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ObjectivesDetermine the role of apolipoprotein M (ApoM) in anthracycline (Dox) cardiotoxicity.BackgroundApoM binds the cardioprotective sphingolipid sphingosine-1-phosphate (S1P). Circulating ApoM is inversely associated with mortality in human heart failure (HF).MethodsIn the Penn HF Study (PHFS), we tested the relationship between ApoM and mortality in a subset with anthracycline-induced cardiomyopathy. We measured ApoM in humans and mice treated with Dox and utilized hepatic ApoM transgenic (ApomTG), ApoM knockout (ApomKO), ApoM knock-in mice with impaired S1P binding, and S1P receptor 3 (S1PR3) knockout mice in Dox cardiotoxicity. We assayed autophagy in left ventricular tissue from anthracycline-induced HF patients versus donor controls.ResultsApoM was inversely associated with mortality in PHFS, and Dox reduced circulating ApoM in mice and breast cancer patients.ApomTGmice were protected from Dox-induced cardiac dysfunction and loss of left ventricular mass.ApomTGattenuated Dox-induced impairment in autophagic flux in vivo and accumulation of insoluble p62, which was also observed in the myocardium of patients with anthracycline-induced HF. In vehicle-treated mice, ApoM negatively regulated transcription factor EB (TFEB), a master regulator of autophagy and lysosomal biogenesis. The effect of ApoM on TFEB required both S1P binding and S1PR3. In the presence of Dox, ApoM preserved TFEB and cardiomyocyte lysosomal abundance assessed as lysosomal associated membrane protein 1 positive structures in vivo, while S1P mimetic pretreatment of cardiomyocytes prevented Dox-induced changes in lysosomal pH.ConclusionsApoM attenuates Dox cardiotoxicity via the autophagy-lysosome pathway. The association between ApoM and reduced mortality may be explained by its role in sustaining autophagy.HighlightsCirculating ApoM is inversely associated with survival in human anthracycline-induced cardiomyopathyAnthracycline treatment reduces circulating ApoM in humans and miceIncreasing ApoM attenuates doxorubicin cardiotoxicity, lysosomal injury and preserves myocardial autophagic flux, but does not impact doxorubicin anti-neoplastic efficacyAutophagic impairment is characteristic of human anthracycline cardiomyopathy

Herein, a cyclodextrin derivative (R6RGD-CMβCD) with tumor target and a carboxymethyl chitosan derivative (M2pep-CMCS) with tumor-associated macrophages 2 (TAM2) target were successfully synthesized, respectively. DOX-loaded nanoparticles (R6RGD-CMβCD@DOX NPs, RCNP

The stimulatory natural killer-dendritic cell axis in the tumor microenvironment could play a critical role in stimulating cytotoxic T cells and driving immune responses against cancer.We established a novel treatment protocol by adroitly combining chemotherapy with doxorubicin and immunotherapy with dendritic cells and natural killer cells against a highly aggressive and malignant lymphoma called Dalton's lymphoma.Our data suggest that binary application of adoptive cell therapy and chemotherapy nearly cures (95%) early-stage experimental lymphoma. In the case of mid-stage cancer, the success rate was significantly lower but still impressive (75%). Our results demonstrated that the application of combination therapy in early-stage cancer significantly reduced the tumor volume and extended the lifespan of the experimental animal in addition to reinvigorating the immune system, including restoring the effector functions of dendritic cells and natural killer cells. The novel protocol limits the metastasis of tumor cells in vascularized organs and rearms the adaptive immune response mediated by dendritic cells and CD4Combination therapy in the early stage alters the cytokine profile, increases interferon-γ and tumor necrosis factor-α in the serum of treated animals and downregulates programmed cell death protein 1 expression in CD8

Natural killer (NK) cells exert cytotoxic effects against infected or stressed cells, such as tumor cells, without the limitation of major histocompatibility complex (MHC) I. NK cells secrete perforins to form tunnels to mediate the entry of granzyme into target cells. This strategy, selected by natural evolution, provides a feasible method for the delivery of antitumor drugs against intracellular targets, and avoids drug-resistant mechanisms in tumor cells, such as the pumping out of drugs mediated by multidrug resistance. We constructed pH-labile artificial NK cells (ANKC) based on nature to mediate high levels of drugs in tumor cells to overcome tumor drug resistance. Mesoporous silicon nanoparticles (MSNs) modified with benzaldehyde were designed to function as scaffolds for ANKC. Doxorubicin (Dox), a model antitumor drug, was loaded into the pores of MSNs. Melittin, a pore-forming peptide, was utilized as the gate for mesopores with an acid-labile Schiff base linkage. pH-labile ANKC released melittin and Dox in slightly acidic tumor microenvironments. Melittin, like perforin, assembled tunnels on the plasma membrane or endosome, ensuring the intracellular transportation of Dox. Dox, similar to granzyme, induced the apoptosis of tumor cells. The combinational treatment partially eased the drug resistance mechanism, such as pumping out of drugs, by continuous intracellular drug accumulation mediated by melittin pores. The pH-labile ANKC demonstrated significant Dox enrichment in drug-resistant MCF-7/Adr cells and MCF-7/Adr-based xenograft tumors in a mouse model, which eventually contributed to efficient inhibition of the proliferation and growth of MCF-7/Adr tumors. PH-labile ANKC provided a potential strategy to treat drug-resistant tumors.

Chemodynamic therapy (CDT) can efficiently kill cancer cells by producing hydroxyl radical (•OH), a kind of high-toxic reactive oxygen species (ROS), via Fenton or Fenton-like reactions. This study involved a versatile nanomedicine, MSN@DOX/GA-Fe/PDA (M@DGP), delivered via microneedles, which was expected to combine chemodynamic/photothermal/chemotherapy and efficiently increase ROS accumulation to achieve significant therapeutic efficacy against melanoma.The composition of the synthesized nanoparticles was confirmed by a series of characterizations including transmission electron microscopy, Fourier transform infrared spectroscopy, and zeta potential. The photothermal properties of the nanomedicine was evaluated via infrared imaging, and •OH-producing ability was evaluated by UV-Vis and electron spin resonance. The mechanisms of ROS accumulation were studied in B16 cells by detecting intracellular •OH, glutathione, and ROS levels. The drug-loaded microneedles (M@DGP-MNs) were prepared, and their morphology and mechanical strength were characterized. The in vivo antimelanoma effect and biosafety evaluation of the nanomedicine were investigated in tumor-bearing C57 mice.M@DGP was successfully prepared and could achieve ROS accumulation through a photothermal-enhanced Fenton reaction, polydopamine-induced glutathione consumption, and doxorubicin-mediated mitochondrial dysfunction which induced oxidative stress and apoptosis of tumor cells. M@DGP-MNs showed superior antitumor efficacy and good biosafety, providing a promising strategy for melanoma treatment.

Doxorubicin is one of the most effective chemotherapeutic agents available for treating various cancers, including lung cancer-the leading cause of cancer death in both men and women. However, its clinical application has been impeded by severe adverse effects, notably cardiotoxicity. Development of cellular resistance to doxorubicin is another major obstacle that must be overcome for broader application of the drug. In the present study, we examined the therapeutic potential of beta-naphthoflavone (BNF), a synthetic derivative of a naturally occurring flavonoid, in combination with doxorubicin for the treatment of lung cancer. Among our novel observations were that BNF enhances the efficacy of doxorubicin by inducing doxorubicin accumulation, mitochondrial ROS generation, and JNK pathway signaling in lung cancer cells. These combined effects were also evident in many other cancer cell types. BNF further exhibited synergistic induction of apoptosis in lung cancer cells when combined with several other cancer drugs, including irinotecan, cisplatin, and 5-fluorouracil. Our results suggest that BNF can be developed as a promising adjuvant agent for enhancing the efficacy of doxorubicin.

