RESUMO
Docetaxel (DTX) has become widely accepted as a first-line treatment for metastatic breast cancer; however, the frequent development of resistance provides challenges in treating the disease.C60 fullerene introduces a unique molecular form of carbon, exhibiting attractive chemical and physical properties. Our study aimed to develop dicarboxylic acid-derivatized C60 fullerenes as a novel DTX delivery carrier. This study investigated the potential of water-soluble fullerenes to deliver the anti-cancer drug DTX through a hydrophilic linker. The synthesis was carried out using the Prato reaction. The spectroscopic analysis confirmed the successful conjugation of DTX molecules over fullerenes. The particle size of nanoconjugate was reported to be 122.13 ± 1.63 nm with a conjugation efficiency of 76.7 ± 0.14%. The designed conjugate offers pH-dependent release with significantly less plasma pH, ensuring maximum release at the target site. In-vitro cell viability studies demonstrated the enhanced cytotoxic nature of the developed nanoconjugate compared to DTX. These synthesized nanoscaffolds were highly compatible with erythrocytes, indicating the safer intravenous route administration. Pharmacokinetic studies confirmed the higher bioavailability (~ 6 times) and decreased drug clearance from the system vis-à-vis plain drug. The histological studies reveal that nanoconjugate-treated tumour cells exhibit similar morphology to normal cells. Therefore, it was concluded that this developed formulation would be a valuable option for clinical use.
Assuntos
Antineoplásicos , Neoplasias da Mama , Ácidos Carboxílicos , Sobrevivência Celular , Docetaxel , Sistemas de Liberação de Medicamentos , Fulerenos , Fulerenos/química , Fulerenos/administração & dosagem , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Docetaxel/farmacologia , Docetaxel/química , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Humanos , Feminino , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Sistemas de Liberação de Medicamentos/métodos , Ácidos Carboxílicos/química , Tamanho da Partícula , Portadores de Fármacos/química , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Nanoconjugados/química , Ratos , Células MCF-7 , Disponibilidade BiológicaRESUMO
The clinical usage of docetaxel (DTX) is severely hindered by the dose-limiting neutropenia and peripheral neurotoxicity of polysorbate 80-solubilized DTX injection, and there are no alternative formulations until now. In this study, we developed a new liposomal formulation of DTX to reduce its toxicities, accompanying with the greatly improved antitumor activity. The DTX was encapsulated into liposomes in the form of hydrophilic glutathione (GSH)-conjugated prodrugs using a click drug loading method, which achieved a high encapsulation efficiency (â¼95 %) and loading capacity (â¼30 % wt). The resulting liposomal DTX-GSH provided a sustained and efficient DTX release (â¼50 % within 48 h) in plasma, resulting in a greatly improved antitumor activities as compared with that of polysorbate 80-solubilized DTX injection in the subcutaneous and orthotopic 4T1 breast tumor bearing mice. Even large tumors > 500 mm3 could be effectively inhibited and shrunk after the administration of liposomal DTX-GSH. More importantly, the liposomal DTX-GSH significantly decreased the neutropenia and peripheral neurotoxicity as compared with that of polysorbate 80-solubilized DTX injection at the equivalent dose. These data suggested that the liposomal DTX-GSH might become a superior alternative formulation to the commercial DTX injection.
Assuntos
Antineoplásicos , Docetaxel , Glutationa , Lipossomos , Camundongos Endogâmicos BALB C , Docetaxel/administração & dosagem , Docetaxel/farmacocinética , Docetaxel/farmacologia , Docetaxel/química , Animais , Camundongos , Glutationa/química , Feminino , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Pró-Fármacos/farmacologia , Taxoides/administração & dosagem , Taxoides/farmacologia , Taxoides/farmacocinética , Taxoides/química , Polissorbatos/química , Neutropenia/induzido quimicamente , Neutropenia/tratamento farmacológicoRESUMO
The high level of accumulation of therapeutic agents in tumors is crucial for cancer treatment. Compared to the passive tumor-targeting effect, active tumor-targeting delivery systems, primarily mediated by peptides with high production costs and reduced circulation time, are highly desired. Platelet-driven technologies have opened new avenues for targeted drug delivery prevalently through a membrane coating strategy that involves intricate manufacturing procedures or the fucoidan-mediated hitchhiking method with limited platelet affinity. Here, a novel type of amphiphilic glycopolymer self-assembled micellar nanoparticle has been developed to adhere to naturally activated platelets in the blood. The simultaneous integration of fucose and sialic acid segments into glycopolymers enables closer mimicry of the structure of P-selectin glycoprotein ligand-1 (PSGL-1), thereby increasing the affinity for activated platelets. It results in the formation of glycopolymeric micelle-platelet hybrids, facilitating targeted drug delivery to tumors. The selective platelet-assisted cellular uptake of docetaxel (DTX)-loaded glycopolymeric micelles leads to lower IC50 values against 4T1 cells than that of free DTX. The directed tumor-targeting effect of activated platelets has significantly improved the tumor accumulation capacity of the glycopolymeric nanoparticles, with up to 21.0% found in tumors within the initial 0.2 h. Additionally, with acid-responsive drug release and inherent antimetastasis properties, the glycopolymeric nanoparticles ensured potent therapeutic efficacy, prolonged survival time, and reduced cardiotoxicity, presenting a new and unexplored strategy for platelet-directed drug delivery to tumors, showing promising prospects in treating localized tumors and preventing tumor metastasis.
