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"A very toxic anthracycline aminoglycoside antineoplastic isolated from Streptomyces peucetius and others, used in treatment of LEUKEMIA and other NEOPLASMS." (MeSH 2013)

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Web Resources: Daunorubicin
Latest Research Publications
Liposomal Daunorubicin

Web Resources: Daunorubicin (6 links)

Latest Research Publications

Nishimura M, Onoe T, Sakai H, et al.
Safety and Relative Dose Intensity of Dose-dense Doxorubicin and Cyclophosphamide Followed by Dose-dense Paclitaxel.
Anticancer Res. 2019; 39(8):4379-4383 [PubMed] Related Publications
BACKGROUND/AIM: Dose-dense doxorubicin and cyclophosphamide (ddAC) followed by dose-dense paclitaxel (ddP) (ddAC-P) has improved disease-free survival of patients with breast cancer. The aim of this study was to evaluate the safety and relative dose intensity (RDI) of ddAC-P administered together with pegfilgrastim.
PATIENTS AND METHODS: Between May 2015 and Aug 2017, 44 patients were retrospectively reviewed; they were administered 4 cycles of ddAC, followed by 4 cycles of ddP. Pegfilgrastim (3.6 mg) was administered in every cycle.
RESULTS: The mean RDIs for ddAC-P, ddAC, and ddP were 95.0%, 94.5%, and 93.3%, respectively. The prevalence of high RDIs (≥85%) for ddAC-P, ddAC, and ddP was 90.9%, 84.1%, and 88.6%, respectively. Seven of the 10 patients with low RDIs experienced grade 1 or 2 fever.
CONCLUSION: DdAC-P administered together with pegfilgrastim (3.6 mg) appears to be feasible and maintains RDI in most of Japanese patients with breast cancer. Rapid evaluation and proper management of fever may prevent low RDI.

Cao Y, Min J, Zheng D, et al.
Vehicle-saving theranostic probes based on hydrophobic iron oxide nanoclusters using doxorubicin as a phase transfer agent for MRI and chemotherapy.
Chem Commun (Camb). 2019; 55(61):9015-9018 [PubMed] Related Publications
A simple approach for constructing theranostic nanobeads is developed by using doxorubicin as a phase transfer agent to solubilize small iron oxide nanoclusters. The nanobeads can be specifically internalized into cancer cells with the guidance of an external magnetic field, resulting in good MRI and chemotherapy.

Naruphontjirakul P, Viravaidya-Pasuwat K
Development of anti-HER2-targeted doxorubicin-core-shell chitosan nanoparticles for the treatment of human breast cancer.
Int J Nanomedicine. 2019; 14:4105-4121 [PubMed] Free Access to Full Article Related Publications

Wang Y, Fu M, Liu J, et al.
Inhibition of tumor metastasis by targeted daunorubicin and dioscin codelivery liposomes modified with PFV for the treatment of non-small-cell lung cancer.
Int J Nanomedicine. 2019; 14:4071-4090 [PubMed] Free Access to Full Article Related Publications

Zhao J, Zhu Y, Ye C, et al.
Photothermal transforming agent and chemotherapeutic co-loaded electrospun nanofibers for tumor treatment.
Int J Nanomedicine. 2019; 14:3893-3909 [PubMed] Free Access to Full Article Related Publications

Mayer LD, Tardi P, Louie AC
CPX-351: a nanoscale liposomal co-formulation of daunorubicin and cytarabine with unique biodistribution and tumor cell uptake properties.
Int J Nanomedicine. 2019; 14:3819-3830 [PubMed] Free Access to Full Article Related Publications
Combination regimens are a standard of care for many cancers. However, components of such regimens are typically first developed individually and subsequently combined using strategies to minimize toxicity. Little or no consideration is given to strategies that potentially maximize efficacy. In contrast, CPX-351 (Vyxeos®) is a dual-drug liposomal encapsulation of cytarabine and daunorubicin that was rationally designed to improve efficacy over the traditional 7+3 cytarabine/daunorubicin chemotherapy regimen for patients with acute myeloid leukemia (AML). The notable clinical efficacy of CPX-351 is achieved through maintenance of a synergistic 5:1 molar ratio of cytarabine and daunorubicin within the liposome after intravenous injection. The CPX-351 liposome, which is formulated to contain bilayers of distearoylphosphatidylcholine, distearoylphosphatidylglycerol, and cholesterol at a 7:2:1 molar ratio and remains in a gel phase at body temperature, provides stability without polyethylene glycol, controlled release of cytarabine and daunorubicin, limited systemic drug distribution, and preferential internalization within malignant myeloblasts in the bone marrow via active uptake of liposomes into cytoplasmic vacuoles. Thus, the CPX-351 liposome protects cytarabine and daunorubicin from metabolism and elimination, while overcoming pharmacokinetic differences between the two agents. In clinical studies, these liposome properties markedly increased the elimination half-life of CPX-351 versus free cytarabine and daunorubicin and maintained a synergistic drug ratio for over 24 hrs after administration. Preferential uptake of liposomes by leukemia cells suggests that relatively large amounts of cytarabine and daunorubicin enter malignant cells via liposomes, potentially bypassing P-glycoprotein-based efflux pumps, which are important mediators of chemotherapy resistance, and contribute to the rapid clearance of leukemia cells from the circulation and bone marrow. These pharmacologic advantages, a direct consequence of properties of the encapsulating liposome, may explain the efficacy of CPX-351 in patients with newly diagnosed high-risk/secondary AML and the reduced drug exposure in off-target tissues that contribute to a manageable safety profile.

