Anthracyclines induce cardiotoxicity through a shared gene expression response signature.

TOP2 inhibitors (TOP2i) are effective drugs for breast cancer treatment. However, they can cause cardiotoxicity in some women. The most widely used TOP2i include anthracyclines (AC) Doxorubicin (DOX), Daunorubicin (DNR), Epirubicin (EPI), and the anthraquinone Mitoxantrone (MTX). It is unclear whether women would experience the same adverse effects from all drugs in this class, or if specific drugs would be preferable for certain individuals based on their cardiotoxicity risk profile. To investigate this, we studied the effects of treatment of DOX, DNR, EPI, MTX, and an unrelated monoclonal antibody Trastuzumab (TRZ) on iPSC-derived cardiomyocytes (iPSC-CMs) from six healthy females. All TOP2i induce cell death at concentrations observed in cancer patient serum, while TRZ does not. A sub-lethal dose of all TOP2i induces limited cellular stress but affects calcium handling, a function critical for cardiomyocyte contraction. TOP2i induce thousands of gene expression changes over time, giving rise to four distinct gene expression response signatures, denoted as TOP2i early-acute, early-sustained, and late response genes, and non-response genes. There is no drug- or AC-specific signature. TOP2i early response genes are enriched in chromatin regulators, which mediate AC sensitivity across breast cancer patients. However, there is increased transcriptional variability between individuals following AC treatments. To investigate potential genetic effects on response variability, we first identified a reported set of expression quantitative trait loci (eQTLs) uncovered following DOX treatment in iPSC-CMs. Indeed, DOX response eQTLs are enriched in genes that respond to all TOP2i. Next, we identified 38 genes in loci associated with AC toxicity by GWAS or TWAS. Two thirds of the genes that respond to at least one TOP2i, respond to all ACs with the same direction of effect. Our data demonstrate that TOP2i induce thousands of shared gene expression changes in cardiomyocytes, including genes near SNPs associated with inter-individual variation in response to DOX treatment and AC-induced cardiotoxicity.

Targeting autophagy with SAR405 alleviates doxorubicin-induced cardiotoxicity.

Anthracycline antitumor agents, such as doxorubicin (DOX), are effective in the treatment of solid tumors and hematological malignancies, but anthracycline-induced cardiotoxicity (AIC) limits their application as chemotherapeutics. Dexrazoxane (DEX) has been adopted to prevent AIC. Using a chronic AIC mouse model, we demonstrated that DEX is insufficient to reverse DOX-induced cardiotoxicity. Although therapies targeting autophagy have been explored to prevent AIC, but whether novel autophagy inhibitors could alleviate or prevent AIC in clinically relevant models needs further investigation. Here, we show that genetic ablation of Atg7, a key regulator in the early phase of autophagy, protected mice against AIC. We further demonstrated that SAR405, a novel autophagy inhibitor, attenuated DOX-induced cytotoxicity. Intriguingly, the combination of DEX and SAR405 protected cells against DOX-induced cardiotoxicity in vivo. Using the cardiomyocyte cell lines AC16 and H9c2, we determined that autophagy was initiated during AIC. Our results suggest that inhibition of autophagy at its early phase with SAR405 combined with DEX represents an effective therapeutic strategy to prevent AIC.

Evaluation of Ameliorative Effect of Quercetin and Candesartan in Doxorubicin-Induced Cardiotoxicity.

