-
Advanced Science (Weinheim,... Jun 2024Multidrug resistance (MDR) is a major obstacle limiting the effectiveness of chemotherapy against cancer. The combination strategy of chemotherapeutic agents and siRNA...
Multidrug resistance (MDR) is a major obstacle limiting the effectiveness of chemotherapy against cancer. The combination strategy of chemotherapeutic agents and siRNA targeting drug efflux has emerged as an effective cancer treatment to overcome MDR. Herein, stimuli-responsive programmable tetrahedral DNA-RNA nanocages (TDRN) have been rationally designed and developed for dynamic co-delivery of the chemotherapeutic drug doxorubicin and P-glycoprotein (P-gp) siRNA. Specifically, the sense and antisense strand sequences of the P-gp siRNA, which are programmable bricks with terminal disulfide bond conjugation, are precisely embedded in one edge of the DNA tetrahedron. TDRN provides a stimuli-responsive release element for dynamic control of functional cargo P-gp siRNA that is significantly more stable than the "tail-like" TDN nanostructures. The stable and highly rigid 3D nanostructure of the siRNA-organized TDRN nanocages demonstrated a notable improvement in the stability of RNase A and mouse serum, as well as long-term storage stability for up to 4 weeks, as evidenced by this study. These biocompatible and multifunctional TDRN nanocarriers with gold nanocluster-assisted delivery (TDRN@Dox@AuNC) are successfully used to achieve synergistic RNAi/Chemo-therapy in vitro and in vivo. This programmable TDRN drug delivery system, which integrates RNAi therapy and chemotherapy, offers a promising approach for treating multidrug-resistant tumors.
PubMed: 38923806
DOI: 10.1002/advs.202404112 -
Marine Drugs May 2024Experiments conducted on triple-negative breast cancer have shown that fucoidan from (FLt) exhibits cytotoxic and antitumor properties. However, further research is...
Experiments conducted on triple-negative breast cancer have shown that fucoidan from (FLt) exhibits cytotoxic and antitumor properties. However, further research is necessary to gain a complete understanding of its bioactivity and level of cytotoxicity. The cytotoxic effect of FLt was determined by the 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. Apoptosis was analyzed using annexin V and caspase 3/7 staining kit and DNA fragmentation. In addition, transcriptional expression of antiapoptotic (Bcl-2 and XIAP) and proapoptotic (caspase 8, caspase 9, and AIF) genes were analyzed in TNBC 4T1 cells. After 72 h of culture, the IC for FLt was 561 μg/mL, while doxorubicin (Dox) had an IC of 0.04 μg/mL. In addition, assays for FLt + Dox were performed. Annexin V and caspase 3/7 revealed that FLt induces early and late-stage apoptosis. DNA fragmentation results support necrotic death of 4T1 cells. Similarly, transcripts that prevent cell death were decreased, while transcripts that promote cell death were increased. This study showed that FLt induces apoptosis by both caspase-dependent and caspase-independent mechanisms. These findings suggest that FLt may have potential applications in breast cancer treatment. Further research will provide more information to elucidate the mechanism of action of FLt.
Topics: Apoptosis; Cell Line, Tumor; Polysaccharides; Animals; Female; Caspases; Mice; Antineoplastic Agents; Doxorubicin; Humans; Adenocarcinoma; DNA Fragmentation; Breast Neoplasms; Triple Negative Breast Neoplasms; Kelp
PubMed: 38921562
DOI: 10.3390/md22060251 -
Metabolites May 2024A multimodal mass spectrometry imaging (MSI) approach was used to investigate the chemotherapy drug-induced response of a Multicellular Tumour Spheroid (MCTS) 3D cell...
