A homologous-targeting cGAS-STING agonist multimodally activates dendritic cells for enhanced cancer immunotherapy.

Herein, we developed a doxorubicin (Dox)-loaded and 4T1 cancer cell membrane-modified hydrogenated manganese oxide nanoparticles (mHMnO-Dox) to elicit systemic antitumor immune responses. The results revealed that mHMnO-Dox actively recognized tumor cells and then effectively delivered Dox into the cells. Upon entering tumor cells, the mHMnO-Dox underwent rapid degradation and abundant release of Mn2+ and chemotherapeutic drugs. The released Mn2+ not only catalysed a Fenton-type reaction to produce excessive reactive oxygen species (ROS) but also activated the cGAS-STING pathway to boost dendritic cell (DC) maturation. This process increased cytotoxic T lymphocyte infiltration as well as natural killer cell recruitment into the tumor site. In addition, the released Dox could contribute to a chemotherapeutic effect, while activating DC cells and subsequently intensifying immune responses through immunogenic cell death (ICD) of tumor cells. Consequently, the mHMnO-Dox suppressed the primary and distal tumor growth and inhibited tumor relapse and metastasis, as well as prolonged the lifespan of tumor-bearing mice. Thus, the mHMnO-Dox multimodally activated DC cells to demonstrate synergistic antitumor activity, which was mediated via the activation of the cGAS-STING signalling pathway to regulate tumor microenvironment, ICD-mediated immunotherapy and ROS-mediated CDT. These findings suggest the therapeutic potential of mHMnO-Dox in cancer immunotherapy. STATEMENT OF SIGNIFICANCE: A cancer cell membrane-camouflaged hydrogenated mesoporous manganese oxide (mHMnO) has been developed as a cGAS-STING agonist and ICD inducer. The mHMnO effectively induced abundance of ROS production in cancer cells, which caused cancer cell death and then promoted DC maturation via tumour-associated antigen presentation. Meanwhile, the mHMnO significantly activated cGAS-STING pathway to facilitate DC maturation and cytotoxic T lymphocyte infiltration as well as natural killer cell recruitment, which further enhanced tumour immune response. In addition, the combination of the mHMnO and Dox could synergistically promote tumour ICD and then multimodally induce DC maturation, achieving an enhanced CIT. Overall, this study provides a potential strategy to design novel immunologic adjuvant for enhanced CIT.

pH/glutathione dual-responsive copper sulfide-coated organic mesoporous silica for synergistic chemo-photothermal therapy.

Nanodrug delivery systems (NDSs), such as mesoporous silica, have been widely studied because of their high specific surface area, high loading rate, and easy modification; however, they are not easily metabolized and excreted by the human body and may be potentially harmful. Hence, we aimed to examine the synergistic anti-tumor effects of ex vivo chemo-photothermal therapy to develop a rational and highly biocompatible treatment protocol for tumors. We constructed a biodegradable NDS using organic mesoporous silica with a tetrasulfide bond structure, copper sulfide core, and folic acid-modified surface (CuS@DMONs-FA-DOX-PEG) to target a tumor site, dissociate, and release the drug. The degradation ability, photothermal conversion ability, hemocompatibility, and in vitro and in vivo anti-tumor effects of the CuS@DMONs-FA-DOX-PEG nanoparticles were evaluated. Our findings revealed that the nanoparticles encapsulated in copper sulfide exhibited significant photothermal activity and optimal photothermal conversion rate. Further, the drug was accurately delivered and released into the target tumor cells, annihilating them. This study demonstrated the successful preparation, safety, and synergistic anti-tumor effects of chemo-photothermal therapeutic nanomaterials.

Melatonin Restores Autophagic Flux by Activating the Sirt3/TFEB Signaling Pathway to Attenuate Doxorubicin-Induced Cardiomyopathy.