Assuntos
Plaquetas , Docetaxel , Micelas , Nanopartículas , Docetaxel/química , Docetaxel/farmacologia , Docetaxel/farmacocinética , Docetaxel/uso terapêutico , Animais , Plaquetas/metabolismo , Plaquetas/efeitos dos fármacos , Nanopartículas/química , Camundongos , Linhagem Celular Tumoral , Antineoplásicos/química , Antineoplásicos/farmacologia , Camundongos Endogâmicos BALB C , Humanos , Feminino , Sistemas de Liberação de Medicamentos , Portadores de Fármacos/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Neoplasias/metabolismoRESUMO
Myeloid cell leukemia 1 (Mcl-1) is a key regulator of the intrinsic apoptosis pathway. Overexpression of Mcl-1 is correlated with high tumor grade, poor survival, and both intrinsic and acquired resistance to cancer therapies. Herein, we disclose the structure-guided design of a small molecule Mcl-1 inhibitor, compound 26, that binds to Mcl-1 with subnanomolar affinity, inhibits growth in cell culture assays, and possesses low clearance in mouse and dog pharmacokinetic (PK) experiments. Evaluation of 26 as a single agent in Mcl-1 sensitive hematological and solid tumor xenograft models resulted in regressions. Co-treatment of Mcl-1-sensitive and Mcl-1 insensitive lung cancer derived xenografts with 26 and docetaxel or topotecan, respectively, resulted in an enhanced tumor response. These findings support the premise that pro-apoptotic priming of tumor cells by other therapies in combination with Mcl-1 inhibition may significantly expand the subset of cancers in which Mcl-1 inhibitors may prove beneficial.
Assuntos
Antineoplásicos , Proteína de Sequência 1 de Leucemia de Células Mieloides , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Proteína de Sequência 1 de Leucemia de Células Mieloides/antagonistas & inibidores , Proteína de Sequência 1 de Leucemia de Células Mieloides/metabolismo , Humanos , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapêutico , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Cães , Relação Estrutura-Atividade , Feminino , Descoberta de Drogas , Taxoides/farmacologia , Taxoides/farmacocinética , Taxoides/uso terapêutico , Taxoides/química , Docetaxel/farmacologia , Docetaxel/uso terapêutico , Docetaxel/farmacocinética , Docetaxel/químicaRESUMO
The invasion and metastasis of tumors pose significant challenges in the treatment of ovarian cancer (OC), making it difficult to cure. One potential treatment approach that has gained attention is the use of matrix metalloproteinase reactive controlled release micelle preparations. In this study, we developed a novel PEG5000-PVGLIG-hyaluronic acid docetaxel/bakuchiol (PP-HA-DTX/BAK) micelles formulation with desirable characteristics such as particle size, narrow polydispersity index, and a ZETA potential of approximately -5 mV. The surface modification with HA facilitates tumor penetration into the tumor interior, while the incorporation of DSPE-PEG2000-PVGLIG-PEG5000helps conceal DSPE-PEG2000-HA, reducing off-target effects and prolonging drug circulation timein vivo. Bothin vitroandin vivoexperiments demonstrated that these micelles effectively inhibit proliferation, invasion, and metastasis of OC cells while promoting apoptosis. Therefore, our findings suggest that PP-HA-DTX/BAK micelles represent a safe and effective therapeutic strategy for treating OC.
Assuntos
Docetaxel , Micelas , Invasividade Neoplásica , Neoplasias Ovarianas , Fenóis , Polietilenoglicóis , Docetaxel/química , Docetaxel/farmacologia , Docetaxel/administração & dosagem , Feminino , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/patologia , Humanos , Animais , Linhagem Celular Tumoral , Polietilenoglicóis/química , Fenóis/química , Fenóis/farmacologia , Camundongos , Apoptose/efeitos dos fármacos , Ácido Hialurônico/química , Taxoides/química , Taxoides/farmacologia , Taxoides/administração & dosagem , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Camundongos Nus , Tamanho da Partícula , Camundongos Endogâmicos BALB C , Metástase Neoplásica , Portadores de Fármacos/químicaRESUMO
Purpose: Docetaxel (DTX) is a valuable anti-tumor chemotherapy drug with limited oral bioavailability. This study aims to develop an effective oral delivery system for DTX using natural nanoparticles (Nnps) derived from Coptidis Rhizoma extract. Methods: DTX-loaded self-assembled nanoparticles (Nnps-DTX) were created using an optimized heat-induction strategy. Nnps-DTX's shape, size, Zeta potential, and in vitro stability were all carefully examined. Additionally, the study investigated the encapsulation efficiency, loading capacity, crystal form, and intermolecular interactions of DTX in Nnps-DTX. Subsequently, the solubility, release, cellular uptake, metabolic stability, and preclinical pharmacokinetics of DTX in Nnps-DTX were systematically evaluated. Finally, the cytotoxicity of Nnps-DTX was assessed in three tumor cell lines. Results: Nnps-DTX was spherical in shape, 138.6 ± 8.2 nm in size, with a Zeta potential of -20.8 ± 0.6 mV, a DTX encapsulation efficiency of 77.6 ± 8.5%, and a DTX loading capacity of 6.8 ± 1.9%. Hydrogen bonds, hydrophobic interactions, and electrostatic interactions were involved in the formation of Nnps-DTX. DTX within Nnps-DTX was in an amorphous form, resulting in enhanced solubility (23.3 times) and release compared to free DTX. Following oral treatment, the mice in the Nnps-DTX group had DTX peak concentrations 8.8, 23.4, 44.6, and 5.7 times higher in their portal vein, systemic circulation, liver, and lungs than the mice in the DTX group. Experiments performed in Caco-2 cells demonstrated a significant increase in DTX uptake by Nnps-DTX compared to free DTX, which was significantly inhibited by indomethacin, an inhibitor of caveolae-mediated endocytosis. Furthermore, compared to DTX, DTX in Nnps-DTX demonstrated better metabolic stability in liver microsomes. Notably, Nnps-DTX significantly reduced the viability of MCF-7, HCT116, and HepG2 cells. Conclusion: The novel self-assembled nanoparticles considerably enhanced the cellular absorption, solubility, release, metabolic stability, and pharmacokinetics of oral DTX and demonstrated strong cytotoxicity against tumor cell lines.
