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1.
Curr Vasc Pharmacol ; 20(1): 69-76, 2022.
Article in English | MEDLINE | ID: mdl-34414873

ABSTRACT

BACKGROUND AND AIM: Negatively charged nanoliposomes have a strong attraction towards plasma lipoprotein particles and can thereby regulate lipid metabolism. Here, the impact of such nanoliposomes on dyslipidaemia and progression of atherosclerosis was investigated in a rabbit model. METHODS: Two sets of negatively-charged nanoliposome formulations including [Hydrogenated Soy Phosphatidylcholine (HSPC)/1,2-distearoyl-sn-glycero-3- phosphoglycerol (DSPG)] and [1,2- Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPC)/1,2-Dimyristoyl-sn-glycero-3-phosphorylcholine (DMPG)/Cholesterol] were evaluated. Rabbits fed a high-cholesterol diet were randomly divided into 3 groups (n=5/group) intravenously administrated with HSPC/DSPG formulation (DSPG group; 100 mmol/kg), DMPC/DMPG formulation (DMPG group; 100 mmol/kg), or the normal saline (control group; 0.9% NaCl) over a 4-week period. The atherosclerotic lesions of the aortic arch wall were studied using haematoxylin and eosin staining. RESULTS: Both DSPG and DMPG nanoliposome formulations showed a nano-sized range in diameter with a negatively-charged surface and a polydispersity index of <0.1. After 4 weeks administration, the nanoliposome formulations decreased triglycerides (-62±3% [DSPG group] and -58±2% [DMPG group]), total cholesterol (-58±9% [DSPG group] and -37±5% [DMPG group]), and lowdensity lipoprotein cholesterol (-64±6% [DSPG group] and -53±10% [DMPG group]) levels, and increased high-density lipoprotein cholesterol (+67±28% [DSPG group] and +35±19% [DMPG group]) levels compared with the controls. The nanoliposomes showed a significant decrease in the severity of atherosclerotic lesions: mean values of the intima to media ratio in DMPG (0.96±0.1 fold) and DSPG (0.54±0.02 fold) groups were found to be significantly lower than that in the control (1.2±0.2 fold) group (p<0.05). CONCLUSION: Anionic nanoliposomes containing [HSPC/DSPG] and [DMPC/DMPG] correct dyslipidaemia and inhibit the progression of atherosclerosis.


Subject(s)
Atherosclerosis , Dyslipidemias , Nanoparticles , Animals , Rabbits , Atherosclerosis/prevention & control , Cholesterol , Dimyristoylphosphatidylcholine , Dyslipidemias/drug therapy , Dyslipidemias/prevention & control , Liposomes , Phosphorylcholine
2.
Vaccines (Basel) ; 9(7)2021 Jul 06.
Article in English | MEDLINE | ID: mdl-34358164

ABSTRACT

BACKGROUND: Our previous studies showed the safe preventive and therapeutic effects of immunization using the nanoliposomal antiPCSK9 vaccine called "Liposomal Immunogenic Fused PCSK9-Tetanus plus Alum adjuvant" (L-IFPTA), in mouse models of atherosclerosis. Here we aimed to ascertain the immunogenicity and safety of the L-IFPTA vaccine in a pre-clinical study in healthy non-human primates. METHODS: Five male rhesus macaque monkeys were subcutaneously immunized with the L-IFPTA vaccine, four times with bi-weekly intervals. To evaluate immunogenicity, the plasma antiPCSK9 antibody in immunized monkeys was detected and quantified using the ELISA method. The functionality of the induced antiPCSK9 antibodies was determined by the PCSK9/LDLR in vitro binding assay kit. The safety of the vaccine was tested using the evaluation of several major circulating indicators including plasma lipid alterations, inflammatory biomarkers and organ injury biomarkers. RESULTS: The resultant data indicated that the L-IFPTA vaccine significantly and highly induced the generation of functional and safe antiPCSK9 antibodies in immunized monkeys. Plasma levels of specific biomarkers indicating organ performance including creatinine, urea, uric acid, bilirubin, ALP, AS, ALT and TSH were not significantly altered. After immunization in healthy monkeys, non-prespecified endpoints (plasma levels of TC, LDL-C, VLDL-C and TG) were non-significantly reduced by 11.6 ± 36%; 16 ± 28%; 22 ± 53% and 24 ± 51%, respectively, while HDL-C was slightly increased by 2 ± 64%. There were also no significant changes in plasma levels of pro- and anti-inflammatory biomarkers. CONCLUSION: The L-IFPTA vaccine could efficiently stimulate the host humoral immune response to produce active antibodies that inhibit plasma PCSK9 while not provoking systemic inflammation and not adversely affecting organ performance.

