RESUMEN
Self-assembled peptide nanofibers have been widely studied in cancer nanotherapeutics with their excellent biocompatibility and low toxicity of degradation products, showing the significant potential in inhibiting tumor progression. However, poor solubility prevents direct intravenous administration of nanofibers. Although water-soluble peptide precursors have been formed via the method of phosphorylation for intravenous administration, their opportunities for broad in vivo application are limited by the weak capacity of encapsulating drugs. Herein, we designed a novel restructured reduced glutathione (GSH)-responsive drug delivery system encapsulating doxorubicin for systemic administration, which achieved the intracellular restructuration from three-dimensional micelles into one-dimensional nanofibers. After a long blood circulation, micelles endocytosed by tumor cells could degrade in response to high GSH levels, achieving more release and accumulation of doxorubicin at desired sites. Further, the synergistic chemotherapy effects of self-assembled nanofibers were confirmed in both in vitro and in vivo experiments.
Asunto(s)
Doxorrubicina/administración & dosificación , Portadores de Fármacos/farmacocinética , Sistemas de Liberación de Medicamentos/métodos , Glutatión/metabolismo , Nanofibras/química , Células A549 , Animales , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/farmacocinética , Portadores de Fármacos/administración & dosificación , Portadores de Fármacos/síntesis química , Liberación de Fármacos , Sinergismo Farmacológico , Endocitosis/efectos de los fármacos , Glutatión/sangre , Células Endoteliales de la Vena Umbilical Humana , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Ratones Endogámicos BALB C , Micelas , Péptidos/química , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Doxorubicin (DOX) is a first-line chemo drug for cancer therapy, yet it fails to treat multi-drug-resistant tumors. Hypoxia is a major causative factor leading to chemotherapy failure. Particularly, hypoxia up-regulates its responsive transcription factor-hypoxia-inducible factors (HIF)-to induce the overexpression of drug resistant genes. Metformin (MET) is recently found to cooperate with DOX against multiple tumors. As a mitochondrial inhibitor, MET could suppress tumor oxygen consumption, and thereby modulate the hypoxic tumor microenvironment. In this study, we used cationic liposomes to codeliver both DOX and MET for treating multi-drug-resistant breast cancer cells-MCF7/ADR. Faster release of MET enhanced the cytotoxicity of DOX through attenuating hypoxic stress both in vivo and in vitro. MET diminished the cellular oxygen consumption and inhibited HIF1α and P-glycoprotein (Pgp) expression in vitro. In addition, the dual-drug-loaded liposomes increased tumor targeting and intratumoral blood oxygen saturation, which suggested that the tumor reoxygenation effect of MET facilitated the exertion of its synergistic activity with DOX against MCF7/ADR xenografts. In general, our study represents a feasible strategy to boost the therapeutic effect in treating multi-drug-resistant cancer by improving the hypoxic tumor microenvironment.
Asunto(s)
Adenocarcinoma/tratamiento farmacológico , Neoplasias de la Mama/tratamiento farmacológico , Hipoxia de la Célula/efectos de los fármacos , Doxorrubicina/uso terapéutico , Sistemas de Liberación de Medicamentos/métodos , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Metformina/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Animales , Doxorrubicina/administración & dosificación , Doxorrubicina/efectos adversos , Doxorrubicina/metabolismo , Composición de Medicamentos/métodos , Liberación de Fármacos , Sinergismo Farmacológico , Femenino , Humanos , Liposomas/química , Células MCF-7 , Metformina/administración & dosificación , Metformina/metabolismo , Ratones , Ratones Desnudos , Distribución Tisular , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Objective: This study was aimed to develop DOX-TPP loaded acetal-PEG-PCCL micelles to improve the clinical efficacy of drug resistance tumor. Significance: Chemotherapy is one of the main treatments for breast cancer but is plagued by multidrug resistance (MDR). DOX-TPP-loaded micelles can enhance the specific concentration of drugs in the tumor and improve the efficacy and overcome MDR. Methods: In this study, DOX-TPP-loaded micelles based on acetal-PEG-PCCL were prepared and their physicochemical properties were characterized. The cellular uptake and ability to induce apoptosis of the micelles was confirmed by flow cytometry in MCF-7/ADR cells. In addition, cytotoxicity of the micelles was studied in MCF-7 cells and MCF-7/ADR cells. Confocal is used to study the subcellular distribution of DOX. Free DOX-TPP or DOX-TPP-loaded acetal-PEG-PCCL micelles were administered via intravenous injection in the tail vain for the biodistribution study in vivo. Results: The diameter of micelles was about 102.4 nm and their drug-loading efficiency is 61.8%. The structural characterization was confirmed by 1H NMR. The micelles exhibited better antitumor efficacy compared to free doxorubicin in MCF-7/ADR cells by MTT assay. The apoptotic rate and the cellular uptake of micelles were significantly higher than free DOX and DOX-TPP. Micelles can efficiently deliver mitochondria-targeting DOX-TPP to tumor cells. The result of bio-distribution showed that the micelles had stronger tumor infiltration ability than free drugs. Conclusions: In this study, mitochondriotropic DOX-TPP was conjugated to the nanocarrier acetal-PEG-PCCL via ionic interaction to form a polymer, which spontaneously formed spherical micelles. The cytotoxicity and cellular uptake of the micelles are superior to free DOX and exhibit mitochondrial targeting and passive tumor targeting, indicating that they have potential prospects.