Targeting the delivery of anti-cancer drugs to a tumor site is essential for effective treatment and to ensure minimal damage to healthy cells and tissues. In this work, a chitosan-based nanoplatform was constructed for combined photothermal therapy and chemotherapy of breast cancer. The pH-sensitive and biocompatible biopolymer chitosan (CS) was grafted with N-vinylcaprolactam (NVCL) and modified with biotin (Bio), imparting it with temperature sensitive property and also the ability for active targeting. The polymer self-assembled to give nanoparticles (NPs) loaded with indocyanine green (ICG) and doxorubicin (DOX). When the NPs are exposed to near-infrared (NIR) laser irradiation, ICG converts the light to heat, inducing a significant phase transition in the NPs and facilitating the release of the drug cargo. In addition, the solubility of chitosan is increased in the slightly acidic microenvironment of the tumor site, which also promotes drug release. A detailed analysis of the NPs both in vitro and in vivo showed that the carrier system is biocompatible, while the drug-loaded NPs are selectively taken up by cancer cells. Particularly when augmented with NIR irradiation, this leads to potent cell death in vitro and also in an in vivo murine xenograft model of breast cancer.

Cancers and the toxic and side effects of their treatment have always been a major problem for human beings. Doxorubicin (DOX) is one of the classical anthracycline antineoplastic drugs, but it can cause different degrees of heart damage and even serious heart failure. The incidence of myocardial toxicity increased significantly when the cumulative dose of the drug was more than 550 mg/m

Metastasis, as one of major challenges in the cancer treatment, is responsible for the high mortality of breast cancer. It has been reported that breast cancer cell invasion and metastasis are related to aquaporin 3 (AQP3), which is the transmembrane transport channel for H

In this study, MgO-doped CNC-g-PAA hydrogel was synthesized by grafting poly (acrylic acid) (PAA) onto cellulose nanocrystals (CNC) and then doped Magnesium oxide (MgO) using pH 7.0 and 12.0 to obtain an efficient nanocomposite hydrogel for antibacterial and anti-cancer activities. The synthesized nanocomposite hydrogels were evaluated by detailed characterization and confirmed the formation of a well-interconnected porous structure. MgO/CNC-g-PAA (pH = 12.0) exhibited improved bactericidal tendencies towards gram-negative and gram-positive bacteria, which was further investigated by in-silico molecular docking analyses and also examined the reactive oxygen species production by photocatalysis and free radical-scavenging assay. After this, Doxorubicin (DOX), a model anticancer drug, was successfully loaded into nanocomposites (∼79 %) by electrostatic interaction and confirmed pH-triggered based release, which was over 53.7 % in 24 h. Finally, in vitro cytotoxicity-based analysis confirmed the improved antitumor efficacy of nanocomposite hydrogels. These findings revealed that MgO/CNC-g-PAA hydrogels might be prospective carriers for controlled drug delivery.

Despite the tremendous theranostics potential of nano-scale drug delivery system (NDDS) in oncology field, their tumor-targeting efficiency and safety remain major challenges due to their proneness of off-target accumulation through widespread vascular endothelial gaps (up to 1 μm). To address this problem, in this research, micro-sized cellular platelet "ghosts" (PGs, 1.32 μm, platelet without inner granules and coagulation) were employed as carriers to ship hollow gold nanoparticles (HGNs, 58.7 nm), forming a hierarchical biosafe system (PG@HGNs) to reduce normal tissue interception and enhance tumor targeting delivery of HGNs for improved photothermal therapy. PGs were prepared by an optimized "swelling-extrusion-elution" method, HGNs were loaded in PGs (PG@HGNs) through a "hypotonic dialysis" method and the safety and biodistribution of the system was evaluated in vitro and in vivo. In in vitro condition that stimulated the tumoral vessel acidic microenvironment (pH = 6.5), PG@HGNs were demonstrated with enhanced membrane fluidity through down-regulation of the glycoprotein Ib expressed on the PGs. This change induced a burst release of nano-sized HGNs which were capable to traverse vascular endothelium layer on a tumor-endothelial cell transwell model, whilst the micro-sized PG carriers were intercepted. In comparison to nano-sized platelet membrane-coated carriers (PM@HGNs), PG@HGNs showed enhanced internalization and cytotoxicity to 4T1 cells. In animal models, PG@HGNs remarkably prolonged circulation most likely due to the presence of "self-recognition" receptor-CD47 of PGs, and effectively reduced normal tissue interception via the micro-scale size effect. These both contributed to the significantly improved tumor targeting efficiency of HGNs. PG@HGNs generated the greater antitumor photothermal efficacy alongside safety in the animals compared to PM@HGNs. Collectively, this study demonstrated the potential of the micro-scale PGs equipped with adjusted membrane GP Ib as biosafe vehicles for HGNs or possibly other nanodrugs. THE STATEMENT OF SIGNIFICANCE: Despite the tremendous theranostics potentials, the safety and tumor-targeting efficiency of nano-scale drug delivery systems (NDDS) are compromised by their undesirable accumulation in normal tissues with widespread vascular endothelial gaps, such as many tumor-targeted NDDSs still accumulated much in liver and/or spleen. Herein, we explored a micro-nano biomimetic cascade delivery system to address the above drawbacks. By forming a hierarchical biosafe system, micro-sized platelet "ghost" (PGs, 1.32 μm) was employed as tumor-targeted delivery carrier to transport hollow gold nanoparticles (HGNs, 58.7 nm). It was demonstrated that this micro-size system could maintain platelet membrane structure thus prolong in vivo circulation, while avoiding extravasation into normal tissues. PG@HGNs could sensitively respond to the acidic microenvironment near tumor vessel via down-regulation of glycoprotein Ib and rapidly release "nano-bullets"-HGNs to further penetrate into the tumor tissues through EPR effect, thus enhancing photothermal efficacy generated by HGNs under NIR irradiation. Collectively, the micro-scaled PGs could be biosafe vehicles for improved tumor-targeted delivery of HGNs or possibly other nanodrugs.

DOX-loaded nanoparticles able to actively target CD44-receptors and respond to redox stimuli were proposed as non-conventional chemotherapeutic strategy in breast cancer. A covalent conjugate of human serum albumin and hyaluronic acid was prepared and assembled by a GSH-mediated desolvation in disulfide-crosslinked solid nanoparticles with mean diameter of 120 nm ± 3.4. The effective internalization of nanoparticles in cancer cells via CD44-receptors, together with the more efficient intracellular release, resulted in a significant increase of drug efficacy, with IC

Reactive oxygen species (ROS) are important signal molecules and imbalanced ROS level could lead to cell death. Elevated ROS levels in tumor tissues offer an opportunity to design ROS-responsive drug delivery systems (DDSs) or ROS-based cancer therapies such as chemodynamic therapy. However, their anticancer efficacies are hampered by the ROS-consuming nature of these DDSs as well as the high concentration of reductive agents like glutathione (GSH). Here we developed a doxorubicin (DOX)-incorporated iron coordination polymer nanoparticle (PCFD) for efficient chemo-chemodynamic cancer therapy by using a cinnamaldehyde (CA)-based ROS-replenishing organic ligand (TCA). TCA can ROS-responsively release CA to supplement intracellular ROS and deplete GSH by a thiol-Michael addition reaction, which together with DOX-triggered ROS upregulation and Fesup3+/sup-enabled GSH depletion facilitated efficient DOX release and enhanced Fenton reaction, thereby inducing redox dyshomeostasis and cancer cell death in a concurrent apoptosis-ferroptosis way. Both in vitro and in vivo studies revealed that ROS-replenishing PCFD exhibited much better anticancer effect than ROS-consuming control nanoparticle PAFD. The ingenious ROS-replenishing strategy could be expanded to construct versatile ROS-responsive DDSs and ROS-based nanomedicines with potentiated anticancer activity. STATEMENT OF SIGNIFICANCE: We develop a doxorubicin (DOX)-incorporated iron coordination polymer nanoparticle (PCFD) for efficient chemo-chemodynamic cancer therapy by using a cinnamaldehyde-based reactive oxygen species (ROS)-replenishing organic ligand. This functional ligand can ROS-responsively release cinnamaldehyde to supplement intracellular Hsub2/subOsub2/suband deplete glutathione (GSH) by a thiol-Michael addition reaction, which together with DOX-triggered ROS upregulation and Fesup3+/sup-enabled GSH depletion facilitates efficient DOX release and enhanced Fenton reaction, thereby inducing redox dyshomeostasis and cancer cell death in a concurrent apoptosis-ferroptosis way. Both in vitro and in vivo studies reveal that ROS-replenishing PCFD exhibit much better anticancer effect than ROS consuming counterpart. This study provides a facile and straightforward strategy to design ROS amplifying nanoplatforms for cancer treatment.

