Sertoli Cells Loaded with Doxorubicin in Lipid Micelles Reduced Tumor Burden and Dox-Induced Toxicity.
Ontology highlight
ABSTRACT:
SUBMITTER: Das M
PROVIDER: S-EPMC5753976 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:Irreversible electroporation (IRE) is a novel non-thermal ablative treatment for cancer patients with unresectable tumor. IRE kills tumor cells by applying a strong electric field across the cell membrane, thereby creating irreparable pores. Compared to conventional thermal ablation, IRE is effective in perivascular tissues and can preserve the surrounding sensitive structures. However, tumor cells may survive in the regions exposed to insufficient electric field strength, and cause tumor relapse afterwards. We prepared a doxorubicin-loaded polymeric micelles system (M-Dox) using oil-in-water emulsion. The resultant M-Dox was 37.9 ± 3.2 nm in size with a Dox loading of 4.3% by weight. M-Dox is toxic to multiple human cancer cell lines with IC50 values in nanomolar and micromolar range. When combined with IRE in a hepatic carcinoma mouse xenograft model, the tumor treated with the combination therapy (IRE + M-Dox) was the highest in both M-Dox uptake and percentage of necrosis. Immunohistochemical staining also confirmed that the fewest proliferating cells were present after the combination therapy. Our data suggested that M-Dox was an effective adjuvant treatment to enhance the anti-tumor efficacy of IRE.
| S-EPMC5435371 | biostudies-literature
Project description:Doxorubicin (DOX) is one of the most widely used anticancer agents. DOX is known for inducing cardiotoxicity, resulting in the long-term development of heart failure. Intravascular delivery of DOX may benefit from the carriage by red blood cells (RBCs), as they can limit the systemic toxicity while delivering the DOX to the tumor. This study proposes a methodology for the synthesis of electrophoretically DOX-loaded red blood cells (RBC-DOX), as well as the assessment of its antitumorigenic effects in human colon cancer cells (HT-29), and in colon cancer xenograft models. In addition, healthy mice without tumors were dosed with RBC-DOX to assess cardiotoxicity via assessment of indexes of cardiac function after multiple doses of RBC-DOX. The HT-29 IC50 was found to be lower for RBC-DOX compared to free DOX. Tumor volume for the RBC-DOX group was smaller than the free DOX groups in HT-29 xenografts models. Statistically higher concentrations of DOX were found in the liver, spleen, and lungs for the RBC-DOX group compared to the free DOX group. However, the heart and the skin had statistically lower DOX concentrations for the RBC-DOX group compared to the free DOX group, with no significant differences in tumor biodistribution. All hemodynamic and cardiac function parameters were closer to control parameters for the RBC-DOX treated compared to for the free DOX-treated mice. These results suggest that RBC-DOX can be an alternative to prolong treatments with DOX, with superior antitumorigenic effects, decreased myelosuppression, and limited cardiac toxicity compared to equivalent doses of free DOX.
| S-EPMC6450495 | biostudies-literature
Project description:Designing stable drug nanocarriers, 10-30 nm in size, would have significant impact on their transport in circulation, tumor penetration, and therapeutic efficacy. In the present study, biological properties of 3-helix micelles loaded with 8 wt % doxorubicin (DOX), ~15 nm in size, were characterized to validate their potential as a nanocarrier platform. DOX-loaded micelles exhibited high stability in terms of size and drug retention in concentrated protein environments similar to conditions after intravenous injections. DOX-loaded micelles were cytotoxic to PPC-1 and 4T1 cancer cells at levels comparable to free DOX. 3-Helix micelles can be disassembled by proteolytic degradation of peptide shell to enable drug release and clearance to minimize long-term accumulation. Local administration to normal rat striatum by convection enhanced delivery (CED) showed greater extent of drug distribution and reduced toxicity relative to free drug. Intravenous administration of DOX-loaded 3-helix micelles demonstrated improved tumor half-life and reduced toxicity to healthy tissues in comparison to free DOX. In vivo delivery of DOX-loaded 3-helix micelles through two different routes clearly indicates the potential of 3-helix micelles as safe and effective nanocarriers for cancer therapeutics.
| S-EPMC3923314 | biostudies-literature
Project description:Docetaxel is an adjuvant chemotherapy drug widely used to treat multiple solid tumors, however its toxicity and side-effect limits its clinical efficacy. Herein, the docetaxel-loaded solid lipid nanoparticles (DSNs) were developed to reduce systemic toxicity while still keeping its anti-cancer activity. To evaluate its anti-cancer activity and toxicity and understand the molecular mechanisms of DSNs, different cellular, molecular and whole genome transcription analysis approaches were utilized. The DSNs showed lower cytotoxicity compared with the commercial formulation of docetaxel-Taxotere and induced more apoptosis at 24 h treatment in vitro. It can cause the treated cancer cells arrested at G2/M phase in a dose-depend manner as Taxotere. The DSNs can also suppress tumor growth very effectively in a murine breast cancer model. Systemic analysis of gene expression profiles by microarray and the following verification experiments suggested that both DSNs and Taxotere regulate expression of series genes and these genes functions involved in DNA replication, DNA damage response, cell proliferation, apoptosis and cell cycle regulation. Some of these genes expressed differentially at protein level although their transcription level was similar under TAX and DSNs treatment. Moreover, DSNs improved main side-effect of Taxotere by greatly lowering myelosuppression toxicity to bone marrow cells from mice. Taken together, our results expound the anti-tumor efficacy and the potential working mechanisms of DSNs in its anti-cancer activity and toxicity, which provide a theoretical foundation to develop and apply more efficient docetaxel formulation to treat cancer patients.