Background: Several mechanisms have been explored for the anthracycline myocardial toxicity. These are free-radical generation, myocyte apoptosis, lipid peroxidation, mitochondrial deterioration, and direct repression of muscle-specific gene expression. Adriamycin (Doxorubicin) is a potent anti-cancer agent. Adriamycin in prolonged use is fatal and generates free radicals that lead to dose-dependent cardiac toxicity. Objective: The intent of the study was to explore the protective activity of candesartan and quercetin in cardiomyopathy induced by doxorubicin in rats. Methods: To induce cardiac toxicity, rats were intraperitoneally treated with doxorubicin (06 equivalent injections of 2.5 mg/kg, i. p. at 48 hour interval for 02 consecutive weeks to achieve a cumulative dose of 15 mg/kg). Individual and combined oral treatment of candesartan (5 mg/kg/day) and quercetin (10 mg/kg/day) was administered for four weeks. Results: Following cardiomyopathy, heart/body weight ratio (3.526 × 10-3), serum creatine kinase (352.4±16.99 IU/L), lactate dehydrogenase (661.7±20.45 IU/L) levels were elevated in addition to altered lipid profile (TC - 118.4±4.25 mg/dL, TG - 263.3±9.99 mg/dL, VLDL - 52.66±1.99 mg/dL, LDL - 52.99±5.80 mg/dL and HDL - 12.78±0.36 mg/dL). The pre-cotreatment of candesartan and quercetin significantly restored the values to normal. The increased level of lipid peroxides (33.12±1.63 µmol/mg protein), serum troponin-T (1.82 ± 0.11 pg/mL) and nitric oxide (13.33±0.73 nmol/mg protein) level along with attenuating antioxidant profile, ie catalase, glutathione and superoxide dismutase (1.43±0.12 nmol/mg protein, 8.48±0.42 nmol/mg protein and 2.09±0.031 U/mg protein) were reversed to normal. Morphometry and histopathologic changes represented a beneficial effect of single and combination pre-cotreatment of drugs which significantly decreases adriamycin cardiac toxicity. Conclusion: The overall result depicts more beneficial and cardioprotective effect of quercetin and candesartan combination as compared to their individual effects in doxorubicin treated animals. Therefore, this combination might be a suitable option to treat the cardiotoxic effect of doxorubicin.

A BioBricks Metabolic Engineering Platform for the Biosynthesis of Anthracyclinones in Streptomyces coelicolor.

Actinomycetes produce a variety of clinically indispensable molecules, such as antineoplastic anthracyclines. However, the actinomycetes are hindered in their further development as genetically engineered hosts for the synthesis of new anthracycline analogues due to their slow growth kinetics associated with their mycelial life cycle and the lack of a comprehensive genetic toolbox for combinatorial biosynthesis. In this report, we tackled both issues via the development of the BIOPOLYMER (BIOBricks POLYketide Metabolic EngineeRing) toolbox: a comprehensive synthetic biology toolbox consisting of engineered strains, promoters, vectors, and biosynthetic genes for the synthesis of anthracyclinones. An improved derivative of the production host Streptomyces coelicolor M1152 was created by deleting the matAB gene cluster that specifies extracellular poly-ß-1,6-N-acetylglucosamine (PNAG). This resulted in a loss of mycelial aggregation, with improved biomass accumulation and anthracyclinone production. We then leveraged BIOPOLYMER to engineer four distinct anthracyclinone pathways, identifying optimal combinations of promoters, genes, and vectors to produce aklavinone, 9-epi-aklavinone, auramycinone, and nogalamycinone at titers between 15-20 mg/L. Optimization of nogalamycinone production strains resulted in titers of 103 mg/L. We structurally characterized six anthracyclinone products from fermentations, including new compounds 9,10-seco-7-deoxy-nogalamycinone and 4-O-ß-d-glucosyl-nogalamycinone. Lastly, we tested the antiproliferative activity of the anthracyclinones in a mammalian cancer cell viability assay, in which nogalamycinone, auramycinone, and aklavinone exhibited moderate cytotoxicity against several cancer cell lines. We envision that BIOPOLYMER will serve as a foundational platform technology for the synthesis of designer anthracycline analogues.

Cinnamamide derivatives with 4-hydroxypiperidine moiety enhance effect of doxorubicin to cancer cells and protect cardiomyocytes against drug-induced toxicity through CBR1 inhibition mechanism.

