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Advanced Healthcare Materials Dec 2023Synergistic chemotherapy and photothermal therapy (PTT) have emerged as a promising anticancer paradigm to achieve expected therapeutic effects while mitigating side...
Phenylboronic Acid-Modified Near-Infrared Region II Excitation Donor-Acceptor-Donor Molecule for 2-Deoxy-d-Glucose Improved Starvation/Chemo/Photothermal Combination Therapy.
Synergistic chemotherapy and photothermal therapy (PTT) have emerged as a promising anticancer paradigm to achieve expected therapeutic effects while mitigating side effects. However, the chemo/PTT combination therapy suffers from limited penetration depth, thermoresistance performance of tumor cells, and low drug bioavailability. Herein, multifunctional nanoparticles (BTP/DOX/2DG NPs) coloaded with near-infrared region II (NIR-II) light excitation donor-acceptor-donor (D-A-D) small molecules, doxorubicin (DOX), and 2-deoxy-d-glucose (2-DG) are developed for reinforced starvation/chemo/NIR-II PTT combination therapy. The synthesized phenylboronic acid (PBA)-modified water-soluble D-A-D molecule (BBT-TF-PBA) not only exhibits high binding ability to DOX and 2-DG through donor-acceptor coordination interactions PBA-diol bonds but also serves as a photoactive agent for NIR-II fluorescence imaging, NIR-II photoacoustic imaging, and NIR-II PTT. Under the acidic and oxidizing conditions in the tumor microenvironment, donor-acceptor coordination interactions and PBA-diol bond are decomposed, simultaneously releasing DOX and 2-DG from BTP/DOX/2DG NPs to achieve effective chemotherapy and starvation therapy. 2-DG also effectively inhibits the expression of heat shock protein and further enhances NIR-II PTT and chemotherapy efficiency. In vitro and in vivo experiments demonstrate the combination effect of BTP/DOX/2DG NPs for chemotherapy, NIR-II PTT, and starvation therapy.
Topics: Photothermal Therapy; Phototherapy; Glucose; Doxorubicin; Deoxyglucose; Nanoparticles; Cell Line, Tumor
PubMed: 37666241
DOI: 10.1002/adhm.202302099 -
Chinese Journal of Integrative Medicine Apr 2024To investigate the in vivo immunomodulatory and anti-tumor mechanisms of the combined treatment of novel Four-Herb formula (4HF) and doxorubicin in triple-negative...
OBJECTIVE
To investigate the in vivo immunomodulatory and anti-tumor mechanisms of the combined treatment of novel Four-Herb formula (4HF) and doxorubicin in triple-negative breast cancer (TNBC).
METHODS
Murine-derived triple-negative mammary carcinoma cell line, 4T1 cells, was cultured and inoculated into mouse mammary glands. Sixty-six mice were randomly assigned into 6 groups (n=11 in ench): naïve, control, LD 4HF (low dose 4HF), HD 4HF (high dose 4HF), LD 4HF + D (low dose and doxorubicin), and D (doxorubicin). Apart from the naïve group, each mouse received subcutaneous inoculation with 5 × 10 4T1 cells resuspended in 100 µL of normal saline in the mammary fat pads. Starting from the day of tumor cell inoculation, tumors were grown for 6 days. The LD and HD groups received daily oral gavage of 658 and 2,630 mg/kg 4HF, respectively. The LD 4HF+D group received daily oral gavage of 658 mg/kg 4HF and weekly intraperitoneal injection of doxorubicin (5 mg/kg). The D group received weekly intraperitoneal injections of doxorubicin (5 mg/kg). The treatment naïve mice received daily oral gavage of 0.2 mL double distilled water and 0.1 mL normal saline via intraperitoneal injection once a week. The control group received daily oral gavage of 0.2 mL double-distilled water. The treatment period was 30 days. At the end of treatment, mice organs were harvested to analyze immunological activities via immunophenotyping, gene and multiplex analysis, histological staining, and gut microbiota analysis.