Doxorubicin (DOX) chemotherapy in cancer patients increases the risk of the occurrence of cardiac dysfunction and even results in congestive heart failure. Despite the great progress of pathology in DOX-induced cardiomyopathy, the underlying molecular mechanisms remain elusive. Here, we investigate the protective effects and the underlying mechanisms of melatonin in DOX-induced cardiomyopathy. Our results clearly show that oral administration of melatonin prevented the deterioration of cardiac function caused by DOX treatment, which was evaluated by left ventricular ejection fraction and fractional shortening as well as cardiac fibrosis. The ejection fraction and fractional shortening in the DOX group were 49.48% and 25.5%, respectively, while melatonin treatment increased the ejection fraction and fractional shortening to 60.33 and 31.39 in wild-type mice. Cardiac fibrosis in the DOX group was 3.97%, while melatonin reduced cardiac fibrosis to 1.95% in wild-type mice. Sirt3 is a mitochondrial deacetylase and shows protective effects in diverse cardiovascular diseases. Therefore, to test whether Sirt3 is a key factor in protection, Sirt3 knockout mice were used, and it was found that the protective effects of melatonin in DOX-induced cardiomyopathy were partly abolished. Further analysis revealed that Sirt3 and its downstream molecule TFEB were downregulated in response to DOX treatment, while melatonin administration was able to significantly enhance the expressions of Sirt3 and TFEB. Our in vitro study demonstrated that melatonin enhanced lysosomal function by increasing the Sirt3-mediated increase at the TFEB level, and the accumulation of autolysosomes induced by DOX treatment was attenuated. Thus, autophagic flux disrupted by DOX treatment was restored by melatonin supplementation. In summary, our results demonstrate that melatonin protects the heart against DOX injury by the restoration of autophagic flux via the activation of the Sirt3/TFEB signaling pathway.

Intratumoral thermo-chemotherapeutic alginate hydrogel containing doxorubicin loaded PLGA nanoparticle and heating agent.

Chemotherapy has been widely used to treat cancer; however, the non-specific systemic toxicity of chemotherapeutic agents has always been an issue. Local injection treatment is a strategy used to reduce the undesired adverse effects of chemotherapeutic drugs. In addition, chemotherapeutic agents combined with thermotherapy are effective in further enhancing therapeutic potency. In the present study, we prepared an injectable hydrogel, namely, doxorubicin (DOX)-loaded poly (lactic-co-glycolic acid) (PLGA) nanoparticle (DPN) and magnetite nanoparticle (MNP) embedded in alginate hydrogel (DPN/MNP-HG), where DPN and MNP were the chemotherapeutic and heating agents, respectively, for intratumoral thermo-chemotherapy. Injectable DPN/MNP-HG, which possesses solid-like elastic properties, was conveniently prepared via ionic cross-linking at room-temperature. When exposed to an alternating magnetic field (AMF), DPN/MNP-HG exhibited controllable heat generation with a reversible temperature-rise profile. Regarding the kinetics of DOX release, both with and without AMF, DPN/MNP-HG exhibited a slow initial burst and sustained release profile. In cytotoxicity studies and subcutaneous mouse cancer models, successful thermo-chemotherapy with DPN/MNP-HG resulted in significantly lower cell viability and increased tumor-growth suppression; mice also exhibited good tolerance to injected DPN/MNP-HG both with(+) and without AMF application. In conclusion, the proposed thermo-chemotherapeutic DPN/MNP-HG for local intratumoral injection is a promising formulation for cancer treatment.

Black phosphorus quantum dots camouflaged with platelet-osteosarcoma hybrid membrane and doxorubicin for combined therapy of osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is the most prevalent primary malignant bone tumor. However, single-agent chemotherapy exhibits limited efficacy against OS and often encounters tumor resistance. Therefore, we designed and constructed an integrated treatment strategy of photothermal therapy (PTT) combined with chemotherapy and used a surface-encapsulated platelet-osteosarcoma hybrid membrane (OPM) that enhances circulation time and enables OS-specific targeting. RESULTS: The OPM functions as a shell structure, encapsulating multiple drug-loaded nanocores (BPQDs-DOX) and controlling the release rate of doxorubicin (DOX). Moreover, near-infrared light irradiation accelerates the release of DOX, thereby extending circulation time and enabling photostimulation-responsive release. The OPM encapsulation system improves the stability of BPQDs, enhances their photothermal conversion efficiency, and augments PTT efficacy. In vitro and ex vivo experiments demonstrate that BPQDs-DOX@OPM effectively delivers drugs to tumor sites with prolonged circulation time and specific targeting, resulting in superior anti-tumor activity compared to single-agent chemotherapy. Furthermore, these experiments confirm the favorable biosafety profile of BPQDs-DOX@OPM. CONCLUSIONS: Compared to single-agent chemotherapy, the combined therapy using BPQDs-DOX@OPM offers prolonged circulation time, targeted drug delivery, enhanced anti-tumor activity, and high biosafety, thereby introducing a novel approach for the clinical treatment of OS.