3.
Eur J Pharmacol ; 908: 174308, 2021 Oct 05.
Article in English | MEDLINE | ID: mdl-34245747

ABSTRACT

Liposomes have been suggested as potential tools for cholesterol deposit mobilization from atherosclerotic lesions. Here, we explored the anti-atherosclerotic effects of phosphatidylserine (PS)-containing liposomes in vivo. High-fat diet-fed New Zealand white rabbits which were divided into groups receiving weekly intravenous injections of PS liposomes, atorvastatin-loaded PS (PSA) liposomes (100 µg phospholipid/kg), or control buffer for four weeks. The size and severity grade of atherosclerotic plaques as well as lipid profile were evaluated at the completion of study. In vitro, the expression and levels of anti/pro-inflammatory genes and proteins, respectively, and macrophage cholesterol efflux capacity (CEC) of nanoliposomes were evaluated. Both PS and PSA lowered serum LDL-C (P = 0.0034, P = 0.0041) and TC (P = 0.029, P = 0.0054) levels but did not alter TG and HDL-C levels. Plaque size and grade were reduced by PS (P = 0.0025, P = 0.0031) and PSA (P = 0.016, P = 0.027) versus control. Moreover, intima-media thickness was significantly reduced in the PS vs. control group (P = 0.01). In cultured cells, ICAM-1 expression in the PS (P = 0.022) and VCAM-1 expression in the PS and PSA groups (P = 0.037, P = 0.004) were suppressed while TGF-ß expression was induced by both PS and PSA (P = 0.048, P = 0.046). Moreover, CEC from macrophages to nanoliposomes was enhanced by PSA (P = 0.003). Administration of anionic PS-containing liposomes could improve lipid profile and promote plaque regression through mechanisms that may involve cholesterol efflux and modulation of adhesion molecules.


Subject(s)
Hypercholesterolemia , Liposomes , Animals , Carotid Intima-Media Thickness , Plaque, Atherosclerotic , Rabbits
4.
J Pharm Pharmacol ; 73(2): 169-177, 2021 Mar 04.
Article in English | MEDLINE | ID: mdl-33793801

ABSTRACT

OBJECTIVES: In view of their biodegradability, biocompatibility, encapsulation efficiency and targeted release, as well as low toxicity, liposomes are being widely used in the context of drug delivery. However, the efficiency of such drug delivery systems might face limitations by macrophage-mediated clearance (CL), which reduces circulation half-life (T½). This problem can be resolved through surface functionalization via poly (ethylene glycol) (PEG) in the process of PEGylation. However, the use of PEG might have its own disadvantages. Accordingly, the main purpose of this study was to produce novel stealth nanoliposomes using CD47 mimicry peptide [namely self-peptide (SP)] as an alternative to PEG for minimizing macrophage-mediated CL and enhancing circulation T½. METHODS: At first, doxorubicin (Dox)-containing liposomes [i.e.liposomal Dox (LD)] were coated with different concentrations of SP (viz. SP-LD) (0.5%, 1% and 2%). In addition, PEG-functionalized LD (i.e. PLD) was fabricated as a standard control group. Then, various types of liposomal formulae were injected into a population of mice, assigned to six groups (four mice per group) for biodistribution. After sacrificing these animals in prespecified time points (namely 0.5, 6, 12, 24, 48, 72, 96 and 168 h), serum, liver, spleen, heart, kidney and lung samples were collected to estimate the encapsulated drug content in different groups through measuring intrinsic autofluorescence signal of Dox. KEY FINDINGS: The tissue distribution results in the liver, spleen, heart, kidney and lung samples indicated a significant difference between the SP-LD and the PLD groups. Furthermore, the examination of Dox content, 6 h after administration, showed a growth rate of 28% in Dox content in the SP group compared with the PLD one. Subsequently, these values were, respectively, 63% and 75% at 24 and 48 h. CONCLUSIONS: The results of tissue distribution and serum kinetic analysis correspondingly revealed that the use of the SP could augment the circulation time of Dox in comparison with PEG, and it could additionally minimize the tissue accumulation of the drug, which is normally the cause of drug-induced toxicity. The use of the SP on nanoliposomes could prolong the circulation of T½ and diminish the tissue accumulation of LD. These findings are relevant for improving therapeutic efficacy and reducing the toxicity of liposomal drugs.


Subject(s)
CD47 Antigen/chemistry , Doxorubicin/analogs & derivatives , Drug Delivery Systems , Nanoparticles , Animals , Antibiotics, Antineoplastic/administration & dosage , Antibiotics, Antineoplastic/pharmacokinetics , Doxorubicin/administration & dosage , Doxorubicin/pharmacokinetics , Half-Life , Mice , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/pharmacokinetics , Time Factors , Tissue Distribution
5.
Anticancer Agents Med Chem ; 21(17): 2379-2384, 2021.
Article in English | MEDLINE | ID: mdl-33596812

ABSTRACT

BACKGROUND: Pyrvinium Pamoate (PP) is an old drug approved by the FDA for the treatment of pinworm infections. Recently, it has been introduced as an anti-tumor agent, however, low aqueous solubility severely limits its potential effects. In this study, we developed a liposomal formulation of pyrvinium pamoate to investigate its in vitro cytotoxicity and in vivo efficacy against melanoma cells. MATERIALS & METHODS: As drug carriers, liposomes were fabricated using the thin-film method. PP was encapsulated within the liposomes using a remote loading method. We evaluated the morphology, particle size, and Zeta potential of the liposomes. Additionally, High-Performance Liquid Chromatography (HPLC) was employed for qualitative and quantitative analysis. Then we investigated our liposomal PP for its in vitro cytotoxicity as well as the tumor growth inhibition in C57BL/6 mice bearing B16F0 melanoma tumors. RESULTS: Based on the analytical result, the liposomal drug delivery system is a homogeneous and stable colloidal suspension of PP particles. The images of Atomic force microscopy and particle size data showed that all the prepared nanocarriers were spherical with a diameter of approximately 101 nm. According to both in vitro and in vivo studies, nanoliposomal PP exhibited an improved anti-proliferative potential against B16F10 melanoma tumor compared to free PP. CONCLUSION: Liposomal encapsulation improves the water solubility of PP and enhances its anti-cancer activity.