Managing double-expressor lymphomas (DEL) is controversial given the dearth of data and lack of standardized guidelines on this high-risk subset of lymphomas. No prospective and few retrospective studies limited by either their sample size or short follow-up address the question of initial treatment of choice for DEL. We performed the largest analysis to date exploring R-CHOP vs DA-EPOCH-R in DEL.Adults with DEL diagnosed from 6/2012-2/2021 at 4 unique sites were retrospectively analyzed. Progression-free survival (PFS) was the primary endpoint. Key secondary endpoints include overall survival (OS), overall and complete response rates (ORR and CRR), cumulative incidence of relapse, and autologous hematopoietic cell transplantation (autoHCT) utilization.155 patients were included, 61 treated with R-CHOP and 94 with DA-EPOCH-R. 3-year PFS and OS were similar between R-CHOP and DA-EPOCH-R, 33.2% vs 57.2%,(P = .063), and 72.2% vs 71.6% (P = .43) after median follow-up times of 2.43 and 2.89 years, respectively. Patients65 had improved PFS with DA-EPOCH-R, hazard ratio 0.41 (P = .01). CRR and ORR rates were also similar. Relapse rates were not statistically different, 51.9% vs 28.6% (P = .069). AutoHCT utilization was higher with R-CHOP vs DA-EPOCH-R, 23.0% vs 8.5% (P = .017).Our findings do not support the use of DA-EPOCH-R over R-CHOP for DEL. Patients65 years may experience longer PFS with DA-EPOCH-R, but limitations to the analysis make this interpretation difficult.

In this work, a novel electrochemical biosensor assisted by multivariate calibration methods was developed for simultaneous estimation of rates of DNA damage induced by doxorubicin (DX), daunorubicin (DR) and idarubicin (ID), and also to simultaneous determination of the drugs. A glassy carbon electrode was efficiently modified and used as the biosensing platform. Binding and interactions of DX, DR and ID with DNA were modeled by molecular docking methods, and theoretical information was completed by experimental results. The methylene blue was able to intercalate within the DNA structure and by incubation of the biosensor with DX or DR or ID, the methylene blue was replaced by drug and therefore, the voltammetric signal of the biosensor was changed due to the exposed DNA and repelling the electrochemical probe molecules carrying negative charge. The DNA damage induced by each drug was individually monitored by differential pulse voltammetry and then, rates of DNA damage were calibrated and validated by mixture design and multivariate calibration methods. The developed multivariate calibration model constructed based on vectorization of the data was able to simultaneous detection of the rates of DNA damage induced by all the three drugs. The change in the biosensor response in the presence of the drugs was also modeled by multivariate calibration methods to simultaneous determination of the drugs.

Despite the progress in assisted reproductive techniques, there is still a lack of rapid and minimally invasive in situ approaches for further enhancements of female fertility. Therefore, we synthesized clinically relevant liposome nanoparticles for ovarian intrafollicular injection to allow in vivo cellular imaging for future drug delivery, using the mare as an animal model. Ovarian follicles of living mares were injected in vivo with fluorescently labeled liposomes. Samples of the follicular wall (mural granulosa, theca interna, and theca externa), granulosa cells, and follicular fluid were harvested 24 h post-injection through the follicle wall biopsy (FWB), flushing, and aspiration techniques, respectively, using a transvaginal ultrasound-guided approach. In parallel, post-mortem dissected, and cultured porcine antral follicles were microinjected with doxorubicin-encapsulated liposomes to assess intracellular delivery potential. All injected mare and pig follicles were macroscopically healthy, and fluorescence imaging revealed successful intrafollicular binding to mural granulosa cells and progressive migration of liposomes to other follicle cell layers (theca interna, and theca externa), regardless of the follicle size. Intracellular delivery of doxorubicin was confirmed in all porcine follicle wall cell types. We conclude that the intrafollicular injection of nanomolecules is a promising approach for real-time monitoring of intrafollicular processes and potential utilization of in vivo cellular drug delivery to assist in follicle disease treatments and fertility improvement.

Natural amphiphilic polymer micelles have garnered considerable research attention as nanocarriers for delivering drugs. The objective of this study was to explore the possibility of applying biocompatible dual-modified starch micelles as drug delivery vehicles. To this end, a dual-modified corn starch polymer (SCD) was synthesized with zwitterionic sulfobetaine and deoxycholic acid; spherical micelles with an average particle size of ~200 nm were prepared through the self-assembly of SCD. The effects of dual modification on the degree of substitution, molecular structure, and functional properties of SCD were investigated. Further, doxorubicin was successfully incorporated into the micelles, and an in vitro drug release study was performed to confirm that the drug-loaded micelles displayed pH-sensitive properties with controlled and sustained release. The dissolve-diffuse-erosion-degradation release process was described according to the dynamic models of drug release for SCD micelles. The results can be used as reference information for further studies in the biotechnology and pharmaceutical domains.

Transarterial chemoembolization (TACE) with free doxorubicin-lipiodol emulsions (free DOX/L) is a favored clinical treatment for advanced hepatocellular carcinoma (HCC) patients ineligible for radical therapies; however, its inferior colloidal stability not only greatly reduces its tumor retention but also hastens drug release into blood circulation, leading to suboptimal clinical outcomes. Here, we find that disulfide-crosslinked polymersomes carrying doxorubicin (Ps-DOX) form super-stable and homogenous water-in-oil microemulsions with lipiodol (Ps-DOX/L). Ps-DOX/L microemulsions had tunable sizes ranging from 14 to 44 μm depending on the amount of Ps-DOX, were stable over 2 months storage as well as centrifugation, and exhibited nearly zero-order DOX release within 15 days. Of note, Ps-DOX induced 2.3-13.4 fold better inhibitory activity in all tested rat, murine and human liver tumor cells than free DOX likely due to its efficient redox-triggered intracellular drug release. Interestingly, transarterial administration of Ps-DOX/L microemulsions in orthotopic rat N1S1 syngeneic HCC model showed minimal systemic DOX exposure, high and long hepatic DOX retention, complete tumor elimination, effective inhibition of angiogenesis, and depleted adverse effects, significantly outperforming clinically used free DOX/L emulsions. This smart polymersome stabilization of doxorubicin-lipiodol microemulsions provides a novel TACE strategy for advanced tumors.

Nanoparticle shape has been recognized as a crucial parameter to affect the transport across various biological barriers, but its impact on drug release and the resulting therapeutic efficacy is less understood. Inspired by erythrocytes with shape-facilitated oxygen-carrying and penetrating abilities, we constructed artificial erythrocyte-like nanoparticles (RNDs) by wrapping discoidal mesoporous silica nanoparticles with red blood cell membrane. We observed that, compared with their spherical and rod-shaped counterparts with monotonic drug release profiles, RNDs displayed an on-demand drug release pattern mimicking natural erythrocytes, that is, they could rapidly release loaded oxygen and doxorubicin (DOX) in hypoxic condition but were relatively stable in high oxygen areas. Besides, the discoidal shape also endowed RNDs with facilitated transport capability in tumor extracellular matrix, contributing to increased tumor permeability. In tumor models, systemically administrated RNDs efficiently infiltrate throughout tumor tissue, successfully relieve tumor hypoxia, and further altered the cancer cell cycle status from G1 to G2 phase, enhancing cancer cell sensitivity to DOX correlated with improved chemotherapy efficacy. In contrast, nanospheres show hampered permeability, and nanorods suffer from insufficient intratumoral drug accumulation. These findings can offer guidelines for the use of particle shape as a design criterion to control drug release, transportation, and therapeutics delivery.