Doxorubicin (DOX) is classified by World Health Organization (WHO) as an essential medicine for cancer. However, its clinical application is limited due to resistance development and cardiotoxicity. Many attempts have been made to address these issues with some focused on finding a potential adjuvant therapy. Recently, inhibition of carbonyl reduction of anthracyclines (ANTs), catalyzed by enzymes from carbonyl reductase (CBR) and aldo-keto reductase (AKR) families, emerged as a potential way to simultaneously bypass cancer resistance and alleviate cardiotoxicity of ANTs. In this context, we evaluated the potential application of l synthetic cinnamic acid derivatives (CA) - 1a (2E)-3-(4- chlorophenyl)-1-(4-hydroxypiperidin-1-yl)prop-2-en-1 and 1b (2E)-1-(4-hydroxypiperidin-1-yl)-3-(2-methylphenyl)prop-2-en-1-one. The tested compounds were found to chemosensitize A549 human lung cancer cell line towards DOX-induced viability reduction and apoptosis, while having no effect in non-cancerous lung fibroblasts. Co-treatment with DOX + 1a/1b significantly inhibited the migration of A549 in a Transwell assay. The addition of 1a/1b alleviated menadione-induced viability reduction in H9c2 rat cardiomyoblast cell line. Accordingly, 1a/1b reduced DOX-induced reactive oxygen species (ROS) generation and increased glutathione levels. The compounds were also found to moderate autophagy process and limit inflammatory response in RAW 264.7 macrophage cell line. Inhibitory properties of the compounds towards CBR1 were simulated by molecular modeling and confirmed in vitro in enzyme inhibition assay with recombinant CBR1 protein. In contrast to 1b, 1a has strong CBR1 inhibition, which correlates well with more profound effect elicited by 1a uniformly throughout the other experiments. Finally, no mutagenic, genotoxic or hepatotoxic activity of the compounds were found. The possible products of cytochrome P450 mediated metabolism of 1a and 1b were also established to evaluate the potential impact of first pass effect. Our results suggest that 1a and 1b are promising candidates for DOX adjuvant therapy that may simultaneously chemosensitize cancer cells and alleviate cardiotoxicity. The higher activity of 1a may be linked with CBR1 inhibition.

Promising cardioprotective effect of baicalin in doxorubicin-induced cardiotoxicity through targeting toll-like receptor 4/nuclear factor-κB and Wnt/ß-catenin pathways.

Doxorubicin (Dox) is an indispensable chemotherapeutic agent associated with damaging cardiotoxicity. Baicalin (BA) is a flavonoid, extracted from the medicinal plant Scutellariae baicalensis Georgi. BA is well known for its anti-inflammatory and antioxidant effects. Our study investigated the potential effect of BA in attenuating Dox-induced cardiotoxicity. To this end, male Swiss albino mice were given BA (100 mg/kg/d, orally) for 4 wk and were challenged with Dox (six intraperitoneal doses, each 2.5 mg/kg, every other day with a final cumulative dose of 15 mg/kg). Serum activities of cardiac biomarkers (cardiac troponin-I, creatine kinase-membrane bound, lactate dehydrogenase, and aspartate aminotransferase) were assessed along with the histopathological examination of the heart tissues. Gene expression of Toll-like receptor 4 (TLR4) was analyzed by quantitative reverse transcription real-time polymerase chain reaction. Analysis of the protein levels of ß-catenin and nuclear factor-κB (NF-κB) was done immunohistochemically. Cardiac Dickkopf-1 (DKK1) and interleukin-1beta (IL-1ß) were quantified by enzyme-linked immuno-sorbent assay. Cardiac levels of reduced glutathione (GSH) and malondialdehyde (MDA) were detected spectrophotometrically. Pretreatment with BA significantly prevented Dox-induced elevation of serum activities of cardiac biomarkers and alterations to the heart. Moreover, BA suppressed the gene overexpression of cardiac TLR4 and subsequently prevented Dox-induced elevation of both cardiac NF-κB and IL-1ß. BA also significantly reduced the cardiac levels of DKK1 and elevated the level of ß-catenin. Dox-induced elevation of MDA and reduction of GSH were reversed by BA. BA exhibited a novel cardioprotective effect against Dox-induced cardiotoxicity. The cardioprotective effect was indicated through the inhibition of the inflammatory TLR4/NF-κB pathway and the activation of the protective Wnt/ß-catenin pathway by the suppression of DKK1.

