin exposure to assess potential cardioprotection. Results Doxorubicin-exposed slices with a pathogenic mutation exhibited reduced mechanical force, increased threshold potential, and impaired ability to follow pacing at higher frequencies. Additionally, aberrations in calcium handling, manifested as arrhythmia-like disconnection of muscle fibers, were notably observed in these slices. Instead, slices from patients without pathogenic mutations showed minimal cardiotoxicity when exposed to doxorubicin. Encouragingly, pretreatment with dexrazoxane demonstrated a protective effect against doxorubicin-induced cardiotoxicity in the genetically susceptible group. Our functional findings corroborated our structural data, highlighting the breakdown of sarcomere structure and cell-cell connections and increased DNA damage, particularly in patients harbouring a genetic cardiovascular mutation. Conclusion In summary, human myocardial tissue slices faithfully recapitulate doxorubicin-induced cardiotoxicity. Importantly, our data suggests the utility of employing genetic testing for known cardiovascular mutations as a valuable step before initiating doxorubicin treatment. Additionally, we demonstrate for the first time the in vitro cardioprotective potential of dexrazoxane in a human tissue model. These findings pave the way for using ex vivo myocardial tissue slices to evaluate cardiotoxicity and their value as a powerful tool for evaluating the efficacy and delivery approaches.

Hybrid cell membranes camouflage liposomes containing payloads to improve breast cancer chemo and photodynamic therapy.

The treatment of unresectable locally advanced triple-negative breast cancer (TNBC) and TNBC with metastasis is challenging. Many anticancer drugs, such as doxorubicin, still hinder positive therapeutic outcomes due to severe side effects. Photodynamic therapy (PDT) has an anticancer effect, and combining PDT with chemotherapy may improve breast cancer therapy. The use of cargo-loaded biomimetic PEGylated liposomes for cancer therapy may enhance efficacy and reduce side effects. In this study, liposomes were formulated to accommodate doxorubicin (Dox) and IR780. Breast cancer cells (4T1 cells) and macrophage cell membranes were isolated and camouflaged onto the PEGylated liposomes, creating a new biomimetic platform called Dox-IR780@Lip@Ms. The Dox-IR780@Lip@Ms platform was characterized and tested in vitro and in vivo. The results showed that the Dox-IR780@Lip@Ms had an ovoid shape with a double lamina structure, monodispersity, and uniform distribution. The size was 132.37 ± 1.22 nm, the PDI was 0.044 ± 0.067, and the zeta potential was -9.67 ± 1.08 mV. The encapsulation efficiency of Dox and IR780 in Dox-IR780@Lip@Ms was 89.36% ± 3.07% and 92.34% ± 0.66%, respectively. The release rate of Dox from Dox-IR780@Lip@Ms was good after laser irradiation. At pH 7.4, the release rate of Dox was 23.85% ± 0.62% at 3 h without laser irradiation and 36.62% ± 1.32% at 3.5 h with laser irradiation. At pH 6.5, the release rate of Dox was 32.54% ± 0.32% at 3 h without laser irradiation and 62.79% ± 2.15% at 3.5 h with laser irradiation. The cytotoxicity of IR780@Lip@Ms was lower than that of Dox-IR780@Lip@Ms. The cell uptake and generation of reactive oxygen species of Dox-IR780@Lip@Ms were significant. Dox-IR780@Lip@Ms exhibited immune escaping ability in vitro, homotypic targeting ability to cancer cells, high capability to kill cancer cells after laser irradiation, minimal cardiotoxicity, increased accumulation of Dox and IR780 in the tumor, and an increased anticancer effect in a tumor-bearing animal model. In conclusion, hybrid cell membranes of breast cancer and macrophages camouflaging PEGylated liposomes loaded with Dox and IR780 can significantly improve breast cancer therapy after laser irradiation in murine models.

Dual delivery of carbon monoxide and doxorubicin using haemoglobin-albumin cluster: proof of concept for well-tolerated cancer therapy.