One key clinical challenge remains in how to sequence treatments in follicular lymphoma (FL). The chemoimmunotherapy rituximab cyclophosphamide, doxorubicin, vincristine (Oncovin), and prednisone (R-CHOP) has been a standard treatment option for two decades. However, there are limited data to suggest in which line R-CHOP should be used for older patients.We leveraged population-based surveillance, epidemiology, and end results-medicare data and identified 675 patients aged ≥65 years newly diagnosed with FL from 2000 to 2009 who received R-CHOP in either the first or second line. We estimated restricted mean survival time using Kaplan-Meier curves, propensity scores (PS), and regression models comparing patients who received R-CHOP as a first versus second line.We found that patients who received R-CHOP as first line had significantly longer 9-year RMST than those who received R-CHOP in the second line using Kaplan-Meier curves (P = .01), PS stratification (P = .002), PS matching (P = .005), and the inverse of PS as the treatment weight (P.0001). The subgroup analyses using linear regression models showed that the 9-year restricted mean survival time of patients who received R-CHOP as the first line was longer in patients aged ≥80 years (P = .002) and with histological grade 1 or 2 (P = .02), compared to those who received R-CHOP as second line.R-CHOP given in the first line was associated with longer overall survival compared to R-CHOP given as second line for older patients with FL.

The abnormal activation of the Wnt/β-catenin signaling pathway and epithelial-mesenchymal transition (EMT) in drug-resistant tumor cells and cancer stem cells (CSCs) stimulate tumor metastasis and recurrence. Here, a promising combined chemotherapeutic strategy of salinomycin (SL) and doxorubicin (DOX) with specific inhibition of tumor stemness by a targeted co-delivery nanosystem was developed to overcome this abnormal progression. This strategy could be benefit drugs to effectively penetrate and infiltrate into spheres of 3D-cultured breast cancer stem cells (BCSCs). The expression of the Wnt/β-catenin signaling pathway-related genes (β-catenin, LRP6, LEF1, and TCF12) and target genes (Cyclin D1, Cmyc, and Fibronectin) as well as CSC stemness-related genes (Oct4, Nanog, and Hes1) was downregulated by redox-sensitive co-delivery micelles decorated with oligohyaluronic acid as the active targeting moiety. The changes in EMT-associated gene expression (E-cadherin and Vimentin) in vitro showed that the EMT process was also effectively inverted. This strategy achieved a strong inhibitory effect on solid tumor growth and an effective reduction in the risk of tumor metastasis in 4T1 tumor-bearing mice in vivo and effectively alleviated splenomegaly caused by the malignant tumor. Immunohistochemical staining analysis of E-cadherin, Vimentin, and β-catenin confirmed that the inversion of the EMT was also achieved in solid tumors. These results highlight the potential of SL and DOX combined chemotherapeutic strategy for eliminating breast carcinoma. STATEMENT OF SIGNIFICANCE: Cancer stem cells (CSCs), as an important part of tumor heterogeneity, can survive against conventional chemotherapy and initiate tumorigenesis, recurrence, and metastasis. Moreover, non-CSCs can convert into the CSC state through the abnormal Wnt/β-catenin pathway, which is closely related to the epithelial-mesenchymal transition (EMT) process. Here, redox-degradable binary drug-loaded micelles (PPH/DOX+SL) were designed to target CSCs and overcome drug resistance of breast cancer cells. The combined chemotherapy of salinomycin (SL) and doxorubicin (DOX) reversed drug resistance, while the PPH/DOX+SL micelles enhanced the intracellular accumulation and drug penetration of BCSC spheres. The introduction of SL downregulated the expression of tumor stemness genes and the Wnt/β-catenin pathway-related genes and inverted the EMT process. PPH/DOX+SL continuously inhibited tumor growth and invasion in vivo.

In this work, novel biocompatible and reduction-responsive soft hydrogels were formulated from norbornene (Nb)-functionalized carboxymethyl cellulose (CMCNb). To cross-link the CMC-Nb via a highly bioorthogonal inverse electron demand Diels-Alder (IEDDA) reaction, we employed a water-soluble and reduction-responsive diselenide-based cross-linker possessing two terminal tetrazine (Tz) groups with varying molar concentrations (Nb/Tz molar ratios of 10/10, 10/05, and 10/2.5). The N

Adriamycin (ADR) is an efficient and common broad-spectrum anticancer drug. However, the cumulative and dose-dependent toxicity induced by ADR severely limits its application in the clinic. Previous studies found that psoralidin (PSO) exhibits remarkable therapeutic effects against multiple cancers.The aim of this study was to determine if PSO has beneficial effects on ADR-induced cardiotoxicity and to investigate the underlying mechanisms.ADR-induced cardiotoxicity models were established in BALB/c mice and HL-1 cardiomyocytes. A series of experimental methods were used to evaluate the effects of PSO on cardiac function indicators, blood biochemical parameters, histopathology, oxidative stress, apoptosis, mitochondrial function, fibrosis, and SIRT1/PPARγ signaling.PSO significantly improved cardiac function indicators, blood biochemical parameters, and mitochondrial function and reduced the degree of myocardial fibrosis, oxidative stress, and apoptosis in ADR-injured mice. PSO significantly increased cell viability, inhibited the release of LDH, reduced oxidative stress and apoptosis, and improved mitochondrial function in ADR-injured HL-1 cells. Moreover, we also demonstrated there was cross-talk between SIRT1 and PPARγ, as shown by SIRT1 siRNA significantly decreasing the expression of PPARγ and GW9662 (a PPARγ antagonist), which remarkably reduced the expression of SIRT1.In summary, this study proved for the first time the beneficial effect of PSO on ADR-induced cardiotoxicity through activation of the SIRT1/PPARγ signaling pathway. Therefore, these findings may favor PSO as a potential cardioprotective drug candidate to alleviate ADR-induced cardiotoxicity in the clinic and improve the application of ADR in oncotherapy.

Breast cancer is the most invasive and life-threatening cancer in women. The treatment options are usually a combination of mastectomy, radiation therapy, hormonal therapy and chemotherapy. As a standard practice, doxorubicin (DOX) is one of the commonly used drugs for breast cancer treatment. However, DOX is known to have many harmful adverse effects including its cardiotoxicity. Hence, recent reports used metformin (MET), an anti-diabetic drug, as an adjuvant therapy to decrease the severity of DOX's adverse effects and to improve its ultimate therapeutic outcome. The current study is aimed at co-loading and enhancing the encapsulation efficiency of the hydrophilic DOX and MET in poly(lactic-co-glycolic acid) (PLGA) nanocapsules (NCs) with oil core for breast cancer treatment. The NCs were developed by single emulsification-solvent diffusion technique, and were optimized through using two types of oils, pluronics and PLGA (50:50) of different molecular weights followed by various physicochemical characterizations. The obtained DOX/MET-loaded NCs showed the size and polydispersity index (PDI) of 203.0 ± 3.4 nm and 0.081 ± 0.03, respectively with a surface charge of -2.15 ± 0.2 mV. The entrapment efficiency of DOX and MET were about 93.7% ± 2.9 and 70% ± 1.6, respectively. The developed PLGA core-shell NCs successfully sustained the DOX/MET release for more than 30 days. The in-vitro results showed a significant enhancement in DOX cytotoxic effect as well as a duplication in its apoptotic effect upon addition of MET for both free DOX/MET combination and DOX/MET-loaded PLGA NCs against MCF-7. Besides, flow cytometry demonstrated that the DOX/MET-loaded NCs possess their antitumor effect by preventing DNA replication and cell division. This study provides a promising facile, rapid and reproducible single emulsification-solvent diffusion technique for improving the encapsulation and release of hydrophilic drugs in nanocapsules for biomedical applications.