RESULTS
Mice treated with the combination of 4HF and doxorubicin resulted in significantly reduced tumor and spleen burdens (P<0.05), altered the hypoxia and overall immune lymphocyte landscape, and manipulated gut microbiota to favor the anti-tumor immunological activities. Moreover, immunosuppressive genes, cytokines, and chemokines such as C-C motif chemokine 2 and interleukin-10 of tumors were significantly downregulated (P<0.05). 4HF-doxorubicin combination treatment demonstrated synergetic activities and was most effective in activating the anti-tumor immune response (P<0.05).
CONCLUSION
The above results provide evidence for evaluating the immune regulating mechanisms of 4HF in breast cancer and support its clinical significance in its potential as an adjunctive therapeutic agent or immune supplement.
Topics: Animals; Mice; Saline Solution; Doxorubicin; Combined Modality Therapy; Immunity; Water; Mice, Inbred BALB C; Cell Line, Tumor; Neoplasms
PubMed: 37594703
DOI: 10.1007/s11655-023-3745-6 -
Carbohydrate Polymers Apr 2024Triple-negative breast cancer (TNBC) poses a serious threat to women's life and health due to its high malignancy, strong invasiveness, and propensity for early...
Triple-negative breast cancer (TNBC) poses a serious threat to women's life and health due to its high malignancy, strong invasiveness, and propensity for early recurrence and metastasis. Therefore, there is an urgent need to develop a highly effective and low-toxic TNBC treatment scheme to enhance the anti-cancer efficacy and prolong the survival of patients. In this work, we designed and synthesized a chemodynamic therapy (CDT) agent (HA-Fc-Mal). The chemo/chemodynamic (CT/CDT) nanoparticle (HCM@DOX) based on hyaluronic acid induces ferroptosis and apoptotic for TNBC therapy was constructed via self-assembled of HA-Fc-Mal and doxorubicin (DOX). HCM@DOX orderly realized the TNBC targeting, controlled DOX release, GSH depletion and induce ROS erupt. In vivo and in vitro experiments confirmed that HCM@DOX inhibited the growth of 4 T1 tumors through ferroptosis and apoptosis, and the tumor inhibition rate was as high as 81.87 %. In addition, HCM@DOX significantly inhibited lung metastasis and exhibited excellent biosafety. Overall, our findings offer a new strategy for TNBC therapy using a CT/CDT nanoparticle that induces ferroptosis and apoptosis.
Topics: Humans; Female; Hyaluronic Acid; Triple Negative Breast Neoplasms; Ferroptosis; Doxorubicin; Apoptosis; Nanoparticles; Cell Line, Tumor
PubMed: 38286559
DOI: 10.1016/j.carbpol.2024.121795 -
Journal For Immunotherapy of Cancer Mar 2024The redundant extracellular matrix (ECM) within tumor microenvironment (TME) such as hyaluronic acid (HA) often impairs intratumoral dissemination of antitumor drugs....
BACKGROUND
The redundant extracellular matrix (ECM) within tumor microenvironment (TME) such as hyaluronic acid (HA) often impairs intratumoral dissemination of antitumor drugs. Oncolytic viruses (OVs) are being studied extensively for cancer therapy either alone or in conjunction with chemotherapy and immunotherapy. Here, we designed a novel recombinant vaccinia virus encoding a soluble version of hyaluronidase Hyal1 (OVV-Hyal1) to degrade the HA and investigated its antitumor effects in combination with chemo drugs, polypeptide, immune cells, and antibodies.
METHODS
We constructed a recombinant oncolytic vaccinia virus encoding the hyaluronidase, and investigated its function in remodeling the ECM of the TME, the antitumor efficacy both in vitro and in several murine solid tumors either alone, or in combination with chemo drugs including doxorubicin and gemcitabine, with polypeptide liraglutide, with immune therapeutics such as PD-L1/PD-1 blockade, CD47 antibody, and with CAR-T cells.
