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Cancer is the second most fatal disease among women. In recent years, utilizing strategies based on carbon quantum dots (CQDs) as targeted drug delivery systems has had a significant impact on advancing and improving cancer treatment. This study is focused on the development of a nanocarrier, based on CQDs, for improving the therapeutic efficiency of mitoxantrone (MTX). Hence, the N-doped CQDs were synthesized by a hydrothermal method. Following its purification, MTX was loaded to the CQD, resulting in an increase in the size from 36.78 ± 0.9 nm to 157.8 ± 12.18 nm, with an ideal drug entrapment efficiency of 97 %. Drug release investigation showed a pH-dependent improvement, from 8 % at pH 7.4 to 11 % at pH 5.2 after 48 h. Based on the Methylthiazolyldiphenyl-tetrazolium bromide (MTT) results after 5 h of treatment on MCF-7 breast cancer cells, the N-doped CQD showed no significant effect on the cancer cells, whereas a half maximal Inhibitory Concentration (IC50) was achieved with the N-doped CQD-MTX complex at a concentration between 0.5 to 0.8 µM. Therefore, the newly developed drug delivery complex was capable of providing a rather identical influence on MCF-7 cells, as the free MTX, however, improving the pharmacokinetic of the drug by its controlled and on-target drug release, due to an alteration in distribution and absorption parameters.
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In recent decades, scientific and medical communities have continuously sought new methods and chemistries to improve the treatment of cancer. Among many types of nanoparticles considered as carriers for drug delivery, the protein ones count among the safest. The present study aimed to investigate the physicochemical and biological effects of the supplementation of albumin nanoparticles with doxorubicin (DOX). DOX was co-precipitated with albumin in a desolvation process and entrapped inside the cross-linked albumin nanoparticles, where it disrupted the protein structure at various levels: (a) it reduced the particle size distribution homogeneity; (b) it extended the peptide bond length; (c) it lowered the thermal stability of albumin; (d) it lowered the crystallinity of the protein. Physicochemical mechanisms underlying these changes are discussed. The drug release was incomplete under the physiological conditions, but the nanoparticles fully released their chemotherapeutic payload when pH was decreased by a single unit from the physiological value. Because the extracellular pH of tumors is usually by a single pH unit lower than that of healthy tissues, this environmentally responsive drug delivery system composed of albumin nanoparticles may be applicable in the targeting of cancer cells. In vitro assays against human lung cancer cells demonstrated that DOX released from albumin nanoparticles had a four times higher apoptotic activity than the equivalent concentration of free DOX. The ability of albumin to prevent the agglomeration of partially hydrophobic DOX and release it at a sustained, zero-order rate over the first 12 h of incubation, with no burst effect, explains this ability to augment the activity of DOX against the lung cancer cells.
Assuntos
Neoplasias Pulmonares , Nanopartículas , Albuminas , Linhagem Celular Tumoral , Doxorrubicina/química , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Pulmonares/metabolismo , Nanopartículas/químicaRESUMO
Chemical coupling of polyethylene glycol (PEG) to proteins or particles (PEGylation), prolongs their circulation half-life by greater than 50-fold, reduces their immunogenicity, and also promotes their accumulation in tumors due to enhanced permeability and retention effect. Herein, phase separation method was used to prepare bovine serum albumin (BSA) nanoparticles. PEGylation of BSA nanoparticles was performed by SPA activated mPEG through their free amino groups. Effect of process variables on PEGylation efficiency of BSA nanoparticles was investigated and optimized through response surface methodology with the amount of free amino groups as response. Optimum conditions was found to be 32.5 g/l of PEG concentration, PEG-nanoparticle incubation time of 10 min, incubation temperature of 27°C, and pH of 7 for 5 mg of BSA nanoparticles in 1 mL phosphate buffer. Analysis of data showed that PEG concentration had the most noticeable effect on the amount of PEGylated amino groups, but pH had the least. Mean diameter and zeta potential of PEGylated nanoparticles under these conditions were 217 nm and -14 mV, respectively. In conclusion, PEGylated nanoparticles demonstrated reduction of the negative surface charge compared to the non modified particles with the zeta potential of -31.7 mV. Drug release from PEGylated nanoparticles was almost slower than non-PEGylated ones, probably due to existence of a PEG layer around PEGylated particles which makes an extra resistance in opposition to drug diffusion.