Stimuli-responsive drug delivery systems based on polymeric nanovehicles are among the most promising treatment regimens for malignant cancers. Such intelligent systems that release payloads in response to the physiological characteristics of tumor sites have several advantages over conventional drug carriers, offering, in particular, enhanced therapeutic effects and decreased toxicity. The tumor microenvironment (TME) is acidic, suggesting the potential of pH-responsive nanovehicles for enhancing treatment specificity and efficacy. The synthetic polypeptide poly(l-histidine) (PLH) is an appropriate candidate for the preparation of pH-responsive nanovehicles because the pK

In this work, glycyrrhetinic acid (GA)-β-cyclodextrin grafted pullulan (GCDPu) was synthesized and used to form nanoparticles for liver-specific drug delivery. GCDPu was characterized by Fourier transform infrared (FT-IR) and proton nuclear magnetic resonance (

Chemotherapy induces tumor cell death and inhibits tumor progression, but the accompanying immune responses in the surrounding dying tissue cause significant inflammation. These responses, such as excessive neutrophil infiltration into tumor tissue, are the main causes of resistance to anticancer treatment. The development of drugs that reduce neutrophil infiltration into tumors is necessary to increase the anticancer effect of chemotherapy. Here, we show that the antitumor effect of the chemotherapy AC regimen (Adriamycin and cyclophosphamide) was increased by 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG) cotreatment in the MDA-MB-231 triple-negative breast cancer xenograft mouse model. Tumor growth was inhibited up to 56% in mice treated with AC and inhibited up to 94% in mice cotreated with AC and PLAG. Side effects of chemotherapy, such as a reduction in body weight, were alleviated in mice cotreated with AC and PLAG. Excessive neutrophil infiltration caused by the AC regimen was successfully cleared in mice cotreated with AC and PLAG. We conclude that PLAG inhibits excessive neutrophil infiltration that aids tumor growth. Reduced neutrophils and increased lymphocytes in PLAG-treated mice can maximize the antitumor effect of the AC regimen and inhibit tumor growth.

Although mesoporous silica nanoparticles (MSNs) are widely used as anticancer drug carriers, unmodified MSNs induce off-target effects and at high doses, there are adverse effects of hemolysis because of the interaction with the silanol group on the surface and cells. In this study, we developed doxorubicin (DOX)-loaded MSNs coated with mannose grafted poly (acrylic acid) copolymer (DOX@MSNs-man-g-PAA) to enhance the hemocompatibility and target efficacy to cancer cells. This uniform nanosized DOX@MSNs-man-g-PAA showed sustained and pH-dependent drug release with improved hemocompatibility over the bare MSNs. The uptake of the DOX@MSN-man-g-PAA in breast cancer cells was significantly improved by mannose receptor-mediated endocytosis, which showed significant increasing intracellular ROS and changes in mitochondrial membrane potential. This formulation exhibited superior tumor-suppressing activity in the MDA-MB-231 cells inoculated mice. Overall, the present study suggested the possibility of the copolymer-coated MSNs as drug carriers for cancer therapy.

Chemo-photothermal therapy is one of the emerging therapies for treating triple-negative breast cancer. In this study, we have used ionotropic gelation method to fabricate chitosan and IR806 dye-based polyelectrolyte complex (CIR-PEx) nanoparticles. These nano-complexes were in size range of 125 ± 20 nm. The complexation of IR 806 dye with chitosan improved photostability, photothermal transduction, and showed excellent biocompatibility. Cancer cells treated with CIR-PEx NPs enhanced intracellular uptake within 5 h of incubation and also displayed mitochondrial localization. With the combination of CIR-PEx NPs and a chemotherapeutic agent (i.e., mitoxantrone, MTX), a significant decline in cancer cell viability was observed in both 2D and 3D cell culture models. The chemo-photothermal effect of CIR-PEx NPs + MTX augmented apoptosis in cancer cells when irradiated with NIR light. Furthermore, when tested in the 4 T1-tumor model, the chemo-photothermal therapy showed a drastic decline in tumor volume and inhibited metastatic lung nodules. The localized hyperthermia caused by photothermal therapy reduced the primary tumor burden, and the chemotherapeutic activity of mitoxantrone further complemented by inhibiting the spread of cancer cells. The proposed chemo-photothermal therapy combination could be a promising strategy for treating triple-negative metastatic breast cancer.

Chemo-immunotherapy has gained increasing attention as one of the most promising combination therapy strategies to battle cancer. In this study, the therapeutic nanoparticles (TNPs) co-delivering doxorubicin (DOX) and IL-12 (IL-12) were developed for chemo-immunotherapy combination therapy on liver cancer. TNPs were synthesized based on the ionic interactions between cationic chitosan (Ch) and anionic poly-(glutamic acid) (PGA). DOX and IL-12 loaded in TNPs presented prolonged circulation in blood, efficient accumulation in tumors, and internalization in tumor cells. After that, DOX and IL-12 were co-released in the tumor microenvironment. The locally responsive property of TNPs could subsequently re-educate macrophages. More significantly, TNPs with no obvious side effects can remarkably inhibit the H22 tumor growth in vivo. A low dosage of loaded IL-12 in TNPs can effectively polarize macrophages toward the M1 phenotype to reduce tumor burden, further enhancing the antitumor efficacy. Our results suggest that the self-stabilized TNPs could be a secure and effective drug carrier for intravenous administration when deprived of protective agents.

Chemotherapeutic agents can trigger the immune response via inducing immunogenic cell death (ICD), but the weak ICD effect induced by chemotherapy alone limits its lasting antitumor immunotherapy effect. A Cro polymerized prodrug carriers (POEG-b-PCro) with immunostimulatory by ICD induction was developed and co-delivered DOX to generate synergistic ICD induction for chemo-immunotherapy on breast cancer. DOX/POEG-b-PCro micelles displayed prolonged circulation in blood, efficient accumulation in tumors, internalization and then co-released DOXCro in tumor cells. Moreover, the DOX/POEG-b-PCro micelles synergistically triggered ICD induction by releasing the nuclear high mobility group box 1 (HMGB1) and down-regulation of c-Met level for generating chemo-immune anti-tumor actions. Importantly, the DOX/POEG-b-PCro micelles synergistically enhanced the tumor cytotoxic T lymphocytes infiltration, concomitant decreasing the immunosuppressive regulatory T (Treg) cells, accompanied with the increased cytokines secretion of IFN-γ and TNF-α, consequently displaying an improved anti-tumor activity in 4 T1 breast cancer mice. Overall, POEG-b-PCro prodrug micelles co-delivered DOX could be served as a promising nano drug delivery system for synergistic ICD induction on breast cancer chemo-immunotherapy.