A serious concern of doxorubicin (DOX) therapy is that it causes severe adverse effects, particularly cardiotoxicity. Carbon monoxide (CO) possesses powerful cytoprotective effects against drug-induced organ injury and is expected to ameliorate DOX-induced cardiotoxicity. In this study, a dual carrier of DOX and CO (CO-HemoAct-DOX) was fabricated based on a haemoglobin-albumin cluster (HemoAct), which is a protein cluster with a haemoglobin core structure wrapped by serum albumin. CO-HemoAct-DOX was synthesised by binding CO to a haemoglobin core and covalently conjugating (6-maleimidocaproyl)hydrazone derivative of DOX to an albumin shell. The average DOX/cluster ratio was about 2.6. In the in vitro cytotoxicity assay against cancer cells, the anti-tumour activity of CO-HemoAct-DOX was 10-fold lower than that of DOX in a 2D-cultured model, whereas CO-HemoAct-DOX suppressed the growth of tumour spheroids to the same extent as DOX in the 3D-cultured model. In colon-26 tumour-bearing mice, CO-HemoAct-DOX achieved DOX delivery to the tumour site and alleviated tumour growth more effectively than DOX. Furthermore, CO-HemoAct attenuated DOX-induced cardiomyocyte atrophy in H9c2 cells and elevated the levels of cardiac biomarkers in mice exposed to DOX. These results suggest that the dual delivery of CO and DOX using HemoAct is a promising strategy as an anti-tumour agent to realise well-tolerated cancer therapy with minimal cardiotoxicity.

Abstract P3-07-25: Efficacy and safety of neoadjuvant pertuzumab biosimilar TQB2440, trastuzumab and docetaxel in HR negative, HER2 positive breast cancer: a single-arm trial

Abstract Background: Despite that dual anti-HER2 therapy (Trastuzumab and Pertuzumab, TP) is one of the commonly used regimens for neoadjuvant treatment of HER2-positive breast cancer, previous studies showed that its pCR rate rarely exceeds 63%. Additionally, it is associated with higher risk of cardiac adverse events. TQB2440, a biosimilar of pertuzumab, with strong affinity and specificity, can effectively bind with HER2 epitope. In the PDX mouse model, TQB2440 showed promising biological activity and minimal cardiotoxicity. In this study, we designed a single-arm trial of dual anti-HER2 therapy (TQB2440 and trastuzumab, TT) plus docetaxel in neoadjuvant therapy of HER2 positive breast cancer. We aimed to examine the efficacy and safety of TQB2440 and study whether new dual anti-HER2 therapy (TT) can boost pCR rate in the neoadjuvant treatment. The cardiotoxicity and other adverse reactions were closely monitored. Methods: Upon approval by the Medical Ethics Committee of Xijing Hospital, patients with HR negative HER2-positive breast cancer (cT2-3/N0-1/M0) receiving neoadjuvant therapy were enrolled. The patients were treated with docetaxel 75 mg/m2, trastuzumab 8 mg/kg loading, then 6 mg/kg, TQB2440 840 mg loading, then 420 mg, iv, q3w for 4 cycles, with strict monitoring of cardiotoxicity. The primary endpoint was pCR rate, and secondary endpoint was cardiotoxicity. Results: From April 2021 to February 2022, a total of 28 patients were recruited. Among the 28 patients with a median age of 52 (28-74), 12 patients had positive lymph node status. Overall, the pCR rate was 67.9% (19/28). The pCR rate was higher than that in the NeoSphere trial (pCR 63.2%) and the PEONY study (pCR 52.5%). The lymph-positive tumor achieved a higher pCR rate than lymph-negative tumor (70.8% vs 52.3%, p = .019). Multivariate regression analysis showed that for participants aged 50 or above, HER2 3+ (IHC) showed a statistically significant positive influence on pCR rate. The common adverse reactions of grade ≥3 were leukopenia (46.4%), neutropenia (35.7%), asthenia (3.6%), and peripheral sensory neuropathy (2.3%). Left ventricular insufficiency was detected in 1 patient, and no cardiotoxic events higher than grade 2 occurred during the neoadjuvant therapy. There was no treatment-related death. Conclusion: TQB2440 and trastuzumab plus docetaxel is a feasible and effective neoadjuvant therapy for early-stage HR negative HER2-positive breast cancer, showing high pCR rate and acceptable cardiotoxicity. These results support a further random controlled trial testing for dual anti-HER2 therapy using TQB2440 in neoadjuvant or adjuvant therapy of HER2 positive breast cancer. Citation Format: Jiang Wu, Jing Yu, Yuqing Yang, Xinxin Wen, Jixin Yang, Hongliang Wei, Xiaolong Xu, Yike Li, Liu Yang, Dongdong Xu, Lei Wang, Yijia Wang, Wen Ma, Nanlin Li. Efficacy and safety of neoadjuvant pertuzumab biosimilar TQB2440, trastuzumab and docetaxel in HR negative, HER2 positive breast cancer: a single-arm trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-25.

