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International Immunopharmacology Jan 2023In clinical practice, major efforts are underway to identify appropriate drug combinations to boost anticancer activity while suppressing unwanted adverse effects. In...
In clinical practice, major efforts are underway to identify appropriate drug combinations to boost anticancer activity while suppressing unwanted adverse effects. In this regard, we evaluated the efficacy of combination treatment with the widely used chemotherapeutic drug doxorubicin along with the TGFβRI inhibitor galunisertib (LY2157299) in aggressive B-cell non-Hodgkin lymphoma (B-NHL). The antiproliferative effects of these drugs as single agents or in combination against several B-NHL cell lines and the synergism of the drug combination were evaluated by calculating the combination index. To understand the putative molecular mechanism of drug synergism, the TGF-β and stress signaling pathways were analyzed after combination treatment. An aggressive lymphoma model was used to evaluate the anticancer activity and post-therapeutic immune response of the drug combination in vivo. Galunisertib sensitized various B-NHL cells to doxorubicin and in combination synergistically increased apoptosis. The antitumor activity of the drug combinations involved upregulation of p-P38 MAPK and inhibition of the TGF-β/Smad2/3 and PI3K/AKT signaling pathways. Combined drug treatment significantly reduced tumor growth and enhanced survival, indicating that the synergism between galunisertib and Dox observed in vitro was most likely retained in vivo. Based on the tumor-draining lymph node analysis, combination therapy results in better prognosis, including disappearance of disease-exacerbating regulatory T cells and prevention of CD8 T-cell exhaustion by downregulating MDSCs. Galunisertib synergistically potentiates the doxorubicin-mediated antitumor effect without aggravating the toxic effects and the ability to kickstart the immune system, supporting the clinical relevance of targeting TGF-βRI in combination with doxorubicin against lymphoma.
Topics: Humans; Phosphatidylinositol 3-Kinases; Doxorubicin; Neoplasms; Lymphoma; Transforming Growth Factor beta; Immune System; Drug Synergism; Cell Line, Tumor; Apoptosis
PubMed: 36470118
DOI: 10.1016/j.intimp.2022.109521 -
Environmental Research Sep 2023The multidisciplinary approaches in treatment of cancer appear to be essential in term of bringing benefits of several disciplines and their coordination in tumor... (Review)
Review
The multidisciplinary approaches in treatment of cancer appear to be essential in term of bringing benefits of several disciplines and their coordination in tumor elimination. Because of the biological and malignant features of cancer cells, they have ability of developing resistance to conventional therapies such as chemo- and radio-therapy. Pancreatic cancer (PC) is a malignant disease of gastrointestinal tract in which chemotherapy and radiotherapy are main tools in its treatment, and recently, nanocarriers have been emerged as promising structures in its therapy. The bioresponsive nanocarriers are able to respond to pH and redox, among others, in targeted delivery of cargo for specific treatment of PC. The loading drugs on the nanoparticles that can be synthetic or natural compounds, can help in more reduction in progression of PC through enhancing their intracellular accumulation in cancer cells. The encapsulation of genes in the nanoparticles can protect against degradation and promotes intracellular accumulation in tumor suppression. A new kind of therapy for cancer is phototherapy in which nanoparticles can stimulate both photothermal therapy and photodynamic therapy through hyperthermia and ROS overgeneration to trigger cell death in PC. Therefore, synergistic therapy of phototherapy with chemotherapy is performed in accelerating tumor suppression. One of the important functions of nanotechnology is selective targeting of PC cells in reducing side effects on normal cells. The nanostructures are capable of being surface functionalized with aptamers, proteins and antibodies to specifically target PC cells in suppressing their progression. Therefore, a specific therapy for PC is provided and future implications for diagnosis of PC is suggested.
Topics: Humans; Multifunctional Nanoparticles; Doxorubicin; Hyperthermia, Induced; Phototherapy; Neoplasms; Nanoparticles; Pancreatic Neoplasms; Cell Line, Tumor
PubMed: 37354932
DOI: 10.1016/j.envres.2023.116490 -
Biomaterials Science May 2022Responsive nano-drug delivery systems, especially multi-responsive systems, based on the complex characteristics of the tumor microenvironment (TME), such as acidic pH,...