Assuntos
Docetaxel , Nanopartículas , Animais , Docetaxel/farmacocinética , Docetaxel/química , Docetaxel/farmacologia , Docetaxel/administração & dosagem , Humanos , Administração Oral , Nanopartículas/química , Medicamentos de Ervas Chinesas/farmacocinética , Medicamentos de Ervas Chinesas/química , Medicamentos de Ervas Chinesas/administração & dosagem , Medicamentos de Ervas Chinesas/farmacologia , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Camundongos , Linhagem Celular Tumoral , Coptis chinensis , Tamanho da Partícula , Masculino , Liberação Controlada de Fármacos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Disponibilidade Biológica , Solubilidade , Ratos Sprague-Dawley , Camundongos Endogâmicos BALB CRESUMO
INTRODUCTION: Esophageal cancer is one of the major cancers in China. Most patients with esophageal cancer are diagnosed at an advanced stage, and the 5 year survival rate is discouraging. Combined chemotherapy is a common method for the treatment of esophageal cancer. METHODS: In this study, distearoyl phosphatidyl ethanolamine polyethylene glycol 2000 (DSPE-PEG2000) nanoliposomes (NLPs) encapsulating the anticancer drugs docetaxel (DOX) and oridonin (ORD) were prepared, and their ability to enhance the release of anticancer drugs was determined. The NLP system was characterized by transmission electron microscopy, particle size and encapsulation efficiency. In addition, the release characteristics and pharmacodynamics of these drugs were also studied in detail. RESULTS: When the DOX/ORD ratio was 2:1, the higher proportion of DOX led to a stronger synergy effect. DOX/ORD NLPs were prepared by the high-pressure homogenization method and had a uniform spherical morphology. The mean particle size and polydispersity index were determined to be 246.4 and 0.163, respectively. The stability results showed that no significant change was observed in particle size, zeta potential, Encapsulation efficiency and dynamic light scattering for DOX/ORD NLPs during the observation period. The results of in vitro release illustrated that the acidic environment of tumor might be beneficial to drug release. The three-dimensional tumorsphere showed that DOX/ORD NLPs can reach the interior of tumor spheres, which destroys the structure of cells, resulting in irregular spherical tumor spheres. The in vivo study results indicated that DOX/ORD NLPs had an obvious targeting effect on subcutaneous tumors and have the potential to actively deliver drugs to tumor tissues. Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining was used to detect apoptosis. The results showed that DOX/ORD NLP treatment could significantly induce apoptosis and inhibit tumor growth. CONCLUSION: The DOX/ORD NLPs prepared in this study can enhance the anti-tumor activity, and are expected to be a promising co-delivery platform for the treatment of esophageal cancer.
Assuntos
Diterpenos do Tipo Caurano , Docetaxel , Neoplasias Esofágicas , Lipossomos , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/química , Diterpenos do Tipo Caurano/administração & dosagem , Neoplasias Esofágicas/tratamento farmacológico , Neoplasias Esofágicas/patologia , Docetaxel/farmacologia , Docetaxel/administração & dosagem , Docetaxel/química , Lipossomos/química , Animais , Humanos , Linhagem Celular Tumoral , Camundongos , Antineoplásicos/farmacologia , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Nanopartículas/química , Tamanho da Partícula , Ensaios Antitumorais Modelo de Xenoenxerto , Liberação Controlada de Fármacos , Sistemas de Liberação de Medicamentos/métodos , Camundongos Nus , Camundongos Endogâmicos BALB C , Sistemas de Liberação de Fármacos por Nanopartículas/químicaRESUMO
Background: Chemotherapeutic drugs have some drawbacks in antineoplastic therapy, mainly containing seriously toxic side effects caused by injection and multi-drug resistance (MDR). Co-delivery with two or more drugs via nanomicelles is a promising strategy to solve these problems. Oral chemotherapy is increasingly preferred owing to its potential to enhance the life quality of patients. Methods and Results: The study intended to develop mixed micelles using D-α-Tocopherol poly(ethylene glycol) 1000 succinate (TPGS) and soluplus for the co-encapsulation of docetaxel (DTX) and curcumin (CUR), marked as (DTX+CUR)-loaded mixed micelles, treating drug-resistant breast cancer by oral administration. The (DTX+CUR)-loaded mixed micelles had a uniform particle size (~64 nm), high drug loading and encapsulation efficiency, in vitro sustained-release properties and good pH-dependent stability. In vitro cell study, the (DTX+CUR)-loaded mixed micelles displayed the highest cellular uptake, cytotoxicity, cell apoptosis-inducing rates and cell ROS-inducing levels on MCF-7/Adr cells. Notably, in vivo pharmacokinetic studies, (DTX+CUR)-loaded mixed micelles enhanced markedly the oral absorption of DTX compared to pure DTX, with a relative oral bioavailability of 574%. The (DTX+CUR)-loaded mixed micelles by oral administration had the same anticancer efficacy as taxotere by injection in resistant breast cancer bearing mice. Conclusion: (DTX+CUR)-loaded mixed micelles could provide a potential formulation for treating drug-resistant breast cancers by oral administration.