Biocatalytic Production of Odor-Active Fatty Aldehydes from Fungal Lipids.

Odor-active fatty aldehydes are important compounds for the flavor and fragrance industry. By a coupled enzymatic reaction using an α-dioxygenase (α-DOX) and an aldehyde dehydrogenase (FALDH), scarcely available aldehydes from the biotransformation of margaroleic acid [17:1(9Z)] were characterized and have shown highly interesting odor profiles, including citrus-like, soapy, herbaceous, and savory notes. In particular, (Z)-8-hexadecenal and (Z)-7-pentadecenal exhibited notable meaty odor characteristics. Submerged cultivation of Mortierella hyalina revealed the accumulation of the above-mentioned, naturally uncommon fatty acid 17:1(9Z). Its production was significantly increased by the modulation of culture conditions, whereas the highest accumulation was observed after 4 days at 24 °C and l-isoleucine supplementation. The lipase-, α-DOX-, and FALDH-mediated biotransformation of M. hyalina lipid extract resulted in a complex aldehyde mixture with a high aldehyde yield of ∼50%. The odor qualities of the formed aldehydes were assessed by means of gas chromatography-olfactometry, and several of the obtained fatty aldehydes have been sensorially described for the first time. To assess the aldehyde mixture's potential as a flavor ingredient, a sensory evaluation was conducted. The obtained product exhibited intense citrus-like, green, and soapy odor impressions.

Mesoporous Polydopamine-Based Nanovehicles as a Versatile Drug Loading Platform to Enable Tumor-Sufficient Synergistic Therapy.

The combination of photothermal therapy and chemotherapy are developing as a promising clinical strategy but it urgently needs the high exploration of intelligent multifunctional drug delivery nanovectors. In this paper, we used a versatile method to construct mesoporous polydopamine nanovehicles (MPDA) with the dendritic mesopores loaded with a clinical chemotherapeutic drug, Doxorubicin (MPDA@DOX). The monodisperse nanoagents are spherical with a size of ∼160 nm and pore size of approximately 10 nm. MPDA could efficiently delivery DOX with π-π stacking interaction and acts as the potent photothermal agents. Importantly, MPDA@DOX are preferentially internalized by cancerous cells, then bursting drug release and local hyperthermia generation were observed in conditions representative of the cytoplasm in tumor cells that highly synergistic cell killing effect were found under 808 nm laser irradiation. The fluorescent imaging results of human breast tumor bearing murine model evidenced that MPDA delivery platform have excellent tumor precise targeting effect and in vivo tumor ablation experiment further revealed that MPDA@DOX showed markedly eradicated tumor growth capability under laser exposure. Therefore, this work provided a fascinating strategy based on biocompatible MPDA based drug delivery system for malignant tumors eradication via synergistic therapy.

Protective effect of green synthesized Selenium Nanoparticles against Doxorubicin induced multiple adverse effects in Swiss albino mice.

AIMS: Doxorubicin (DOX) is a widely used drug against multiple cancers. However, its clinical Use is often restricted due to multiple adverse effects. Recently, Selenium Nanoparticles (SeNPs) are gaining attention due to their low toxicity and higher biocompatibility, making them attractive nanoparticles (NPs) in medical and pharmaceutical sciences. Therefore, the current study aimed to assess if our biosynthesized SeNP from the endophytic fungus Fusarium oxysporum conjugated with DOX could alleviate the DOX-induced adverse effects. MAIN METHODS: For this purpose, we investigated various genotoxic, biochemical, histopathological, and immunohistochemical parameters and finally analyzed the metabolite profile by LC-MS/MS. KEY FINDINGS: We observed that DOX causes an increase in reactive oxygen and nitrogen species (ROS, RNS), 8-OHdG, and malondialdehyde (MDA), decreases antioxidant defense systems and reduces BCL-2 expression in cardiac tissue. In addition, a significant increase in DNA damage and alteration in the cytoarchitecture of the liver, kidney, and heart tissues was observed by Comet Tail Length and histopathological studies, respectively. Interestingly, the DOX-SeNP conjugate reduced ROS/RNS, 8-OHdG, and MDA levels in the liver, kidney, and heart tissues. It also restored the antioxidant enzymes and cytoarchitectures of the examined tissues, reduced genotoxicity, and increased the BCL-2 levels. Finally, metabolic profiling showed that DOX reduced the number of cardioprotective metabolites, which DOX-SeNP restored. SIGNIFICANCE: Collectively, the present results describe the protective effect of DOX-conjugated SeNP against DOX-induced toxicities. In conclusion, DOX-SeNP conjugate might be better for treating patients receiving DOX alone. However, it warrants further thorough investigation.