2014-12-31 | GSE54091 | GEO
Project description:OBJECTIVE:Nano micelles (NMs) have been widely used for various biomedical applications due to its unique physiochemical properties. This study aimed to investigated the anti-tumor effect of doxorubicin (Dox)-loaded Pluronic P123 (P123) and PEG2000-DSPE mixed NMs in drug-resistant breast cancer cells. RESULTS:The expression of P-gp and MDR1 gene was highly expressed in MCF-7R but not MCF-7 cells. The cellular uptake of P123-PEG2000-DSPE (Dox) was higher than that of free Dox and PEG2000-DSPE (Dox) in MCF-7R cells. Furthermore, compared with free Dox, both PEG2000-DSPE (Dox) and P123-PEG2000-DSPE (Dox) significantly diminished cell viability, and promoted cell apoptosis in MCF-7R cells. In addition, the P123-modified NMs obviously inhibited the expression of P-gp and MDR1. CONCLUSIONS:P123-PEG2000-DSPE (Dox) had a superior anti-tumor activity than PEG2000-DSPE (Dox) in MCF-7R cells through P-gp-mediated drug excretion and drug resistance mechanisms. METHODS:The PEG2000-DSPE NMs (PEG2000-DSPE), P123 and PEG2000-DSPE mixed NMs (P123-PEG2000-DSPE), Dox-loaded PEG2000-DSPE NMs (PEG2000-DSPE (Dox)), and Dox-loaded Pluronic P123 and PEG2000-DSPE mixed NMs (P123-PEG2000-DSPE (Dox)) were prepared, and then the morphologies and the size distribution of PEG2000-DSPE (Dox) and P123-PEG2000-DSPE (Dox) were observed by transmission electron microscopy (TEM) and dynamic light scattering (DLS), respectively.
| S-EPMC7244042 | biostudies-literature
Project description:Docetaxel is an adjuvant chemotherapy drug widely used to treat multiple solid tumors; however, its toxicity and side effects limit its clinical efficacy. Herein, docetaxel-loaded solid lipid nanoparticles (DSNs) were developed to reduce systemic toxicity of docetaxel while still keeping its anticancer activity. To evaluate its anticancer activity and toxicity, and to understand the molecular mechanisms of DSNs, different cellular, molecular, and whole genome transcription analysis approaches were utilized. The DSNs showed lower cytotoxicity compared with the commercial formulation of docetaxel (Taxotere(®)) and induced more apoptosis at 24 hours after treatment in vitro. DSNs can cause the treated cancer cells to arrest in the G2/M phase in a dose-dependent manner similar to Taxotere. They can also suppress tumor growth very effectively in a mice model with human xenograft breast cancer. Systemic analysis of gene expression profiles by microarray and subsequent verification experiments suggested that both DSNs and Taxotere regulate gene expression and gene function, including DNA replication, DNA damage response, cell proliferation, apoptosis, and cell cycle regulation. Some of these genes expressed differentially at the protein level although their messenger RNA expression level was similar under Taxotere and DSN treatment. Moreover, DSNs improved the main side effect of Taxotere by greatly lowering myelosuppression toxicity to bone marrow cells from mice. Taken together, these results expound the antitumor efficacy and the potential working mechanisms of DSNs in its anticancer activity and toxicity, which provide a theoretical foundation to develop and apply a more efficient docetaxel formulation to treat cancer patients.
| S-EPMC4207579 | biostudies-literature
Project description:In this study, a graft copolymer, poly(N-(2-hydroxypropyl) methacrylamide dilactate)-co-(N-(2-hydroxypropyl) methacrylamide-co-histidine)-graft-poly(d,l-lactide), and a diblock copolymer, methoxy poly(ethylene glycol)-b-poly(d,l-lactide), were assembled into a mixed micellar system to encapsulate the anticancer drug doxorubicin (Dox). This mixed micellar system possesses the hydrophobic lactide segment of both copolymers, which reinforces its stability in physiological milieus; the histidine molecules appended on the graft copolymer provide the desired pH-responsive behavior to release Dox during internalization in cancer cells. The results demonstrate that the two copolymers were successfully prepared, and their ratios in the mixed micelles were optimized on the basis of the results of the stability tests. Under acidic conditions, the mixed micelles swell and are able to release their payloads. Therefore, the in vitro results indicate that the Dox in the mixed micelles is released effectively in response to the environmental pH of the mimetic internalization process, increasing cancer cells' sensitivity toward Dox. The mixed micelles display low cytotoxicity due to the degradability of the polymers. The in vivo images show that the high stability of the mixed micelles ensures a high tumor accumulation. This selective tumor accumulation results in an excellent inhibition of in vivo tumor growth and a high rate of apoptosis in cancerous tissues, with low toxicity. This highly stable, mixed micellar system with a pH-dependent drug release, which enables the precise delivery of drugs to the tumor lesions, is feasible to employ clinically in cancer therapy.