Abstract P4-02-05: Predictors of long-term durable response in de novo HER2 positive metastatic breast cancer and the real world treatment experience at two institutions

Abstract Purpose Modern HER2-directed therapies enable some patients with de novo HER2+ metastatic breast cancer (MBC) to achieve long-term, durable responses (DR), which can be defined as no progression of disease since initial diagnosis. Clinical and pathologic factors that predict DR continue to be elucidated. Expert opinion dictates indefinite HER2-directed therapies for patients who achieve DRs, but real-world examples of this practice are lacking in the literature. Methods This is a retrospective study of all patients with de novo HER2+ MBC at two major academic institutions who received at least one dose of trastuzumab between 2012-2019. DR is defined as absence of progression/death at any point after diagnosis. Controls are patients with evidence of progression/death. Age, ER/PR status, sites of metastasis, surgical resection of primary tumor and initial treatment were analyzed as predictors of DR using an unpaired T test, with p< 0.05 chosen as threshold for significance. For patients with DR, time to complete (CR) and partial response (PR) according to RECIST 1.1 were recorded, as was the duration and treatment patterns surrounding trastuzumab and pertuzumab. Patients were defined as having cardiotoxicity if they experienced a decline in cardiac ejection fraction at any point while on trastuzumab therapy leading to treatment delays or discontinuation. Results 96 patients with de novo HER2+ MBC, 28 with DR and 68 with progression, were identified. The average follow up of patients with DR was 90 months (range 27-224), compared to 58 months (range 1-208) in controls. The entire cohort of 96 patients had a median PFS of 23.5 months and a median OS of 88 months. Among the 28 patients with DR, 2 achieved stable disease, 10 patients had documented PR at 4 months on average (range 2-6 months), and 26 patients had CR at 7.7 months on average (range 2-19 months). Among patients with DR, nine patients have been receiving trastuzumab for over ten years with no evidence of disease and one patient opted to discontinue trastuzumab. 75% of patients with DR had a single metastatic site, compared with 47% of patients with progression (OR 3.7, p=0.01). 64% of patients with DR received a regimen containing trastuzumab, pertuzumab, and a taxane, while 28% of patients who progressed did (OR 4.5, p< 0.001). 57% of patients with DR underwent surgical removal of breast primary, compared with 24% of patients who progressed (OR 4.3, p=0.002.) Age, and ER/PR status did not predict DR. (Table 1) Six patients (6.3%) developed reduced ejection fraction requiring treatment interruption or cessation, five in the group who progressed, one in the DR group. Conclusion Nearly a third of patients with de novo HER2+ MBC achieved DR. Factors that correlate with DR include single metastatic site, initial trastuzumab, pertuzumab and taxane therapy, and surgical resection of primary tumor. This suggests that in selected patients, a more aggressive up front approach including surgical resection, and agents such as carboplatin, and trastuzumab deruxtecan deserves further study. Among patients with DR, indefinite trastuzumab administration is the norm with minimal cardiotoxicity but the impact of this on quality of life and financial toxicity are not well described. Table 1: Clinical characteristics of de novo HER2 positive metastatic breast cancer that predict durable response Citation Format: Claire E. Smith, Paul K. Marcom, Mitri Zahi, Naomi Ko. Predictors of long-term durable response in de novo HER2 positive metastatic breast cancer and the real world treatment experience at two institutions [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-02-05.