RESULTS
Compared with control OVV, intratumoral injection of OVV-Hyal1 showed superior antitumor efficacies in a series of mouse subcutaneous tumor models. Moreover, HA degradation by OVV-Hyal1 resulted in increased intratumoral dissemination of chemo drugs, infiltration of T cells, NK cells, macrophages, and activation of CD8 T cells. When OVV-Hyal1 was combined with some antitumor therapeutics, for example, doxorubicin, gemcitabine, liraglutide, anti-PD-1, anti-CD47 blockade, or CAR-T cells, more profound therapeutic outcomes were obtained.
CONCLUSIONS
OVV-Hyal1 effectively degrades HA to reshape the TME, therefore overcoming some major hurdles in current cancer therapy, such as limited OVs spread, unfavored dissemination of chemo drugs, polypeptides, antibodies, and insufficient infiltration of effector immune cells. OVV-Hyal1 holds the promise to improve the antitumor outcomes of current cancer therapeutics.
Topics: Mice; Animals; Oncolytic Viruses; Vaccinia virus; Hyaluronoglucosaminidase; Oncolytic Virotherapy; Gemcitabine; CD8-Positive T-Lymphocytes; Liraglutide; Neoplasms; Immunotherapy; Disease Models, Animal; Peptides; Extracellular Matrix; Doxorubicin; Tumor Microenvironment
PubMed: 38458640
DOI: 10.1136/jitc-2023-008431 -
Pakistan Journal of Pharmaceutical... Sep 2023In order to achieve the benefits of targeted drug delivery, this study intended to encapsulate doxorubicin in a linear polyamidoamine and its PEGylated co-polymer. The...
In order to achieve the benefits of targeted drug delivery, this study intended to encapsulate doxorubicin in a linear polyamidoamine and its PEGylated co-polymer. The drug was loaded by using the emulsion solvent evaporation method. By adjusting the doxorubicin to polymer ratios to 1:10, 1:20 and 1:30, three formulations of each polymer/copolymer were prepared. The drug release profile was investigated using phosphate buffered saline. In vitro cytotoxicity investigation was executed on liver cancer cell line (Hep G2 cell lines) by 3-[4,5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide assay. The outcome demonstrated that doxorubicin had been successfully loaded on polyamidoamine and its PEGylated co-polymer with a drug loading efficiency of about 90%. Nanocarrier sizes were between 245±1.10 nm -579±1.00 nm and the zeta potential range was +22.4±0.5 mV-+37.9±0.3 mV. In-vitro drug release investigations revealed a characteristic pH-dependent drug release. The cytotoxicity testing of optimal formulation revealed that the doxorubicin was successfully released from the formulations and exerted therapeutic effect. According to our research, doxorubicin could be loaded onto linear polyamidoamines for potent antitumor effects on the target liver cancer cell lines (Hep G2).
Topics: Humans; Doxorubicin; Polymers; Cell Line; Liver Neoplasms; Polyethylene Glycols; Drug Carriers
PubMed: 38008955
DOI: No ID Found -
Chemico-biological Interactions Sep 2023Morphine is the most common opioid analgesic administered to treat pain in patients undergoing cancer chemotherapy. This study aimed to evaluate the cytotoxic and...