Assuntos
Antineoplásicos , Neoplasias da Mama , Curcumina , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Micelas , Polietilenoglicóis , Curcumina/farmacocinética , Curcumina/química , Curcumina/administração & dosagem , Curcumina/farmacologia , Docetaxel/farmacocinética , Docetaxel/administração & dosagem , Docetaxel/química , Docetaxel/farmacologia , Humanos , Feminino , Animais , Neoplasias da Mama/tratamento farmacológico , Administração Oral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Células MCF-7 , Polietilenoglicóis/química , Polietilenoglicóis/farmacocinética , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Vitamina E/química , Vitamina E/administração & dosagem , Vitamina E/farmacocinética , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Polivinil/química , Polivinil/farmacocinética , Polivinil/administração & dosagem , Camundongos , Camundongos Endogâmicos BALB C , Tamanho da Partícula , Taxoides/farmacocinética , Taxoides/administração & dosagem , Taxoides/química , Taxoides/farmacologia , Liberação Controlada de Fármacos , Ratos Sprague-DawleyRESUMO
Morphological modulation in covalent organic frameworks (COFs) with particular emphasis on the correlation between structure and target applications in biomedical fields, is currently in its early stage of evolution. Herein, a multifunctional rattle-architecture imine-based COF with a mobile core of gold nanoparticles (Au NPs) and an outer polydopamine (PDA) shell, tailored for cancer treatment, has been developed to effectively integrate dual responsive release capabilities with the potential for multiple therapeutic applications. The engineered COF displays outstanding crystallinity, a suitable size and precisely controlled morphological characteristics. By leveraging COF and PDA attributes, the successful co-delivery of hydrophilic doxorubicin (DOX) and hydrophobic docetaxel (DTX) within discrete compartments is achieved responsive to both pH and near-infrared triggers. Designed nanocarrier outperforms prior COFs with a superior 83.7% DOX loading capacity, thanks to its expansive internal space and porous shell. Taking advantage of the inclusion of Au core and the concurrent presence of COF and PDA outer shells, the nanocarrier exhibits a significant photothermal-conversion capability. The rattle-architecture double-shelled Au@RCOF@PDA were functionalized with poly(ethylene glycol)-folic acid (PEG-FA) to confer the system with active-targeting capability and enhanced biocompatibility. Through in vitro and in vivo evaluations, the designed system demonstrates an exceptional synergistic anti-tumor effect, along with favorable biosafety and histocompatibility. This study not only sheds light on the remarkable merits offered by regulating the morphology of COF-based systems in cancer therapy but also highlights the potential for synergistic therapeutic approaches in advancing cancer treatment strategies.
Assuntos
Antineoplásicos , Docetaxel , Doxorrubicina , Ouro , Indóis , Estruturas Metalorgânicas , Terapia Fototérmica , Doxorrubicina/química , Doxorrubicina/farmacologia , Estruturas Metalorgânicas/química , Estruturas Metalorgânicas/farmacologia , Estruturas Metalorgânicas/síntese química , Humanos , Docetaxel/química , Docetaxel/farmacologia , Ouro/química , Ouro/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Animais , Indóis/química , Indóis/farmacologia , Polímeros/química , Polímeros/farmacologia , Camundongos , Ensaios de Seleção de Medicamentos Antitumorais , Tamanho da Partícula , Propriedades de Superfície , Nanopartículas Metálicas/química , Liberação Controlada de Fármacos , Sobrevivência Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Portadores de Fármacos/químicaRESUMO
Development of resistance to therapy-induced cell death is a major hurdle in the effective treatment of advanced solid tumors. Erastin and RSL3 were originally found to induce synthetic lethality by induction of a novel form of cell death termed ferroptosis. Emerging evidence suggests that ferroptosis inducers enhance chemosensitivity of classic therapeutic agents by triggering ferroptotic cell death. In this study we evaluated the effects of erastin and RSL3 on the resistance of docetaxel, doxorubicin, and cisplatin, and revealed a mechanism whereby these ferroptosis inducers augment docetaxel efficacy in non-small cell lung cancer by regulating redox signaling to promote ferroptosis. Transcriptome analysis revealed that combination treatment modulated not only p53 signaling pathway but also immune responses and several signaling pathways including MAPK, NF-κB and PI3K/Akt. Considering that glutathione peroxidase 4 (GPX4) serves as the main effector to protect cells from ferroptosis, this study identified three novel non-covalent GPX4 inhibitors with the aid of pharmacophore-based virtual screening. The new ferroptosis-inducing compounds synergized with docetaxel to increase the cytotoxicity by promoting ferroptotic cell death in docetaxel-resistant A549/DTX cells. Collectively, the induction of ferroptosis contributed to docetaxel-induced cytotoxic effects and overcame drug resistance in A549/DTX cells. Ferroptosis has a great potential to become a new approach to attenuate resistance to some classic therapeutic drugs in cancer patients.