Hamidu A, Mokrish A, Mansor R, et al.
Modified methods of nanoparticles synthesis in pH-sensitive nano-carriers production for doxorubicin delivery on MCF-7 breast cancer cell line.
Int J Nanomedicine. 2019; 14:3615-3627 [PubMed] Free Access to Full Article Related Publications

Mokkarala M, Noda C, Malone C, et al.
Comparison of Response and Outcomes of Drug-eluting Bead Chemoembolization (DEB-TACE)
Anticancer Res. 2019; 39(6):3071-3077 [PubMed] Related Publications
BACKGROUND: To compare outcomes for patients with colorectal cancer liver metastases (CRCLM) treated by drug-eluting bead chemoembolization (DEB-TACE) or radioembolization (TARE).
PATIENTS AND METHODS: A single-center retrospective review was carried out on 202 patients with CRCLM, treated by DEB-TACE (n=47) or TARE (n=155) patients. Propensity-matching yielded 44 pairs. Paired statistical analysis was performed on matched pair demographics, treatment response, and survival.
RESULTS: Patients treated with DEB-TACE had worse extra-hepatic metastasis (68.1 vs. 47.7%, p=0.014) and ≥10 liver lesions (42.2 vs. 68.8%, p=0.001). Matched patients treated with DEB-TACE had a trend towards worse toxicity (27% vs. 9.1% (p=0.057). Index DEB-TACE treatment was not a prognostic factor for overall survival (hazard ratio=0.94, 95% confidence intervaI=0.54-1.65; p=0.83).
CONCLUSION: In the matched CRCLM cohort, there was a trend towards worse toxicity post-DEB-TACE treatment, but it was not an independent prognostic factor for survival.

Kiss K, Biri-Kovács B, Szabó R, et al.
Sequence modification of heptapeptide selected by phage display as homing device for HT-29 colon cancer cells to improve the anti-tumour activity of drug delivery systems.
Eur J Med Chem. 2019; 176:105-116 [PubMed] Related Publications
Development of peptide-based conjugates for targeted tumour therapy is a current research topic providing new possibilities in cancer treatment. In this study, VHLGYAT heptapeptide selected by phage display technique for HT-29 human colon cancer was investigated as homing peptide for drug delivery. Daunomycin was conjugated to the N-terminus of the peptide directly or through Cathepsin B cleavable spacers. Conjugates showed moderate in vitro cytostatic effect. Therefore, sequence modifications were performed by Ala-scan and positional scanning resulting in conjugates with much higher bioactivity. Conjugates in which Gly was replaced by amino acids with bulky apolaric side chains provided the best efficacy. The influence of the cellular uptake, stability and drug release on the anti-tumour activity was investigated. It was found that mainly the difference in the cellular uptake of the conjugates generated the distinct effect on cell viability. One of the most efficient conjugate Dau = Aoa-LRRY-VHLFYAT-NH

Frión-Herrera Y, Gabbia D, Díaz-García A, et al.
Chemosensitizing activity of Cuban propolis and nemorosone in doxorubicin resistant human colon carcinoma cells.
Fitoterapia. 2019; 136:104173 [PubMed] Related Publications
Propolis is a natural product obtained from bees, used since ancient times for its multiple pharmacological properties. Several evidences indicate that the antiproliferative effect of propolis against different cancer cell lines can be ascribed to its components. However, little is known about the possible use of this natural product in the treatment of chemo-resistant tumors. Combination experiments were carried out in order to study the ability of Cuban propolis extracts (CP) and its main component (nemorosone) to chemosensitize doxorubicin-resistant human colon carcinoma cells (LoVo Dox) compared to the sensitive cells (LoVo). Antiproliferative effect was determined by MTT assay after 24, 48 and 72 h exposure. Synergistic, additive or antagonistic effects of different combined treatments (CP-Dox and nemorosone-Dox), was evaluated by isobologram-combination index method. The interaction mechanisms between CP or nemorosone with doxorubicin were studied by flow cytometry to investigate cell death pathway and cell cycle arrest. Reactive oxygen species production (ROS) and mitochondrial membrane potential (ΔΨm) modification were also evaluated. Data showed that both CP and its main component nemorosone were able to reduce cell proliferation in a concentration- and time-dependent manner. Combined treatments induced a cell growth inhibition with a significantly synergistic antiproliferative and cytotoxic effect. Co-treatments induced also cell cycle arrest which results in apoptosis by a marked ROS production and drastic alteration of ΔΨm. In summary, our findings evidence the potential role of Cuban propolis extracts and their main component nemorosone as new chemosensitizing agents against drug-resistant human colon carcinoma cells.

