Liposomal Formulation of a Melphalan Lipophilic Prodrug: Studies of Acute Toxicity, Tolerability, and Antitumor Efficacy

2020 ◽  
Vol 17 (4) ◽  
pp. 312-323
Author(s):  
Daria Tretiakova ◽  
Elena Svirshchevskaya ◽  
Natalia Onishchenko ◽  
Anna Alekseeva ◽  
Ivan Boldyrev ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Acute Toxicity ◽  
Tumor Growth ◽  
Hematological Parameters ◽  
Antitumor Efficacy ◽  
Liposomal Formulation ◽  
Toxic Effects ◽  
Exponential Growth Phase ◽  
Tumor Growth Inhibition ◽  
Lipophilic Prodrug

Background:: Recently we developed a scalable scheme of synthesis of melphalan ester conjugate with 1,2-dioleoyl-sn-glycerol (MlphDG) and a protocol for the fabrication of its lyophilized liposomal formulation. Objective: Herein we compared this new convenient in use formulation of MlphDG with parent drug Alkeran® in rats concerning several toxicological parameters and evaluated its antitumor efficacy in the model of breast cancer in mice. Method: Liposomes of approximately 100 nm in diameter, consisting of egg phosphatidylcholine, soybean phosphatidylinositol, and MlphDG, or placebo liposomes without the drug were produced by extrusion and lyophilized. Alkeran® or liposomes recovered by the addition of water were injected into the tail vein of animals. Clinical examination of rats consisted of detailed inspection of the behavior, general status, and hematological parameters. Mice with transplanted breast cancer WNT-1 were subjected to multiple treatments with the drugs; tumor growth inhibition was assessed, together with cellular immunity parameters. Results: Liposomes showed approximately two times lower acute toxicity and better tolerability than Alkeran® in terms of behavioral criteria. The toxic effects of liposomes on hemopoiesis were manifested at higher doses than in the case of Alkeran®, proportionally to the difference in LD50 values. The formulation inhibited tumor growth significantly more effectively than Alkeran®, delaying the start of the exponential growth phase and exhibiting no additional toxic effects toward bone marrow. Conclusion: Lower toxicity of the liposomal formulation of MlphDG promises improved quality of life for cancer patients in need of treatment with melphalan. Presumably, the list of indications for melphalan therapy could be extended.

scholarly journals Untargeted Metabolomics Reveals Molecular Effects of Ketogenic Diet on Healthy and Tumor Xenograft Mouse Models

2019 ◽  
Author(s):  
David Licha ◽  
Silvia Vidali ◽  
Sepideh Aminzadeh-Gohari ◽  
Oliver Alka ◽  
Leander Breitkreuz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Ketogenic Diet ◽  
High Performance ◽  
Control Diet ◽  
Tumor Xenograft ◽  
Tumor Growth Inhibition ◽  
Molecular Evidence ◽  
Fatty Acid Transport ◽  
Metabolome Analysis

Ketogenic diet (KD) is getting in the focus as auxiliary cancer therapy, since it provides sufficient energy supply for healthy cells, while impairing energy production in tumor cells underlying the Warburg effect. Thereby, it can assist in inhibiting tumor growth and simultaneously counteract cachexia, which is frequently observed in cancer patients under chemotherapy. In order to provide molecular evidence for the proposed synergistic inhibition of tumor growth, we applied untargeted quantitative metabolome analysis on a breast cancer xenograft mouse model. Healthy mice and such bearing breast cancer xenografts and receiving chemotherapy were compared after treatment with control diet and KD. Metabolomic profiling was performed on plasma samples, applying high-performance liquid chromatography coupled to tandem mass spectrometry. Statistical analysis revealed metabolic fingerprints comprising numerous significantly regulated features in the group of mice bearing breast cancer. This fingerprint disappeared after treatment with KD, resulting in recovery to the metabolic status observed in healthy mice receiving control diet. Moreover, amino acid metabolism as well as fatty acid transport were found to be affected by both, the tumor and the applied KD. Our results provide clear evidence of a significant molecular effect of KD in the context of tumor growth inhibition.

Polymalic Acid–Based Nanobiopolymer Provides Efficient Systemic Breast Cancer Treatment by Inhibiting both HER2/neu Receptor Synthesis and Activity

2020 ◽  
Author(s):  
Lungwani Muungo
Keyword(s):  
Breast Cancer ◽  
Cancer Therapy ◽  
Tumor Growth ◽  
Cancer Cells ◽  
Breast Cancer Cells ◽  
Tumor Growth Inhibition ◽  
Human Breast ◽  
Akt Phosphorylation