Optimizing cardio, hepato and phospholipidosis toxicity of the Bedaquiline by chemoinformatics and molecular modelling approach

ABSTRACT The FDA granted expedited approval for Johnson and Johnson’s Bedaquiline to treat pulmonary multidrug resistant tuberculosis on 28 December 2012 which is more common in China, Russian Federation and India. Bedaquiline is the first anti-tubercular drug approved by the FDA in the last 40 years, and it has become a cynosure in the circles of synthetic chemists researching new anti-tubercular drugs. Bedaquiline’s highly lipophilic nature raises major concerns like suppression of the hERG gene, hepatotoxicity, and phospholipidosis despite its potential antitubercular profile. To address these toxicity concerns, in the present work, we have employed the structural optimization of Bedaquiline using the ADMETopt web server, which optimizes lead with scaffold hopping and ADMET screening. The ADMETopt web server yielded the 476 structures through optimization of three sites in Bedaquiline. Further, we have validated the optimized structures for their activity by performing molecular docking and molecular dynamics (MD) simulations against the mycobacterial ATP synthase enzyme and density functional theory (DFT) study further provides insight into the reactivity of the compounds. After screening and analysis, compound #449 was observed to be the most promising mycobacterial ATP synthase inhibitor with minimal cardiotoxicity, hepatotoxicity and phospholipidosis.

Cardiotoxicity of trastuzumab emtansine (T-DM1): a single-center experience.

ObjectiveNew anti-cancer drugs promise to increased survival benefits and reduce adverse events. Trastuzumab emtansine (T-DM1) is a novel anti-human epidermal growth factor receptor 2 agent that has shown minimal cardiotoxicity in clinical trials. However, data on real-life outcomes are required.MethodsA retrospective review of our center’s medical records was performed, including female patients aged ≥18 years with a diagnosis of metastatic breast cancer who were treated with T-DM1. Descriptive statistics were used to investigate clinical features that could increase the risk of cardiotoxicity. Cardiotoxicity was determined by comparing pre and post-T-DM1 echocardiogram results and was defined as a decrease in the left ventricular ejection fraction (LVEF) >10% to below 55%.ResultsData from 41 female patients with a mean age of 52 ± 11.5 years were evaluated. A significant LVEF decrease (from 59% to 33%) was observed in one patient during T-DM1 treatment. Further investigation showed that this decrease was due to underlying coronary artery disease, and LVEF recovered to the baseline value after coronary revascularization.ConclusionT-DM1 seems to be safe in terms of cardiotoxicity. Real-life data with a larger sample size are still needed to confirm the cardiac safety of T-DM1.

Abstract 11697: Associations of Soluble Urokinase-Type Plasminogen Activator Receptor and Doxorubicin-Related Cardiotoxicity at Standard Treatment Doses for Breast Cancer

Introduction: Elevated soluble urokinase type plasminogen activator (suPAR) is a risk factor for renal and cardiovascular (CV) diseases in the general population. Hypothesis: We evaluated associations between suPAR and markers of subclinical cardiotoxicity in breast cancer (BCa) patients receiving standard (std) dose doxorubicin (DOX) therapy. Methods: We conducted a prospective study of patients at Rush University Medical Center who received std (≤240 mg/m2, 4 cycles) DOX-based chemotherapy for BCa between January 2017 and May 2019. We used mixed effects linear regression models to evaluate associations between suPAR and global longitudinal strain (GLS), NT-proBNP, troponin-I, and hsCRP at baseline, cycle 2 and 4 of DOX, and 3, 6, and 12 months post-DOX treatment with adjustment for baseline demographics, CV risk factors, and CV medications. Results: Of the 37 women in our study (age 47±9.3 years, 60% White, 60% left-sided BCa, and 86% adjuvant radiation therapy), the median baseline suPAR was normal at 1.83 (1.31, 3.68) ng/dL. No woman experienced clinically significant cardiotoxicity during treatment (>10% decrease in LVEF to <50%). Baseline GLS was normal (-20.2±2.3%) and the mean change in GLS following DOX therapy was +1.1%. Neither baseline suPAR nor suPAR levels during treatment were associated with GLS, NT-proBNP, hsCRP, and troponin-I (all p<0.05). Surrogate biomarkers of cardiotoxicity such as troponin-I and hsCRP were not associated with GLS (p<0.05) while NT-proBNP was negatively associated with GLS with marginal significance (p=0.04). Conclusions: In patients receiving std DOX treatment for BCa ± radiation therapy, there was minimal subclinical cardiotoxicity as evidenced by minimal changes in GLS and lack of associations between cardiac biomarkers and GLS. Furthermore, suPAR was not associated with any of these markers at this std DOX dose for BCa. A normal baseline suPAR level may be associated with low risk for DOX-associated cardiotoxicity.