Yu D, Zhang S, Feng A, et al.
Methotrexate, doxorubicin, and cisplatinum regimen is still the preferred option for osteosarcoma chemotherapy: A meta-analysis and clinical observation.
Medicine (Baltimore). 2019; 98(19):e15582 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: We designed the study to investigate whether methotrexate, doxorubicin, and cisplatinum (MAP) chemotherapy strategy was still the preferred option for the survival of osteosarcoma patients.
METHOD: We collected some trials of osteosarcoma to make a meta-analysis first. Then, we retrospectively collected data from 115 patients with osteosarcoma and performed further analysis to verify the impact of MAP regimen on the survival of patients.
RESULTS: Seven studies including 3433 participants met the preliminary inclusion criteria. Meta-analysis of the 3-year disease-free survival (odds ratio [OR] = 1.06, 95% confidence interval [CI]: 0.88-1.28; P = .52) and overall survival (OR = 1.21, 95% CI: 0.70-2.11; P = .54), 5-year disease-free survival (OR = 1.07, 95% CI: 0.87-1.30; P = .54) and overall survival (OR = 0.86, 95% CI: 0.65-1.12; P = .26), and mortality rate (OR = 0.90, 95% CI: 0.70-1.17; P = .44), showed no statistically significant differences. The most common grade 3/4 adverse events were neutropenia (498 [85.9%] patients in MAP vs 533 [93.3%] in MAP plus ifosfamide and etoposide, or other adjuvant therapy drugs [MAP]). MAP was associated with less frequent toxicities than MAP group with statistical significance in thrombocytopenia, febrile neutropenia, anemia, and hypophosphatemia. The same phenomenon could also be seen in the analysis of clinical data.
CONCLUSION: MAP regimen remains the preferred option for osteosarcoma chemotherapy.

Tao M, Liu J, He S, et al.
In situ hydrogelation of forky peptides in prostate tissue for drug delivery.
Soft Matter. 2019; 15(20):4200-4207 [PubMed] Related Publications
Herein, we have designed and synthesized a novel forky peptide D3F3 that transforms into a hydrogel through crosslinking induced by ZIs stimuli. We have employed D3F3 as a suitable drug carrier that is conjugated with DOX. Since the concentration of zinc ions necessary for triggering gelation falls into the physiological range present in prostate tissue, while other cationic ions fail to trigger at physiological concentrations, the peptide-based drug delivery system (DDS) is injectable and would achieve prostate tissue-specific self-assembly in situ. The D3F3 hydrogels exhibited an optimal gelation time, satisfactory mechanical strength (can be enhanced after incorporation of DOX) as well as excellent thixotropic properties. The DDS reserved some DOX in the prostate 24 h after the injection, making local sustained release possible. In addition, the peptide materials demonstrated no cytotoxicity against normal fibroblast cells and no damage was observed to the prostate tissue of rats. The drug release followed a non-Fickian diffusion model, with no burst release observed. Importantly, the DOX-hydrogel system exhibited good anti-cancer efficacy when incubated with prostate cancer cells DU-145. Therefore, this study lays the groundwork for the future design of tissue-specific DDSs that are triggered by cationic ions (e.g. zinc ions), and the platform could be further developed to incorporate other potent drugs utilized in the field of prostate cancer therapy, thereby increasing their potency and reducing their side effects.

Li Q, Ma L, Su M
Single identical cell toxicity assay on coordinately ordered patterns.
Anal Chim Acta. 2019; 1065:56-63 [PubMed] Related Publications
Toxicity assay is crucial in identifying biological mechanisms, detecting disease and screening therapeutics. Single cell toxicity assay reveals heterogeneous responses of each cell without ensemble average, but still cannot indicate responses of the same individual cells to multiple treatments. This article reports an identical cell assay that can be used at high throughput to locate each cell and track its responses to multiple treatments (chemicals and radiation), thus greatly facilitates toxicity based drug screening and testing. Each cell is located through its coordinators pre-engraved on a patterned substrate with soft lithography. Cell responses to X-ray radiation, chemical reagents or a combination of both are obtained by probing reactive oxygen species (ROS) signals and quantified by fluorescent intensity in MATLAB. The method can provide toxicities of over thousands of identical cells with superior statistics power to allow deep analysis of toxicity data.