Assuntos
Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Ferroptose , Neoplasias Pulmonares , Ferroptose/efeitos dos fármacos , Humanos , Docetaxel/farmacologia , Docetaxel/química , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/metabolismo , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/metabolismo , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Ensaios de Seleção de Medicamentos Antitumorais , Estrutura Molecular , Piperazinas/farmacologia , Piperazinas/química , Sinergismo Farmacológico , Relação Dose-Resposta a Droga , Relação Estrutura-Atividade , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/metabolismo , Fosfolipídeo Hidroperóxido Glutationa Peroxidase/antagonistas & inibidores , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , CarbolinasRESUMO
Innovation chemotherapeutic nano drug delivery systems (NDDSs) with various pharmacological achievement have become one of the hopeful therapeutic strategies in cancer therapy. This study focused on low pH, and high levels of glutathione (GSH) as two prominent characteristics of the tumor microenvironment (TME) to design a novel TME-targeted pH/redox dual-responsive P (AMA-co-DMAEMA)-b-PCL-SS-PCL-b-P (AMA-co-DMAEMA) nanoparticles (NPs) for deep tumor penetration and targeted anti-tumor therapy. The positively charged NPs exhibit strong electrostatic interactions with negatively charged cell membranes, significantly enhancing cellular uptake. Moreover, these NPs possess the unique size-shrinkable property, transitioning from 98.24 ± 27.78 to 45.56 ± 20.62 nm within the TME. This remarkable size change fosters an impressive uptake of approximately 100% by MDA-MB-231 cells within just 30 min, thereby greatly improving drug delivery efficiency. This size switchability enables passive targeting through the enhanced permeability and retention (EPR) effect, facilitating deep penetration into tumors. The NPs also demonstrate improved pH/redox-triggered drug release (â¼70% at 24 h) within the TME and exhibit no toxicity in cell viability test. The cell cycle results of treated cells with docetaxel (DTX)-loaded NPs revealed G2/M (84.6 ± 1.16%) arrest. The DTX-loaded NPs showed more apoptosis (62.6 ± 3.7%) than the free DTX (51.8 ± 3.2%) in treated cells. The western blot and RT-PCR assays revealed that apoptotic genes and proteins expression of treated cells were significantly upregulated with the DTX-loaded NPs vs. the free DTX (Pvalue<.001). In conclusion, these findings suggest that this novel-engineered NPs holds promise as a TME-targeted NDDS.
Assuntos
Docetaxel , Liberação Controlada de Fármacos , Nanopartículas , Oxirredução , Microambiente Tumoral , Concentração de Íons de Hidrogênio , Microambiente Tumoral/efeitos dos fármacos , Humanos , Docetaxel/química , Docetaxel/farmacologia , Linhagem Celular Tumoral , Nanopartículas/química , Portadores de Fármacos/química , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Taxoides/química , Taxoides/farmacologia , Taxoides/administração & dosagem , Taxoides/farmacocinética , Tamanho da Partícula , Apoptose/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacosRESUMO
Background: The commercial docetaxel (DTX) formulation causes severe side effects due to polysorbate 80 and ethanol. Novel surfactant-free nanoparticle (NP) systems are needed to improve bioavailability and reduce side effects. However, controlling the particle size and stability of NPs and improving the batch-to-batch variation are the major challenges. Methods: DTX-loaded bovine serum albumin nanoparticles (DTX-BSA-NPs) were prepared by a novel thermal-driven self-assembly/microfluidic technology. Single-factor analysis and orthogonal test were conducted to obtain the optimal formulation of DTX-BSA-NPs in terms of particle size, encapsulation efficiency (EE), and drug loading (DL). The effects of oil/water flow rate and pump pressure on the particle size, EE, and DL were investigated to optimize the preparation process of DTX-BSA-NPs. The drug release, physicochemical properties, stability, and pharmacokinetics of NPs were evaluated. Results: The optimized DTX-BSA-NPs were uniform, with a particle size of 118.30 nm, EE of 89.04%, and DL of 8.27%. They showed a sustained release of 70% over 96 hours and an increased stability. There were some interactions between the drug and excipients in DTX-BSA-NPs. The half-life, mean residence time, and area under the curve (AUC) of DTX-BSA-NPs increased, but plasma clearance decreased when compared with DTX. Conclusion: The thermal-driven self-assembly/microfluidic combination method effectively produces BSA-based NPs that improve the bioavailability and stability of DTX, offering a promising alternative to traditional formulations.
Assuntos
Disponibilidade Biológica , Docetaxel , Estabilidade de Medicamentos , Nanopartículas , Tamanho da Partícula , Soroalbumina Bovina , Docetaxel/farmacocinética , Docetaxel/química , Docetaxel/administração & dosagem , Animais , Soroalbumina Bovina/química , Soroalbumina Bovina/farmacocinética , Soroalbumina Bovina/administração & dosagem , Nanopartículas/química , Taxoides/farmacocinética , Taxoides/química , Taxoides/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/química , Antineoplásicos/administração & dosagem , Liberação Controlada de Fármacos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Ratos Sprague-Dawley , Masculino , Composição de Medicamentos/métodos , RatosRESUMO
Chemotherapeutic agents hold significant clinical potential in combating tumors. However, delivering these drugs to the tumor site for controlled release remains a crucial challenge. In this study, we synthesize and construct a glutathione (GSH) and acid dual-responsive bismuth-based nano-delivery platform (BOD), aiming for sonodynamic enhancement of docetaxel (DTX)-mediated tumor therapy. The bismuth nanomaterial can generate multiple reactive oxygen species under ultrasound stimulation. Furthermore, the loading of DTX to form BOD effectively reduces the toxicity of DTX in the bloodstream, ensuring its cytotoxic effect is predominantly exerted at the tumor site. DTX can be well released in high expression of GSH and acidic tumor microenvironment. Meanwhile, ultrasound can also promote the release of DTX. Results from bothin vitroandin vivoexperiments substantiate that the synergistic therapy involving chemotherapy and sonodynamic therapy significantly inhibits the growth and proliferation of tumor cells. This study provides a favorable paradigm for developing a synergistic tumor treatment platform for tumor microenvironment response and ultrasound-promoted drug release.