Genome-wide CRISPR screen identified Rad18 as a determinant of doxorubicin sensitivity in osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is a malignant bone tumor mostly occurring in children and adolescents, while chemotherapy resistance often develops and the mechanisms involved remain challenging to be fully investigated. METHODS: Genome-wide CRISPR screening combined with transcriptomic sequencing were used to identify the critical genes of doxorubicin resistance. Analysis of clinical samples and datasets, and in vitro and in vivo experiments (including CCK-8, apoptosis, western blot, qRT-PCR and mouse models) were applied to confirm the function of these genes. The bioinformatics and IP-MS assays were utilized to further verify the downstream pathway. RGD peptide-directed and exosome-delivered siRNA were developed for the novel therapy strategy. RESULTS: We identified that E3 ubiquitin-protein ligase Rad18 (Rad18) contributed to doxorubicin-resistance in OS. Further exploration revealed that Rad18 interact with meiotic recombination 11 (MRE11) to promote the formation of the MRE11-RAD50-NBS1 (MRN) complex, facilitating the activation of the homologous recombination (HR) pathway, which ultimately mediated DNA damage tolerance and leaded to a poor prognosis and chemotherapy response in patients with OS. Rad18-knockout effectively restored the chemotherapy response in vitro and in vivo. Also, RGD-exosome loading chemically modified siRad18 combined with doxorubicin, where exosome and chemical modification guaranteed the stability of siRad18 and the RGD peptide provided prominent targetability, had significantly improved antitumor activity of doxorubicin. CONCLUSIONS: Collectively, our study identifies Rad18 as a driver of OS doxorubicin resistance that promotes the HR pathway and indicates that targeting Rad18 is an effective approach to overcome chemotherapy resistance in OS.

Construction of a sequentially responsive nanocarrier for chemotherapy and cascade amplified NIR photodynamic therapy.

A sequentially responsive nanocarrier was fabricated with three-in-one functional integration: bio-imaging, tumor microenvironment responsive chemotherapy and cascade activation of upconversion photodynamic therapy. The designed DNA outer nanoshell displayed site-specific degradation and controlled degradation speed. Significantly, the developed controllable nanotheranostic agent displayed high cell apoptosis ratios and obvious tumor inhibition.

Mitochondrial Dysfunction and Antioxidation Dyshomeostasis-Enhanced Tumor Starvation Synergistic Chemotherapy Achieved using a Metal-Organic Framework-Based Nano-Enzyme Reactor.

Exploiting zeolitic imidazolate framework (ZIF)-based nanoparticles to synergistically enhance starvation-combined chemotherapy strategies remains an urgent demand. Herein, glucose oxidase (GOX) and doxorubicin (DOX) were facilely incorporated into ZIFs for starvation-combined chemotherapy. The as-prepared DOX/GOX-loaded ZIF (DGZ) exhibited uniform size with good dispersity, effective protection of the GOX activity, and stable delivery of the drugs into tumor. Correspondingly, it could achieve the glucose- and pH-responsive degradation and thus the controllable drug release. As a result, the acidification of glucose accompanied with reactive oxygen species (ROS) production was observed for the starvation-enhanced chemotherapy and the improved degradation. Most importantly, adjustable Zn2+ release was achieved with the biodegradation of DGZ, which thus contributed to an augmented therapeutic outcome via the Zn2+-induced mitochondrial dysfunction and antioxidation dyshomeostasis. These findings, synergized with the enhancement of starvation-combined chemotherapy by inhibiting the mitochondrial energy metabolism and boosting the ROS accumulation using pristine ZIF-based nanoparticles, provide a new insight into the metal-organic framework-based nanomedicine for further cancer treatments.

Influence of lipophilicity of anthracyclines on the interactions with cholesterol in the model cell membranes - Langmuir monolayer and SEIRAS studies.