Gao Y, Jia L, Wang Q, et al.
pH/Redox Dual-Responsive Polyplex with Effective Endosomal Escape for Codelivery of siRNA and Doxorubicin against Drug-Resistant Cancer Cells.
ACS Appl Mater Interfaces. 2019; 11(18):16296-16310 [PubMed] Related Publications
The enhanced endo-lysosomal sequestration still remains a big challenge in overcoming multidrug resistance (MDR). Herein, a dual-responsive polyplex with effective endo-lysosomal escape based on methoxypoly(ethylene glycol)-polylactide-polyhistidine-ss-oligoethylenimine (mPEG- b-PLA-PHis-ssOEI) was developed for codelivering MDR1 siRNA and doxorubicin (DOX). The polyplex showed good encapsulation of DOX and siRNA as well as triggered payload release in response to pH/redox stimuli because of the PHis protonation and the disulfide bond cleavage. The polyplex at an N/P ratio of 7 demonstrated a much higher payload delivery efficiency, MDR1 gene silence efficiency, cytotoxicity against MCF-7/ADR cell, and stronger MCF-7/ADR tumor growth inhibition than the polyplexes at higher N/P ratios. This was attributed to the stronger electrostatic attraction between siRNA and OEIs at higher N/P ratios that suppressed the release of MDR1 siRNA and OEIs, which played a dominant role in overcoming payload endo-lysosomal sequestration by the OEI-induced membrane permeabilization effect. Consequently, the polyplex with effective endo-lysosomal escape provides a rational approach for codelivery of siRNAs and chemotherapy agents for MDR reversal.

Liu T, Wan Q, Luo Y, et al.
On-Demand Detaching Nanosystem for the Spatiotemporal Control of Cancer Theranostics.
ACS Appl Mater Interfaces. 2019; 11(18):16285-16295 [PubMed] Related Publications
Engineering multiple theranostic modalities into a single nanoscale entity holds great potential to rejuvenate cancer treatments; however, enabling the sophisticated spatiotemporal control of each component for maximizing theranostic improvement and minimizing side effects concurrently remains a challenge. Herein, an intelligent detachable "nanorocket" is developed to sequentially manipulate and optimize multitheranostic processes for magnetic resonance-assisted ultrasound-drug combined therapy (MR-HIFU-Drug). The "nanorocket" is constructed by integrating multicomponent (MnCO

Yang T, Du G, Cui Y, et al.
pH-sensitive doxorubicin-loaded polymeric nanocomplex based on β-cyclodextrin for liver cancer-targeted therapy.
Int J Nanomedicine. 2019; 14:1997-2010 [PubMed] Free Access to Full Article Related Publications
Background: Doxorubicin (DOX) is one of the most effective treatments for hepatocellular carcinoma (HCC), but is restricted by its poor pharmacokinetics. Herein, we exploited efficient targeted drug delivery systems and they have been found to be a worthy strategy for liver cancer therapy.
Materials and methods: We investigated polymeric nanoparticles which were synthesized based on host-guest interaction between β-cyclodextrin and benzimidazole. The properties of nanoparticles with regard to size/shape, encapsulation efficiency, and drug release were investigated using conventional experiments. Cell proliferation assay in vitro, cell uptake assay, and cell apoptosis analysis were used to investigate cytotoxicity, uptake, and mechanism of targeted supramolecular prodrug complexes (TSPCs)-based self-assemblies and supramolecular prodrug complexes (SPCs)-based self-assemblies.
Results: The pH-sensitive lactobionic acid (LA)-modified pH-sensitive self-assemblies were synthesized successfully. The results of in vitro released assay showed that the accelerated released of DOX from TSPCs-based self-assemblies with the decrease of pH value. When TSPCs-based self-assemblies were taken up by HepG2 cells, they demonstrated a faster release rate under acidic conditions and proved to have higher cytotoxicity than in the presence of LA. A mechanistic study revealed that TSPCs-based self-assemblies inhibited liver cell proliferation by inducing cell apoptosis.
Conclusion: The pH-sensitive nanocomplex, as liver-targeted nanoparticles, facilitated the efficacy of DOX in HepG2 cells, offering an appealing strategy for the treatment of HCC.

Li K, Liu W, Zhao Q, et al.
Combination of tanshinone IIA and doxorubicin possesses synergism and attenuation effects on doxorubicin in the treatment of breast cancer.
Phytother Res. 2019; 33(6):1658-1669 [PubMed] Related Publications
Doxorubicin (Dox) is a first-line drug for breast cancer chemotherapy. However, with the prolongation of chemotherapy cycle, breast cancer cells are increasingly tempt to resist Dox, and meanwhile, high cumulative dose of Dox brings enhancing toxic side effects, and these effects may lead to chemotherapy failure. Hence, it is necessary to search an agent in combination medication with Dox, which can not only enhance the chemosensitivity of Dox but also reduce the toxic side effects. Tanshinone IIA (Tan IIA) is reported to have antitumor activity in addition to its cardiovascular protective effects. We employed human breast cancer MCF-7 and MCF-7/dox cells in order to assess whether Tan IIA might perform such function. Our in vitro studies showed that Tan IIA could enhance the sensitivity of breast cancer cells to Dox through inhibiting the PTEN/AKT pathway and downregulating the expression of efflux ABC transporters including P-gp, BCRP, and MRP1. In addition, our in vivo studies showed Tan IIA enhanced the chemotherapeutic effect of Dox against breast cancer while reducing its toxic side effects including weight loss, myelosuppression, cardiotoxicity, and nephrotoxicity. Therefore, Tan IIA could be used as a novel agent combined with Dox in breast cancer therapy.