Biodegradable nanopolymers are believed to offer great potential in cancer therapy. Here, we report thecharacterization of a novel, targeted, nanobiopolymeric conjugate based on biodegradable, nontoxic, andnonimmunogenic PMLA [poly(b-L-malic acid)]. The PMLA nanoplatform was synthesized for repetitive systemictreatments of HER2/neu-positive human breast tumors in a xenogeneic mouse model. Various moieties werecovalently attached to PMLA, including a combination of morpholino antisense oligonucleotides (AON) directedagainst HER2/neu mRNA, to block new HER2/neu receptor synthesis; anti-HER2/neu antibody trastuzumab(Herceptin), to target breast cancer cells and inhibit receptor activity simultaneously; and transferrin receptorantibody, to target the tumor vasculature and mediate delivery of the nanobiopolymer through the hostendothelial system. The results of the study showed that the lead drug tested significantly inhibited the growth ofHER2/neu-positive breast cancer cells in vitro and in vivo by enhanced apoptosis and inhibition of HER2/neureceptor signaling with suppression of Akt phosphorylation. In vivo imaging analysis and confocal microscopydemonstrated selective accumulation of the nanodrug in tumor cells via an active delivery mechanism. Systemictreatment of human breast tumor-bearing nude mice resulted in more than 90% inhibition of tumor growth andtumor regression, as compared with partial (50%) tumor growth inhibition in mice treated with trastuzumab orAON, either free or attached to PMLA. Our findings offer a preclinical proof of concept for use of the PMLAnanoplatform for combination cancer therapy.

scholarly journals Antitumor efficiency of contact radiotherapy in combination with a chlorin-based photosensitizer in experiment

2021 ◽  
Vol 10 (2) ◽  
pp. 25-33
Author(s):  
D. A. Tzerkovsky ◽  
Ya. L. Protopovich ◽  
D. I. Kozlovsky ◽  
V. A. Suslova
Keyword(s):  
Radiation Therapy ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Tumor Model ◽  
Growth Patterns ◽  
Antitumor Efficacy ◽  
Laboratory Animals ◽  
Tumor Growth Inhibition ◽  
Histological Structure ◽  
Complete Tumor

Authors have studied the antitumor efficacy of contact radiation therapy (CRT) in combination with a chlorin-based photosensitizer (PS) in an experiment on laboratory animals with transplanted tumors. The experimental study was performed in 50 white outbred rats weighing 250±50 g. Subcutaneously transplanted Pliss lymphosarcoma (PLS) and alveolar liver cancer RS1 (RS1) were used as tumor models. Chlorinbased PS photolon (RUE «Belmedpreparaty», Republic Belarus) was injected intravenously at a dose of 2.5 mg/kg. The radiation sessions were carried out 2.5–4 hours (depending on the tumor model) after the administration of the PS using the device «microSelectron HDR V3 Digital» («Nucletron», Netherlands) with a 192-Ir radiation source in single focal doses 5 and 10 Gy. All laboratory animals (for PLS and RS1) were subdivided into 5 groups of 5 animals each: intact control, CRT 5 Gy, CRT 10 Gy, PS + CRT 5 Gy, PS + CRT 10 Gy. For the PLS tumor model – on the 14th day from the beginning of the experiment Vav. in groups were 26.31±5.81; 22.45±6.97; 18.99±4.86; 10.75±5.18 and 28.06±2.85 cm3, respectively (p˂0.05). The coefficients of tumor growth inhibition in the experimental groups were 14.67%, 27.82%, 59.14% and 6.65%, respectively. The frequency of complete tumor regressions 60 days after the start of the experiment was 0%, 20%, 20%, 60%, and 20%, respectively. On RS1 tumor model – on the 14th day from the beginning of the experiment Vav. in groups were 4.48±1.03; 0.80±0.21; 0.29±0.09; 0.19±0.07 and 0.32±0.08 cm3, respectively (p=0.009). The coefficients of tumor growth inhibition in the experimental groups were 82.14%, 93.53%, 95.76% and 92.86%, respectively. The frequency of complete tumor regressions 60 days after the start of the experiment was 0%, 0%, 20%, 0%, and 0%, respectively. Systemic administration of chlorin-based PS before the CRT session increases the antitumor efficacy of radiation therapy in animals with transplantable tumors of different histological structure and growth patterns. The data obtained indicate that further studies of the radiosensitizing properties of PS are promising.

scholarly journals STUDY OF THE EFFECT OF LOMUSTIN ON HER2-POSITIVE BREAST CANCER IN FVB/N HER-2 TRANSGENIC MICE

2019 ◽  
Vol 18 (5) ◽  
pp. 54-60
Author(s):  
A. N. Stukov ◽  
S. F. Vershinina ◽  
N. A. Koziavin ◽  
T. Yu. Semiglazova ◽  
L. V. Filatova ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Transgenic Mice ◽  
Tumor Growth ◽  
Growth Inhibition ◽  
Growth Index ◽  
Tumor Growth Inhibition ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Her 2 ◽  
Positive Breast Cancer