The interactions of anthracyclines with biological membranes strongly depend on the drug lipophilicity, which might also determine the specific affinity to cholesterol molecules. Therefore, in this work we show the studies concerning the effect of two selected anthracyclines, daunorubicin (DNR) and idarubicin (IDA) on simple models of healthy (DMPC:Chol 7:3) and cancer cells membranes with increased level of cholesterol (DMPC:Chol 3:7) as well as pure cholesterol monolayers prepared at the air-water interface and supported on gold surface. It has been shown that more lipophilic IDA is able to penetrate cholesterol monolayers more effectively than DNR due to the formation of IDA-cholesterol arrangements at the interface, as proved by the thermodynamic analysis of compression-expansion cycles. The increased interactions of IDA were also confirmed by the time measurements of pre-compressed monolayers exposed to drug solutions as well as grazing incidence X-ray diffraction studies demonstrating differences in the 2D organization of cholesterol monolayers. Langmuir studies of mixed DMPC:Chol membranes revealed the reorganization of molecules in the cancer cell models at the air-water interface at higher surface pressures due to the removal of DNR, while increased affinity of IDA towards cholesterol allowed this drug to penetrate the layer more efficiently without its removal. The SEIRAS spectra obtained for supported DMPC:Chol bilayers proved that IDA locates both in the ester group and in the acyl chain region of the bilayer, while DNR does not penetrate the membranes as deeply as IDA. The increased penetration of the mixed phospholipid layers by idarubicin might be attributed to the higher lipophilicity caused by the lack of methoxy group and resulting in a specific affinity towards cholesterol.

miR-197-5p increases Doxorubicin-mediated anticancer cytotoxicity of HT1080 fibrosarcoma cells by decreasing drug efflux.

Doxorubicin (Dox) is one of the most used drugs in the treatment of Soft tissue sarcoma. However, acquired resistance linked with poor survival and numerous side effects are the major challenges. Meanwhile, miRNAs are reported to influence the chemotherapeutic responses. However, there is hardly any evidence on the involvement of tumor-suppressive miR-197 reported in our previous study in augmenting the sensitivity of fibrosarcoma cells to Dox. Therefore, in this study, we intend to decipher if miR-197-5p combined with Dox could increase the anticancer cytotoxicity. For this, we evaluated the antitumorigenic effects of Dox and miR-197-5p individually and in combination by performing a series of molecular assays. We noticed that the sub-lethal concentration of miR-197-5p markedly enhanced the sensitivity of HT1080 fibrosarcoma cells to Dox by promoting apoptosis and G2/M cell cycle arrest. We also observed miR-197-5p sensitizes HT1080 cells to Dox by increasing drug influx, possibly due to suppression of MDR genes (ABCC1, MVP). Moreover, we found that KIAA0101, a target of miR-197-5p is inhibited by Dox, which is further repressed when treated in combination with miRNA. We also observed a marked upregulation of p53, known to be negatively correlated with KIAA0101 in Dox and miR-197-5p combination treatment compared to Dox alone. Taken together, our study revealed that Dox chemotherapy in combination with miR-197-5p could overcome the problem of drug efflux and enhance its antitumor effects on fibrosarcoma.

Ideal Nozzle Position During Pressurized Intraperitoneal Aerosol Chemotherapy in an Ex Vivo Model.

BACKGROUND/AIM: Pressurized intraperitoneal aerosol chemotherapy (PIPAC) is known to show uneven distribution and penetration of agents based on the nozzle position. Thus, this study aimed to investigate the ideal nozzle position for maximizing drug delivery during PIPAC. MATERIALS AND METHODS: We created 2 cm-, 4 cm- and 8 cm-ex vivo models according to the distance from the bottom to the nozzle using 21×15×16 cm-sized sealable plastic boxes. After each set of eight normal peritoneal tissues from swine were placed at eight different points (A to H), we performed PIPAC, compared the methylene blue staining areas to investigate the distribution, and estimated the depth of concentrated diffusion (DCD) and the depth of maximal diffusion (DMD) of doxorubicin. RESULTS: In terms of distribution, the 4 cm- and 8 cm-ex vivo models showed more stained faces than the 2 cm-ex vivo model. Regarding the penetration depth, the 4 cm- ex vivo model showed the highest DCD (mean; 244.1 µm, C; 105.1 µm, D; 80.9 µm, E; 250.2 µm, G; 250.2 µm, H) and DMD (mean; 174.8 µm, D; 162.7 µm, E; 511.7 µm, F; 522.2 µm, G; 528.1 µm, H) in the most points corresponding to 62.5%. CONCLUSION: The ideal nozzle position during PIPAC might be halfway between the nozzle inlet and the bottom in the ex vivo model.