Assuntos
Antineoplásicos , Bismuto , Docetaxel , Glutationa , Microambiente Tumoral , Terapia por Ultrassom , Bismuto/química , Animais , Glutationa/metabolismo , Docetaxel/farmacologia , Docetaxel/química , Camundongos , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Linhagem Celular Tumoral , Terapia por Ultrassom/métodos , Espécies Reativas de Oxigênio/metabolismo , Neoplasias/terapia , Neoplasias/tratamento farmacológico , Camundongos Endogâmicos BALB C , Liberação Controlada de Fármacos , Nanopartículas/química , FemininoRESUMO
Docetaxel is one of the most effective and safe chemotherapy drugs according to the World Health Organization, but its clinical use has been discontinued due to its various side effects. To reduce these side effects, the amount of docetaxel drug should be kept at the most effective level, it should be monitored in body fluids. Due to the limitations of traditional analytical methods used for this purpose, such as expensive and low sensitivity, labor-intensive and time-consuming complex preliminary preparation, efficient methods are required for the determination of the docetaxel level in the body. The increasing demand for the development of personalized therapy has recently spurred significant research into biosensors for the detection of drugs and other chemical compounds. In this study, an electrochemical-based portable nanobiosensor system was developed for the rapid, low-cost, and sensitive determination of docetaxel. In this context, mg-p(HEMA)-IMEO nanoparticles to be used as nanobiosensor bioactive layer was synthesized, characterized, and docetaxel determination conditions were optimized. According to the results obtained, the developed nanobiosensor system can detect docetaxel with a sensitivity of 2.22 mg/mL in a wide calibration range of 0.25-10 mg/mL, in only 15 min, in mixed media such as commercially available artificial blood serum and urine. determined. We concluded that the developed nanobiosensor system can be successfully used in routine drug monitoring as a low-cost biomedical device capable of direct, rapid, and specific drug determination within the scope of personalized treatment, providing point-of-care testing.
Therapeutic drug monitoring on-site has the potential to significantly save healthcare expenditures while also improving patient outcomes.Chromatography's applicability as a routine procedure is restricted by its lack of standardization, expensive equipment, lengthy turnaround times, and labor-intensive sample preparation.Overcoming these drawbacks, nanobiosensors provide an inexpensive, user-friendly, on-site analytical approach to fully explore the possibilities of therapeutic drug monitoring.
Assuntos
Antineoplásicos , Técnicas Biossensoriais , Docetaxel , Monitoramento de Medicamentos , Nanopartículas , Neoplasias , Medicina de Precisão , Docetaxel/farmacologia , Docetaxel/química , Monitoramento de Medicamentos/instrumentação , Monitoramento de Medicamentos/métodos , Técnicas Biossensoriais/instrumentação , Humanos , Neoplasias/tratamento farmacológico , Antineoplásicos/sangue , Nanopartículas/química , Nanotecnologia , Técnicas Eletroquímicas/instrumentação , Técnicas Eletroquímicas/métodosRESUMO
BACKGROUND: Low-dose chemotherapy is a promising treatment strategy that may be improved by controlled delivery. OBJECTIVE: This study aimed to design polyethylene glycol-stabilized bilayer-decorated magnetic Cationic Liposomes (CLs) as a drug delivery system for integrated functional studies of lung cancer cell therapy and imaging. METHODS: A novel multifunctional folic acid targeting magnetic CLs docetaxel drug-loading system (FA-CLs-Fe- DOC) was prepared and tested for its physical properties, encapsulation rate and drug release performance. The feasibility of FA-CLs-Fe-DOC ability to inhibit tumor cells and act as an MRI contrast agent was investigated in vitro, and the target recognition and therapeutic ability of FA-CLs-Fe-DOC was studied in vivo. RESULTS: FA-CLs-Fe-DOC had a particle size of 221.54 ± 6.42 nm and a potential of 28.64 ± 3.56 mv, with superparamagnetic properties and better stability. The encapsulation rate was 95.36 ± 1.63%, and the drug loading capacity was 9.52 ± 0.22%, which possessed the drug slow-release performance and low cytotoxicity and could effectively inhibit the proliferation of lung cancer cells, promoting apoptosis of lung cancer cells. MRI showed that it had the function of tracking and localization of lung cancer cells. In vivo experiments confirmed the targeted recognition property and therapeutic function of lung cancer cells. CONCLUSION: In this study, we successfully prepared an FA-CLs-Fe-DOC capable of specifically targeting lung cancer cells with integrated functions of efficient lung cancer cell killing and imaging localization. This targeted drug packaging technology may provide a new strategy for the design of integrated carriers for targeted cancer therapy and imaging.