Real-word incidence and management of durable complete response in de novo metastatic HER2-positive breast cancer.

e13017 Background: HER2-directed therapies enable a small number of patients with de novo HER2+ metastatic breast cancer (MBC) to achieve long term durable responses (DR). However, clinic-pathologic factors that correlate with DRs in de novo HER2+ MBC are unknown. Expert opinion dictates indefinite HER2-directed therapies for patients who achieve DRs, but real-world examples of this practice, especially the effect on cardiotoxicity, are lacking in the literature. Methods: This is a retrospective case control study of patients with de novo HER2+ MBC who received treatment with trastuzumab at two NCI designated cancer centers between the years 2012-2017. Patients were included if ≥2 years of follow up data were available or if patients were deceased. DRs are defined as radiographic complete or partial response without progression or death at any point after diagnosis. Controls are patients with evidence of radiographic progression or death any point after diagnosis. Age at diagnosis, ER/PR status, site of metastasis, and initial treatment were analyzed. An un-paired T test for age and fisher exact test for categorical variables were used. Results: A total of 96 patients with de novo HER2+ MBC, 28 with DRs and 68 with progression, were identified. Average follow up length for patients with DR was 90 months (range 27-224 months). Patients who progressed had a mPFS of 17.5 months and a mOS of 60 months. Results are shown in Table. Additionally, six patients (6.3%) developed reduced ejection fraction, one with DR, five with progression. Nine patients have been receiving trastuzumab for over ten years with no evidence of disease. Only one patient opted to discontinue this therapy a year after complete response and is disease free five years from diagnosis. Conclusions: Nearly a third of patients with de novo metastatic HER2+ MBC in our dataset achieved DR. Factors that predict DRs include single organ involved by metastatic disease and more intensive upfront chemotherapy including trastuzumab and pertuzumab. The majority of patients with DR continued HER2 directed therapy indefinitely with minimal cardiotoxicity. In the absence of predictive biomarkers of DRs, indefinite trastuzumab administration is common practice for these patients. [Table: see text]

Monocyclic Quinone Structure-Activity Patterns: Synthesis of Catalytic Inhibitors of Topoisomerase II with Potent Antiproliferative Activity.

The monocyclic 1,4-benzoquinone, HU-331, the direct oxidation product of cannabidiol, inhibits the catalytic activity of topoisomerase II but without inducing DNA strand breaks or generating free radicals, and unlike many fused-ring quinones exhibits minimal cardiotoxicity. Thus, monocyclic quinones have potential as anticancer agents, and investigation of the structural origins of their biological activity is warranted. New syntheses of cannabidiol and (±)-HU-331 are here reported. Integrated synthetic protocols afforded a wide range of polysubstituted resorcinol derivatives; many of the corresponding novel 2-hydroxy-1,4-benzoquinone derivatives are potent inhibitors of the catalytic activity of topoisomerase II, some more so than HU-331, whose monoterpene unit replaced by a 3-cycloalkyl unit conferred increased antiproliferative properties in cell lines with IC50 values extending below 1 mM, and greater stability in solution than HU-331. The principal pharmacophore of quinones related to HU-331 was identified. Selected monocyclic quinones show potential for the development of new anticancer agents.

Incidence of and risk factors for cardiotoxicity after fluorouracil-based chemotherapy in locally advanced or metastatic gastric cancer patients