Caffeic Acid, an Active Ingredient in Coffee, Combines with DOX for Multitarget Combination Therapy of Lung Cancer.

Adjuvant diet therapy is an important means of comprehensive treatment of cancer. It is recognized by patients for its high safety, painlessness, and ease to operate. However, the development of adjuvant dietary therapy is limited by unclear targets and unclear anticancer mechanisms. In this work, caffeic acid was found as an inhibitor of TMEM16A with an IC50 of 29.47 ± 3.19 µM by fluorescence quenching and whole-cell patch-clamp experiments. Caffeic acid regulated the proliferation, migration, and apoptosis of lung cancer cells targeting TMEM16A, which was detected by CCK-8, colony formation, wound healing, and Annexin V assays. In addition, molecular docking combined with site-directed mutagenesis confirmed that the binding sites of caffeic acid to TMEM16A were D439, E448, and R753. Western blot results indicated that caffeic acid regulated the growth of lung cancer through the MAPK pathway. In vitro experiments showed that the inhibitory effect of caffeic acid combined with hydroxydaunorubicin (DOX) on lung cancer cell growth was better than a double concentration of any single dose. In vivo pharmacokinetic experiments and tumor xenograft experiments indicated that the combination of 5.4 mg/kg caffeic acid and 4.1 mg/kg DOX achieved 85.6% tumor suppression rate and offset the side effects. Therefore, caffeic acid is a safe and efficient antitumor active ingredient of food that can enhance the antitumor effect of DOX.

In vivo and in vitro protective effects of shengmai injection against doxorubicin-induced cardiotoxicity.

CONTEXT: Shengmai injection (SMI) has been used to treat heart failure. OBJECTIVE: This study determines the molecular mechanisms of SMI against cardiotoxicity caused by doxorubicin (DOX). MATERIALS AND METHODS: In vivo, DOX (15 mg/kg) was intraperitoneally injected in model, Dex (dexrazoxane), SMI-L (2.7 mL/kg), SMI-M (5.4 mL/kg), and SMI-H (10.8 mL/kg) for 7 consecutive days. Hematoxylin-eosin (HE) and Masson staining were used to evaluate histological changes, and cardiomyocyte apoptosis was identified using TdT-mediated dUTP nick-end labelling (TUNEL). Enzymatic indexes were determined. mRNA and protein expressions were analysed through RT-qPCR and Western blotting. In vitro, H9c2 cells were divided into control group, model group (2 mL 1 µM DOX), SMI group, ML385 group, and SMI + ML385 group, the intervention lasted for 24 h. mRNA and protein expressions were analysed. RESULTS: SMI markedly improved cardiac pathology, decreased cardiomyocyte apoptosis, increased creatine kinase (CK), lactate dehydrogenase (LDH), malondialdehyde (MDA), decreased superoxide dismutase (SOD). Compared with the model group, the protein expression of nuclear factor erythroid2-related factor 2 (Nrf2) (SMI-L: 2.42-fold, SMI-M: 2.67-fold, SMI-H: 3.07-fold) and haem oxygenase-1(HO-1) (SMI-L: 1.64-fold, SMI-M: 2.01-fold, SMI-H: 2.19-fold) was increased and the protein expression of kelch-like ECH-associated protein 1 (Keap1) (SMI-L: 0.90-fold, SMI-M: 0.77-fold, SMI-H: 0.66-fold) was decreased in SMI groups and Dex group in vivo. Additionally, SMI dramatically inhibited apoptosis, decreased CK, LDH and MDA levels, and enhanced SOD activity. Our results demonstrated that SMI reduced DOX-induced cardiotoxicity via activation of the Nrf2/Keap1 signalling pathway. CONCLUSIONS: This study revealed a new mechanism by which SMI alleviates DOX-induced 45 cardiomyopathy by modulating the Nrf2/Keap1 signal pathway.