Enzyme-Induced Transformable Peptide Nanocarriers with Enhanced Drug Permeability and Retention to Improve Tumor Nanotherapy Efficacy.

Temporal persistence is as important for nanocarriers as spatial accuracy. However, because of the insufficient aggreagtion and short retention time of chemotherapy drugs in tumors, their clinical application is greatly limited. A drug delivery approach dependent on the sensitivity to an enzyme present in the microenvironment of the tumor is designed to exhibit different sizes in different sites, achieving enhanced drug permeability and retention to improve tumor nanotherapy efficacy. In this work, we report a small-molecule peptide drug delivery system containing both tumor-targeting groups and enzyme response sites. This system enables the targeted delivery of peptide nanocarriers to tumor cells and a unique response to alkaline phosphatase (ALP) in the tumor microenvironment to activate morphological transformation and drug release. The amphiphilic peptide AYR self-aggregated into a spherical nanoparticle structure after encapsulating the lipid-soluble model drug doxorubicin (DOX) and rapidly converted to nanofibers via the induction of ALP. This morphological transformation toward a high aspect ratio allowed rapid, as well as effective drug release to tumor location while enhancing specific toxicity to tumor cells. Interestingly, this "transformer"-like drug delivery strategy can enhance local drug accumulation and effectively inhibit drug efflux. In vitro along with in vivo experiments further proved that the permeability and retention of antitumor drugs in tumor cells and tissues were significantly enhanced to reduce toxic side effects, and the therapeutic effect was remarkably improved compared with that of nondeformable drug-loaded peptide nanocarriers. The developed AYR nanoparticles with the ability to undergo morphological transformation in situ can improve local drug aggregation and retention time at the tumor site. Our findings provide a new and simple method for nanocarrier morphology transformation in novel cancer treatments.

Cancer cell membrane-coated nanogels as a redox/pH dual-responsive drug carrier for tumor-targeted therapy.

Nanocarriers have shown great advantages in increasing the efficiency of drug delivery and reducing drug side effects. However, their lack of targeting and on-demand drug release abilities will seriously limit their clinical application. Herein, we report tumor cell membrane coated nanogels (NGs) with redox/pH dual-responsive behavior for enhanced tumor chemotherapy. The cell membrane coating improves the tumor targeting efficiency, and stimuli-responsive drug release enhances the therapeutic effects. These NGs are well dispersed in PBS with an average size of 109.1 ± 5.2 nm and a narrow polydispersity index of 0.12. Both in vitro and in vivo studies indicate that these NGs can responsively release the therapeutic drug DOX under acidic conditions or high GSH concentrations and effectively inhibit tumor growth. Based on the results, this nanogel shows promise as a platform for tumor-targeted chemotherapy for future clinical translation.

The Value of Convolutional Neural Network-Based Magnetic Resonance Imaging Image Segmentation Algorithm to Guide Targeted Controlled Release of Doxorubicin Nanopreparation.