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Técnicas de Química Combinatória/métodos , Portadores de Fármacos/síntese química , Nanopartículas/química , Polietilenoglicóis/química , Soroalbumina Bovina/química , Animais , Bovinos , Composição de Medicamentos/métodos , Tamanho da PartículaRESUMO
Separation of tumor cells is a promising approach that helps not only in early detection of cancer but also as an efficient tool that holds great importance in prohibiting cancer cell mutation, drug resistance to treatments, and in granting successful adjuvant therapies. As one of the highly efficient processes for the separation of single cells, tumor cells, and specific proteins from fresh whole blood, a magnetic iron oxide nanoparticle (IONP)-based immunomagnetic separation technique has been developed in this article. The synthesized IONPs were modified with antibodies (Abs) against human epithelial growth factor receptor 2 (HER2), which is overexpressed and/or amplified in about 15% of breast cancer patients with several types of human cancer cells. The prepared Ab-conjugated IONPs (Ab-IONPs) attach HER2-positive cancer cells exclusively and can serve as specific high-efficient single-cell separation agents. The results showed that the magnetic IONPs have been successfully attached to the Abs via 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide/N-hydroxysuccinimide linkers. Maximum targeting efficiency of the Ab-IONP complex, which was 94.5 ± 0.8% for BT474 and 70.6 ± 0.4% for mixture of cells (BT474 and MCF7), was achieved with a minimum amount of Abs, to provide an economically efficient single-cell detection device.
Assuntos
Anticorpos Antineoplásicos/química , Separação Celular/métodos , Nanopartículas de Magnetita , Animais , Especificidade de Anticorpos , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Estabilidade de Medicamentos , Feminino , Humanos , Imunotoxinas , Tamanho da Partícula , Receptor ErbB-2/genéticaRESUMO
Modification of recombinant proteins with polyethylene-glycol (PEG) can improve their pharmacokinetic properties, although their bioactivity may be reduced after PEGylation due to structural changes. In this study, simultaneous optimization of PEGylation efficiency and preserved bioactivity of recombinant human growth hormone (rhGH) was investigated. In this regard, experiments were designed by the response surface methodology (RSM)-central composite design (CCD) utilizing design expert software. Under the obtained optimum conditions of 6.73 molar ratio of PEG to protein and pH 7.71 as the main factors affect the process, 54% PEGylation efficiency and 63% preserved bioactivity can be achieved. Based on the ANOVA table, model F-values equal to 31.16 and 20.8 for PEGylation efficiency and preserved bioactivity, respectively, demonstrated the validity and importance of the models. High performance liquid chromatography (HPLC) and gel electrophorese analyses verified the purity of the PEGylated form of rhGH. Findings showed that the modified protein would be stable for six months at 4⯰C. In vitro cell growth assessments revealed Nb2-11 cell proliferation during 48â¯h, although proliferation rate decrease with the increase of PEGylated rhGH concentration. Half-life prolongation in serum observed for PEGylated form in comparison with the non-modified one on in vivo. In overall, the results are promising for the utilization of the PEGylated form of rhGH for the treatment of human growth deficiency after further investigations.
Assuntos
Hormônio do Crescimento Humano , Polietilenoglicóis , Animais , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Desenho de Fármacos , Hormônio do Crescimento Humano/administração & dosagem , Hormônio do Crescimento Humano/sangue , Hormônio do Crescimento Humano/química , Hormônio do Crescimento Humano/farmacocinética , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Ratos Sprague-Dawley , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/sangue , Proteínas Recombinantes/química , Proteínas Recombinantes/farmacocinéticaRESUMO
Harvesting involves nearly thirty percent of total production cost of microalgae that needs to be done efficiently. Utilizing inexpensive and highly available biopolymer-based flocculants can be a solution for reducing the harvest costs. Herein, flocculation process of Chlorella vulgaris microalgae using cationic starch nanoparticles (CSNPs) was evaluated and optimized through the response surface methodology (RSM). pH, microalgae and CSNPs concentrations were considered as the main independent variables. Under the optimum conditions of microalgae concentration 0.75gdry weight/L, CSNPs concentration 7.1mgdry weight/L and pH 11.8, the maximum flocculation efficiency (90%) achieved. Twenty percent increase in flocculation efficiency observed with the use of CSNPs instead of the non-particulate starch which can be due to the more electrostatic interactions between the cationic nanoparticles and the microalgae. Therefore, the synthesized CSNPs can be employed as a convenient and economical flocculants for efficient harvest of Chlorella vulgaris microalgae at large scale.