Morphine is the most common opioid analgesic administered to treat pain in patients undergoing cancer chemotherapy. This study aimed to evaluate the cytotoxic and mutagenic effects of morphine alone and in combination with doxorubicin (Dox), an antineoplastic agent largely used in patients with solid cancers. Cytotoxicity was evaluated in neuroblastoma (SH-SY5Y) and fibroblast (V79) cells using 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) colorimetric assay while mutagenicity was assessed using the Salmonella/microsome assay in the absence and in the presence of S9 mix. Morphine showed a cytotoxic effect mainly on SH-SY5Y cells and reduced the cytotoxic effects of Dox when evaluated in a co-treatment procedure. In the Salmonella/microsome assay, it was observed that morphine did not induce mutations and, in fact, decreased the mutagenic effects induced by Dox in TA98 and TA102 strains in the absence of metabolic activation. Furthermore, in the presence of metabolic activation, no induction of mutations was observed with morphine. In conclusion, morphine decreased Dox cytotoxicity in both neuronal and non-neuronal cells and showed antimutagenic effects in the TA102 strain which detects mutagens inducing DNA oxidative damages. However, morphine decreased frameshift mutations induced by Dox in non-cytotoxic concentrations, an effect suggesting interference of Dox intercalation activity that could decrease its chemotherapeutic efficacy. These compelling findings highlight the importance of conducting further studies to explore the potential implications of co-administering morphine and Dox during cancer chemotherapy.
Topics: Humans; Mutagens; Morphine; Mutagenicity Tests; Neuroblastoma; Doxorubicin
PubMed: 37524295
DOI: 10.1016/j.cbi.2023.110652 -
International Journal of Nanomedicine 2024While nanoplatform-based cancer theranostics have been researched and investigated for many years, enhancing antitumor efficacy and reducing toxic side effects is still...
BACKGROUND
While nanoplatform-based cancer theranostics have been researched and investigated for many years, enhancing antitumor efficacy and reducing toxic side effects is still an essential problem.
METHODS
We exploited nanoparticle coordination between ferric (Fe) ions and telomerase-targeting hairpin DNA structures to encapsulate doxorubicin (DOX) and fabricated Fe-DNA@DOX nanoparticles (BDDF NPs). This work studied the NIR fluorescence imaging and pharmacokinetic studies targeting the ability and biodistribution of BDDF NPs. In vitro and vivo studies investigated the nano formula's toxicity, imaging, and synergistic therapeutic effects.
RESULTS
The enhanced permeability and retention (EPR) effect and tumor targeting resulted in prolonged blood circulation times and high tumor accumulation. Significantly, BDDF NPs could reduce DOX-mediated cardiac toxicity by improving the antioxidation ability of cardiomyocytes based on the different telomerase activities and iron dependency in normal and tumor cells. The synergistic treatment efficacy is enhanced through Fe-mediated ferroptosis and the β-catenin/p53 pathway and improved the tumor inhibition rate.
CONCLUSION
Harpin DNA-based nanoplatforms demonstrated prolonged blood circulation, tumor drug accumulation via telomerase-targeting, and synergistic therapy to improve antitumor drug efficacy. Our work sheds new light on nanomaterials for future synergistic chemotherapy.
Topics: Doxorubicin; Animals; Humans; Telomerase; Cell Line, Tumor; Mice; DNA; Tissue Distribution; Nanoparticles; Neoplasms; Ferroptosis; Antibiotics, Antineoplastic; Mice, Inbred BALB C; Drug Carriers
PubMed: 38882546
DOI: 10.2147/IJN.S461774 -
ACS Applied Bio Materials Aug 2023The development of a multifunctional cancer diagnosis and treatment platform offers excellent prospects for the effective eradication of malignant solid tumors. Herein,...
The development of a multifunctional cancer diagnosis and treatment platform offers excellent prospects for the effective eradication of malignant solid tumors. Herein, a doxorubicin hydrochloride (DOX)-loaded tannic acid (TA)-coated liquid metal (LM) multifunctional nanoprobe was synthesized and applied as a highly efficient platform for the photoacoustic (PA) imaging-guided photothermal/chemotherapy of tumor. The multifunctional nanoprobes exhibited strong near-infrared absorption, a remarkable photothermal conversion efficiency (PCE) of 55%, and high DOX loading capacity. Combined with the large intrinsic thermal expansion coefficient of LM, highly efficient PA imaging and effective drug release were realized. The LM-based multifunctional nanoprobes were specifically adsorbed into the cancer cells and tumor tissues via glycoengineering biorthogonal chemistry. The and photothermal/chemo-anticancer activity confirmed their promising potential in cancer treatment. The subcutaneous breast tumor-bearing mice completely recovered in 5 days under light illumination with clear PA imaging presentation, which showed better antitumor outcomes than single-mode chemotherapy or photothermal therapy (PTT), while keeping side effects at a minimum. Such an LM-based PA imaging-guided photothermal/chemotherapy strategy provided a valuable platform for resistant cancer precise treatment and intelligent biomedicine.