A multimodal mass spectrometry imaging (MSI) approach was used to investigate the chemotherapy drug-induced response of a Multicellular Tumour Spheroid (MCTS) 3D cell culture model of osteosarcoma (OS). The work addresses the critical demand for enhanced translatable early drug discovery approaches by demonstrating a robust spatially resolved molecular distribution analysis in tumour models following chemotherapeutic intervention. Advanced high-resolution techniques were employed, including desorption electrospray ionisation (DESI) mass spectrometry imaging (MSI), to assess the interplay between metabolic and cellular pathways in response to chemotherapeutic intervention. Endogenous metabolite distributions of the human OS tumour models were complemented with subcellularly resolved protein localisation by the detection of metal-tagged antibodies using Imaging Mass Cytometry (IMC). The first application of matrix-assisted laser desorption ionization-immunohistochemistry (MALDI-IHC) of 3D cell culture models is reported here. Protein localisation and expression following an acute dosage of the chemotherapy drug doxorubicin demonstrated novel indications for mechanisms of region-specific tumour survival and cell-cycle-specific drug-induced responses. Previously unknown doxorubicin-induced metabolite upregulation was revealed by DESI-MSI of MCTSs, which may be used to inform mechanisms of chemotherapeutic resistance. The demonstration of specific tumour survival mechanisms that are characteristic of those reported for in vivo tumours has underscored the increasing value of this approach as a tool to investigate drug resistance.
PubMed: 38921450
DOI: 10.3390/metabo14060315 -
Gels (Basel, Switzerland) May 2024Mesoporous silica nanoparticles (MSNs) are inorganic nanocarriers presenting versatile properties and the possibility to deliver drug molecules via different routes of...
Mesoporous silica nanoparticles (MSNs) are inorganic nanocarriers presenting versatile properties and the possibility to deliver drug molecules via different routes of application. Their modification with lipids could diminish the burst release profile for water-soluble molecules. In the case of oleic acid (OA) as a lipid component, an improvement in skin penetration can be expected. Therefore, in the present study, aminopropyl-functionalized MSNs were modified with oleic acid through carbodiimide chemistry and were subsequently incorporated into a semisolid hydrogel for dermal delivery. Doxorubicin served as a model drug. The FT-IR and XRD analysis as well as the ninhydrin reaction showed the successful preparation of the proposed nanocarrier with a uniform particle size (352-449 nm) and negative zeta potential. Transmission electron microscopy was applied to evaluate any possible changes in morphology. High encapsulation efficiency (97.6 ± 1.8%) was achieved together with a sustained release profile over 48 h. The composite hydrogels containing the OA-modified nanoparticles were characterized by excellent physiochemical properties (pH of 6.9; occlusion factor of 53.9; spreadability of factor 2.87 and viscosity of 1486 Pa·s) for dermal application. The in vitro permeation study showed 2.35 fold improvement compared with the hydrogel containing free drug. In vitro cell studies showed that loading in OA-modified nanoparticles significantly improved doxorubicin's cytotoxic effects toward epidermoid carcinoma cells (A431). All of the results suggest that the prepared composite hydrogel has potential for dermal delivery of doxorubicin in the treatment of skin cancer.
PubMed: 38920903
DOI: 10.3390/gels10060356 -
Molecular Pharmaceutics Jun 2024Prostate cancer is a prevalently detected malignancy with a dismal prognosis. Luteinizing-hormone-releasing-hormone (LHRH) receptors are overexpressed in such cancer...
Prostate cancer is a prevalently detected malignancy with a dismal prognosis. Luteinizing-hormone-releasing-hormone (LHRH) receptors are overexpressed in such cancer cells, to which the LHRH-decapeptide can specifically bind. A lipid-polyethylene glycol-conjugated new LHRH-decapeptide analogue (D-P-HLH) was synthesized and characterized. D-P-HLH-coated and anticancer drug doxorubicin (DX)-loaded solid lipid nanoparticles (F-DX-SLN) were formulated by the cold homogenization technique and characterized by Fourier transform infrared spectroscopy, X-ray diffraction, X-ray photoelectron spectroscopy, differential scanning calorimetry, dynamic light scattering, electron microscopy, entrapment efficiency, and drug-release profile studies. F-DX-SLN allows site-specific DX delivery by reducing the side effects of chemotherapy. Cancer cells could precisely take up F-DX-SLN by targeting specific receptors, boosting the cytotoxicity at the tumor site. The efficacy of F-DX-SLN on PC3/SKBR3 cells by the MTT assay revealed that F-DX-SLN was more cytotoxic than DX and/or DX-SLN. Flow cytometry and confocal microscopic studies further support F-DX-SLNs' increased intracellular absorption capability in targeting LHRH overexpressed cancer cells. F-DX-SLN ensured high apoptotic potential, noticeably larger mitochondrial transmembrane depolarization action, as well as the activation of caspases, a longer half-life, and greater plasma concentration. F-DX-SLN/DX-SLN was radiolabeled with technetium-99m; scintigraphic imaging studies established its tumor selectivity in PC3 tumor-bearing nude mice. The efficacy of the formulations in cancer treatment, in vivo therapeutic efficacy tests, and histopathological studies were also conducted. Results clearly indicate that F-DX-SLN exhibits sustained and superior targeted administration of anticancer drugs, thus opening up the possibility of a drug delivery system with precise control and targeting effects. F-DX-SLN could also provide a nanotheranostic approach with improved efficacy for prostate cancer therapy.