Acid-Sensitive Nanoparticles Based on Molybdenum Disulfide for Photothermal-Chemo Therapy.

The combination of multiple treatments has recently been investigated for tumor treatment. In this study, molybdenum disulfide (MoS2) with excellent photothermal conversion performance was used as the core, and manganese dioxide (MnO2), which responds to the tumor microenvironment, was loaded on its surface by liquid deposition to form a mesoporous core-shell structure. Then, the chemotherapeutic drug Adriamycin (DOX) was loaded into the hole. To further enhance its water solubility and stability, the surface of MnO2 was modified with mPEG-NH2 to prepare the combined antitumor nanocomposite MoS2@DOX/MnO2-PEG (MDMP). The results showed that MDMP had a diameter of about 236 nm, its photothermal conversion efficiency was 33.7%, and the loading and release rates of DOX were 13 and 65%, respectively. During in vivo and in vitro studies, MDMP showed excellent antitumor activity. Under the combined treatment, the tumor cell viability rate was only 11.8%. This nanocomposite exhibits considerable potential for chemo-photothermal combined antitumor therapy.

Pure drug nano-assemblies: A facile carrier-free nanoplatform for efficient cancer therapy.

Nanoparticulate drug delivery systems (Nano-DDSs) have emerged as possible solution to the obstacles of anticancer drug delivery. However, the clinical outcomes and translation are restricted by several drawbacks, such as low drug loading, premature drug leakage and carrier-related toxicity. Recently, pure drug nano-assemblies (PDNAs), fabricated by the self-assembly or co-assembly of pure drug molecules, have attracted considerable attention. Their facile and reproducible preparation technique helps to remove the bottleneck of nanomedicines including quality control, scale-up production and clinical translation. Acting as both carriers and cargos, the carrier-free PDNAs have an ultra-high or even 100% drug loading. In addition, combination therapies based on PDNAs could possibly address the most intractable problems in cancer treatment, such as tumor metastasis and drug resistance. In the present review, the latest development of PDNAs for cancer treatment is overviewed. First, PDNAs are classified according to the composition of drug molecules, and the assembly mechanisms are discussed. Furthermore, the co-delivery of PDNAs for combination therapies is summarized, with special focus on the improvement of therapeutic outcomes. Finally, future prospects and challenges of PDNAs for efficient cancer therapy are spotlighted.

Novel doxorubicin / folate-targeted trans-ferulic acid-loaded PLGA nanoparticles combination: In-vivo superiority over standard chemotherapeutic regimen for breast cancer treatment.

AIM: Doxorubicin/Cyclophosphamide (AC) is one of the standard adjuvant anthracycline-containing regimens that is still in use for breast cancer treatment. Cancer cell resistance and AC-induced side effects make treatment suboptimal and worsen patients' quality of life. This study aimed to improve trans-ferulic acid's (TFA) efficiency via loading into folate-receptor-targeted-poly lactic-co-glycolic acid nanoparticles (FA-PLGA-TFA NPs). Also, investigating both the antitumor efficacy of Doxorubicin (Dox)/FA-PLGA-TFA NPs combination against dimethylbenz[a]anthracene (DMBA)-induced breast cancer and its safety profile. METHODS: FA-PLGA-TFA NPs were optimally fabricated and characterized. Levels of Notch1, Hes1, Wnt-3a, ß-catenin, MMP-9, cyclin D1, Permeability-Glycoprotein (P-gp), ERα, PR, and HER2 were assessed as a measure of the antitumor efficacy of different treatment protocols. Histopathological examination of heart and bone, levels of ALT, AST, ALP, CK-MB, and WBCs count were evaluated to ensure the combination's safety profile. KEY FINDINGS: Dox/FA-PLGA-TFA NPs not only inhibited Notch signaling but also suppressed Notch synergy with Wnt, estrogen, progesterone, and HER2 pathways. Interestingly, Dox/FA-PLGA-TFA NPs decreased P-gp level and preserved heart, bone, and liver health as well as WBCs count. SIGNIFICANCE: Dox/FA-PLGA-TFA NPs reduced the side-effects of each single drug, and at the same time exerted excellent antitumor activity that surpass the AC regimen in evading cancer cell resistance and having a superior safety profile.