Sun GY, Du YC, Cui YX, et al.
Terminal Deoxynucleotidyl Transferase-Catalyzed Preparation of pH-Responsive DNA Nanocarriers for Tumor-Targeted Drug Delivery and Therapy.
ACS Appl Mater Interfaces. 2019; 11(16):14684-14692 [PubMed] Related Publications
Developing a highly efficient carrier for tumor-targeted delivery and site-specific release of anticancer drugs is a good way to overcome the side effects of traditional cancer chemotherapy. Benefiting from the nontoxic and biocompatible characteristics, DNA-based drug carriers have attracted increasing attention. Herein, we reported a novel and readily manipulated strategy to construct spherical DNA nanocarriers. In this strategy, terminal deoxynucleotidyl transferase (TdT)-catalyzed DNA extension reaction is used to prepare a thick DNA layer on a gold nanoparticle (AuNP) surface by extending long poly(C) sequences from DNA primers immobilized on AuNPs. The poly(C) extension products can then hybridize with G-rich oligonucleotides to give CG-rich DNA duplexes (for loading anticancer drug doxorubicin, Dox) and multiple AS1411 aptamers. Via synergic recognition of multiple aptamer units to nucleolin proteins, biomarker of malignant tumors, Dox-loaded DNA carrier can be efficiently internalized in cancer cells and achieve burst release of drugs in acidic organelles because of i-motif formation-induced DNA duplex destruction. An as-prepared pH-responsive drug carrier was demonstrated to be promising for highly efficient delivery of Dox and selective killing of cancer cells in both in vitro and in vivo experiments, thus showing a huge potential in anticancer therapy.

Locatelli E, Li Y, Monaco I, et al.
A novel theranostic gold nanorods- and Adriamycin-loaded micelle for EpCAM targeting, laser ablation, and photoacoustic imaging of cancer stem cells in hepatocellular carcinoma.
Int J Nanomedicine. 2019; 14:1877-1892 [PubMed] Free Access to Full Article Related Publications
Introduction and purpose: Cancer stem cells (CSCs) present a higher capacity to evade being killed by cancer agents and developing chemoresistance, thus leading to failure of conventional anticancer therapeutics. Nanomaterials specifically designed for targeting and treating not only tumor cells, but also CSCs, may encompass therapeutic and diagnostic tools, thus successfully eradicating the tumor.
Materials and methods: Polymeric micelles simultaneously loaded with gold nanorods (GNRs) and Adriamycin were prepared and used as a novel therapeutic and diagnostic weapon. Epithelial cell adhesion molecule (EpCAM) is an important CSC surface marker and has been exploited in this work as an active targeting agent. Photoacoustic imaging was applied for GNR individuation and tissue recognition.
Results: The nanosystem was demonstrated to be able to elicit effective targeting of cancer cells and cause their killing, in particular under laser ablation. Moreover, ex vivo photoacoustic imaging is able to clearly identify tumor regions thanks to GNR's contrast.
Conclusion: The nanosystem can be considered a powerful and promising theranostic weapon for hepatocellular carcinoma treatment.

Lucas A, Lam D, Cabrales P
Doxorubicin-loaded red blood cells reduced cardiac toxicity and preserved anticancer activity.
Drug Deliv. 2019; 26(1):433-442 [PubMed] Free Access to Full Article Related Publications
Doxorubicin (DOX) is one of the most widely used anticancer agents. DOX is known for inducing cardiotoxicity, resulting in the long-term development of heart failure. Intravascular delivery of DOX may benefit from the carriage by red blood cells (RBCs), as they can limit the systemic toxicity while delivering the DOX to the tumor. This study proposes a methodology for the synthesis of electrophoretically DOX-loaded red blood cells (RBC-DOX), as well as the assessment of its antitumorigenic effects in human colon cancer cells (HT-29), and in colon cancer xenograft models. In addition, healthy mice without tumors were dosed with RBC-DOX to assess cardiotoxicity via assessment of indexes of cardiac function after multiple doses of RBC-DOX. The HT-29 IC