PubMed: 38920398
DOI: 10.1021/acs.molpharmaceut.4c00528 -
Biodesign Research 2024Recently, there has been increasing interest in the use of bacteria for cancer therapy due to their ability to selectively target tumor sites and inhibit tumor growth....
Recently, there has been increasing interest in the use of bacteria for cancer therapy due to their ability to selectively target tumor sites and inhibit tumor growth. However, the complexity of the interaction between bacteria and tumor cells evokes unpredictable therapeutic risk, which induces inflammation, stimulates the up-regulation of cyclooxygenase II (COX-2) protein, and stimulates downstream antiapoptotic gene expression in the tumor microenvironment to reduce the antitumor efficacy of chemotherapy and immunotherapy. In this study, we encapsulated celecoxib (CXB), a specific COX-2 inhibitor, in liposomes anchored to the surface of Nissle 1917 (ECN) through electrostatic absorption (C@ECN) to suppress ECN-induced COX-2 up-regulation and enhance the synergistic antitumor effect of doxorubicin (DOX). C@ECN improved the antitumor effect of DOX by restraining COX-2 expression. In addition, local T lymphocyte infiltration was induced by the ECN to enhance immunotherapy efficacy in the tumor microenvironment. Considering the biosafety of C@ECN, a hypoxia-induced lysis circuit, pGEX-Pvhb-Lysis, was introduced into the ECN to limit the number of ECNs in vivo. Our results indicate that this system has the potential to enhance the synergistic effect of ECN with chemical drugs to inhibit tumor progression in medical oncology.
PubMed: 38919710
DOI: 10.34133/bdr.0038 -
Frontiers in Oncology 2024Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL), also known as MALT lymphoma, is an extranodal multiorgan-invasive proliferative lymphoma...
Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (EMZL), also known as MALT lymphoma, is an extranodal multiorgan-invasive proliferative lymphoma composed of small B cells with variable morphology. It most commonly occurs in the digestive tract, with a high prevalence in the stomach, but EMZL originating in the small intestine is rare and lacks specificity in clinical manifestations, which makes it easy to be misdiagnosed. Herein, we report a rare case of small intestinal EMZL presentation as intussusception in a 32-year-old man. A colonoscopy performed at the local hospital revealed a pedicled polyp about 5 cm × 5 cm in size with a rough surface, and hyperemia was seen in the ileocecal region. He was admitted to our hospital for a polypectomy. A contrast-enhanced computed tomographic (CT) scan suggested ileocolic intussusception, which was subsequently confirmed by a colonoscopy in our hospital. Adult intussusception is relatively rare, with 90% of cases having a known causative mechanism and 40% of cases caused by primary or secondary malignancies. Therefore, we performed a laparoscopic-assisted right hemicolectomy for the patient. The resected specimen showed that the terminal ileum was intussuscepted into the ascending colon, and the intussusception was hyperemia and edema. A 2.5 cm × 2.5 cm × 1.5 cm mass was seen at the end of the intussusception. Postoperative pathology revealed that the mass was EMZL, partially transformed into a large B-cell lymphoma. The patient was transferred to the hematology department and completed a PET-CT showing postoperative manifestations of primary intestinal lymphoma, Lugano staging IE2. Although EMZL was an indolent lymphoma and the patient was in the early stages, the rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) regimen was given in view of the histological transformation. The patient is in regular follow-up. This was a rare case of small intestinal mass due to EMZL presented as intussusception in adults, which highlighted laparoscopic-assisted enterectomy as a potential therapeutic approach in the multidisciplinary collaborative therapy of small intestine EMZL.