Cardiotoxicity is an important side effect in patients receiving chemotherapy and the application of anthracycline drugs for gastric cancer treatment is uncommon. The purpose of this study was to determine the incidence rate of and risk factors for cardiotoxicity in gastric cancer patients treated with fluorouracil-based chemotherapy. We retrospectively enrolled patients with locally advanced or metastatic gastric cancer from 2011 to 2016. Patients were treated with multiple cycles of fluorouracil-based chemotherapy at Peking University First Hospital. The incidence of cardiotoxicity and patients' clinical data were obtained from hospital clinical databases and manually reviewed. A total of 129 patients were eligible for and were enrolled in this study. A median of 6 chemotherapy cycles were administered (range 1-18 cycles). Cardiotoxicity was observed in 38 of 129 patients (29.5%). Twelve patients (9.3%) exhibited toxicity greater than grade 2, and 2 (1.6%) patients died of cardiac toxicity. The only independent risk factor for serious cardiotoxicity identified by multivariable analysis was a history of cardiac disease (OR 4.108, 95% CI 2.778-6.074, P < 0.001). Chemotherapy-related cardiotoxicity may be underestimated in Chinese gastric cancer patients. Close monitoring for cardiotoxicity and enhanced cardiac management are recommended for patients who receive fluorouracil-based chemotherapy, especially for patients with high-risk factors for serious cardiotoxicity. New strategies, such as identifying the administration schedule of fluorouracil with minimal cardiotoxicity, and cardio-oncology, are necessary to prevent and treat chemotherapy-induced cardiotoxicity.

Design and synthesis of novel 2,4-disubstituted aminopyrimidines: reversible non-covalent T790M EGFR inhibitors

Cardiotoxicity is one amongst the adverse effect of Osimertinib delineate in clinical trials and related to escalating doses. To triumph over the drawbacks of Osimertinib, in this study, we tend to delineate the design, synthesis, in vitro biological analysis of a series of novel reversible selective T790M inhibitors with minimal cardiotoxicity. Amongst the virtually sorted compounds; compound 18 and 74 have been located to be the foremost active compounds of the series with IC50 value of 0.88, 0.92 μM in cellular assay and 0.56, 0.62 μM in enzymatic assay, against double mutant L858R/T790M EGFR. Additionally, they showed much less affinity toward wild-type (WT)-EGFR with minimal cardiotoxicity.

Imaging doxorubicin and polymer-drug conjugates of doxorubicin-induced cardiotoxicity with bispecific anti-myosin-anti-DTPA antibody and Tc-99m-labeled polymers

BackgroundRadiolabeled anti-myosin imaging is well-established for imaging doxorubicin-induced cardiotoxicity. However, to enable imaging of drug-induced cardiotoxicity in small experimental animals, pretargeting with bispecific anti-myosin-anti-DTPA-Fab-Fab’ and targeting with high-specific radioactivity Tc-99m-DTPA-succinylated-polylysine (DSPL) was developed. MethodsMice were injected biweekly with 10 mg/kg Dox or its equivalent as D-Dox-PGA. Tc-99m-DSPL myocardial activity after pretargeting with bsAb-Fab-Fab’ was determined after gamma imaging performed at day 7 for Dox-treated mice and day 39 for all others. ResultsMice treated with 10 mg/kg Dox lost 10% total body weight in 1 week and 20% after a second dose. Pretargeted mice treated with 30 mg/kg cumulative D-Dox-PGA dose showed no loss of body weight for the duration of the study. Cardiotoxicity was confirmed by gamma imaging and scintillation counting (1.9 ± 0.25 [mean% ID/g ± SD]) after 1 dose of Dox. Mice injected with 3 × 10 mg/kg Dox equivalent as D-Dox-PGA (0.4 ± 0.04, P < .01) and untreated 2 control groups (0.20 ± 0.05 and 0.19 ± 0.04, P < .01) showed significantly lower myocardial anti-myosin radioactivity relative to the 10 mg/kg Dox group. ConclusionPretargeting with bsAb-Fab-Fab’ and targeting with Tc-99m labeled high-specific activity polymers enabled early visualization of doxorubicin induce cardiotoxicity in mice. Tolerated dose of D-Dox-PGA was greater than to 30 mg/kg Dox-equivalent dose with minimal cardiotoxicity.