Subject(s)
Antineoplastic Agents/pharmacology , Disease Models, Animal , Melanoma, Experimental/drug therapy , Nanoparticles/chemistry , Pyrvinium Compounds/pharmacology , Animals , Antineoplastic Agents/chemistry , Cell Proliferation/drug effects , Drug Carriers/chemistry , Drug Screening Assays, Antitumor , Female , Liposomes/chemistry , Melanoma, Experimental/pathology , Mice , Mice, Inbred C57BL , Pyrvinium Compounds/chemistry , Tumor Cells, Cultured
6.
Expert Opin Drug Deliv ; 17(7): 1049-1058, 2020 07.
Article in English | MEDLINE | ID: mdl-32434390

ABSTRACT

BACKGROUND: We hypothesized if phagocytosis of liposomes by macrophages could be mitigated through incorporation of a CD47 mimicry peptide (Self peptide: SP) on the surface of liposomes. METHODS: Thin film hydration method followed by extrusion was used to prepare nanoliposomes, and Dox encapsulation in liposomes was done via remote-loading method. Decorated liposomes with SP peptide (SP-LD) at different peptide densities (300 and 600 peptides on the surface of each liposome) were prepared using a pre-insertion technique. Macrophage cell lines were used to compare the cellular uptake of decorated and unmodified liposomes. For biodistribution studies, tumor-bearing mice received the preparations, and fluorescence signals of Dox in different tissues were measured. To evaluate anti-tumor efficacy, tumor size and survival rates were assessed. Also, pharmacokinetic parameters were determined. RESULTS: Compared with PEGylated liposomes, uptake by macrophages was largely decreased when SP was incorporated on liposomes. Following intravenous injection, SP-liposomes were cleared more slowly compared with PEGylated liposomes. Eventually, SP-liposomes were highly distributed to tumor tissues compared with PEGylated liposomes, and significantly reduced tumor size and improved the survival of tumor-bearing mice. CONCLUSIONS: This research showed reduced macrophage uptake, increased blood circulation, and enhanced tumor accumulation of liposomes through SP incorporation on the surface of particles.


Subject(s)
Antibiotics, Antineoplastic/administration & dosage , CD47 Antigen/metabolism , Doxorubicin/administration & dosage , Peptides/metabolism , Animals , Antibiotics, Antineoplastic/pharmacokinetics , Cell Line, Tumor , Humans , Liposomes , Male , Mice , Mice, Inbred BALB C , Polyethylene Glycols/chemistry , Tissue Distribution
7.
Protein Pept Lett ; 27(10): 1029-1037, 2020.
Article in English | MEDLINE | ID: mdl-32282292

ABSTRACT

INTRODUCTION: Bio-degradable nano-particles have many applications as drug delivery vehicles because of their good bio-availability, controlled release, low toxicity and potential for encapsulation. However, the most important obstacle to nanoparticulate drug delivery is elimination by macrophages which reduces the residence time of nanoparticles in the blood. To overcome this problem, the surface of the nanoparticle can be passivated by coating with Polyethylene glycol (PEG). However, the use of PEG has its own disadvantages. CD47 receptor acts as a self marker on the surface of many cells and inhibits phagocytosis. This study used a CD47 mimicry peptide as a substitute for PEG to fabricate "stealth" nanoliposome with reduced macrophage clearance. METHODS: Doxorubibin was used as a model drug because of its inherent fluorescence. Doxorubicin- containing liposomes were coated with different percentages of CD47 mimicry peptide (0.5% and 1%). PEG-functionalized doxorubicin-containing liposomes, were used as a comparator. The liposomal formulations were intravenously injected into mice. Serum was collected at pre-defined time points and tissue samples were taken at 24 hours. Fluorescence was used to determine the concentration doxorubicin in serum, heart, spleen, kidney, liver and lung tissues. RESULTS: Tissue biodistribution and serum kinetic studies indicated that compared with PEG, the use of CD47 mimicry peptide increased the circulation time of doxorubicin in the circulation. Moreover, unwanted accumulation of doxorubicin in the reticuloendothelial tissues (liver and spleen), kidney and heart was significantly decreased by the CD47 mimicry peptide. CONCLUSION: The use of a CD47 mimicry peptide on the surface of nanoliposomes improved the residence time of liposomal doxorubicin in the circulation. The accumulation of drug in non-target tissues was reduced, thereby potentially reducing toxicity.