There was an investigation of the auxiliary role of convolutional neural network- (CNN-) based magnetic resonance imaging (MRI) image segmentation algorithm in MRI image-guided targeted drug therapy of doxorubicin nanomaterials so that the value of drug-controlled release in liver cancer patients was evaluated. In this study, 80 patients with liver cancer were selected as the research objects. It was hoped that the CNN-based MRI image segmentation algorithm could be applied to the guided analysis of MRI images of the targeted controlled release of doxorubicin nanopreparation to analyze the imaging analysis effect of this algorithm on the targeted treatment of liver cancer with doxorubicin nanopreparation. The results of this study showed that the upgraded three-dimensional (3D) CNN-based MRI image segmentation had a better effect compared with the traditional CNN-based MRI image segmentation, with significant improvement in indicators such as accuracy, precision, sensitivity, and specificity, and the differences were all statistically marked (p < 0.05). In the monitoring of the targeted drug therapy of doxorubicin nanopreparation for liver cancer patients, it was found that the MRI images of liver cancer patients processed by 3D CNN-based MRI image segmentation neural algorithm could be observed more intuitively and guided to accurately reach the target of liver cancer. The accuracy of targeted release determination of nanopreparation reached 80 ± 6.25%, which was higher markedly than that of the control group (66.6 ± 5.32%) (p < 0.05). In a word, the MRI image segmentation algorithm based on CNN had good application potential in guiding patients with liver cancer for targeted therapy with doxorubicin nanopreparation, which was worth promoting in the adjuvant treatment of targeted drugs for cancer.

A chitosan/mesoporous silica nanoparticle-based anticancer drug delivery system with a "tumor-triggered targeting" property.

To enhance drug utilization and reduce their side effects, the strategy of "tumor-triggered targeting" was introduced to fabricate dual-pH-sensitive chitosan (CHI)/mesoporous silica nanoparticle (MSN)-based anticancer drug delivery system (DDS) in this work. Model drug doxorubicin hydrochloride (DOX) was loaded in MSN, which was modified with benzimidazole (Bz) group. Then chitosan-graft-ß-cyclodextrin (CHI-g-CD) was applied as the "gatekeeper" to cover MSN through host-guest interaction between ß-CD and Bz. After being coated with targeting peptide adamantane-glycine-arginine-glycine-aspartic acid-serine (Ad-GRGDS), methoxy poly(ethylene glycol) benzaldehyde (mPEG-CHO) was finally grafted on CHI through the pH-sensitive benzoic imine bond. Due to the dynamic protection of PEG, the obtained carriers were "stealthy" at pH 7.4, but could reveal the shielded targeting peptide and the positive charge of CHI in the weakly acidic environment achieved a "tumor-triggered targeting". Inside cancer cells, the interaction between ß-CD and Bz group could be destroyed due to the lower pH, resulted in DOX release. Both in vitro and in vivo studies proved the DDS could targeting induce cancer cell apoptosis, inhibit tumor growth, and reduce the cytotoxicity of DOX against normal cells. It is expected that the system named DOX@MSN-CHI-RGD-PEG could be a potential choice for cancer therapy.

Biotransformation of Doxorubicin Promotes Resilience in Simplified Intestinal Microbial Communities.

Chemotherapeutic drugs can cause harmful gastrointestinal side effects, which may be modulated by naturally occurring members of our microbiome. We constructed simplified gut-associated microbial communities to test the hypothesis that bacteria-mediated detoxification of doxorubicin (i.e., a widely used chemotherapeutic) confers protective effects on the human microbiota. Mock communities composed of up to five specific members predicted by genomic analysis to be sensitive to the drug or resistant via biotransformation and/or efflux were grown in vitro over three generational stages to characterize community assembly, response to perturbation (doxorubicin exposure), and resilience. Bacterial growth and drug concentrations were monitored with spectrophotometric assays, and strain relative abundances were evaluated with 16S rRNA gene sequencing. Bacteria with predicted resistance involving biotransformation significantly lowered concentrations of doxorubicin in culture media, permitting growth of drug-sensitive strains in monoculture. Such protective effects were not produced by strains with drug resistance conferred solely by efflux. In the mixed communities, resilience of drug-sensitive members depended on the presence and efficiency of transformers, as well as drug exposure concentration. Fitness of bacteria that were resistant to doxorubicin via efflux, though not transformation, also improved when the transformers were present. Our simplified community uncovered ecological relationships among a dynamic consortium and highlighted drug detoxification by a keystone species. This work may be extended to advance probiotic development that may provide gut-specific protection to patients undergoing cancer treatment. IMPORTANCE While chemotherapy is an essential intervention for treating many forms of cancer, gastrointestinal side effects may precede infections and risks for additional health complications. We developed an in vitro model to characterize key changes in bacterial community dynamics under chemotherapeutic stress and the role of bacterial interactions in drug detoxification to promote microbiota resilience. Our findings have implications for developing bio-based strategies to promote gut health during cancer treatment.