Biodegradable Polymeric Nanocapsules Prevent Cardiotoxicity of Anti-Trypanosomal Lychnopholide

Chagas disease is a neglected parasitic disease caused by the protozoan Trypanosoma cruzi. New antitrypanosomal options are desirable to prevent complications, including a high rate of cardiomyopathy. Recently, a natural substance, lychnopholide, has shown therapeutic potential, especially when encapsulated in biodegradable polymeric nanocapsules. However, little is known regarding possible adverse effects of lychnopholide. Here we show that repeated-dose intravenous administration of free lychnopholide (2.0 mg/kg/day) for 20 days caused cardiopathy and mortality in healthy C57BL/6 mice. Echocardiography revealed concentric left ventricular hypertrophy with preserved ejection fraction, diastolic dysfunction and chamber dilatation at end-stage. Single cardiomyocytes presented altered contractility and Ca2+ handling, with spontaneous Ca2+ waves in diastole. Acute in vitro lychnopholide application on cardiomyocytes from healthy mice also induced Ca2+ handling alterations with abnormal RyR2-mediated diastolic Ca2+ release. Strikingly, the encapsulation of lychnopholide prevented the cardiac alterations induced in vivo by the free form repeated doses. Nanocapsules alone had no adverse cardiac effects. Altogether, our data establish lychnopholide presented in nanocapsule form more firmly as a promising new drug candidate to cure Chagas disease with minimal cardiotoxicity. Our study also highlights the potential of nanotechnology not only to improve the efficacy of a drug but also to protect against its adverse effects.

Doxorubicin/heparin composite nanoparticles for caspase-activated prodrug chemotherapy.

Caspase-activated prodrug chemotherapy is introduced and demonstrated using the composite nanoparticles (NPs), which deliver doxorubicin (DOX) and DEVD-S-DOX together to the tumor tissue. DEVD-S-DOX, DOX linked to a peptide moiety (DEVD), is a prodrug that is cleaved into free DOX by caspase-3 upon apoptosis. DEVD-S-DOX has no therapeutic efficacy, but it changes into free DOX with the expression of caspase-3. With the accumulation of the composite NPs in the tumor tissue by the enhanced permeation and retention (EPR) effect, a small exposure of DOX in the tumor cells initiated apoptosis in a localized area of the tumor tissue, which induced caspase-3 activation. Cleavage of DEVD-S-DOX into free DOX by caspase-3 continued with repetitive activation of caspase-3 and cleavage of DEVD-S-DOX at the tumor site. The composite NPs were characterized with transmittance electron microscopy (TEM) and particle size analyzer. We then evaluated the nanoparticle drug release, therapeutic efficacy, and invivo biodistribution for tumor targeting using a non-invasive live animal imaging technology and the quantification of DOX with high performance liquid chromatography. DOX-induced apoptosis-targeted chemotherapy (DIATC) was verified by invitro/invivo DEVD-S-DOX response to free DOX and cellular uptake behavior of the composite NPs with flow cytometry analysis. Significant antitumor efficacy with minimal cardiotoxicity was also observed, which supported DIATC for improved chemotherapy.

Folic Acid and Trastuzumab Functionalized Redox Responsive Polymersomes for Intracellular Doxorubicin Delivery in Breast Cancer.

Redox responsive biodegradable polymersomes comprising of poly(ethylene glycol)-polylactic acid-poly(ethylene glycol) [PEG-s-s-PLA-s-s-PLA-s-s-PEG] triblock copolymer with multiple disulfide linkages were developed to improve intracellular delivery and to enhance chemotherapeutic efficacy of doxorubicin in breast cancer with minimal cardiotoxicity. Folic acid and trastuzumab functionalized monodispersed polymersomes of size ∼150 nm were prepared by nanoprecipitation method while achieving enhanced doxorubicin loading of ∼32% in the polymersomes. Multiple redox responsive disulfide linkages were incorporated in the polymer in order to achieve complete disintegration of polymersomes in redox rich environment of cancer cells resulting in enhanced doxorubicin release as observed in in vitro release studies, where ∼90% doxorubicin release was achieved in pH 5.0 in the presence of 10 mM glutathione (GSH) as compared to ∼20% drug release in pH 7.4. Folic acid and trastuzumab mediated active targeting resulted in improved cellular uptake and enhanced apoptosis in in vitro studies in breast cancer cell lines. In vivo studies in Ehrlich ascites tumor bearing Swiss albino mice showed enhanced antitumor efficacy and minimal cardiotoxicity of polymersomes with ∼90% tumor regression as compared to ∼38% tumor regression observed with free doxorubicin. The results highlight therapeutic potential of the polymersomes as doxorubicin delivery nanocarrier in breast cancer therapy with its superior antitumor efficacy and minimal cardiotoxicity.