Subject(s)
CD47 Antigen/chemistry , Coated Materials, Biocompatible , Doxorubicin , Peptides , Animals , Cell Line , Coated Materials, Biocompatible/chemistry , Coated Materials, Biocompatible/pharmacokinetics , Coated Materials, Biocompatible/pharmacology , Doxorubicin/chemistry , Doxorubicin/pharmacokinetics , Doxorubicin/pharmacology , Liposomes , Mice , Mice, Inbred BALB C , Organ Specificity , Peptides/chemistry , Peptides/pharmacokinetics , Peptides/pharmacology
8.
Anticancer Agents Med Chem ; 20(6): 643-650, 2020.
Article in English | MEDLINE | ID: mdl-31985384

ABSTRACT

Cancer is a condition where there is an uncontrolled growth of cells resulting in high mortality. It is the second most frequent cause of death worldwide. Bortezomib (BTZ) is a Proteasome Inhibitor (PI) that is used for the treatment of a variety of cancers. It is the first PI that has received the approval of the US Food and Drug Administration (FDA) to treat mantle cell lymphoma and multiple myeloma. High incidence of sideeffects, limited dose, low water solubility, fast clearance, and drug resistance are the significant limitations of BTZ. Therefore, various drug delivery systems have been tried to overcome these limitations of BTZ in cancer therapy. Nanotechnology can potentially enhance the aqueous solubility of BTZ, increase its bioavailability, and control the release of BTZ at the site of administration. The lipid-based nanocarriers, such as liposomes, solid lipid NPs, and microemulsions, are some of the developments in nanotechnology, which could potentially enhance the therapeutic benefits of BTZ.


Subject(s)
Antineoplastic Agents/administration & dosage , Bortezomib/administration & dosage , Drug Carriers/chemistry , Lipids/chemistry , Nanoparticles/chemistry , Proteasome Inhibitors/administration & dosage , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Bortezomib/pharmacokinetics , Bortezomib/pharmacology , Drug Delivery Systems/methods , Emulsions/chemistry , Humans , Liposomes/chemistry , Nanotechnology/methods , Neoplasms/drug therapy , Proteasome Inhibitors/pharmacokinetics , Proteasome Inhibitors/pharmacology
9.
Anticancer Agents Med Chem ; 20(6): 700-708, 2020.
Article in English | MEDLINE | ID: mdl-31893998

ABSTRACT

AIMS: Here, three liposomal formulations of DPPC/DPPG/Chol/DSPE-mPEG2000 (F1), DPPC/DPPG/Chol (F2) and HSPC/DPPG/Chol/DSPE-mPEG2000 (F3) encapsulating BTZ were prepared and characterized in terms of their size, surface charge, drug loading, and release profile. Mannitol was used as a trapping agent to entrap the BTZ inside the liposomal core. The cytotoxicity and anti-tumor activity of formulations were investigated in vitro and in vivo in mice bearing tumor. BACKGROUND: Bortezomib (BTZ) is an FDA approved proteasome inhibitor for the treatment of mantle cell lymphoma and multiple myeloma. The low solubility of BTZ has been responsible for the several side effects and low therapeutic efficacy of the drug. Encapsulating BTZ in a nano drug delivery system; helps overcome such issues. Among NDDSs, liposomes are promising diagnostic and therapeutic delivery vehicles in cancer treatment. OBJECTIVE: Evaluating anti-tumor activity of bortezomib liposomal formulations. METHODS: Data prompted us to design and develop three different liposomal formulations of BTZ based on Tm parameter, which determines liposomal stiffness. DPPC (Tm 41°C) and HSPC (Tm 55°C) lipids were chosen as variables associated with liposome rigidity. In vitro cytotoxicity assay was then carried out for the three designed liposomal formulations on C26 and B16F0, which are the colon and melanoma cancer mouse-cell lines, respectively. NIH 3T3 mouse embryonic fibroblast cell line was also used as a normal cell line. The therapeutic efficacy of these formulations was further assessed in mice tumor models. RESULT: MBTZ were successfully encapsulated into all the three liposomal formulations with a high entrapment efficacy of 60, 64, and 84% for F1, F2, and F3, respectively. The findings showed that liposomes mean particle diameter ranged from 103.4 to 146.8nm. In vitro cytotoxicity studies showed that liposomal-BTZ formulations had higher IC50 value in comparison to free BTZ. F2-liposomes with DPPC, having lower Tm of 41°C, showed much higher anti-tumor efficacy in mice models of C26 and B16F0 tumors compared to F3-HSPC liposomes with a Tm of 55°C. F2 formulation also enhanced mice survival compared with untreated groups, either in BALB/c or in C57BL/6 mice. CONCLUSION: Our findings indicated that F2-DPPC-liposomal formulations prepared with Tm close to body temperature seem to be effective in reducing the side effects and increasing the therapeutic efficacy of BTZ and merits further investigation.


