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Einstein (Sao Paulo, Brazil) 2016The use of nanocarriers as drug delivery systems for therapeutic or imaging agents can improve the pharmacological properties of commonly used compounds in cancer... (Review)
Review
The use of nanocarriers as drug delivery systems for therapeutic or imaging agents can improve the pharmacological properties of commonly used compounds in cancer diagnosis and treatment. Advances in the surface engineering of nanoparticles to accommodate targeting ligands turned nanocarriers attractive candidates for future work involving targeted drug delivery. Although not targeted, several nanocarriers have been approved for clinical use and they are currently used to treat and/or diagnosis various types of cancers. Furthermore, there are several formulations, which are now in various stages of clinical trials. This review examined some approved formulations and discussed the advantages of using nanocarriers in cancer therapy.
Topics: Antineoplastic Agents; Doxorubicin; Drug Carriers; Humans; Nanoparticles; Neoplasms; Polyethylene Glycols
PubMed: 27074238
DOI: 10.1590/S1679-45082016RB3475 -
International Journal of Molecular... Jul 2023Treatment of highly malignant soft tissue sarcomas (STSs) requires multicomponent therapy including surgery, radiotherapy, and chemotherapy. Despite the advancements in...
Treatment of highly malignant soft tissue sarcomas (STSs) requires multicomponent therapy including surgery, radiotherapy, and chemotherapy. Despite the advancements in targeted cancer therapies, cytostatic drug combinations remain the gold standard for STS chemotherapy. The lack of algorithms for personalized selection of STS chemotherapy leads to unhelpful treatment of chemoresistant tumors, causing severe side effects in patients. The goal of our study is to assess the applicability of in vitro chemosensitivity/resistance assays (CSRAs) in predicting STS chemoresistance. Primary cell cultures were obtained from 148 surgery samples using enzymatic and mechanical disaggregation. CSRA was performed using resazurin-based metabolic activity measurement in cells cultured with doxorubicin, ifosfamide, their combination and docetaxel, gemcitabine, and also their combination for 7 days. Both the clinical data of patients and the CSRA results demonstrated a higher resistance of some cancer histotypes to specific drugs and their combinations. The correlation between the CSRA results for doxorubicin and ifosfamide and clinical responses to the combination chemotherapy with these drugs was demonstrated via Spearman rank order correlation. Statistically significant differences in recurrence-free survival were also shown for the groups of patients formed, according to the CSRA results. Thus, CSRAs may help both practicing physicians to avoid harmful and useless treatment, and researchers to study new resistance markers and to develop new STS drugs.
Topics: Humans; Ifosfamide; Antineoplastic Combined Chemotherapy Protocols; Sarcoma; Soft Tissue Neoplasms; Doxorubicin
PubMed: 37569668
DOI: 10.3390/ijms241512292 -
Annals of Palliative Medicine Dec 2021Dose-limiting neurotoxicity is the major side effect caused by oxaliplatin treatment. Optimization of oxaliplatin-containing chemotherapeutic regimens may potentially...
BACKGROUND
Dose-limiting neurotoxicity is the major side effect caused by oxaliplatin treatment. Optimization of oxaliplatin-containing chemotherapeutic regimens may potentially benefit advanced gastric cancer (AGC) patients. We tried to reduce the dose of oxaliplatin and add a drug to compensate for the efficacy. This cohort study evaluated the efficacy and side effects of low-dose oxaliplatin combined with pegylated liposomal doxorubicin and S-1 (D-SOX) as first-line treatment for AGC.
METHODS
64 AGC patients treated in our hospital between January 2015 and December 2018 were included in this study. Among them, 29 cases received standard S-1 and oxaliplatin (SOX) regimen, and 35 cases received D-SOX. Progression-free survival (PFS), overall survival (OS), response rate (RR), and safety were analyzed.
DISCUSSION
The median PFS was 7.0 months [95% confidence interval (CI): 5.77 to 8.23 months] in the SOX group and 9.3 months (95% CI: 8.145 to 10.45 months) in the D-SOX group (P=0.021). The median OS was 12.5 months (95% CI: 7.00 to 17.97 months) in the SOX group and 18.7 months (95% CI: 14.485 to 22.9 months) in the D-SOX group (P=0.027). The incidence of treatment-related grade III-IV adverse events (AEs) was less than 10%. The RRs to these 2 regimens were similar (P=0.609). The incidence of neurotoxicity was significantly reduced in the D-SOX group (62.8% vs. 82.7%).