PubMed: 38919535
DOI: 10.3389/fonc.2024.1395144 -
Current Pharmaceutical Biotechnology Jun 2024Doxorubicin (DOX) is one of the most potent anticancer drugs that has ubiquitous usage in oncology; however, its marked adverse effects, such as cardiotoxicity, are...
INTRODUCTION
Doxorubicin (DOX) is one of the most potent anticancer drugs that has ubiquitous usage in oncology; however, its marked adverse effects, such as cardiotoxicity, are still a major clinical issue. Plant extracts have shown cardioprotective effects and reduced the risk of cardiovascular diseases.
METHOD
The current study is intended to explore the cardioprotective effect of ethanolic Moringa oleifera extracts (MOE) leaves loaded into niosomes (MOE-NIO) against DOXinduced cardiotoxicity in rats. MOE niosomes nanoparticles (NIO-NPs) were prepared and characterized by TEM. Seventy male Wistar rats were randomly divided into seven groups: control, NIO, DOX, DOX+MOE, DOX+MOE-NIO, MOE+DOX, and MOE-NIO+DOX. DOX (4 mg/kg, IP) was injected once per week for 4 weeks with daily administration of MOE or MOENIO (250 mg/kg, PO) for 4 weeks; in the sixth and seventh groups, MOE or MOE-NIO (250 mg/kg, PO) was administered one week before DOX injection. Various parameters were assessed in serum and cardiac tissue. Pre and co-treatment with MOE-NIO have mitigated the cardiotoxicity induced by DOX as indicated by serum aspartate aminotransferase (AST), creatine kinase - MB(CK-MB) and lactate dehydrogenase (LDH), cardiac Troponin 1(cTn1) and lipid profile. MOE-NIO also alleviated lipid peroxidation (MDA), nitrosative status (NO), and inflammatory markers levels; myeloperoxidase (MPO) and tumor necrosis factor-alpha (TNF-α) obtained in DOX-treated animals. Additionally, ameliorated effects have been recorded in glutathione content and superoxide dismutase activity. MOE-NIO effectively neutralized the DOXupregulated nuclear factor kappa B (NF-kB) and p38 mitogen-activated protein kinases (p38 MAPK), and DOX-downregulated nuclear factor-erythroid 2-related factor 2 (Nrf2) expressions in the heart.
RESULTS
It is concluded that pre and co-treatment with MOE-NIO could protect the heart against DOX-induced cardiotoxicity by suppressing numerous pathways including oxidative stress, inflammation, and apoptosis and by the elevation of tissue antioxidant status.
CONCLUSION
Thus, it may be reasonable to suggest that pre and co-treatment with MOE-NIO can provide a potential cardioprotective effect when doxorubicin is used in the management of carcinoma.
PubMed: 38918977
DOI: 10.2174/0113892010303097240605105013 -
Asian Pacific Journal of Cancer... Jun 2024Cytochrome P450 (CYP) are phase I metabolizing enzymes involved in detoxification of chemotherapeutic agents. Among the CYP gene family, including CYP1A1, CYP1B1, CYP2C,...
BACKGROUND
Cytochrome P450 (CYP) are phase I metabolizing enzymes involved in detoxification of chemotherapeutic agents. Among the CYP gene family, including CYP1A1, CYP1B1, CYP2C, CYP2D, CYP2E and CYP17, their significance in cancer susceptibility is well established. However, there remains limited understanding regarding the polymorphisms of CYP2C19*2 and CYP17 and their potential correlation with chemotherapy-induced toxicity reactions in breast cancer (BC) patients. In this study we intended to identify the association of CYP2C19*2 and CYP17 gene polymorphisms on drug response as well as toxicity reactions in BC patients undergoing adriamycin/paclitaxel based chemotherapy within Indian population.