Shea LK, Uy GL
Choosing induction chemotherapy in therapy-related acute myeloid leukemia.
Best Pract Res Clin Haematol. 2019; 32(1):89-97 [PubMed] Related Publications
Patients with AML that develops after cytotoxic therapy (tAML) have overall inferior outcomes relative to de novo AML due to both patient-related factors and the intrinsic biology of the disease. Treatment of patients with tAML is challenging. The key initial clinical decision is whether a patient is a candidate for or likely to benefit from intensive induction chemotherapy, a determination which we argue should not be predicated on chronologic age alone. For those determined likely to tolerate intensive induction chemotherapy, CPX-351 is likely superior to conventional induction with cytarabine and daunorubicin. For those deemed inappropriate for intensive induction, hypomethylating agents have the strongest evidence base in elderly adults with AML, and are an attractive option in tAML. This is particularly true in patients with TP53 mutations who are less likely to respond to conventional induction chemotherapy. Exciting options on the therapeutic horizon for tAML include combination therapies incorporating BCL2 inhibitors, Hedgehog pathway inhibitors, and isocitrate dehydrogenase inhibitors.

Beladi-Mousavi SM, Khezri B, Krejčová L, et al.
Recoverable Bismuth-Based Microrobots: Capture, Transport, and On-Demand Release of Heavy Metals and an Anticancer Drug in Confined Spaces.
ACS Appl Mater Interfaces. 2019; 11(14):13359-13369 [PubMed] Related Publications
Self-propelled microrobots are seen as the next step of micro- and nanotechnology. The biomedical and environmental applications of these robots in the real world need their motion in the confined environments, such as in veins or spaces between the grains of soil. Here, self-propelled trilayer microrobots have been prepared using electrodeposition techniques, coupling unique properties of green bismuth (Bi) with a layered crystal structure, magnetic nickel (Ni), and a catalytic platinum (Pt) layer. These Bi-based microrobots are investigated as active self-propelled platforms that can load, transfer, and release both doxorubicin (DOX), as a widely used anticancer drug, and arsenic (As) and chromium (Cr), as hazardous heavy metals. The significantly high loading capability for such variable cargoes is due to the high surface area provided by the rhombohedral layered crystal structure of bismuth, as well as the defects introduced through the oxide layer formed on the surface of bismuth. The drug release is based on an ultrafast electroreductive mechanism in which the electron injection into microrobots and consequently into the loaded objects causes an electrostatic repulsion between them and thus an ultrafast release of the loaded cargos. Remarkably, we have presented magnetic control of the Bi-based microrobots inside a microfluidic system equipped with an electrochemical setup as a proof-of-concept to demonstrate (i) heavy metals/DOX loading, (ii) a targeted transport system, (iii) the on-demand release mechanism, and (iv) the recovery of the robots for further usage.

Bhandari A, Bansal A, Singh A, et al.
Comparison of transport of chemotherapeutic drugs in voxelized heterogeneous model of human brain tumor.
Microvasc Res. 2019; 124:76-90 [PubMed] Related Publications
Systemic administration of chemotherapeutic drugs is widely used in the treatment of cancer. However, a good understanding of drug transport barriers that influence the treatment efficacy is still lacking. In this study, a voxelized numerical model based on dynamic contrast enhanced-magnetic resonance imaging (DCE-MRI) and computational fluid dynamics (CFD) is employed to study the transport and efficacy of three different chemotherapeutic drugs, namely methotrexate, doxorubicin and cisplatin in human brain tumors. DCE-MRI data provides realistic heterogeneous vasculature of the tumor, the permeability of tissue to contrast agent, interstitial volume fraction (porosity) of the tissue and patient-specific arterial input function (AIF). The permeability of tissue to aforementioned drugs is determined by correlating it with the permeability of tissue to the contrast agent. The model is employed to simulate drug concentration in the tissue and compare the effect of heterogeneous vasculature on the distribution of the drugs in the tumor. The drug accumulation is observed to be higher in high permeability areas initially, and in higher porosity areas at later times. Furthermore, it is observed that methotrexate remains in the interstitial space of the tumor in higher concentration for a longer duration as compared to other two drugs, facilitating more tumor cell killing.

Lorusso D, Sabatucci I, Maltese G, et al.
Treatment of recurrent ovarian cancer with pegylated liposomal doxorubicin: a reappraisal and critical analysis.
Tumori. 2019; 105(4):282-287 [PubMed] Related Publications
The vast majority of ovarian cancer relapses on front-line therapy and the optimal treatment of recurrent ovarian cancer remains controversial. This review is based on the relevant published literature indexed in PubMed on pegylated liposomal doxorubicin (PLD), either alone or in combination with other drugs, as one option in relapsed disease. PLD showed an improved pharmacokinetic profile, with a slower plasma clearance and a longer circulation time, compared to other conventional doxorubicin formulations. PLD is considered to have little potential for cardiotoxicity, even at prolonged and high cumulative doses, although there appears to be room for improvement in terms of maximal dose allowed. Notwithstanding, there remain some concerns about cardiac safety, and patient monitoring is generally advocated. No data are available on the possibility to rechallenge PLD treatment in recurrent ovarian cancer, as already known for other drugs. Optimization of treatment regimens with PLD will allow a more rational treatment in advanced ovarian cancers for which few therapeutic options are available.