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Chlorella vulgaris , Nanopartículas , Amido , Chlorella , Floculação , MicroalgasRESUMO
Non-specific distribution of chemotherapeutic agents in the body where they affect both cancer as well as normal cells resulting in serious side effects is the major reason for the high mortality rate of cancer. Thus, there is a need for developing targeted delivery strategies specially employing nanoplatform-based cancer therapies that provide specific targeting to tumor cells. In this regard, biopolymeric nanoplatforms such as liposomes, protein- and polysaccharide- based nanoparticles have gained more attention due to their biocompatibility, biodegradability and less toxicity. In terms of targeting, monoclonal antibodies (mAbs), folic acid (FA) and transferrin (Tf) can be considered as the moieties to be attached to the nanoplatforms to deliver their payload to its site of action. This review article focuses on the recent progress in the field of targeted drug and gene delivery systems with emphasizes on liposomes, protein (specially human and bovine serum albumin)-based nanoparticles and polysaccharide (specially chitosan and dextran)-based nanoparticles as the biopolymeric nanoplatforms, which are decorated with mAbs, FA and Tf as the targeting ligands.
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Antineoplásicos/administração & dosagem , Biopolímeros/administração & dosagem , Sistemas de Liberação de Medicamentos/tendências , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Animais , Antineoplásicos/metabolismo , Biopolímeros/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Humanos , Ligantes , Nanopartículas/metabolismo , Neoplasias/metabolismo , Resultado do TratamentoRESUMO
Nanotherapeutics has the potential of providing limitless opportunities in the area of drug and gene delivery for treatment of cancer. Although the path toward commercialization of nanoparticulate oncology drugs is long and carries significant risks, there is still considerable excitement for utilizing nanoparticle technologies in cancer drug development. Recently, there has been a significant growth in the number of nanoparticle delivery systems, used in clinical trials. Several incorporations have been established between pharmaceutical and nanotechnology companies striving to understand, develop and utilize effective interactions between nanomaterials and biological systems for cancer treatment by means of colloidal delivery systems. Protein-based nanoparticles, with one already approved and several under-development products in the commercial market, are of the pioneers of the successful employment of nanoparticulate systems in improving the cancer treatment techniques. The main reason behind the widely tendency to the usage of protein-based systems is their possibility of functionalization, biocompatibility, nonimmunogenicity, and high loading capacity for both hydrophobic and hydrophilic therapeutics. The aim of this review is to provide a comprehensive overview on the most recent findings in the area of utilization of protein-based nanoparticles for delivery of anticancer agents, as well as interpretation of the challenges encountered in the field.
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Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Proteínas/química , Animais , Antineoplásicos/química , Humanos , Nanomedicina , Nanopartículas/químicaRESUMO
Albumin nanoparticles are one of the most important drug carriers for the delivery of therapeutic drugs, especially for the treatment of malignancies. This potential is due to their high binding capacity for both hydrophobic and hydrophilic drugs and the possibility of surface modification. Accumulation of albumin-bound drugs in the tumor interstitium occurs by the enhanced permeability and retention effect, which is also facilitated by the 60-kDa glycoprotein transcytosis pathway and binding to secreted protein, acidic and rich in cysteine located in the tumor extracellular matrix. In addition, specific ligands such as monoclonal antibodies, folic acid, transferrin, and peptides can be conjugated to the surface of albumin nanoparticles to actively target the drug to its site of action. The albumin-bound paclitaxel, Abraxane, is one of the several therapeutic nanocarriers that have been approved for clinical use. By the development of Abraxane that demonstrates a higher response rate and improved tolerability and therapeutic efficiency in comparison with solvent-based formulation, and with consideration of its commercial success, albumin is attracting the interest of many biotechnological and pharmaceutical companies. This chapter explores the current targeted and nontargeted albumin-based nanoparticles that are in various stages of development for the delivery of therapeutic agents in order to enhance the efficacy of cancer treatment.