Hypoxia-induced intratumoral heterogeneity poses a major challenge in tumor therapy due to the varying susceptibility to chemotherapy. Moreover, the spatial distribution patterns of hypoxic and normoxic tissues makes conventional combination therapy less effective. In this study, a tumor-acidity and bioorthogonal chemistry mediated in situ size transformable nanocarrier (NP@DOX

A natural killer (NK)-92 cell membrane-camouflaged mesoporous MnO

Ribosomal protein S6 (rpS6) phosphorylation mediates the hypertrophic growth of kidney proximal tubule cells. However, the role of rpS6 phosphorylation in podocyte hypertrophy and podocyte loss during the pathogenesis of focal segmental glomerulosclerosis (FSGS) remains undefined. Here, we examined rpS6 phosphorylation levels in kidney biopsy specimens from patients with FSGS and in podocytes from mouse kidneys with Adriamycin-induced FSGS. Using genetic and pharmacologic approaches in the mouse model of FSGS, we investigated the role of rpS6 phosphorylation in podocyte hypertrophy and loss during development and progression of FSGS. Phosphorylated rpS6 was found to be markedly increased in the podocytes of patients with FSGS and Adriamycin-induced FSGS mice. Genetic deletion of the Tuberous sclerosis 1 gene in kidney glomerular podocytes activated mammalian target of rapamycin complex 1 signaling to rpS6 phosphorylation, resulting in podocyte hypertrophy and pathologic features similar to those of patients with FSGS including podocyte loss, leading to segmental glomerulosclerosis. Since protein phosphatase 1 is known to negatively regulate rpS6 phosphorylation, treatment with an inhibitor increased phospho-rpS6 levels, promoted podocyte hypertrophy and exacerbated formation of FSGS lesions. Importantly, blocking rpS6 phosphorylation (either by generating congenic rpS6 knock-in mice expressing non-phosphorylatable rpS6 or by inhibiting ribosomal protein S6 kinase 1-mediated rpS6 phosphorylation with an inhibitor) significantly blunted podocyte hypertrophy, inhibited podocyte loss, and attenuated formation of FSGS lesions. Thus, our study provides genetic and pharmacologic evidence indicating that specifically targeting rpS6 phosphorylation can attenuate the development of FSGS lesions by inhibiting podocyte hypertrophy and associated podocyte depletion.

Activation of canonical Wnt signaling has been implicated in podocyte injury and proteinuria. As Wnts are secreted proteins, whether Wnts derived from podocytes are obligatory for promoting proteinuria remains unknown. To address this, we generated conditional knockout mice where Wntless, a cargo receptor protein required for Wnt secretion, was specifically deleted in glomerular podocytes. Mice with podocyte-specific ablation of Wintless (Podo-Wntless−/−) were phenotypically normal. However, after inducing kidney damage with Adriamycin for six days, Podo-Wntless−/− mice developed more severe podocyte injury and albuminuria than their control littermates. Surprisingly, ablation of Wntless resulted in upregulation of β-catenin, accompanied by reduction of nephrin, podocin, podocalyxin, and Wilms tumor 1 proteins. In chronic injury induced by Adriamycin, increased albuminuria, aggravated podocyte lesions and extracellular matrix deposition were evident in Podo-Wntlessl−/− mice, compared to wild type mice. Mechanistically, specific ablation of Wintless in podocytes caused down-regulation of the nuclear factor of activated T cell 1 (NFAT1) and Nemo-like kinase (NLK), key downstream mediators of non-canonical Wnt/calcium signaling. In vitro, knockdown of either NFAT1 or NLK induced β-catenin activation while overexpression of NLK significantly repressed β-catenin induction and largely preserved nephrin in glomerular podocytes. Thus, our results indicate that podocyte-derived Wnts play an important role in protecting podocytes from injury by repressing β-catenin via activating non-canonical Wnt/calcium signaling.

The utility of dose escalation after positive positron emission tomography following 2 cycles of ABVD (PET2) for Hodgkin Lymphoma (HL) remains controversial. We describe the United States real-world practice patterns for PET2 positive patients.Data was collected from 15 sites on PET2 positive HL patients after receiving frontline treatment between January, 2015 and June, 2019. Descriptive analyses between those with therapy change and those continuing initial therapy were assessed.A total of 129 patients were identified; 111 (86%) were treated with ABVD therapy and 18 (14%) with an alternate regimen. At PET2 assessment, 74.4% (96/129) had Deauville score (DS) 4 and 25.6% (33/129) had DS 5. Of the 66 limited stage (LS) patients with PET2 DS score of 4/5, 77.3% (51/66) continued initial therapy and 22.7% (15/66) changed to escalated therapy. The 12-month progression-free survival (PFS) for DS 4/5 LS patients was 67.0% (95% CI; 54.9-81.7) for patients without escalation compared with 51.4% (95% CI; 30.8-85.8) for those who escalated. Of the 63 DS 4/5 patients with advanced stage (AS) disease, 76.2% (48/63) continued initial therapy and 23.8% (15/63) changed to escalated therapy. The 12-month PFS for DS 4/5 AS patients was 38.3% (95% CI: 26.3%-55.7%) for patients without escalation compared with 57.1% (95% CI: 36.3-89.9) for those with escalation.A minority of PET2 positive HL patients undergo therapy escalation and outcomes remain overall suboptimal. Improved prognostics markers and better therapeutics are required to improve outcomes for high-risk PET2 positive HL patients.

Tumor microenvironment responsive nanomedicine has drawn considerable attention for combination therapy, but still remains a significant challenge for less side effects and enhanced anti-tumor efficiency. Herein, we develop a pH/ROS dual-responsive supramolecular polypeptide nanoprodrug (PFW-DOX/GOD) by using pillar[5]arene-based host-guest strategy for combined glucose degradation, chemodynamic therapy (CDT), and chemotherapy (CT). The PFW-DOX/GOD consists of a pH-responsive ferrocene/pillar[5]arene-containing polypeptide, a ROS-responsive polyprodrug, and encapsulated glucose oxidase (GOD). Upon into intracellular acidic environment, PFW-DOX/GOD exhibits rapid pH-triggered disassembly behavior. Simultaneously, the released GOD can catalyze intratumoral glucose into massive H

Polyethylene glycol drug-eluting microspheres (PEG-DEMs) can be loaded to elute doxorubicin. The current study evaluated the pharmacokinetic profile and safety of PEG-DEMs in the treatment of patients with hepatocellular carcinoma (HCC).The current prospective, multicenter, dose-escalation study enrolled 25 patients (68% men) with early or intermediate stage HCC and a performance status of 0. Patients in Cohort I were assigned to receive target doxorubicin doses of 75, 100, or 150 mg. Analyses were performed on the basis of the specific dose of doxorubicin that the patients received because some patients received less than the assigned dose. Patients in Cohort II received the maximum safe tested dose. Adverse events were classified according to the Common Terminology Criteria for Adverse Events version 4.03. The tumor response was evaluated every 3 months according to the European Association for the Study of the Liver criteria and modified Response Evaluation Criteria in Solid Tumors.The maximum tested safe dose of doxorubicin was 150 mg. For the groups that received ≤75, 75-100, and 101-150 mg of doxorubicin, the peak plasma concentrations were 286.7 ng/mL ± 220.1, 157.1 ng/mL ± 94.6, and 245.4 ng/mL ± 142.8, respectively; the areas under the curves calculated from 0 to 24 h were 421.7 (ng × h)/mL ± 221.2, 288.1 (ng × h)/mL ± 100.9, and 608.3 (ng × h)/mL ± 319.3, respectively, with almost complete clearance at 24 h. There was no death within 30 d. The best objective response rate was 81%, and the disease control rate was 91%. The median overall survival was 27.2 months (95% confidence interval [CI], 17.5 months to not evaluated [n.e.]); the median progression-free survival was 9.8 months (95% CI, 5.5 months to n.e.).PEG-DEMs demonstrated a favorable safety profile with low systemic concentration of doxorubicin, and promising efficacy.