Xing Y, Ding T, Wang Z, et al.
Temporally Controlled Photothermal/Photodynamic and Combined Therapy for Overcoming Multidrug Resistance of Cancer by Polydopamine Nanoclustered Micelles.
ACS Appl Mater Interfaces. 2019; 11(15):13945-13953 [PubMed] Related Publications
Currently, the simple integration of multiple therapeutic agents within a single nanostructure for combating multidrug resistance (MDR) tumors yet remains a challenge. Herein, we report a photoresponsive nanocluster (NC) system prepared by installing polydopamine (PDA) nanoparticle clusters on the surface of d-α-tocopheryl poly(ethylene glycol) 1000 succinate (TPGS) (a drug efflux inhibitor) micelles solubilized with IR780 (a photosensitizer) to achieve a combined chemotherapy (CT)/photothermal therapy (PTT)/photodynamic therapy (PDT) for drug-resistant breast cancer. Mediated by the fluorescence resonance energy transfer and radical scavenging properties of PDA, NC shows prominently quenched fluorescence emission (∼78%) and inhibited singlet oxygen generation (∼67%) upon exposure to near-infrared (NIR) light (808 nm, 0.5 W cm

Wang H, Deng Z, Chen X, et al.
Downregulation of miR-222-3p Reverses Doxorubicin-Resistance in LoVo Cells Through Upregulating Forkhead Box Protein P2 (FOXP2) Protein.
Med Sci Monit. 2019; 25:2169-2178 [PubMed] Free Access to Full Article Related Publications
BACKGROUND Doxorubicin (DOX) is a potent chemotherapeutic agent used to treat colon cancer. Despite impressive initial clinical responses, drug resistance has dramatically compromised the effectiveness of DOX. However, the underlying mechanisms of chemotherapeutic resistance in colon cancer remain poorly understood. MATERIAL AND METHODS In this study, we compared the expression of miR-222-3p in DOX-resistant colon cancer cells (LoVo/ADR) with the corresponding DOX-sensitive parental cells (LoVo/S) using quantitative real-time PCR. In addition, miR-222-3p inhibitors were infected into LoVo/ADR cell lines and the effects of this treatment were assessed. The Cell Counting Kit 8 assay was employed to verify the sensitivity of colon cancer cell lines to DOX. EdU (5-ethynyl-2'-deoxyuridine) assay, flow cytometry, and in vivo subcutaneous tumorigenesis were used to assess cell proliferation and apoptosis. Transwell and wound healing assays were used to investigate cell migration after adding DOX. Additionally, the expression of forkhead box protein P2 (FOXP2), P-glycoprotein (P-gp) and caspase pathway-associated markers was assessed by western blotting. RESULTS Our results showed that miR-222-3p was upregulated in LoVo/ADR compared with the expression in LoVo/S cells. Additionally, downregulation of miR-222-3p in LoVo/ADR cells increased their sensitivity to DOX, reduced P-gp expression, and activated the caspase pathway. However, the downregulation of FOXP2 could efficiently reverse the effect of miR-222-3p inhibitors on LoVo/ADR cells. CONCLUSIONS Taken together, our results showed that miR-222-3p induced DOX resistance via suppressing FOXP2, upregulating P-gp, and inhibiting the caspase pathway.

Lian F, Chen W, Liu Y, et al.
Intra-arterial chemotherapy combined with intravesical chemotherapy is effective in preventing recurrence in non-muscle invasive bladder cancer.
J Cancer Res Clin Oncol. 2019; 145(6):1625-1633 [PubMed] Related Publications
OBJECTIVE: To evaluate the efficacy and safety of intra-arterial chemotherapy (IAC) combined with intravesical chemotherapy (IC) in non-muscle invasive bladder cancer (NMIBC) and identify the risk factors for recurrence and progression.
METHODS: This is a retrospective cohort study of NMIBC patients in south China. Ninety-nine patients underwent IAC combined with transurethral resection of bladder tumor (TURBT) and IC, and 50 patients underwent TURBT plus IC without IAC. The 5-year outcomes of the two groups were compared. Cox regression was used to evaluate risk factors. Kaplan-Meier curves were used to assess the significant differences of recurrence-free survival and progression-free survival.
RESULTS: At 5 years, IAC significantly reduced the recurrence of high-grade NMIBC, 54.5% (18/33) in the non-IAC group vs 30.5% (18/59) in the IAC group (p = 0.028). IAC significantly reduced the recurrence of high-risk NMIBC, 56.3% (18/32) in the non-IAC group vs 26.1% (18/69) in the IAC group (p = 0.007). IAC significantly reduced the recurrence of intermediate-risk NMIBC, 44.4% (8/18) in the non-IAC group vs 22.2% (6/27) in the IAC group (p = 0.030). Tumors numbering from 2 to 7 had the highest recurrence rate (18.1%, 27/149). In this aspect, there was a significantly lower recurrence rate in the IAC group (30.8%, 12/30) than in the non-IAC group (68.2%, 15/22) (p = 0.007). No significant difference was found in the progression rate between the two groups. Only two cases (2/99, 2.0%) in the IAC group showed progression. The results of univariate and multivariate analyses suggested that the number of tumors, grade and risk level were risk factors for recurrence. No difference was found with respect to gender, age, tumor diameter, and T category. In the Kaplan-Meier plot, recurrence-free survival was significantly associated with treatment strategies (p < 0.01). Recurrence-free survival was shorter in the non-IAC group (12.73 ± 7.56 months) than in the IAC group (17.88 ± 12.26 months).
CONCLUSIONS: Combined IAC is a promising procedure to prevent recurrence and may be useful to suppress progression in NMIBC patients. The independent risk factors for the recurrence of NMIBC were multifocal tumors, grade and risk level. Intra-arterial chemotherapy is an effective and safe procedure and may be a promising choice in areas where BCG is not available or for patients who are intolerant to BCG.