METHODS
Two hundred BC patients receiving adriamycin and paclitaxel chemotherapy were enrolled in this study and chemotherapy induced hematological and non-hematological toxicity reactions were noted. The polymorphisms of CYP2C19*2 (681G>A) and CYP17 (34T>C) isoforms of cytochrome p 450 gene was studied by PCR and RFLP analysis.
RESULTS
The univariate logistic regression analysis revealed significant associations between CYP2C19*2 (681 G>A) polymorphisms with hematological toxicities i.e., anemia (OR=9.77, 95% CI: 2.84-33.52; p=0.0003), neutropenia (OR=5.72, 95% CI: 1.75-18.68; p=0.003), febrile neutropenia (OR=4.29, 95% CI: 1.32-13.87; p=0.014) and thrombocytopenia (OR=5.86, 95% CI: 1.15-29.72); p=0.032) in BC patients. Additionally BC patients treated with adriamycin exhibited significant association between CYP2C19*2 polymorphism with chemotherapy induced nausea and vomiting (CINV) (OR=99.73, 95% CI: 5.70-174.64); p=0.001), fatigue (OR=83.29, 95% CI: 4.77-145.69); p=0.002), bodyache (OR=4.44, 95% CI: 1.24-15.91); p=0.021) and peripheral neuropathy (OR=12.00, 95% CI: 1.80-79.89); p=0.010. Furthermore, the regression analysis indicated an association between CYP17 with body ache (OR=2.77, 95% CI: 1.21-6.34; p=0.015) and peripheral neuropathy (OR=3.90, 95% CI: 1.59-9.53; p=0.002) in BC patients treated with paclitaxel chemotherapy.
CONCLUSION
The findings obtained from this study illustrated significant association of CYP2C9*2 (681G>A) polymorphism with adreamicin based chemotherapy induced toxicities and CYP17 (34T>C) polymorphism with paclitaxel induced bodyache and peripheral neuropathy in BC patients.
Topics: Humans; Female; Breast Neoplasms; Paclitaxel; Doxorubicin; Cytochrome P-450 CYP2C19; Middle Aged; Antineoplastic Combined Chemotherapy Protocols; Polymorphism, Single Nucleotide; Adult; Steroid 17-alpha-Hydroxylase; Prognosis; Follow-Up Studies; Aged
PubMed: 38918659
DOI: 10.31557/APJCP.2024.25.6.1977 -
European Journal of Pharmaceutics and... Jun 2024Carrier materials always account for the majority particularly in nanosized formulations, which are administrated along with the active ingredient part might result in...
Carrier materials always account for the majority particularly in nanosized formulations, which are administrated along with the active ingredient part might result in metabolism related toxicity. The usage of bioactive excipients could not only reduce the sided effect but also provide additional therapeutic effects. In the present study, a triterpene based micellar drug delivery system was developed using a bioactive solanesol derivative. Solanesylamine was prepared firstly followed by conjugating with poly (ethylene glycol) using maleic acid amide linkage. The amphiphilic drug carrier PEGylated (2-propyl-3-methylmaleic acid)-block-solanesol amine (mPEG-CDM-NH-SOL) could be formed into micelles and loaded with doxorubicin (DOX) inside. The micelles were about 112 nm in size and the drug loading content was about 5.97 wt%. An acid triggered drug release behavior was obviously observed for the DOX loaded pH-sensitive micelle mPEG-CDM-NH-SOL-DOX. While not for DOX-loaded micelles without pH-sensitivity (mPEG-NHS-NH-SOL). CCK8 assay showed that the micelles of PEGylated solanesylamines exhibited certain inhibitory effect on tumor cells at high concentration and the pH sensitive ones seemed more toxic. In vivo studies showed that the pH sensitive mPEG-CDM-NH-SOL-DOX had a superior anti-tumor effect, indicating its great potential in cancer treatment.
PubMed: 38917949
DOI: 10.1016/j.ejpb.2024.114378