Nerolidol, a Sesquiterpene from the Essential Oils of Aromatic Plants, Attenuates Doxorubicin-Induced Chronic Cardiotoxicity in Rats.

The clinical usage of doxorubicin (DOX), a potent anthracycline antineoplastic drug, is limited due to its cardiotoxicity. The aim of this study was to assess the possible cardioprotective effects of nerolidol (NERO) in a rat model of DOX-induced chronic cardiotoxicity and the underlying molecular mechanisms. DOX (2.5 mg/kg) was injected intraperitoneally once in a week for 5 weeks to induce chronic cardiotoxicity in male albino Wistar rats. The rats were treated with NERO (50 mg/kg, orally) 6 days a week for a duration of 5 weeks. DOX-injected rats showed a significant decline in cardiac function, elevated levels of serum cardiac marker enzymes, and enhanced oxidative stress markers along with altered PI3K/Akt and Nrf2/Keap1/HO-1 signaling pathways. DOX also triggered the activation of NF-κB/MAPK signaling and increased the levels/expression of proinflammatory cytokines (TNF-α, IL-6, and IL-1ß) and expression of inflammatory mediators (iNOS and COX-2) in the heart. DOX activated NLRP3 inflammasome-mediated pyroptotic cell death along with fibrosis, mitochondrial dysfunction, DNA damage, and apoptosis in the myocardium. Additionally, histological studies, TUNEL staining, and myocardial lesions revealed structural alterations of the myocardium. NERO treatment showed considerable protective effects on the biochemical and molecular parameters studied. The findings demonstrate that NERO protects against DOX-induced chronic cardiotoxicity and the observed cardioprotective effects are attributed to its potent antioxidant and free radical scavenging properties.

Morphologically homogeneous, pH-responsive gold nanoparticles for non-invasive imaging of HeLa cancer.

Gold nanoparticles (AuNPs) have been widely used as nanocarriers in drug delivery to improve the efficiency of chemotherapy treatment and enhance early disease detection. The advantages of AuNPs include their excellent biocompatibility, easy modification and functionalization, facile synthesis, low toxicity, and controllable particle size. This study aimed to synthesize a conjugated citraconic anhydride link between morphologically homogeneous AuNPs and doxorubicin (DOX) (DOX-AuNP). The carrier was radiolabeled for tumor diagnosis using positron emission tomography (PET). The systemically designed DOX-AuNP was cleaved at the citraconic anhydride linker site under the mild acidic conditions of a cancer cell, thereby releasing DOX. Subsequently, the AuNPs aggregated via electrostatic attraction. HeLa cancer cells exhibited a high uptake of the radiolabeled DOX-AuNP. Moreover, PET tumor images were obtained using radiolabeled DOX-AuNP in cancer xenograft mouse models. Therefore, DOX-AuNP is expected to provide a valuable insight into the use of radioligands to detect tumors using PET.

A comprehensive review on alginate-based delivery systems for the delivery of chemotherapeutic agent: Doxorubicin.

Doxorubicin (DOX), an anthracycline drug, is widely used for the treatment of several cancers like osteosarcoma, cervical carcinoma, breast cancer, etc. DOX lacks target specificity; thereby it also affects normal cells thus resulting in several side-effects. A drug delivery system (DDS) can be used to deliver the drug in a controlled and sustained manner at a targeted site within the body. Various DDS like nanoemulsions, polymeric nanoparticles, and liposomes are used for loading DOX. Alginate, a polysaccharide is widely used for fabricating DDS due to its biodegradable and bio-compatible properties. Alginates, in combination with other biomaterials, have been extensively used as a novel drug delivery carrier for DOX. Alginate provides a platform for drug delivery in different forms like hydrogels, nanogels, nanoparticles, microparticles, graphene oxide systems, magnetic systems, etc. Herein, we briefly describe alginate in combination with other materials as a nanocarrier for targeted delivery of DOX for anti-cancer treatment.