Responsive nano-drug delivery systems, especially multi-responsive systems, based on the complex characteristics of the tumor microenvironment (TME), such as acidic pH, hypoxia, and hydrogen peroxide (HO) overexpression, could enhance the biological activity of the drugs and reduce the side effects. In this study, a HO/glutathione (GSH) procedurally activatable nanoplatform (CuS-PEG/DOX NSs) was prepared as a vector of drugs released by responsive morphologic transformation and the co-activated Fenton agent for tumor-specific synergistic therapy. After endocytosis into tumor cells, CuS-PEG/DOX NSs were initially oxidized by over-expressed HO and transformed from nanosheets to nanoflowers, leading to the release of doxorubicin (DOX). Subsequently, CuS nanoflowers (CuS NFs) reacted with the local GSH, liberated a large number of copper ions, and induced GSH depletion. The released DOX promoted the generation of intracellular HO through cascade reactions, which were further utilized to facilitate the release of DOX and generate toxic hydroxyl radicals (˙OH) a copper-based Fenton-like reaction. CuS-PEG/DOX NSs sequentially activated by HO and GSH in tumor cells exhibited relatively high cytotoxicity, whereas normal cells were still alive. This nanoplatform, as a procedurally activatable delivery system, may have excellent potential for tumor-specific synergistic therapy.
Topics: Cell Line, Tumor; Copper; Doxorubicin; Glutathione; Hydrogen Peroxide; Tumor Microenvironment
PubMed: 35437541
DOI: 10.1039/d1bm01940f -
Biomedicine & Pharmacotherapy =... Feb 2021pH-sensitive liposomes are interesting carriers for drug-delivery, undertaking rapid bilayer destabilization in response to pH changes, allied to tumor accumulation, a...
pH-sensitive liposomes are interesting carriers for drug-delivery, undertaking rapid bilayer destabilization in response to pH changes, allied to tumor accumulation, a desirable behavior in the treatment of cancer cells. Previously, we have shown that pH-sensitive liposomes accumulate in tumor tissues of mice, in which an acidic environment accelerates drug delivery. Ultimately, these formulations can be internalized by tumor cells and take the endosome-lysosomal route. However, the mechanism of doxorubicin release and intracellular traffic of pH-sensitive liposomes remains unclear. To investigate the molecular mechanisms underlying the intracellular release of doxorubicin from pH-sensitive liposomes, we followed HeLa cells viability, internalization, intracellular trafficking, and doxorubicin's intracellular delivery mechanisms from pH-sensitive (SpHL-DOX) and non-pH-sensitive (nSpHL-DOX) formulations. We found that SpHL-DOX has faster internalization kinetics and intracellular release of doxorubicin, followed by strong nuclear accumulation compared to nSpHL-DOX. The increased nuclear accumulation led to the activation of cleaved caspase-3, which efficiently induced apoptosis. Remarkably, we found that chloroquine and E64d enhanced the cytotoxicity of SpHL-DOX. This knowledge is paramount to improve the efficiency of pH-sensitive liposomes or to be used as a rational strategy for developing new formulations to be applied in vivo.
Topics: Animals; Antibiotics, Antineoplastic; Apoptosis; Caspase 3; Cell Survival; Chloroquine; Doxorubicin; Drug Compounding; Drug Delivery Systems; HeLa Cells; Humans; Hydrogen-Ion Concentration; Intracellular Space; Leucine; Liposomes; Mice
PubMed: 33348307
DOI: 10.1016/j.biopha.2020.110952 -
International Journal of Molecular... Dec 2022Different gold nanosystems covered with DNA and doxorubicin (Doxo) were designed and synthesized for cancer therapy, starting from Au@16-Ph-16 cationic nanoparticles and...
Different gold nanosystems covered with DNA and doxorubicin (Doxo) were designed and synthesized for cancer therapy, starting from Au@16-Ph-16 cationic nanoparticles and DNA-Doxo complexes prepared under saturation conditions. For the preparation of stable, biocompatible, and small-sized compacted Au@16-Ph-16/DNA-Doxo nanotransporters, the conditions for the DNA-Doxo compaction process induced by gold nanoparticles were first explored using fluorescence spectroscopy, circular dichroism and atomic force microscopy techniques. The reverse process, which is fundamental for Doxo liberation at the site of action, was found to occur at higher C concentrations using these techniques. Zeta potential, dynamic light scattering and UV-visible spectroscopy reveal that the prepared compacted nanosystems are stable, highly charged and of adequate size for the effective delivery of Doxo to the cell. This fact is verified by in vitro biocompatibility and internalization studies using two prostate cancer-derived cell lines (LNCaP and DU145) and one hepatocellular carcinoma-derived cell line (SNU-387), as well as a non-tumor prostate (PNT2) cell line and a non-hepatocarcinoma hepatoblastoma cell line (Hep-G2) model used as a control in liver cells. However, the most outstanding results of this work are derived from the use of the C+N combined treatments which present strong action in cancer-derived cell lines, while a protective effect is observed in non-tumor cell lines. Hence, novel therapeutic targets based on gold nanoparticles denote high selectivity compared to conventional treatment based on free Doxo at the same concentration. The results obtained show the viability of both the proposed methodology for internalization of compacted nanocomplexes inside the cell and the effectiveness of the possible treatment and minimization of side effects in prostate and liver cancer.