Because of the high risk of brain metastases from HER2-positive breast cancer, the study of the anticancer activity of drugs used to treat brain tumors, in particular lomustine, is of great importance. In the FVB/N Her-2 transgenic mice bearing HER2-positive breast cancer (BC HER2+), a single oral administration of lomustine at a dose of 50 mg/kg resulted in a significant tumor growth inhibition (up to 96 %, p<0.0001). The tumor growth index (TGI) expressed as a ratio between the areas under the kinetic curves of tumor growth in the study and control groups and amounted to 33 % (p<0.001) indicated the high activity of lomustine. However, the effect of lomustine on intramuscularly transplanted Ehrlich tumor was insignificant (tumor growth inhibition and tumor growth index were <39 % and 68 %, respectively). Lomustine administered orally at a single dose of 50 mg/kg 24 hours after intracranial transplantation of BC HER2+ increased the median survival time up to 30 days in FVB/N mice compared to 21 days in the control group mice (p<0.001). The high therapeutic effect of lomustine in HER2-positive breast cancer mice is likely can be explained by the biological characteristics of this tumor; therefore clinical trials of lomustine for HER2-positive tumors are needed.

scholarly journals Untargeted Metabolomics Reveals Molecular Effects of Ketogenic Diet on Healthy and Tumor Xenograft Mouse Models

2019 ◽  
Vol 20 (16) ◽  
pp. 3873 ◽  
Author(s):  
David Licha ◽  
Silvia Vidali ◽  
Sepideh Aminzadeh-Gohari ◽  
Oliver Alka ◽  
Leander Breitkreuz ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Tumor Cells ◽  
Ketogenic Diet ◽  
Energy Supply ◽  
Control Diet ◽  
Tumor Xenograft ◽  
Tumor Growth Inhibition ◽  
Molecular Evidence ◽  
Fatty Acid Transport

The application of ketogenic diet (KD) (high fat/low carbohydrate/adequate protein) as an auxiliary cancer therapy is a field of growing attention. KD provides sufficient energy supply for healthy cells, while possibly impairing energy production in highly glycolytic tumor cells. Moreover, KD regulates insulin and tumor related growth factors (like insulin growth factor-1, IGF-1). In order to provide molecular evidence for the proposed additional inhibition of tumor growth when combining chemotherapy with KD, we applied untargeted quantitative metabolome analysis on a spontaneous breast cancer xenograft mouse model, using MDA-MB-468 cells. Healthy mice and mice bearing breast cancer xenografts and receiving cyclophosphamide chemotherapy were compared after treatment with control diet and KD. Metabolomic profiling was performed on plasma samples, applying high-performance liquid chromatography coupled to tandem mass spectrometry. Statistical analysis revealed metabolic fingerprints comprising numerous significantly regulated features in the group of mice bearing breast cancer. This fingerprint disappeared after treatment with KD, resulting in recovery to the metabolic status observed in healthy mice receiving control diet. Moreover, amino acid metabolism as well as fatty acid transport were found to be affected by both the tumor and the applied KD. Our results provide clear evidence of a significant molecular effect of adjuvant KD in the context of tumor growth inhibition and suggest additional mechanisms of tumor suppression beyond the proposed constrain in energy supply of tumor cells.

scholarly journals Antitumor Effect of Fever Range Whole Body Hyperthermia with Curcumin in Breast Cancer-induced Mice

2019 ◽  
Vol 8 (2S2) ◽  
pp. 297-301
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Combination Treatment ◽  
Tumor Volume ◽  
Whole Body ◽  
Tumor Growth Inhibition ◽  
Tumor Treatment ◽  
Treatment Groups ◽  
Whole Body Hyperthermia ◽  
Cancer Types

Breast cancer is a complex and heterogeneous disease and also one of the major cancer types among female worldwide. Fever range whole-body hyperthermia and curcumin as a single treatment have been tested against breast cancer and showed some promising anti-tumor effect. However, their combination as an effective anti- tumor treatment against breast cancer has never been explored. The effects of combined wholebody fever range hyperthermia and curcumin on tumor growth was examined in this study. Mice were inoculated with EMT6 cells subcutaneously and allocated to 4 treatment groups: (i) control (control), (ii) curcumin (50mg/kg bodyweight), (iii) twice fever range whole-body hyperthermia 39.0°C (± 0.5) for 15 minutes, (iv) a combination of curcumin (50mg/kg bodyweight) and twice fever range whole-body hyperthermia 39.0°C (± 0.5) for 15 minutes. Following treatment, mice body weight and tumor volume were measured. The greatest tumor growth inhibition exhibited in combination treatment (68.45%, p<0.05) and showed no general toxicity. As conclusion, the combination treatment can be a potential anti-tumor treatment of breast cancer.

Sign in / Sign up

Export Citation Format

Share Document