Subject(s)
Antineoplastic Agents/administration & dosage , Bortezomib/administration & dosage , Colonic Neoplasms/drug therapy , Liposomes/chemistry , Melanoma, Experimental/drug therapy , Phase Transition , Animals , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Bortezomib/pharmacokinetics , Bortezomib/pharmacology , Bortezomib/therapeutic use , Colonic Neoplasms/pathology , Drug Liberation , Female , Humans , Melanoma, Experimental/pathology , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , NIH 3T3 Cells , Transition Temperature
10.
Curr Mol Pharmacol ; 13(3): 245-250, 2020.
Article in English | MEDLINE | ID: mdl-31433764

ABSTRACT

BACKGROUND AND AIMS: Niclosamide is an established anti-helminthic drug, which has recently been shown to inhibit the growth of various cancer cells. To exploit the potential anti-tumor activity of this drug for systemic use, the problem of low aqueous solubility should be addressed. The present study tested the in vivo anti-tumor effects of a recently developed nanoliposomal preparation of niclosamide in an experimental model of colon carcinoma. METHODS: The cytotoxicity of nanoliposomal niclosamide on CT26 colon carcinoma cells was evaluated using the MTT test. Inhibition of tumor growth was investigated in BALB/c mice bearing CT26 colon carcinoma cells. The animals were randomly divided into 4 groups including: 1) untreated control, 2) liposomal doxorubicin (15 mg/kg; single intravenous dose), 3) liposomal niclosamide (1 mg/kg/twice a week; intravenously for 4 weeks), and 4) free niclosamide (1 mg/kg/twice a week; intravenously for 4 weeks). To study therapeutic efficacy, tumor size and survival were monitored in 2-day intervals for 40 days. RESULTS: In vitro results indicated that nanoliposomal and free niclosamide could exert cytotoxic effects with IC50 values of 4.5 and 2.5 µM, respectively. According to in vivo studies, nanoliposomal niclosamide showed a higher growth inhibitory activity against CT26 colon carcinoma cells compared with free niclosamide as revealed by delayed tumor growth and prolongation of survival. CONCLUSION: Nnaoliposomal encapsulation enhanced anti-tumor properties of niclosamide in an experimental model of colon carcinoma.


Subject(s)
Adenocarcinoma/drug therapy , Antineoplastic Agents/therapeutic use , Colonic Neoplasms/drug therapy , Niclosamide/therapeutic use , Adenocarcinoma/pathology , Animals , Antineoplastic Agents/administration & dosage , Cell Line, Tumor , Colonic Neoplasms/pathology , Doxorubicin/administration & dosage , Doxorubicin/analogs & derivatives , Doxorubicin/therapeutic use , Drug Carriers/administration & dosage , Drug Screening Assays, Antitumor , Inhibitory Concentration 50 , Liposomes/administration & dosage , Male , Mice , Mice, Inbred BALB C , Nanocapsules/administration & dosage , Niclosamide/administration & dosage , Polyethylene Glycols/administration & dosage , Polyethylene Glycols/therapeutic use , Random Allocation , Solubility
11.
Curr Rheumatol Rev ; 16(2): 158-164, 2020.
Article in English | MEDLINE | ID: mdl-31868149

ABSTRACT

OBJECTIVE: Osteoarthritis is a degenerative disease of the joints. Non-steroidal antiinflammatory drugs (NSAIDs) are being used for the treatment of osteoarthritis. However, their use is limited due to complications, such as gastrointestinal bleeding. Therefore, it is necessary to find alternative treatments for osteoarthritis. Recently, nanomicelle curcumin has been developed to increase the oral bioavailability of curcumin. The aim of this study was to evaluate the effect of nano curcumin on the alleviation of the symptoms of knee osteoarthritis patients. METHODS: In this randomized, double-blind controlled trial, the intervention group was administered 40 mg of nanocurcumin capsule every 12 hours over a period of six weeks, and the control group received the placebo (similar components of nanomicelle curcumin capsules yet without curcumin). In the final analysis, 36 patients in the nanocurcumin group and 35 patients in the placebo group were enrolled. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) was filled for patients in their first visit and at the end of six weeks. Differences were statistically significant at P-value < 0.05. RESULTS: There were no significant differences between the two groups regarding gender, age, Kellgren score, and the duration of the disease before the intervention. A significant decrease was observed in the overall score, along with the scores of pain, stiffness and physical activity subscales of the WOMAC questionnaire in patients of the nano curcumin group compared with the placebo group. CONCLUSION: Nanocurcumin significantly improves the symptoms of osteoarthritis patients.


Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Curcumin/therapeutic use , Osteoarthritis, Knee/drug therapy , Aged , Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Curcumin/administration & dosage , Double-Blind Method , Female , Humans , Male , Middle Aged , Pain Measurement , Treatment Outcome
12.
Cell Oncol (Dordr) ; 43(1): 19-30, 2020 Feb.
Article in English | MEDLINE | ID: mdl-31485984

ABSTRACT

BACKGROUND: CD47 is a widely expressed cellular receptor well known for its immunoregulatory functions. By interacting with its ligands, including thrombospondin-1 (TSP-1), signal regulatory protein α (SIRPα), integrins, and SH2-domain bearing protein tyrosine phosphatase substrate-1 (SHPS-1), it modulates cellular phagocytosis by macrophages, transmigration of neutrophils and activation of dendritic cells, T cells and B cells. Ample studies have shown that various types of cancer express high levels of CD47 to escape from the immune system. Based on this observation, CD47 is currently considered as a prominent target in cancer therapy. CONCLUSIONS: Here, we review the role of CD47 in the maintenance of immune system homeostasis. We also depict three emerging CD47-targeting strategies for cancer therapy, including the use of mimicry peptides, antibodies, and gene silencing strategies. Among these approaches, the most advanced one is the use of anti-CD47 antibodies, which enhances cancer cell phagocytosis via inhibition of the CD47-SIRPα axis. These antibodies can also achieve higher anti-cancer efficacies when combined with chemotherapy and immunotherapy and hold promise for improving the survival of patients with cancer.