Topics: Animals; Mice; Photoacoustic Techniques; Combined Modality Therapy; Neoplasms; Doxorubicin
PubMed: 37432729
DOI: 10.1021/acsabm.3c00348 -
Small (Weinheim An Der Bergstrasse,... Oct 2023Triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer, currently lacks a targeted therapy and has a high clinical recurrence rate. The...
Triple-negative breast cancer (TNBC), one of the most aggressive types of breast cancer, currently lacks a targeted therapy and has a high clinical recurrence rate. The present study reports an engineered magnetic nanodrug based on Fe O vortex nanorods coated with a macrophage membrane loaded with doxorubicin (DOX) and Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) siRNA. This novel nanodrug displays excellent tissue penetration and preferential tumor accumulation. More importantly, it significantly increases tumor suppression compared to chemotherapy, suggesting the synergistic activity of the combination of doxorubicin and EZH2-inhibition. Importantly, owing to tumor-targeted delivery, nanomedicine shows an excellent safety profile after systemic delivery, unlike conventional chemotherapy. In summary, chemotherapy and gene therapy are combined into a novel magnetic nanodrug carrying doxorubicin and EZH2 siRNA, which shows promising clinical application potential in TNBC therapy.
Topics: Humans; Triple Negative Breast Neoplasms; RNA, Small Interfering; Enhancer of Zeste Homolog 2 Protein; Doxorubicin; Magnetic Phenomena; Cell Line, Tumor
PubMed: 37376877
DOI: 10.1002/smll.202301307 -
International Journal of Biological... Nov 2023The combined diagnostic imaging, chemotherapy, and gene therapy based on DNA nanocarriers can reduce the toxic side effects and overcome multidrug resistance (MDR). In...
The combined diagnostic imaging, chemotherapy, and gene therapy based on DNA nanocarriers can reduce the toxic side effects and overcome multidrug resistance (MDR). In this study, we designed an antisense oligonucleotides (ASOs)-linked DNA tetrahedron (ASOs-TD). The detection limit of ASOs-TD for MDR1 mRNA was 0.05 μM. By using fluorescence spectroscopy and isothermal titration calorimetry (ITC), the interactions between doxorubicin (DOX) /daunorubicin (DAU) and ASOs-TD were investigated. The number of binding sites (n), binding constant (K), entropy change (ΔS), enthalpy change (ΔH) and Gibbs free energy change (ΔG) were obtained. The intercalation of DOX/DAU with ASOs-TD was demonstrated by differential scanning calorimetry (DSC) and quenching researches of potassium ferricyanide K[Fe(CN)]. The in vitro release rate of DOX/DAU loaded in ASOs-TD was accelerated by deoxyribonuclease I (DNase I). In vitro cytotoxicity proved the good gene therapy effect of ASOs-TD and the increased cytotoxicity of DOX/DAU to MCF-7/ADR cells. The results of confocal laser scanning microscope (CLSM) suggested that ASOs-TD could effectively identify drug-resistant cells due to its good imaging ability for MDR1 mRNA. This work offers theoretical significance for overcoming MDR using DNA nanostructures which combine diagnostic imaging, chemotherapy, and gene therapy.
Topics: Doxorubicin; Humans; Thermodynamics; DNA; Genetic Therapy; Daunorubicin; MCF-7 Cells; Drug Carriers; Oligonucleotides, Antisense
PubMed: 37562474
DOI: 10.1016/j.ijbiomac.2023.126245