| S-EPMC8345050 | biostudies-literature
Project description:Multidrug resistance (MDR) against chemotherapeutic agents has become one of the major obstacles to successful cancer therapy and MDR-associated proteins (MRPs)-mediated drug efflux is the key factor for MDR. In this study, a redox-responsive polymer based on dextran (DEX) and indomethacin (IND), which could reduce MRPs-mediated efflux of chemotherapeutics, was synthesized, and the obtained polymer could spontaneously form stable micelles with well-defined core-shell structure and a uniform size distribution with an average diameter of 50 nm and effectively encapsulate doxorubicin (DOX); the micelles contain a disulfide bridge (cystamine, SS) between IND and DEX (DEX-SS-IND). In vitro drug release results indicated that DEX-SS-IND/DOX micelles could maintain good stability in a stimulated normal physiological environment and promptly depolymerized and released DOX in a reducing environment. After incubating DEX-SS-IND/DOX micelles with drug-resistant tumor (MCF-7/ADR) cells, the intracellular accumulation and retention of DOX were significantly increased under the synergistic effects of redox-responsive delivery and the inhibitory effect of IND on MRPs. In vitro cytotoxicity showed that DEX-SS-IND/DOX micelles exhibited higher cytotoxicity against MCF-7/ADR cells. Moreover, DEX-SS-IND/DOX micelles showed significantly enhanced inhibition of tumor in BALB/c nude mice bearing MCF-7/ADR tumors and reduced systemic toxicity. Overall, the cumulative evidence indicates that DEX-SS-IND/DOX micelles hold significant promise for overcoming MDR for cancer therapy.
| S-EPMC5574666 | biostudies-literature
Project description:Stimuli-responsive nanotherapeutics hold great promise in precision oncology. In this study, a facile strategy was used to develop a new class of pH-responsive micelles, which contain methoxy polyethylene glycol (mPEG) and poly(carbobenzoxy-l-glutamic acid, BLG) as amphiphilic copolymer, and β-thiopropionate as acid-labile linkage. The mPEG-S-PBLG copolymer was synthesized through one-step ring-opening polymerization (ROP) and thiol-ene click reaction, and was able to efficiently encapsulate doxorubicin (DOX) to form micelles. The physicochemical characteristics, cellular uptake, tumor targeting, and anti-tumor efficacy of DOX-loaded micelles were investigated. DOX-loaded micelles were stable under physiological conditions and disintegrated under acidic conditions. DOX-loaded micelles can be internalized into cancer cells and release drugs in response to low pH in endosomes/lysosomes, resulting in cell death. Furthermore, the micellar formulation significantly prolonged the blood circulation, reduced the cardiac distribution, and selectively delivered more drugs to tumor tissue. Finally, compared with free DOX, DOX-loaded micelles significantly improved the anti-tumor efficacy and reduced systemic and cardiac toxicity in two different tumor xenograft models. These results suggest that mPEG-S-PBLG micelles have translational potential in the precise delivery of anti-cancer drugs.
| S-EPMC8635546 | biostudies-literature
Project description:Doxorubicin (Dox) has widespread use as a cancer chemotherapeutic agent, but Dox is limited by several side effects including irreversible cardiomyopathy. Although liposomal Dox formulations, such as Doxil, mitigate side effects, they do not prolong survival in many patients. As a result, efforts have continued to discover improved formulations of Dox. We previously found that a peptide-based nanoplex delivered plasmid DNA efficiently to tumors in murine models. Unlike the majority of nanoparticles that depend solely on enhanced permeability and retention (EPR) for their transport into the tumor, our peptide-based nanoplex has a potential advantage in that its uptake primarily depends on neuropilin-1 receptor targeting. Because Dox binds to DNA, we tested whether this delivery platform could effectively deliver Dox to tumors and reduce their size. The nanoplexes increased the levels of Dox in tumors by about 5.5-fold compared to aqueous (free) Dox controls. Consistent with enhanced levels in the tumor, the nanoplex-Dox treatment had significantly greater anti-tumor activity. Whereas low dose free Dox did not reduce the size of tumors compared to untreated controls, the low dose nanoplex-Dox reduced the size of tumors by nearly 55% (p < 0.001). The high dose nanoplex-Dox also inhibited the size of tumor significantly more than the comparable high-dose free Dox (p < 0.001). Furthermore, apoptosis and proliferation markers (Ki67) of tumors observed in the different treatment groups correlated with their ability to inhibit tumor size. This study shows the efficacy of an NRP-1 targeted nanoplexes to deliver Dox to tumors in vivo and lays the groundwork for more complex and effective formulations.
| S-EPMC6531033 | biostudies-literature