Subject(s)
B-Lymphocytes/immunology , CD47 Antigen/physiology , Dendritic Cells/immunology , Macrophages/immunology , Neoplasms/immunology , Phagocytosis/immunology , T-Lymphocytes/immunology , Animals , Antigens, Differentiation/metabolism , CD47 Antigen/metabolism , CD47 Antigen/therapeutic use , Dendritic Cells/metabolism , Humans , Integrins/metabolism , Macrophages/metabolism , Neoplasms/metabolism , Neoplasms/therapy , Neutrophils/metabolism , Receptors, Immunologic/metabolism , Signal Transduction/genetics , Signal Transduction/immunology
13.
Anticancer Agents Med Chem ; 19(13): 1618-1626, 2019.
Article in English | MEDLINE | ID: mdl-31284876

ABSTRACT

BACKGROUND: Niclosamide is an FDA-approved and old anti-helminthic drug used to treat parasitic infections. Recent studies have shown that niclosamide has broad anti-tumor effects relevant to the treatment of cancer. However, this drug has a low aqueous solubility hindering its systemic use. Herein, we report the preparation and characterization of niclosamide nanoliposomes and their in vivo anti-tumor effects. METHODS: Nanoliposomes were prepared using thin-film method and the drug was encapsulated with a remote loading method. The nanoliposomes were investigated by the observation of morphology, analysis of particle size and zeta potential. Additionally, qualitative and quantitative analyses were performed using HPLC. We assessed the in vitro cytotoxicity of the nanoliposomal niclosamide on B16F10 melanoma cells. Inhibition of tumor growth was investigated in C57BL/6 mice bearing B16F0 melanoma cancer. RESULTS: Analytical results indicated that the nanoliposomal system is a homogeneous and stable colloidal dispersion of niclosamide particles. Atomic force microscopy images and particle size analysis revealed that all niclosamide particles had a spherical shape with a diameter of approximately 108nm. According to in vitro and in vivo studies, nanoliposomal niclosamide exhibited a better anti-tumor activity against B16F10 melanoma tumor compared with free niclosamide. CONCLUSION: Nanoliposomal encapsulation enhanced the aqueous solubility of niclosamide and improved its anti-tumor properties.


Subject(s)
Antineoplastic Agents/administration & dosage , Drug Carriers , Liposomes , Melanoma, Experimental/drug therapy , Nanostructures , Niclosamide/administration & dosage , Animals , Antineoplastic Agents/pharmacokinetics , Cell Line, Tumor , Drug Compounding , Male , Mice , Mice, Inbred C57BL , Niclosamide/pharmacokinetics , Tumor Microenvironment
14.
J Cell Physiol ; 234(3): 2329-2336, 2019 03.
Article in English | MEDLINE | ID: mdl-30191994

ABSTRACT

The hypoxic niche of tumor leads to a tremendous increase in the extracellular adenosine concentration through alteration of adenosine metabolism in the tumor microenvironment (TME). This consequently affects cancer progression, local immune responses, and apoptosis of tumor cells. Regulatory effect of adenosine on apoptosis in TME depends on the cancer cell type, pharmacological characteristics of adenosine receptor subtypes, and the adenosine concentration in the tumor niche. Exploiting specific pharmacological adenosine receptor agonist and antagonist inducing apoptosis in cancer cells can be considered as a proper procedure to control cancer progression. This review summarizes the regulatory role of adenosine in cancer cell apoptosis for a better understanding, and hence better management of the disease.


Subject(s)
Neoplasms/drug therapy , Purinergic P1 Receptor Agonists/therapeutic use , Purinergic P1 Receptor Antagonists/therapeutic use , Receptors, Purinergic P1/genetics , Adenosine Triphosphate/genetics , Apoptosis/drug effects , Neoplasms/genetics , Neoplasms/pathology , Signal Transduction/drug effects , Tumor Microenvironment/drug effects
15.
J Cell Physiol ; 233(10): 6951-6964, 2018 10.
Article in English | MEDLINE | ID: mdl-29741759