Assuntos
Antineoplásicos , Cátions , Proliferação de Células , Ensaios de Seleção de Medicamentos Antitumorais , Lipossomos , Neoplasias Pulmonares , Lipossomos/química , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Humanos , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Cátions/química , Proliferação de Células/efeitos dos fármacos , Animais , Camundongos , Apoptose/efeitos dos fármacos , Docetaxel/química , Docetaxel/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/síntese química , Tamanho da Partícula , Sistemas de Liberação de Medicamentos , Estrutura Molecular , Ácido Fólico/química , Relação Dose-Resposta a Droga , Relação Estrutura-Atividade , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/metabolismo , Sobrevivência Celular/efeitos dos fármacos , Camundongos Endogâmicos BALB C , Camundongos Nus , Liberação Controlada de FármacosRESUMO
Docetaxel (Doc), as a first-line chemotherapy drug for prostate cancer (PC), often loses its therapeutic efficacy due to acquired resistance and lack of targeting specificity. Therefore, there is a need to develop a novel drug that can overcome Doc resistance and enhance its targeting ability to inhibit PC progression. In this study, we prepared Au/Doc/Quer@PDA/A10-3.2 nanoparticles (NPs) composite drug by encapsulating Doc and quercetin (Quer) within polydopamine (PDA)-coated Au NPs and further modifying them with RNA oligonucleotide aptamer A10-3.2. A10-3.2 was used for specific targeting of prostate-specific membrane antigen (PSMA)-positive PC cells (LNCaP). Quer was employed to reverse the resistance of Doc-resistant cell line (LNCaP/R) to Doc. Physical characterization using ultraviolet-visible spectroscopy (UV-vis), transmission electron microscopy (TEM), dynamic light scattering (DLS), X-ray photoelectron spectroscopy (XPS), and Fourier-transform infrared spectroscopy (FTIR) confirmed the successful preparation of Au/Doc/Quer@PDA/A10-3.2 NPs. Fluorescence imaging and flow cytometry experiments demonstrated the targeting ability of Au/Doc/Quer@PDA/A10-3.2 NPs towards PSMA-positive LNCaP/R cells. Cell proliferation, apoptosis, invasion, and migration experiments revealed that Quer reversed the resistance of LNCaP/R cells to Doc. Immunoblotting experiments further confirmed the mechanism behind sensitization of chemotherapy by Quer. Finally, we evaluated the therapeutic efficacy of Au/Doc/Quer@PDA/A10-3.2 NPs in a mouse model of PC. In conclusion, this study synthesized and validated a novel nano-composite drug (Au/Doc/Quer@PDA/A10-3.2 NPs) for combating Doc-resistant PC, which could potentially be applied in clinical treatment of PC.
Assuntos
Antineoplásicos , Aptâmeros de Nucleotídeos , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Ouro , Indóis , Polímeros , Neoplasias da Próstata , Quercetina , Masculino , Docetaxel/química , Docetaxel/farmacologia , Ouro/química , Ouro/farmacologia , Humanos , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Animais , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Indóis/química , Indóis/farmacologia , Polímeros/química , Polímeros/farmacologia , Antineoplásicos/química , Antineoplásicos/farmacologia , Aptâmeros de Nucleotídeos/química , Aptâmeros de Nucleotídeos/farmacologia , Quercetina/química , Quercetina/farmacologia , Camundongos , Portadores de Fármacos/química , Nanopartículas Metálicas/química , Glutamato Carboxipeptidase II/metabolismo , Liberação Controlada de Fármacos , Apoptose/efeitos dos fármacos , Nanopartículas/química , Antígenos de SuperfícieRESUMO
Tumour cells secrete various proangiogenic factors like VEGF, PDGF, and EGF that result in the formation of highly vascularized tumours with an immunosuppressive tumour microenvironment. As tumour growth and metastasis are highly dependent on angiogenesis, targeting tumour vasculature along with rapidly dividing tumour cells is a potential approach for cancer treatment. Here, we specifically engineered sub-100 sized nanomicelles (DTX-CA4 NMs) targeting proliferation and angiogenesis using an esterase-sensitive phosphocholine-tethered docetaxel conjugate of lithocholic acid (LCA) (PC-LCA-DTX) and a poly(ethylene glycol) (PEG) derivative of an LCA-combretastatin A4 conjugate (PEG-LCA-CA4). DTX-CA4 NMs effectively inhibit the tumour growth in syngeneic (CT26) and xenograft (HCT116) colorectal cancer models, inhibit tumour recurrence, and enhance the percentage survival in comparison with individual drug-loaded NMs. DTX-CA4 NMs enhance the T cell-mediated anti-tumour immune response and DTX-CA4 NMs in combination with an immune checkpoint inhibitor, anti-PDL1 antibody, enhance the anti-tumour response. We additionally showed that DTX-CA4 NMs effectively attenuate the production of ceramide-1-phosphate, a key metabolite of the sphingolipid pathway, by downregulating the expression of ceramide kinase at both transcriptional and translational levels. Therefore, this study presents the engineering of effective DTX-CA4 NMs for targeting the tumour microenvironment that can be explored further for clinical applications.