Topics: Male; Humans; Gold; Prostate; Metal Nanoparticles; Doxorubicin; Liver Neoplasms; Carcinoma, Hepatocellular; DNA; Cell Line, Tumor
PubMed: 36555216
DOI: 10.3390/ijms232415575 -
International Journal of Molecular... Jul 2022In this work, we report the fabrication and functional demonstration of a kind of dually responsive nanoparticles (NPs) as a potential drug delivery vector. The pH...
In this work, we report the fabrication and functional demonstration of a kind of dually responsive nanoparticles (NPs) as a potential drug delivery vector. The pH value, corresponding to the acidic microenvironment at the tumor site, and mannitol, to the extracellular trigger agent, were employed as the dually responsive factors. The function of dual responses was achieved by breaking the dynamic covalent bonds between phenylboronic acid (PBA) groups and diols at low pH value (pH 5.0) and/or under the administration of mannitol, which triggered the decomposition of the complex NPs and the concomitant release of anticancer drug of doxorubicin (DOX) loaded inside the NPs. The NPs were composed of modified chitosan (PQCS) with quaternary ammonium and PBA groups on the side chains, heparin (Hep), and poly(vinyl alcohol) (PVA), in which quaternary ammonium groups offer the positive charge for the cell-internalization of NPs, PBA groups serve for the formation of dynamic bonds in responding to pH change and mannitol addition, PVA furnishes the NPs with diol groups for the interaction with PBA groups and the formation of dynamic NPS, and Hep plays the roles of reducing the cytotoxicity of highly positively-charged chitosan and forming of complex NPs for DOX up-loading. A three-step fabrication process of drug-loaded NPs was described, and the characterization results were comprehensively demonstrated. The sustained drug release from the drug-loaded NPs displayed obvious pH and mannitol dependence. More specifically, the cumulative DOX release was increased more than 1.5-fold at pH 5.0 with 20 mg mL mannitol. Furthermore, the nanoparticles were manifested with effective antitumor efficient and apparently enhanced cytotoxicity in response to the acidic pH value and/or mannitol.
Topics: Ammonium Compounds; Chitosan; Doxorubicin; Drug Carriers; Drug Delivery Systems; Drug Liberation; Hydrogen-Ion Concentration; Mannitol; Nanoparticles
PubMed: 35806347
DOI: 10.3390/ijms23137342 -
Biomaterials Feb 2022Although chemo-photodynamic therapy demonstrates promising synergetic therapeutic effects in malignant tumors, the light-controlled drug release, synergism and...
Although chemo-photodynamic therapy demonstrates promising synergetic therapeutic effects in malignant tumors, the light-controlled drug release, synergism and biocompatibility of current nanocarriers are limited. Herein, we report a red light-responsive, self-destructive carrier constructed using polyethylene glycol-modified, diselenide-bridged mesoporous silica nanoparticles. The carrier is co-encapsulated with the chemo-drug doxorubicin and the photosensitizer methylene blue for chemo-photodynamic therapy. Upon low-dose red light irradiation during photodynamic therapy (PDT), the reactive oxygen species (ROS) mediates a diselenide bond cleavage resulting in the degradation of the organosilica matrix and a dual drug release. This, in turn, results in a synergistic chemo-photodynamic performance in vitro and in vivo. More importantly, such cascade chemo-PDT boosts immunogenic cell death and robust anti-tumor immunity responses. Combination with a PD-1 checkpoint blockade further evokes a series of systemic immunity responses that suppress distant tumor growth and the pulmonary metastasis of breast cancer, as well as offer long-term protection against recurrent tumors. The presented work offers a controllable self-destruction nanoplatform for cascade-amplifying chemo-photodynamic therapy in response to external red light radiation.
Topics: Cell Line, Tumor; Doxorubicin; Humans; Immunity; Nanoparticles; Neoplasm Recurrence, Local; Photochemotherapy; Photosensitizing Agents; Silicon Dioxide
PubMed: 35030436
DOI: 10.1016/j.biomaterials.2022.121368 -
Angewandte Chemie (International Ed. in... Feb 2021Molecular self-assembly has been widely used to develop nanocarriers for drug delivery. However, most of them have unsatisfactory drug loading capacity (DLC) and the...
Molecular self-assembly has been widely used to develop nanocarriers for drug delivery. However, most of them have unsatisfactory drug loading capacity (DLC) and the dilemma between stimuli-responsiveness and stability, stagnating their translational process. Herein, we overcame these drawbacks using dynamic combinatorial chemistry. A carrier molecule was spontaneously and quantitatively synthesized, aided by co-self-assembly with a template molecule and an anti-cancer drug doxorubicin (DOX) from a dynamic combinatorial library that was operated by disulfide exchange under thermodynamic control. The highly selective synthesis guaranteed a stable yet pH- and redox- responsive nanocarrier with a maximized DLC of 40.1 % and an enhanced drug potency to fight DOX resistance in vitro and in vivo. Our findings suggested that harnessing the interplay between synthesis and self-assembly in complex chemical systems could yield functional nanomaterials for advanced applications.