Usmani A, Mishra A, Arshad M, Jafri A
Development and evaluation of doxorubicin self nanoemulsifying drug delivery system with Nigella Sativa oil against human hepatocellular carcinoma.
Artif Cells Nanomed Biotechnol. 2019; 47(1):933-944 [PubMed] Related Publications
OBJECTIVE: The development of self nano emulsifying co-delivery system of doxorubicin and Nigella sativa oil for potentiating the anticancer effects against HepG2 cell lines.
MATERIALS AND METHODS: SNEDDS were formulated by using Labrafil and N. sativa oil (3:2% w/w), Kolliphor RH40 (15% w/w), glycerol (5% w/w) as oil phase, surfactant and co-surfactant while deionized water (75% v/v) used as an aqueous phase. Optimized SNEDDS was evaluated for drug release and in vitro anticancer efficacy in liver cancer (HepG2) cell line.
RESULTS AND DISCUSSION: The selected formulation (F6) has a mean particle size of 79.7 nm with PDI 0.098 and the minimum viscosity of 16.42 cps with % transmittance of 1.332 with maximum drug release of 96.968% in 32 h as compared to DOX alone. Stability data showed stable emulsion in both 25
CONCLUSION: The overall study displayed that co-delivery of DOX and Nigella sativa oil in the form of SNEDDS may be an efficient carrier for further in vivo studies using oral delivery in human hepatocellular carcinoma in mammals.

Wang L, Pei J, Cong Z, et al.
Development of anisamide-targeted PEGylated gold nanorods to deliver epirubicin for chemo-photothermal therapy in tumor-bearing mice.
Int J Nanomedicine. 2019; 14:1817-1833 [PubMed] Free Access to Full Article Related Publications
Background: Gold nanorods (AuNRs), due to the optical and electronic properties namely the surface plasma resonance, have been developed to achieve the light-mediated photothermal therapy (PTT) for cancer. However, PTT alone may suffer from inefficient tumor killing. Recently, the combination of PTT and chemotherapy has been utilized to achieve synergistic anticancer effects.
Methods: In this study, AuNRs capped with hexadecyltrimethylammonium bromide (CTAB), poly(acrylic acid) (PAA), and PEGylated anisamide (a ligand known to target the sigma receptor) have been developed to produce a range of negatively charged anisamide-targeted PEGylated AuNRs (namely Au-CTAB-PAA-PEG-AA) for the combination of PTT and chemotherapy (termed as chemo-photothermal therapy [CPTT]). Epirubicin (EPI, an anthracycline drug) was efficiently loaded onto the surface of Au
Results: The resultant complex demonstrated pH-dependent drug release, facilitated nucleus trafficking of EPI, and induced antiproliferative effects in human prostate cancer PC-3 cells. When Au
Conclusion: These results demonstrate a promising strategy for clinical application of CPTT in cancer.

Liu P, Chen N, Yan L, et al.
Preparation, characterisation and in vitro and in vivo evaluation of CD44-targeted chondroitin sulphate-conjugated doxorubicin PLGA nanoparticles.
Carbohydr Polym. 2019; 213:17-26 [PubMed] Related Publications
The purpose of this study was to ascertain the effect of chondroitin sulphate-modified doxorubicin (Dox) nanoparticles on enhancing the tumour-targeting effect and tumour growth inhibition effect of doxorubicin both in vitro and in vivo. The chondroitin sulphate-doxorubicin conjugate and its poly(lactic-co-glycolic acid) (PLGA) nanoparticles (CS-Dox-PLGA) were successfully synthesised, and then characterized by Fourier-transform infrared spectroscopy (FTIR), proton magnetic resonance (

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