On-demand designed theranostics nanoagents show promising applications for next-generation precision-and-personalized oncotherapy. Researchers have since aimed to develop nanoplatforms that can efficiently deliver drugs and contrast medium to tumor and release active ingredients in response to tumor microenvironment (TME) conditions. Herein, we propose a modular strategy, and develop a series of nanoplatforms based on metal-coordinated-polyprodrugs for cancer theranostics. The polyprodrugs were synthesized through a click-reaction between amino acid and doxorubicin (DOX) with dipropiolate. The backbones of the polyprodrugs had intrinsic sensitivities to pH and/or GSH, and provided abundant -COOH, -NH2, or -S-S- to chelate with functional metal ions and further self-assembled to form different morphologies. Dicysteine, which contains disulfide bond (-S-S-), was chosen to copolymerize with DOX and triethylene glycol dipropiolate (TEP) to prepare the pH/GSH dual-responsive polyprodrug poly(dicysteine-co-TEP-co-DOX) (pDTD), then separately coordinated with Gd3+, Fe3+, and Mn2+ to construct nanoplatforms pDTD@M (M representing the metal ions). In vitro and in vivo investigations suggest the metal-coordinated-polyprodrug nanoplatforms have good magnetic resonance imaging (MRI) ability and efficient tumor-growth inhibition with high safety. The design strategy of nanoplatforms based on metal-coordinated-polyprodrugs provides a new idea for on-demand construction of promising theranostics agents. STATEMENT OF SIGNIFICANCE: Compared to small molecule antitumor drugs, polymeric drugs have high drug loading ratio and are easily enriched at the tumor site to achieve improved therapy efficacy. This work utilizes click reactions to link amino acids with anticancer drugs to produce polymeric drugs that are degraded in response to tumor microenvironment and released small molecule antitumor drugs mainly in tumor sites, and subtly utilizes the coordination of amino acid to chelate MRI functional metal ion to realize enhanced MRI imaging mediated tumor therapy. This strategy provides a new idea for the convenient construction of polymeric drugs for tumor theranostics.

Background: Doxorubicin is an essential cancer treatment, but its usefulness is hampered by the occurrence of cardiotoxicity. Nevertheless, the pathophysiology underlying doxorubicin-induced cardiotoxicity and the respective molecular mechanisms are poorly understood. Recent studies have suggested involvement of cellular senescence.Objectives: The aims of this study were to establish whether senescence is present in patients with doxorubicin-induced cardiotoxicity and to investigate if this could be used as a potential treatment target.Methods: Biopsies from the left ventricles of patients with severe doxorubicin-induced cardiotoxicity were compared with control samples. Additionally, senescence-associated mechanisms were characterized in 3-dimensional dynamic engineered heart tissues (dyn-EHTs) and human pluripotent stem cell–derived cardiomyocytes. These were exposed to multiple, clinically relevant doses of doxorubicin to recapitulate patient treatment regimens. To prevent senescence, dyn-EHTs were cotreated with the senomorphic drugs 5-aminoimidazole-4-carboxamide ribonucleotide and resveratrol.Results: Senescence-related markers were significantly up-regulated in the left ventricles of patients with doxorubicin-induced cardiotoxicity. Treatment of dyn-EHTs resulted in up-regulation of similar senescence markers as seen in the patients, accompanied by tissue dilatation, decreased force generation, and increased troponin release. Treatment with senomorphic drugs led to decreased expression of senescence-associated markers, but this was not accompanied by improved function.Conclusions: Senescence was observed in the hearts of patients with severe doxorubicin-induced cardiotoxicity, and this phenotype can be modeled in vitro by exposing dyn-EHTs to repeated clinically relevant doses of doxorubicin. The senomorphic drugs 5-aminoimidazole-4-carboxamide ribonucleotide and resveratrol prevent senescence but do not result in functional improvements. These findings suggest that preventing senescence by using a senomorphic during doxorubicin administration might not prevent cardiotoxicity.

The primary objective of this study was to investigate the potential protective effect of Vitamin D (Vit D) on DOX induced cardio toxicity (DIC) in early breast cancer patients receiving adjuvant DOX based chemotherapy (AC). The secondary objective was to investigate the anti-inflammatory effect of Vit D by measuring serum IL-6 and its correlation with cardio toxicity.This study was carried out on 150 newly diagnosed women with breast cancer who were planned to receive four cycles of adjuvant AC chemotherapy regimen (60 mg/mVit D supplementation in Vit D group patients was associated with a significant decrease (P0.001) in serum levels of LDH, cTnT, and IL-6 compared to the control group .The present work provides a promising clinical evidence to support the cardio protective effects of Vit D against DIC through attenuating the evoked pro-inflammatory cytokines induced by DOX.

Multidrug resistance (MDR) to chemotherapeutic drugs and targeted drug delivery are recurring issues in clinical cancer treatment. Here, a multifunctional fusion protein-DNA conjugate was designed as a co-delivery vehicle for anticancer peptides and chemotherapeutic drugs to combat both drug-resistant and drug-sensitive tumor cells. The fusion protein was constructed by fusing a PsTag polypeptide, a matrix metalloproteinase 2 (MMP2)-degradable domain, and the mitochondria-targeted pro-apoptotic peptide KLAKLAKKLAKLAK. Doxorubicin was efficiently loaded into the fusion protein pre-conjugated dendrimer-like DNA nanostructure. With the incorporation of enhanced stability, tumor targeting, and controlled-release elements, the tailored nanostructure can selectively enter tumor cells and synergistically exert antitumor activity with no significant adverse effects. Thus, these protein-conjugated DNA nanocarriers could be a potential co-delivery system for protein/peptide and chemotherapeutic drugs delivery in synergistic cancer therapy.

Calcimimetic agents allosterically increase the calcium ion sensitivity of the calcium-sensing receptor (CaSR), which is expressed in the tubular system and to a lesser extent in podocytes. Activation of this receptor can reduce glomerular proteinuria and structural damage in proteinuric animal models. However, the precise role of the podocyte CaSR remains unclear. Here, a CaSR knockdown in cultured murine podocytes and a podocyte-specific CaSR knockout in BALB/c mice were generated to study its role in proteinuria and kidney function. Podocyte CaSR knockdown abolished the calcimimetic R-568 mediated calcium ion-influx, disrupted the actin cytoskeleton, and reduced cellular attachment and migration velocity. Adriamycin-induced proteinuria enhanced glomerular CaSR expression in wild type mice. Albuminuria, podocyte foot process effacement, podocyte loss and glomerular sclerosis were significantly more pronounced in adriamycin-treated podocyte-specific CaSR knockout mice compared to wild type littermates. Co-treatment of wild type mice with adriamycin and the calcimimetic cinacalcet reduced proteinuria in wild type, but not in podocyte-specific CaSR knockout mice. Additionally, four children with nephrotic syndrome, whose parents objected to glucocorticoid therapy, were treated with cinacalcet for one to 33 days. Proteinuria declined transiently by up to 96%, serum albumin increased, and edema resolved. Thus, activation of podocyte CaSR regulates key podocyte functions in vitro and reduced toxin-induced proteinuria and glomerular damage in mice. Hence, our findings suggest a potential novel role of CaSR signaling in control of glomerular disease.