ABSTRACT

Atherosclerosis is a systemic disease characterized by the deposition of cholesterol and inflammatory cells within the arterial wall. Removal of cholesterol from the vessel wall may have an impact on the size and composition of atherosclerotic lesions. Anionic phospholipids or liposome vesicles composed of a lipid bilayer such as nanoliposomes have been suggested as treatments for dyslipidemia. In this study, we investigated the effect of anionic nanoliposomes on atherosclerosis in a mouse model. Low-density lipoprotein receptor knockout mice (Ldlr-/- ) were fed with an atherosclerosis promoting high fat and cholesterol (HFC) diet for 12 weeks. Anionic nanoliposomes including hydrogenated soy phosphatidylcholine (HSPC) and distearoyl phosphatidylglycerol (DSPG) (molar ratio: 1:3) were injected intravenously into HFC-fed Ldlr-/- mice once a week for 4 weeks. Mice receiving nanoliposomes had significantly reduced atherosclerosis within the aortic arch as assessed by Sudan IV staining area (p = 0.007), and reduced intima/media ratio (p = 0.030) and greater collagen deposition within atherosclerosis plaques within the brachiocephalic artery (p = 0.007), compared to control mice. Administration of nanoliposomes enhanced markers of reverse cholesterol transport (RCT) and increased markers of plaque stability in HFC-fed Ldlr-/- mice. Reduced cholesterol accumulation was observed in the liver along with the up-regulation of the major genes involved in the efflux of cholesterol such as hepatic ATP-binding cassette transporters (ABC) including Abc-a1, Abc-g1, Abc-g5, and Abc-g8, Scavenger receptor class B, member 1 (Scarb1), and Liver X receptor alpha (Lxr)-α. Lecithin Cholesterol Acyltransferase activity within the plasma was also increased in mice receiving nanoliposomes. Anionic nanoliposome administration reduced atherosclerosis in HFC-fed Ldlr-/- mice by promoting RCT and upregulating the ABC-A1/ABC-G1 pathway.


Subject(s)
Atherosclerosis/drug therapy , Cholesterol/metabolism , Diet, High-Fat , Receptors, LDL/deficiency , ATP-Binding Cassette Transporters/metabolism , Animals , Atherosclerosis/genetics , Biological Transport/drug effects , Liver/metabolism , Mice, Inbred C57BL , Mice, Knockout , Plaque, Atherosclerotic/drug therapy , Receptors, LDL/metabolism
16.
J Cell Physiol ; 233(4): 2815-2823, 2018 04.
Article in English | MEDLINE | ID: mdl-28475219

ABSTRACT

Cell therapy is an emerging fields in the treatment of various diseases such as cardiovascular, pulmonary, hepatic, and neoplastic diseases. Stem cells are an integral tool for cell therapy. Multipotent stem cells are an important class of stem cells which have the ability to self-renew through dividing and developing into multiple specific cell types in a specific tissue or organ. These cells are capable to activate or inhibit a sequence of cellular and molecular pathways leading to anti-inflammatory and anti-apoptotic effects which might contribute to the treatment of various diseases. It has been showed that multipotent stem cells exert their therapeutic effects via inhibition/activation of a sequence of cellular and molecular pathways. Although the advantages of multipotent stem cells are numerous, further investigation is still necessary to clarify the biology and safety of these cells before they could be considered as a potential treatment for different types of diseases. This review summarizes different features of multipotent stem cells including isolation, differentiation, and therapeutic applications.


Subject(s)
Multipotent Stem Cells/cytology , Multipotent Stem Cells/transplantation , Stem Cell Transplantation , Animals , Cell Separation , Clinical Trials as Topic , Humans , Neoplasms/therapy
17.
J Cell Biochem ; 119(6): 4251-4264, 2018 06.
Article in English | MEDLINE | ID: mdl-29243841

ABSTRACT

Solid lipid nanoparticles (SLNs), as alternative colloidal carriers, have been used for the sustained release of lipophilic drugs with poor water solubility. One of the most important parameters in the characterization of SLNs is entrapment efficiency (EE). Despite the importance of this factor in estimating the drug loading capacity, EE does not always represent the exact percentage of the entrapped drug. Several variables such as the stirring speed and duration, and concentration of surfactant, emulsifier, and drug play important roles in determining the final EE. In addition, EE is mainly affected by the type and concentration of the lipid. There are two major methods for the measurement of EE are in which the encapsulated drug in SLNs is either directly measured (direct method) or the amount of unencapsulated drug in the supernatant is measured (indirect method). Accuracy of drug analysis is the main challenge for EE calculation, and is either performed in the separated aqueous medium or the particles. In this review, we aimed to introduce the available methods for EE determination in SLNs and discuss the advantages and shortcomings of each method.


Subject(s)
Lipids/chemistry , Lipids/therapeutic use , Nanocapsules/chemistry , Nanocapsules/therapeutic use , Animals , Humans
18.
J Cell Physiol ; 233(4): 2949-2965, 2018 04.
Article in English | MEDLINE | ID: mdl-28608549

ABSTRACT

Angiogenesis is known as one of the hallmarks in cancer which could play a key role in providing oxygen and nutrients for tumor cells. It has been shown that tumor cannot grow without sufficient development of new blood vessels. Accordingly, targeting angiogenesis, especially endothelial cells, could be considered as a common therapeutic target in tumors and more investigation on already existing biomarkers and potentially new biomarkers of endothelial cells seems to be necessary in cancer therapy. Moreover, the use of effective targeting approaches such as proteins and peptides, aptamers, and small molecules is an important step for targeting biomarkers associated with endothelial cells and angiogenesis in cancer therapy. These agents are FDA approved, or are currently under investigation in pre-clinical and clinical studies. Among various biomarkers for angiogenesis microRNAs are suitable candidates for target therapy. These molecules play key roles in tumor angiogenesis which exert their effect via targeting a variety of cellular and molecular pathways involved in tumor angiogenesis. Here, we summarize a variety of biomarkers which their expressions or their functions could change the function of endothelial cells in tumor microenvironments. Moreover, we highlighted various therapeutic agents which could target these biomarkers.