Anticancer Activity of Ω-6 Fatty Acids through Increased 4-HNE in Breast Cancer Cells.

Her2-amplified breast cancers resistant to available Her2-targeted therapeutics continue to be a challenge in breast cancer therapy. Dox is the mainstay of chemotherapy of all types of breast cancer, but its usefulness is limited by cumulative cardiotoxicity. Because oxidative stress caused by dox generates the pro-apoptotic Ω-6 PUFA metabolite 4-hydroxynonenal (4-HNE), we surmised that Ω-6 PUFAs would increase the effectiveness of dox chemotherapy. Since the mercapturic acid pathway enzyme RALBP1 (also known as RLIP76 or Rlip) that limits cellular accumulation of 4-HNE also mediates dox resistance, the combination of Ω-6 PUFAs and Rlip depletion could synergistically improve the efficacy of dox. Thus, we studied the effects of the Ω-6 PUFA arachidonic acid (AA) and Rlip knockdown on the antineoplastic activity of dox towards Her2-amplified breast cancer cell lines SK-BR-3, which is sensitive to Her2 inhibitors, and AU565, which is resistant. AA increased lipid peroxidation, 4-HNE generation, apoptosis, cellular dox concentration and dox cytotoxicity in both cell lines while sparing cultured immortalized cardiomyocyte cells. The known functions of Rlip including clathrin-dependent endocytosis and dox efflux were inhibited by AA. Our results support a model in which 4-HNE generated by AA overwhelms the capacity of Rlip to defend against apoptosis caused by dox or 4-HNE. We propose that Ω-6 PUFA supplementation could improve the efficacy of dox or Rlip inhibitors for treating Her2-amplified breast cancer.

A biocompatible theranostic agent based on stable bismuth nanoparticles for X-ray computed tomography/magnetic resonance imaging-guided enhanced chemo/photothermal/chemodynamic therapy for tumours.

Cancer is a leading cause of death worldwide and seriously threatens the health of humans. The current clinical treatments for cancer are not efficient and always lead to significant side effects. Herein, a biocompatible and powerful theranostic agent (Bi@mSiO2@MnO2/DOX) is fabricated using a facile stepwise reaction method. The Bi nanoparticles (NPs) are coated by mesoporous silica to protect the Bi NPs from oxidation, which guarantees the stable photothermal effect of the Bi NPs. When the Bi@mSiO2@MnO2/DOX nanocomposites (NCs) accumulate in the tumour site, hyperthermia is generated by Bi NPs under near-infrared (NIR) light irradiation for photothermal therapy (PTT), and the generated heat triggers the release of DOX for chemotherapy in the tumour. In addition, the MnO2 of the NCs responsively catalyses endogenous H2O2 to generate O2, raising the oxygen level to enhance the effect of chemotherapy in the tumour microenvironment (TME), and consumes glutathione (GSH) to produce Mn2+ for magnetic resonance (MR) imaging. Under acidic TME conditions, H2O2 and Mn2+ also produce toxic hydroxyl radical (·OH) for chemodynamic therapy (CDT). Furthermore, the Bi NPs can also be used as excellent contrast agents for X-ray computed tomography (CT) imaging of tumours with a high CT value (6.865 HU mM-1). The Bi@mSiO2@MnO2/DOX NCs exhibit a powerful theranostic performance for CT/MR imaging-guided enhanced PTT/CDT/chemotherapy, which opens a new prospect to rationally design theranostic agents for tumour imaging.

Antitumor activity of the combination of artemisinin and epirubicin in human leukemia cells.