Assuntos
Proliferação de Células , Ceramidas , Docetaxel , Micelas , Neovascularização Patológica , Animais , Ceramidas/química , Ceramidas/farmacologia , Humanos , Camundongos , Proliferação de Células/efeitos dos fármacos , Docetaxel/farmacologia , Docetaxel/química , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Ácido Litocólico/química , Ácido Litocólico/farmacologia , Polietilenoglicóis/química , Linhagem Celular Tumoral , Camundongos Endogâmicos BALB C , Estilbenos/química , Estilbenos/farmacologia , Células HCT116 , Antineoplásicos/farmacologia , Antineoplásicos/química , Antineoplásicos/síntese química , Microambiente Tumoral/efeitos dos fármacos , Nanopartículas/química , Ensaios Antitumorais Modelo de Xenoenxerto , Feminino , AngiogêneseRESUMO
The development of nanoparticles could help to improve the efficacy/toxicity balance of drugs. This project aimed to develop liposomes and immunoliposomes using microfluidic mixing technology.Various formulation tests were carried out to obtain liposomes that met the established specifications. The liposomes were then characterized in terms of size, polydispersity index (PDI), docetaxel encapsulation rate and lamellarity. Antiproliferative activity was tested in human breast cancer models ranging from near-negative (MDA-MB-231), positive (MDA-MB-453) to HER2 positive. Pharmacokinetic studies were performed in C57BL/6 mice.Numerous batches of liposomes were synthesised using identical molar ratios and by varying the microfluidic parameters TFR, FRR and buffer. All synthesized liposomes have a size < 200 nm, but only Lipo-1, Lipo-6, Lipo-7, Lipo-8 have a PDI < 0.2, which meets our initial requirements. The size of the liposomes was correlated with the total FRR, for a 1:1 FRR the size is 122.2 ± 12.3 nm, whereas for a 1:3 FRR the size obtained is 163.4 ± 34.0 nm (p = 0.019. Three batches of liposomes were obtained with high docetaxel encapsulation rates > 80 %. Furthermore, in vitro studies on breast cancer cell lines demonstrated the efficacy of liposomes obtained by microfluidic mixing technique. These liposomes also showed improved pharmacokinetics compared to free docetaxel, with a longer half-life and higher AUC (3-fold and 3.5-fold increase for the immunoliposome, respectively).This suggests that switching to the microfluidic process will produce batches of liposomes with the same characteristics in terms of in vitro properties and efficacy, as well as the ability to release the encapsulated drug over time in vivo. This time-efficiency of the microfluidic technique is critical, especially in the early stages of development.
Assuntos
Antineoplásicos , Neoplasias da Mama , Docetaxel , Lipossomos , Camundongos Endogâmicos C57BL , Polietilenoglicóis , Docetaxel/farmacocinética , Docetaxel/administração & dosagem , Docetaxel/química , Animais , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Humanos , Polietilenoglicóis/química , Linhagem Celular Tumoral , Antineoplásicos/administração & dosagem , Antineoplásicos/farmacocinética , Antineoplásicos/química , Microfluídica/métodos , Camundongos , Tamanho da Partícula , Proliferação de Células/efeitos dos fármacosRESUMO
While temozolomide (TMZ) has been a cornerstone in the treatment of newly diagnosed glioblastoma (GBM), a significant challenge has been the emergence of resistance to TMZ, which compromises its clinical benefits. Additionally, the nonspecificity of TMZ can lead to detrimental side effects. Although TMZ is capable of penetrating the blood-brain barrier (BBB), our research addresses the need for targeted therapy to circumvent resistance mechanisms and reduce off-target effects. This study introduces the use of PEGylated mesoporous silica nanoparticles (MSN) with octyl group modifications (C8-MSN) as a nanocarrier system for the delivery of docetaxel (DTX), providing a novel approach for treating TMZ-resistant GBM. Our findings reveal that C8-MSN is biocompatible in vitro, and DTX@C8-MSN shows no hemolytic activity at therapeutic concentrations, maintaining efficacy against GBM cells. Crucially, in vivo imaging demonstrates preferential accumulation of C8-MSN within the tumor region, suggesting enhanced permeability across the blood-brain tumor barrier (BBTB). When administered to orthotopic glioma mouse models, DTX@C8-MSN notably prolongs survival by over 50%, significantly reduces tumor volume, and decreases side effects compared to free DTX, indicating a targeted and effective approach to treatment. The apoptotic pathways activated by DTX@C8-MSN, evidenced by the increased levels of cleaved caspase-3 and PARP, point to a potent therapeutic mechanism. Collectively, the results advocate DTX@C8-MSN as a promising candidate for targeted therapy in TMZ-resistant GBM, optimizing drug delivery and bioavailability to overcome current therapeutic limitations.
Assuntos
Barreira Hematoencefálica , Docetaxel , Resistencia a Medicamentos Antineoplásicos , Glioblastoma , Nanopartículas , Dióxido de Silício , Temozolomida , Temozolomida/química , Temozolomida/farmacologia , Temozolomida/uso terapêutico , Temozolomida/farmacocinética , Glioblastoma/tratamento farmacológico , Glioblastoma/patologia , Glioblastoma/metabolismo , Docetaxel/química , Docetaxel/farmacologia , Docetaxel/farmacocinética , Docetaxel/uso terapêutico , Dióxido de Silício/química , Barreira Hematoencefálica/efeitos dos fármacos , Barreira Hematoencefálica/metabolismo , Animais , Nanopartículas/química , Humanos , Camundongos , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Linhagem Celular Tumoral , Porosidade , Portadores de Fármacos/química , Camundongos Nus , Antineoplásicos/química , Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacosRESUMO
Challenges for glioma treatment with nanomedicines include physio-anatomical barriers (the blood-brain barrier and blood-brain tumor barrier), low drug loading capacity, and limited circulation time. Here, a red blood cell membrane-coated docetaxel drug nanocrystal (pV-RBCm-NC(DTX)), modified with pHA-VAP (pV) for all-stage targeting of glioma, was designed. The NC(DTX) core exhibited a high drug loading capacity but low in vivo stability, and the RBCm coating significantly enhanced the stability and prolonged in vivo circulation. Moreover, the Y-shaped targeting ligand pV was modified by a mild avidin-biotin interaction, which endowed RBCm-NC(DTX) with superior barrier-crossing ability and therapeutic efficacy. The integration of nanocrystal technology, cell membrane coating, and the avidin-biotin insertion method into this active targeting biomimetic formulation represents a promising drug delivery strategy for glioma.