Subject(s)
Biomarkers, Tumor/metabolism , Neoplasms/blood supply , Neovascularization, Pathologic/metabolism , Animals , Humans , Ligands , Neoplasm Proteins/metabolism , Signal Transduction
19.
Article in English | MEDLINE | ID: mdl-28630182

ABSTRACT

1,2-Distigmasterylhemisuccinoyl-sn-glycero-3-phosphocholine (DSHemsPC) is a new lipid in which two molecules of stigmasterol (an inexpensive plant sterol) are covalently linked via a succinic acid to glycerophosphocholine. Our previous study revealed that liposome (Lip)-intercalated amphotericin B (AMB) prepared from DSHemsPC (DSHemsPC-AMB-Lip) possesses excellent colloidal properties and in vitro antifungal and antileishmanial activities similar to those of the liposomal AMB preparation AmBisome. The aim of this study was to determine the biodistribution and evaluate the antileishmanial effects of DSHemsPC-AMB-Lip in Leishmania major-infected BALB/c mice. The serum profile and tissue concentrations of AMB were similar in DSHemsPC-AMB-Lip- and AmBisome-treated mice after intravenous (i.v.) injection. Multiple i.v. doses of the micellar formulation of AMB (Fungizone; 1 mg/kg of body weight), DSHemsPC-AMB-Lip (5 mg/kg), and AmBisome (5 mg/kg) were used in L. major-infected BALB/c mouse models of early and established lesions. In a model of the early lesions of cutaneous leishmaniasis (CL), the results indicated that the level of footpad inflammation was significantly (P < 0.001) lower in mice treated with DSHemsPC-AMB-Lip and AmBisome than mice treated with empty liposomes or 5% dextrose. The splenic and footpad parasite load was also significantly (P < 0.001) lower in these groups of mice than in control mice that received 5% DW or free liposome. The in vivo activity of DSHemsPC-AMB-Lip was comparable to that of AmBisome, and both provided improved results compared to those achieved with Fungizone at the designated doses. The results suggest that systemic DSHemsPC-AMB-Lip administration may be useful for the treatment of leishmaniasis, and because it costs less to produce DSHemsPC-AMB-Lip than AmBisome, DSHemsPC-AMB-Lip merits further investigation.


Subject(s)
Amphotericin B/pharmacokinetics , Amphotericin B/therapeutic use , Antiprotozoal Agents/therapeutic use , Leishmania major/drug effects , Leishmaniasis, Cutaneous/drug therapy , Phosphatidylcholines/pharmacokinetics , Phosphatidylcholines/therapeutic use , Stigmasterol/analogs & derivatives , Animals , Antiprotozoal Agents/pharmacokinetics , Disease Models, Animal , Drug Administration Routes , Drug Carriers/therapeutic use , Female , Leishmania major/pathogenicity , Leishmaniasis, Cutaneous/parasitology , Liposomes/therapeutic use , Mice , Mice, Inbred BALB C , Parasite Load , Spleen/parasitology , Stigmasterol/pharmacokinetics , Stigmasterol/therapeutic use
20.
Curr Med Chem ; 23(5): 455-63, 2016.
Article in English | MEDLINE | ID: mdl-26674785

ABSTRACT

Melanoma is a leading cause of mortality from skin cancer and has a poor prognosis. Despite rapid advances in the treatment of this tumor type, the efficacy of current chemo-/targeted-therapies is still limited owing to the lack of sufficient drug accumulation in the tumor tissue and development of chemo-resistance. Recently, the application of mesenchymal stem cells (MSCs) in cancer therapy has gained substantial attention, suggesting their potential roles as an intriguing vehicle in improving the delivery of targeted agents. MSCs are genetically modified with suicide tumor suppressor genes to inhibit cell signaling pathways associated with the progression and metastatic features of melanoma. Here we describe the clinical application of MSCs in melanoma with a particular emphasis on recent findings on the role of MSC expressing a distinct set of biologically functional chemokines and tumor suppressing agents. Accumulating data has shown the tumor- oriented homing capacity of MSCs and their applications as a vehicle (e.g., adipose derived mesenchymal stem cells expressing TRAIL, interferon-α/γ, pigment epithelium-derived factor and cytosine deaminase). Several questions regarding possible potential and intrinsic mechanisms that might induce tumorigenesis and drug resistance are yet to be addressed for tailoring MSC-nbased treatment of melanoma.


Subject(s)
Cell- and Tissue-Based Therapy/methods , Drug Carriers/metabolism , Melanoma/therapy , Mesenchymal Stem Cells/metabolism , Cytokines/metabolism , Humans , Melanoma/metabolism , Melanoma/pathology
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