AIM: We evaluated the tumor-inhibiting effect of artemisinin applied separately and in combination with epirubicin on leukemia HL-60 and HL-60/Dox cell lines, its dose modulation effect and its potency to  influence iron-induced oxidative damage of biologically relevant molecules. MATERIALS AND METHODS: MTT assay and the method of Chou-Talalay were used to show the inhibition of tumor cell proliferation and to evaluate the synergistic effect and modulation effect of artemisinin and epirubicin at varying concentrations. We also used spectrophotometric assays to determine the potency of artemisinin to influence iron-induced molecular degradation of lecithin and deoxyribose. RESULTS: Artemisinin exhibits tumor-inhibiting effect on both the anthracycline-sensitive and anthracycline-resistant promyelocytic cell lines, reaching 88% and 61% (T/C), respectively, when applied at higher concentrations in a dose-dependent manner. The combination of artemisinin and epirubicin shows synergistic effects in all tested concentrations on doxorubicin-resistant cells (CI<0.7). Artemisinin sensitizes the resistant cells towards epirubicin as shown by the CI (combination index) values and has a dose-modulation effect as shown by DRI (dose reduction index). Artemisinin induces deoxyribose oxidative degradation when applied alone and exerts synergistic deoxyribose degradation effect when applied with iron. However, artemisinin does not influence the studied processes in the lecithin-containing model system and has no potential to induce lipid peroxidation. CONCLUSIONS: This study presents a new opportunity to enhance the effectiveness of epirubicin-based treatment regimens with addition of artemisinins for resistant tumors.

Remote loading paclitaxel-doxorubicin prodrug into liposomes for cancer combination therapy.

The combination of paclitaxel (PTX) and doxorubicin (DOX) has been widely used in the clinic. However, it remains unsatisfied due to the generation of severe toxicity. Previously, we have successfully synthesized a prodrug PTX-S-DOX (PSD). The prodrug displayed comparable in vitro cytotoxicity compared with the mixture of free PTX and DOX. Thus, we speculated that it could be promising to improve the anti-cancer effect and reduce adverse effects by improving the pharmacokinetics behavior of PSD and enhancing tumor accumulation. Due to the fact that copper ions (Cu2+) could coordinate with the anthracene nucleus of DOX, we speculate that the prodrug PSD could be actively loaded into liposomes by Cu2+ gradient. Hence, we designed a remote loading liposomal formulation of PSD (PSD LPs) for combination chemotherapy. The prepared PSD LPs displayed extended blood circulation, improved tumor accumulation, and more significant anti-tumor efficacy compared with PSD NPs. Furthermore, PSD LPs exhibited reduced cardiotoxicity and kidney damage compared with the physical mixture of Taxol and Doxil, indicating better safety. Therefore, this novel nano-platform provides a strategy to deliver doxorubicin with other poorly soluble antineoplastic drugs for combination therapy with high efficacy and low toxicity.

A Novel Long-circulating DOX Liposome: Formulation and Pharmacokinetics Studies.

BACKGROUND: Doxorubicin (DOX) is a leading chemotherapeutic in cancer treatment because of its high potency and broad spectrum. Liposomal doxorubicin (Doxil®) is the first FDA-approved PEG-liposomes of DOX for the treatment of over 600,000 cancer patients, and it can overcome doxorubicin-induced cardiomyopathy and other side effects and prolong life span. The addition of MPEG2000-DSPE could elevate the total cost of cancer treatment. OBJECTIVE: We intended to prepare a novel DOX liposome that was prepared with inexpensive materials egg yolk lecithin and Kolliphor HS15, thus allowing it to be much cheaper for clinical application. METHODS: DOX liposomes were prepared using the combination of thin-film dispersion ultrasonic method and ammonium sulfate gradient method and the factors that influenced formulation quality were optimized. After formulation, particle size, entrapment efficiency, drug loading, stability, and pharmacokinetics were determined. RESULTS: DOX liposomes were near-spherical morphology with the average size of 90 nm and polydispersity index (PDI) of less than 0.30. The drug loading was up to 7.5%, and the entrapment efficiency was over 80%. The pharmacokinetic studies showed that free DOX could be easily removed and the blood concentration of free DOX group was significantly lower than that of DOX liposomes, which indicated that the novel DOX liposome had a certain sustainedrelease effect. CONCLUSION: In summary, DOX liposome is economical and easy-prepared with prolonged circulation time. Lay Summary: Doxorubicin (DOX) is a leading chemotherapeutic in cancer treatment because of its high potency and broad spectrum. Liposomal doxorubicin (Doxil®) is the first FDAapproved PEG-liposomes of DOX to treat over 600.000 cancer patients, overcoming doxorubicin- induced cardiomyopathy and other side effects and prolonging life span. The addition of MPEG2000-DSPE could elevate the total cost of cancer treatment. We intend to prepare a novel DOX liposome prepared with inexpensive materials egg yolk lecithin and Kolliphor HS15, thus allowing it to be much cheaper for clinical use. The novel DOX liposome is economical and easy-prepared with prolonged circulation time.