CONCLUSIONS
Low-dose oxaliplatin combined with S-1 and pegylated liposomal doxorubicin (PLD) regimen improved OS and PFS, while exhibiting better toxicity profile as compared with standard SOX regimen for AGC.
Topics: Antineoplastic Combined Chemotherapy Protocols; Cohort Studies; Doxorubicin; Humans; Oxaliplatin; Polyethylene Glycols; Stomach Neoplasms
PubMed: 35016420
DOI: 10.21037/apm-21-3584 -
Molecules (Basel, Switzerland) Mar 2023Recently, targeted nanoparticles (NPs) have attracted much attention in cancer treatment due to their high potential as carriers for drug delivery. In this article, we...
Recently, targeted nanoparticles (NPs) have attracted much attention in cancer treatment due to their high potential as carriers for drug delivery. In this article, we present a novel bioconjugate (DOX-AuNPs-Tmab) consisting of gold nanoparticles (AuNPs, 30 nm) attached to chemotherapeutic agent doxorubicin (DOX) and a monoclonal antibody, trastuzumab (Tmab), which exhibited specific binding to HER2 receptors. The size and shape of synthesized AuNPs, as well as their surface modification, were analyzed by the TEM (transmission electron microscopy) and DLS (dynamic light scattering) methods. Biological studies were performed on the SKOV-3 cell line (HER2+) and showed high specificity of binding to the receptors and internalization capabilities, whereas MDA-MB-231 cells (HER2-) did not. Cytotoxicity experiments revealed a decrease in the metabolic activity of cancer cells and surface area reduction of spheroids treated with DOX-AuNPs-Tmab. The bioconjugate induced mainly cell cycle G2/M-phase arrest and late apoptosis. Our results suggest that DOX-AuNPs-Tmab has great potential for targeted therapy of HER2-positive tumors.
Topics: Humans; Trastuzumab; Gold; Metal Nanoparticles; Nanoparticles; Doxorubicin; Neoplasms; Cell Line, Tumor
PubMed: 36985421
DOI: 10.3390/molecules28062451 -
International Journal of Molecular... Sep 2022Several semisynthetic, low-cardiotoxicity doxorubicin (DOXO) conjugated have been extensively described, considering the risk of cytotoxicity loss against resistant...
Naked and Decorated Nanoparticles Containing HS-Releasing Doxorubicin: Preparation, Characterization and Assessment of Their Antitumoral Efficiency on Various Resistant Tumor Cells.
Several semisynthetic, low-cardiotoxicity doxorubicin (DOXO) conjugated have been extensively described, considering the risk of cytotoxicity loss against resistant tumor cells, which mainly present drug efflux capacity. Doxorubicin 14-[4-(4-phenyl-5-thioxo-5H-[1,2]dithiol-3-yl)]-benzoate (HS-DOXO) was synthetized and tested for its ability to overcome drug resistance with good intracellular accumulation. In this paper, we present a formulation study aimed to develop naked and decorated HS-DOXO-loaded lipid nanoparticles (NPs). NPs prepared by the "cold dilution of microemulsion" method were decorated with hyaluronic acid (HA) to obtain active targeting and characterized for their physicochemical properties, drug entrapment efficiency, long-term stability, and in vitro drug release. Best formulations were tested in vitro on human-sensitive (MCF7) and human/mouse DOXO-resistant (MDA-MDB -231 and JC) breast cancer cells, on human (U-2OS) osteosarcoma cells and DOXO-resistant human/mouse osteosarcoma cells (U-2OS/DX580/K7M2). HA-decoration by HA-cetyltrimethyl ammonium bromide electrostatic interaction on NPs surface was confirmed by Zeta potential and elemental analysis at TEM. NPs had mean diameters lower than 300 nm, 70% HS-DOXO entrapment efficiency, and were stable for almost 28 days. HA-decorated NPs accumulated HS-DOXO in Pgp-expressing cells reducing cell viability. HA-decorated NPs result in the best formulation to increase the inter-cellular HS-DOXO delivery and kill resistant cells, and therefore, as a future perspective, they will be taken into account for further in vivo experiments on tumor animal model.