Among the most lethal forms of cancer, malignant brain tumors persist as one of the greatest challenges faced by oncologists, where nanotechnology-driven theranostics can play a critical role in developing novel polymer-based supramolecular nanoarchitectures with multifunctional and multi-modal characteristics to fight cancer. However, it is virtually a consensus that, besides the complexity of active delivering anticancer drugs by the nanocarriers to the tumor site, the current evaluation methods primarily relying on in vitro assays and in vivo animal models have been accounted for the low translational effectiveness to clinical applications. In this view, the chick chorioallantoic membrane (CAM) assay has been increasingly recognized as one of the best preclinical models to study the effects of anticancer drugs on the tumor microenvironment (TME). Thus, in this study, we designed, characterized, and developed novel hybrid nanostructures encompassing chemically functionalized carboxymethylcellulose (CMC) with mitochondria-targeting pro-apoptotic peptide (KLA) and cell-penetrating moiety (cysteine, CYS) with fluorescent inorganic semiconductor (Ag-In-S, AIS) for simultaneously bioimaging and inducing glioblastoma cancer cell (U-87 MG, GBM) death. The results demonstrated that the CMC-peptide macromolecules produced supramolecular vesicle-like nanostructures with aqueous colloidal stability suitable as nanocarriers for passive and active targeting of cancer tumors. The optical properties and physicochemical features of the nanoconjugates confirmed their suitability as photoluminescent nanoprobes for cell bioimaging and intracellular tracking. Moreover, the results in vitro demonstrated a notable killing activity towards GBM cells of cysteine-bearing CMC conjugates coupled with pro-apoptotic KLA peptides. More importantly, compared to doxorubicin (DOX), a model anticancer drug in chemotherapy that is highly toxic, these innovative nanohybrids nanoconjugates displayed higher lethality against U-87 MG cancer cells. In vivo CAM assays validated these findings where the nanohybrids demonstrated a significant reduction of GBM tumor progression (41% area) and evidenced an antiangiogenic activity. These results pave the way for developing polymer-based hybrid nanoarchitectonics applied as targeted multifunctional theranostics for simultaneous imaging and therapy against glioblastoma while possibly reducing the systemic toxicity and side-effects of conventional anticancer chemotherapeutic agents.

Doxorubicin (DOX) is a commonly used antitumor drug. However, it may cause severe cardiotoxicity, apoptosis being a major change. A recent report indicates that miR-147 expression is decreased in the myocardium of a myocardial infarction model, suggesting a potential role of this miRNA in DOX-induced cardiomyocyte toxicity. In this study, freshly isolated neonatal pig cardiomyocytes were used; following transfection of a miR-147-y mimic, the cell death induced by DOX was alleviated, represented by augmented mitophagy [indicated by a decrease in P62, and increases in LC3, PINK1, parkin mRNA, LC3Ⅱ/Ⅰ, beclin-1, PINK1, and parkin including p-parkin (Ser65) protein expression], prohibited cell apoptosis as determined by TUNEL staining, and the suppression of caspase-3 transcription and cleaved caspase-3 translation. In cells transfected with an miR-147-y inhibitor, DOX-induced mitophagy was decreased, while apoptosis was increased. Additionally, RAPTOR gene silencing in cardiomyocytes exposed to DOX increased the rate of mitophagy and decreased that of apoptosis as compared with the treatment with DOX alone. Moreover, RAPTOR overexpression downregulated the rate of mitophagy and increased that of apoptosis in cells exposed to DOX. RAPTOR was confirmed as the target gene of miR-147-y based on the results of luciferase reporter gene assays and the opposite effects of the miR-147-y mimic and miR-147-y inhibitor on RAPTOR expression. In summary, our study suggests that miR-147-y mediates DOX-induced cardiomyocyte mitophagy while suppresses apoptosis by targeting RAPTOR, thus playing a protective role in DOX-induced cardiomyocyte damage.

The long-circulating effect is revisited by simultaneous monitoring of the drug payloads and nanocarriers following intravenous administration of doxorubicin (DOX)-loaded methoxy polyethylene glycol-polycaprolactone (mPEG-PCL) nanoparticles. Comparison of the kinetic profiles of both DOX and nanocarriers verifies the long-circulating effect, though of limited degree, as a result of pegylation. The nanocarrier profiles display fast clearance from the blood despite dense PEG decoration; DOX is cleared faster than the nanocarriers. The nanocarriers circulate longer than DOX in the blood, suggesting possible leakage of DOX from the nanocarriers. Hepatic accumulation is the highest among all organs and tissues investigated, which however is reversely proportionate to blood circulation time. Pegylation and reduction in particle size prove to extend circulation of drug nanocarriers in the blood with simultaneous decrease in uptake by various organs of the mononuclear phagocytic system. It is concluded that the long-circulating effect of mPEG-PCL nanoparticles is reconfirmed by monitoring of either DOX or the nanocarriers, but the faster clearance of DOX suggests possible leakage of a fraction of the payloads. The findings of this study are of potential translational significance in design of nanocarriers towards optimization of both therapeutic and toxic effects.

Lung cancer is the most common malignancy in the world, with high mortality rate. Nevertheless, therapies to act effectively against lung cancer remain elusive. So far, chemotherapy is still the frontline treatment of lung cancer. Doxorubicin (DOX) is a broad-spectrum anti-tumor drug. However, DOX often has serious side effects and causes multi-drug resistance, which greatly limits its clinical application. In this work, biodegradable methoxy poly(ethylene glycol)-block-poly(lactic acid) (MPEG-PLA) nanomicelles modified by Cyclo(Arg-Gly-Asp-d-Phe-Lys) (cRGD) polypeptide was used for the co-delivery of curcumin (CUR) and DOX (CUR-DOX/cRGD-M). The particle size of the self-assembled drug-loaded nano-micelle approximately was 27.4 nm and the zeta potential was −2.7 mV. Interestingly, CUR can enhance the uptake of DOX by Lewis lung carcinoma (LL/2) cells. The experimental results in vivo and in vitro showed that CUR-DOX/cRGD-M combination therapy could promote apoptosis of lung cancer cells, and conspicuously inhibit the tumor growth. Our data indicate that CUR-DOX/cRGD-M will be biodegradable and sustainable, which may have potential clinical application value in the treatment of lung cancer.

The current study aimed to explore the pretreatment of bone marrow mesenchymal stem cells (BMSCs) with hyaluronic acid (HA) on renal fibrosis in Adriamycin- induced CKD in rats.Sixty male SD rats were alienated into 4 equal groups; The control group: rats received two saline injections at 1 and 14 days, adriamycin (ADR) group: rats were injected i.v. twice via tail vein at day one and after 2 weeks, BMSCs group; rats were injected i.v. twice after 5 days of each ADR injection, and HA+BMSCs; rats were i.v. injected twice with BMSCs pretreated with 1 mg/ml HA after 5 days of each ADR injection. Protective role of BMSCs on renal function and morphology was detected using biochemical analysis, molecular studies, histopathological, and immunohistohemical investigations.Pretreatment of BMSCs with HA showed significant decrease in KIM-1, and increase in serum albumin compared to CKD group (p 0.05). Moreover, it reduced the expression of the apoptotic marker Caspase-3, the inflammatory markers TNF and IL-6, and the fibrotic markers Wnt7a, β-catenin, and fibronectin1 than the CKD group (p 0.05).The current outcomes suggested that BMSCs preconditioned with HA could attenuate the renal fibrosis in adriamycin- induced CKD.

Overexpression of the BCL2 protein has been reported as a poor prognostic factor for diffuse large B-cell lymphoma (DLBCL). However, there are currently no standardized criteria for evaluating BCL2 protein expression. We aimed to evaluate the prognostic value of BCL2 expression determined by immunohistochemistry (IHC), incorporating both the staining intensity and proportion, in patients with de novo DLBCL who received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) as first-line treatment. We defined tumors with BCL2 expression in nearly all tumor cells with a uniformly strong intensity by IHC as BCL2 super-expressor. The BCL2 super-expressors (n = 35) showed significantly worse event-free survival (EFS; HR, 1.903; 95% CI, 1.159-3.126, P = 0.011) and overall survival (OS; HR, 2.467; 95% CI, 1.474-4.127, P = 0.001) compared with the non-BCL2 super-expressors (n = 234) independent of the international prognostic index (IPI), cell of origin (COO), and double expressor status in the training set (n = 269). The adverse prognostic impact of BCL2 super-expression was confirmed in the validation set (n = 195). When the survival outcomes were evaluated in the entire cohort (n = 464), BCL2 super-expressor group was significantly associated with inferior EFS and OS regardless of IPI, COO, MYC expression, and stages. BCL2 super-expressors had genetic aberrations enriched in the NOTCH and TP53 signaling pathways. This study suggests that the BCL2 super-expressor characterizes a distinct subset of DLBCL with a poor prognosis and warrants further investigation as a target population for BCL-2 inhibitors.