The carotenoid fucoxanthin can sensitize multidrug resistant cancer cells to doxorubicin via induction of apoptosis, inhibition of multidrug resistance proteins and metabolic enzymes.

BACKGROUND: Multidrug resistance (MDR) causes failure of doxorubicin therapy of cancer cells, which develops after or during doxorubicin treatment resulting in cross-resistance to structurally and functionally-unrelated other anticancer drugs. MDR is multifactorial phenomenon associated with overexpression of ATP-binding cassette (ABC) transporters, metabolic enzymes, impairment of apoptosis, and alteration of cell cycle checkpoints. The cancer-prevention of the dietary carotenoid; fucoxanthin (FUC) has been extensively explored. Nevertheless, the underlying mechanism of its action is not full elucidated. HYPOTHESIS/PURPOSE: Investigation of the underlying mechanism of MDR reversal by the dietary carotenoid fucoxanthin (FUC) and its ability to enhance the doxorubicin (DOX) cytotoxicity in resistant breast (MCF-7/ADR), hepatic (HepG-2/ADR), and ovarian (SKOV-3/ADR) cell lines. METHODS: The synergistic interaction of FUC and DOX was evaluated using several techniques, viz.; MTT assay, ABC transporter function assays using FACS and fluorimetry, enzyme activity via spectroscopy and luminescence assays, and apoptosis assay using FACS, and gene expression using RTPCR. RESULTS: FUC (20 µM) synergistically enhanced the cytotoxicity of DOX and significantly reduced the dose of DOX (FR) in DOX resistant cells (MCF-7/ADR), hepatic (HepG-2/ADR), and ovarian (SKOV-3/ADR) to 8.42-(CI= 0.25), 6.28-(CI= 0.32), and 4.56-fold (CI=0.37) (P<0.001). FUC significantly increased the accumulation of DOX more than verapamil in resistant cells by 2.70, 2.67, and 3.95-fold of untreated cells (p<0.001), respectively. A FUC and DOX combination significantly increased the Rho123 accumulation higher than individual drugs by 2.36-, 2.38-, 1.89-fold verapamil effects in tested cells (p<0.001), respectively. The combination of the FUC and DOX decreased ABCC1, ABCG2, and ABCB1 expression. The FUC and DOX combination increased the levels and activity of caspases (CASP3, CASP8) and p53, while decreased the levels and activity of CYP3A4, GST, and PXR in resistant cancer cells. The combination induced early/late apoptosis to 91.9/5.4% compared with 0.0/0.7% of untreated control. CONCLUSION: Our data suggests a new dietary and therapeutic approach of combining the FUC with DOX to overcome multidrug resistance in cancer cells. However, animal experiments should be conducted to confirm the findings before applying the results into clinical trials.

Hypocrellin B triggered sonodynamic therapy reverses multidrug resistance of doxorubicin-resistant SGC7901/ADR cells via down-regulation of P-gp expression.

The combating of multidrug resistance (MDR) plays a crucial role in effective chemotherapy. However, current strategies for cancer of MDR remain unsatisfactory for their limited efficacy and severe side effects. In this study, we sought to determine the anti-MDR effects of a traditional chinese herb, Hypocrellin B (HB)-mediated sonodynamic therapy (HB-SDT) on human gastric multidrug resistance cancer SGC-7901cell/ADR cells and its underlying mechanisms. HB-SDT can synergistically increase the cytotoxicity of DOX on SGC-7901cell/ADR cells in which the mechanism is related to significant promotion of apoptosis, ROS level and drop of MMP in the resistant cells after combining treatment of DOX and HB-SDT. Meanwhile, western blotting assays display the expression of apoptosis related proteins Bax and Bcl-2 changed markedly after the combination treatment. In addition, the expression of P-gp was significantly down-regulated after treatment of HB-SDT and DOX. HB-SDT can increase DOX-induced mitochondrial-dependent apoptosis by inhibiting the expression of P-gp, thereby increasing the cytotoxic effect into SGC7901/ADR cells.