Topics: Animals; Benzoates; Bone Neoplasms; Cell Line, Tumor; Doxorubicin; Humans; Hyaluronic Acid; Liposomes; Mice; Nanoparticles; Osteosarcoma
PubMed: 36232858
DOI: 10.3390/ijms231911555 -
Biomaterials Advances Aug 2023Cell-membrane-coated biomimetic nanoparticles (NPs) have attracted great attention due to their prolonged circulation time, immune escape mechanisms and homotypic...
Cell-membrane-coated biomimetic nanoparticles (NPs) have attracted great attention due to their prolonged circulation time, immune escape mechanisms and homotypic targeting properties. Biomimetic nanosystems from different types of cell -membranes (CMs) can perform increasingly complex tasks in dynamic biological environments thanks to specific proteins and other properties inherited from the source cells. Herein, we coated doxorubicin (DOX)-loaded reduction-sensitive chitosan (CS) NPs with 4T1 cancer cell -membranes (CCMs), red blood cell -membranes (RBCMs) and hybrid erythrocyte-cancer membranes (RBC-4T1CMs) to enhance the delivery of DOX to breast cancer cells. The physicochemical properties (size, zeta potential and morphology) of the resulting RBC@DOX/CS-NPs, 4T1@DOX/CS-NPs and RBC-4T1@DOX/CS-NPs, as well as their cytotoxic effect and cellular NP uptake in vitro were thoroughly characterized. The anti-cancer therapeutic efficacy of the NPs was evaluated using the orthotopic 4T1 breast cancer model in vivo. The experimental results showed that DOX/CS-NPs had a DOX-loading capacity of 71.76 ± 0.87 %, and that coating of DOX/CS-NPs with 4T1CM significantly increased the NP uptake and cytotoxic effect in breast cancer cells. Interestingly, by optimizing the ratio of RBCMs:4T1CMs, it was possible to increase the homotypic targeting properties towards breast cancer cells. Moreover, in vivo tumor studies showed that compared to control DOX/CS-NPs and free DOX, both 4T1@DOX/CS-NPs and RBC@DOX/CS-NPs significantly inhibited tumor growth and metastasis. However, the effect of 4T1@DOX/CS-NPs was more prominent. Moreover, CM-coating reduced the uptake of NPs by macrophages and led to rapid clearance from the liver and lungs in vivo, compared to control NPs. Our results suggest that specific self-recognition to source cells resulting in homotypic targeting increased the uptake and the cytotoxic capacity of 4T1@DOX/CS-NPs by breast cancer cells in vitro and in vivo. In conclusion, tumor-disguised CM-coated DOX/CS-NPs exhibited tumor homotypic targeting and anti-cancer properties, and were superior over targeting with RBC-CM or RBC-4T1 hybrid membranes, suggesting that the presence of 4T1-CM is critical for treatment outcome.
Topics: Humans; Female; Breast Neoplasms; Doxorubicin; Antineoplastic Agents; Nanoparticles; Erythrocyte Membrane
PubMed: 37196459
DOI: 10.1016/j.bioadv.2023.213456 -
Journal of Nanobiotechnology Jun 2022Acute myeloid leukemia (AML) showed limited clinical therapeutic efficiency with chemotherapy for its multi-distributed lesions and hard-to-kill leukemia cells deep in...
BACKGROUND
Acute myeloid leukemia (AML) showed limited clinical therapeutic efficiency with chemotherapy for its multi-distributed lesions and hard-to-kill leukemia cells deep in the bone marrow.
RESULTS
Here, a biomimetic nanosystem (DR@PLip) based on platelet membrane (PM) coating and doxorubicin (DOX)/ginsenoside (Rg3) co-loading was developed to potentiate the local-to-systemic chemoimmunotherapy for AML. The PM was designed for long-term circulation and better leukemia cells targeting. The participation of Rg3 was proved to enhance the tumor sensitivity to DOX, thus initiating the anti-tumor immune activation and effectively combating the leukemia cells hiding in the bone marrow.
CONCLUSIONS
In conclusion, the strategy that combining immediate chemotherapy with long-term immunotherapy achieved improved therapeutic efficiency and prolonged survival, which provided a new perspective for the clinical treatment of AML.