Modeling localized delivery of Doxorubicin to the brain following focused ultrasound enhanced blood-brain barrier permeability

Doxorubicin (Dox) is a well-established chemotherapeutic agent, however it has limited efficacy in treating brain malignancies due to the presence of the blood-brain barrier (BBB). Recent preclinical studies have demonstrated that focused ultrasound induced BBB disruption (BBBD) enables efficient delivery of Dox to the brain. For future treatment planning of BBBD-based drug delivery, it is crucial to establish a mathematical framework to predict the effect of transient BBB permeability enhancement on the spatiotemporal distribution of Dox at the targeted area. The constructed model considers Dox concentrations within three compartments (plasma, extracellular, intracellular) that are governed by various transport processes (e.g. diffusion in interstitial space, exchange across vessel wall, clearance by cerebral spinal fluid, uptake by brain cells). By examining several clinical treatment aspects (e.g. sonication scheme, permeability enhancement, injection mode), our simulation results support the experimental findings of optimal interval delay between two consecutive sonications and therapeutically-sufficient intracellular concentration with respect to transfer constant Ktrans range of 0.01–0.03 min−1. Finally, the model suggests that infusion over a short duration (20–60 min) should be employed along with single-sonication or multiple-sonication at 10 min interval to ensure maximum delivery to the intracellular compartment while attaining minimal cardiotoxicity via suppressing peak plasma concentration.

Tolerability and toxicological profile of pixantrone (Pixuvri®) in juvenile mice. Comparative study with doxorubicin

The tolerability of pixantrone dimaleate (Pixuvri®), an aza-anthracenedione for non-Hodgkin lymphoma, was assessed in juvenile mice after intraperitoneal injection.Twenty animals/sex/dose received pixantrone 15 or 27mg/kg/day on Post-Natal-Days (PND) 10, 13, 17, 20, 35, 39 and 42 in comparison with doxorubicin, 3mg/kg/day. Animals were sacrificed on PND 42, 73 and 96.All pixantrone animals survived, while doxorubicin induced 52.5% mortality and the surviving animals were sacrificed early due to severe toxicity. Recoverable bone marrow toxicity (pixantrone), and toxicity to thymus and reproductive organs (pixantrone, doxorubicin) were observed without nephro- or hepatotoxicity. Pixantrone was measurable in plasma up to 2h (occasionally 6h) post-dose. At PND 42, mean Cmax and AUC values increased proportionally with dose, without gender difference or accumulation.Pixantrone showed minimal cardiotoxicity in males and negligible in females at PND 96. Doxorubicin induced significant heart weight reduction at PND 42, however early sacrifice impeded further cardiac assessments.

Comparison of Cardiac Troponin I and T, Including the Evaluation of an Ultrasensitive Assay, as Indicators of Doxorubicin-induced Cardiotoxicity

Cardiac troponin (cTn) has been utilized to assess acute myocardial injury, but the cTn response in active/ongoing chronic injury is not well documented. The purpose of this study was to characterize the cardiac troponin I (cTnI), cardiac troponin T (cTnT), high-sensitivity cTnI, hematology, and clinical chemistry responses in rats treated with doxorubicin. Rats treated with 1, 2, or 3 mg/kg/week (wk) of doxorubicin for 2, 4, or 6 wks were sacrificed after 0, 2, or 4 wks of recovery and compared to untreated controls and animals treated with doxorubicin/dexrazoxane (50 mg/kg/wk) or etoposide (1 and 3 mg/kg/wk). The incidence and mean magnitude of cTn response increased with increasing dose and/or duration of doxorubicin treatment. Conversely, dexrazoxane/doxorubicin was partially protective for cardiotoxicity, and minimal cardiotoxicity occurred with etoposide treatment. Both cTnI and cTnT effectively identified doxorubicin-induced injury as indicated by vacuolation of cardiomyocytes of the atria/ventricles. The association between the cTn responses and histological changes was greater at the higher total exposures, but the magnitude of cTn response did not match closely with histologic grade. The high-sensitivity cTnI assay was also effective in identifying cardiac injury. Alterations occurred in the hematology and clinical chemistry parameters and reflected both dose and duration of doxorubicin treatment.