Topics: Animals; Antineoplastic Agents; Cell Line, Tumor; Cell Proliferation; Doxorubicin; Drug Carriers; Drug Resistance, Neoplasm; Humans; Hydrogen-Ion Concentration; Mice; Mice, Nude; Nanotubes; Neoplasms; Oxidation-Reduction; Transplantation, Heterologous
PubMed: 33112477
DOI: 10.1002/anie.202010937 -
Acta Biomaterialia Mar 2023Methods capable of distributing antitumour therapeutics uniformly throughout an entire tumour and that can suppress metastasis at the same time, would be of great...
Methods capable of distributing antitumour therapeutics uniformly throughout an entire tumour and that can suppress metastasis at the same time, would be of great significance in improving cancer treatment. Bacteria-mediated synergistic therapies have been explored for better specificity, temporal and spatial controllability, as well for providing regulation of the immune microenvironment, in order to provide improved cancer treatment. To achieve this goal, here we developed an engineered bacteria delivery system (GDOX@HSEc) using synthetic biology and interfacial chemistry technologies. The engineered bacteria were concurrently modified to express heparin sulfatase 1 (HSulf-1) inside (HSEc), to attach doxorubicin-loaded glycogen nanoparticles (GDOX NPs) on their surface. Here we demonstrate that HSEc can actively target and colonise tumour sites resulting in HSulf-1 overexpression, thereby suppressing angiogenesis and metastasis. Simultaneously, the GDOX NPs were able to penetrate into tumour cells, leading to intracellular DNA damage. Our results confirmed that a combination of biotherapy and chemotherapy using GDOX@HSEc resulted in significant melanoma suppression in murine models, with reduced side effects. This study provides a powerful platform for the simultaneous delivery of biomacromolecules and chemotherapeutic drugs to tumours, representing an innovative strategy potentially more effective in treating solid tumours. STATEMENT OF SIGNIFICANCE: An original engineered bacteria-based system (GDOX@HSEc) was developed using synthetic biology and interfacial chemistry technologies to concurrently produce naturally occurring heparin sulfatase 1 (HSulf-1) inside and anchor doxorubicin-loaded glycogen nanoparticles on the surface. GDOX@HSEc allowed for combined local delivery of chemotherapeutic agents along with the enzymes and immunostimulatory bacterial adjuvants, which resulted in a synergistic action in the inhibition of tumour growth and metastasis. The study provides a potential therapeutic approach that allows therapeutic agents to be distributed in a spatiotemporally controllable manner in tumours for combinatorial enhanced therapy.
Topics: Animals; Mice; Cell Line, Tumor; Doxorubicin; Melanoma; Nanoparticles; Sulfatases; Tumor Microenvironment
PubMed: 36563772
DOI: 10.1016/j.actbio.2022.12.027 -
Colloids and Surfaces. B, Biointerfaces Aug 2022Phenylboronic acid (PBA) is a tumor-targeting molecule which selectively recognizes sialic acid (SA) overexpressed in tumors. In the study, PBA, F127 and ethanolamine...
Phenylboronic acid (PBA) is a tumor-targeting molecule which selectively recognizes sialic acid (SA) overexpressed in tumors. In the study, PBA, F127 and ethanolamine were conjugated with poly(maleic anhydride) by one-step reaction to form amphiphilic polymer for doxorubicin encapsulation. Two drug-carrying micelles with different mass ratio of polymer to drug were prepared by dialysis method to study effect of PBA on doxorubicin release, tumor-targeting and antitumor activity. The study results showed that doxorubicin release from the formulations was acid-sensitive and affected by the polymer dosage, and its acid-induced release behavior improved its insertion into DNA base pairs. Formulation with high polymer dosage showed better tumor targeting and antitumor activity, and activity of inhibiting HepG2 with higher content of SA-containing glycosphingolipids was higher than that of anti-B16. In vivo studies on the activity of B16-bearing mice showed that the doxorubicin-loaded micelles could inhibit the tumor growth and were safer than free doxorubicin. Thus, the PBA-modified nano-polymer micelles have potential biomedical applications due to their nanostructure and tumor-targeting ability.
Topics: Animals; Boronic Acids; Cell Line, Tumor; Doxorubicin; Drug Carriers; Hydrogen-Ion Concentration; Maleic Anhydrides; Mice; Micelles; Neoplasms; Polyethylenes; Polymers; Polypropylenes
PubMed: 35576880
DOI: 10.1016/j.colsurfb.2022.112559