Topics: Biomimetics; Doxorubicin; Ginsenosides; Humans; Immunotherapy; Leukemia, Myeloid, Acute
PubMed: 35701846
DOI: 10.1186/s12951-022-01491-w -
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 -
Cell Proliferation May 2023Cancer cell spheroids have been shown to mimic in vivo tumour microenvironment and are therefore suitable for in vitro drug screening. Microfluidic technology can...
Cancer cell spheroids have been shown to mimic in vivo tumour microenvironment and are therefore suitable for in vitro drug screening. Microfluidic technology can provide conveniences for spheroid assays such as high-throughput, simplifying manual operation and saving reagent. Here, we propose a concentration gradient generator based on microfluidic technology for cell spheroid culture and assay. The chip consists of upper microchannels and lower microwells. After partitioning HepG2 suspension into the microwells with concave and non-adhesive bottoms, spheroids can spontaneously form. By controlling the fluid replacement and flow in microchannels, the doxorubicin solution is diluted automatically into a series of concentration gradients, which spanning more than one order of magnitude. And then the effect of doxorubicin on spheroids is measured in situ by fluorescent staining. This chip provides a very promising approach to achieve the high-throughput and standardized anti-cancer drug screening in future.
Topics: Spheroids, Cellular; Cell Culture Techniques; Antineoplastic Agents; Drug Evaluation, Preclinical; Doxorubicin
PubMed: 37199072
DOI: 10.1111/cpr.13473 -
Cells Jan 2022Doxorubicin (Dox) is an anthracycline chemotherapeutic agent used to treat breast, leukemia, and lymphoma malignancies. However, cardiotoxicity and inherent acquired...
Doxorubicin (Dox) is an anthracycline chemotherapeutic agent used to treat breast, leukemia, and lymphoma malignancies. However, cardiotoxicity and inherent acquired resistance are major drawbacks, limiting its clinical application. We have previously shown that cyclic peptide [WR] containing alternate tryptophan (W) and arginine (R) residues acts as an efficient molecular transporter. An amphiphilic cyclic peptide containing a lysine (K) residue and alternative W and R was conjugated through a free side chain amino group with Dox via a glutarate linker to afford [(WR)WKβA]-Dox conjugate. Antiproliferative assays were performed in different cancer cell lines using the conjugate and the corresponding physical mixture of the peptide and Dox to evaluate the effectiveness of synthesized conjugate compared to the parent drug alone. [(WR)WKβA]-Dox conjugate showed higher antiproliferative activity at 10 µM and 5 µM than Dox alone at 5 μM. The conjugate inhibited the cell viability of ovarian adenocarcinoma (SK-OV-3) by 59% and the triple-negative breast cancer cells MDA-MB-231 and MCF-7 by 71% and 77%, respectively, at a concentration of 5 μM after 72 h of incubation. In contrast, Dox inhibited the proliferation of SK-OV-3, MDA-MB-231, and MCF-7 by 35%, 63%, and 57%, respectively. Furthermore, [(WR)WKβA]-Dox conjugate (5 µM) inhibited the cell viability of Dox-resistant cells (MES-SA/MX2) by 92%, while the viability of cells incubated with free Dox was only 15% at 5 μM. Confocal microscopy images confirmed the ability of both Dox conjugate and the physical mixture of the peptide with the drug to deliver Dox through an endocytosis-independent pathway, as the uptake was not inhibited in the presence of endocytosis inhibitors. The stability of Dox conjugate was observed at different time intervals using analytical HPLC when the conjugate was incubated with 25% human serum. Half-life (t) for [(WR)WKβA]-Dox conjugate was (∼6 h), and more than 80% of the conjugate was degraded at 12 h. The release of free Dox was assessed intracellularly using the CCRF-CEM cell line. The experiment demonstrated that approximately 100% of free Dox was released from the conjugate intracellularly within 72 h. These data confirm the ability of the cyclic cell-penetrating peptide containing tryptophan and arginine residues as an efficient tool for delivery of Dox and for overcoming resistance to it.
Topics: Cell Line, Tumor; Cell Proliferation; Doxorubicin; Drug Delivery Systems; Drug Liberation; Drug Resistance, Neoplasm; Endocytosis; Humans; Peptides, Cyclic
PubMed: 35053417
DOI: 10.3390/cells11020301