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Paclitaxel Ligado a Albumina/uso terapêutico , Albuminas/química , Antineoplásicos/uso terapêutico , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Paclitaxel Ligado a Albumina/química , Anticorpos Monoclonais/química , Anticorpos Monoclonais/metabolismo , Antineoplásicos/química , Ensaios Clínicos como Assunto , Matriz Extracelular/química , Matriz Extracelular/metabolismo , Ácido Fólico/química , Ácido Fólico/metabolismo , Humanos , Interações Hidrofóbicas e Hidrofílicas , Terapia de Alvo Molecular , Nanopartículas/ultraestrutura , Neoplasias/metabolismo , Neoplasias/patologia , Paclitaxel/química , Paclitaxel/uso terapêutico , Transferrina/química , Transferrina/metabolismoRESUMO
Herein, 1F2, an anti-HER2 monoclonal antibody (mAb), was covalently coupled to the surface of 5-Fluorouracil (5-FU) loaded bovine serum albumin (BSA) nanoparticles. Concerning two different crosslinkers for conjugation of 1F2, Maleimide-poly (ethylene glycol)-Succinimidyl carbonate (Mal-PEG5000-NHS) was selected due to its higher conjugation efficiency (23 ± 4%) obtained in comparison to N-succinimidyl 3-(2-Pyridyl Dithio) Propionate (SPDP) (8 ± 2%). A slight increase in the average particle size with a negligible prolongation of the 5-FU release was observed after 1F2 coupling. The 1F2-coupled 5-FU-loaded BSA nanoparticles interacted with nearly all HER2 receptors available on the surface of HER2-positive SKBR3 cells. No cellular uptake was observed for HER2-negative MCF7 cells. Physicochemical and biological properties of the mAb-modified nanoparticles did not significantly alter after three months of storage at room temperature. The in-vitro cytotoxicity evaluation by MTT assay, demonstrated lower SKBR3 viability (50.7 ± 9 %) after 5 hours contact with 1F2-coupled 5-FU-loaded BSA nanoparticles in comparison with the other control systems due to their cell attachment and internalization after washing. In addition, no significant toxicity was observed on MCF7 cells. This novel system can efficiently be employed for targeted delivery of 5-FU to HER2-positive cancerous cells.
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Human serum albumin (HSA) nanoparticles represent an attractive strategy for active targeting of therapeutics into tumor cells due to the presence of superficial functional groups. HER2 is highly expressed in a significant proportion of cancers and monoclonal antibodies (mAbs) directed against HER2 hold great promise for effective therapy. Herein, covalent coupling of a novel mAb (1F2) directed against the extracellular domain of HER2 to the surface of HSA nanoparticles was evaluated to obtain nanoparticles with highest cellular uptake. HER2 reactivity of 1F2-conjugated nanoparticles produced under different conditions was screened by an indirect ELISA and flow cytometry techniques. Monoclonal antibody thiolation with 100-fold molar excess of 2-iminothiolane and the ratio of 10:1 for the thiolated 1F2 (µg) to PEGylated nanoparticles (mg), were optimum for the attachment process. Under this condition, 23±4% of 1F2 was conjugated to nanoparticles. The flow cytometry results show that 1F2-modified nanoparticles interact with nearly all HER2 receptors on the surface of BT474 cells. In addition, no cellular uptake was observed on MCF7 cells. In vitro analyses showed no significant cytotoxicity of produced system against BT474 cells. Therefore, 1F2-attached HSA nanoparticles represent a potential delivery system for targeted transport of therapeutic agents into HER2-positive tumor cells.
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Anticorpos Monoclonais/química , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Polietilenoglicóis/química , Receptor ErbB-2/imunologia , Albumina Sérica/química , Anticorpos Monoclonais/administração & dosagem , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Estabilidade de Medicamentos , Humanos , Nanopartículas/administração & dosagem , Tamanho da PartículaRESUMO
With PR81 as a murine monoclonal antibody (mAb) that was prepared against the human breast cancer, the MUC1 receptor specific targeting is possible. In this study, PR81-conjugated bovine serum albumin (BSA) nanoparticles loaded with anticancer drug 5-fluorouracil (5-FU) were developed. Enzyme linked immunosorbant assay (ELISA) results showed high immunoreactivity of PR81 mAb conjugated to nanoparticles towards MUC1 related peptide or native cancerous MUC1 and almost no cross-reaction to non-specific proteins. In vitro experiments were performed to determine the ability of this new drug delivery system on overcoming MCF-7 breast cancer cells in comparison with four other systems. The results revealed that these cell-type specific drug loaded nanoparticles could achieve more cell death as compared to when the 5-FU was used with no carriers. Stability studies of produced drug delivery system proved high immunoreactivity of conjugated PR81 even after 11 days of storage in room temperature.