Asunto(s)
Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/administración & dosificación , Nanoconjugados/química , Compuestos Organofosforados/administración & dosificación , Acetales/química , Animales , Antineoplásicos/química , Antineoplásicos/farmacocinética , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacocinética , Composición de Medicamentos , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Humanos , Células MCF-7 , Micelas , Mitocondrias/efectos de los fármacos , Mitocondrias/patología , Compuestos Organofosforados/química , Compuestos Organofosforados/farmacocinética , Poliésteres/química , Polietilenglicoles/química , Distribución TisularRESUMEN
Multidrug resistance (MDR) is the major obstacle for chemotherapy. In a previous study, we have successfully synthesized a novel doxorubicin (DOX) derivative modified by triphenylphosphonium (TPP) to realize mitochondrial delivery of DOX and showed the potential of this compound to overcome DOX resistance in MDA-MB-435/DOX cells. (1) To introduce specificity for DOX-TPP to cancer cells, here we report on the conjugation of DOX-TPP to hyaluronic acid (HA) by hydrazone bond with adipic acid dihydrazide (ADH) as the acid-responsive linker, producing HA- hydra-DOX-TPP nanoparticles. Hyaluronic acid (HA) is a natural water-soluble linear glycosaminoglycan, which was hypothesized to increase the accumulation of nanoparticles containing DOX-TPP in the mitochondria of tumor cells upon systemic administration, overcoming DOX resistance, in vivo. Our results showed HA- hydra-DOX-TPP to self-assemble to core/shell nanoparticles of good dispersibility and effective release of DOX-TPP from the HA- hydra-DOX-TPP conjugate in cancer cells, which was followed by enhanced DOX mitochondria accumulation. The HA- hydra-DOX-TPP nanoparticles also showed improved anticancer effects, better tumor cell apoptosis, and better safety profile compared to free DOX in MCF-7/ADR bearing mice.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/administración & dosificación , Mitocondrias/metabolismo , Nanoconjugados/química , Animales , Antibióticos Antineoplásicos/química , Apoptosis/efectos de los fármacos , Neoplasias de la Mama/patología , Doxorrubicina/química , Liberación de Fármacos , Resistencia a Múltiples Medicamentos , Resistencia a Antineoplásicos , Femenino , Humanos , Receptores de Hialuranos/metabolismo , Ácido Hialurónico/química , Concentración de Iones de Hidrógeno , Lisosomas/efectos de los fármacos , Lisosomas/metabolismo , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Compuestos Organofosforados/administración & dosificación , Compuestos Organofosforados/química , Distribución Tisular , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Breast cancer is the leading cause of cancer-related death for women, and multidrug resistance (MDR) is the major obstacle faced by chemotherapy for breast cancer. We have previously synthesized a doxorubicin (DOX) derivative by conjugating DOX with triphenylphosphonium (TPP) to achieve mitochondrial delivery, which induced higher cytotoxicity in drug-resistant breast cancer cells than DOX itself. Due to its amphiphilicity, TPP-DOX is difficult to physically entrap in nanocarriers. Thus, we linked it to hyaluronic acid (HA) by a novel ionic bond utilizing the specific bromide ion of TPP to form supra-molecular self-assembled structures (HA-ionic-TPP-DOX). The product was analyzed uisng 1H-NMR, 13C-NMR and mass spectrometry. The HA nanocarriers (HA-ionic-TPP-DOX) were shown to self-assemble into spherical nanoparticles, and sensitive to acidic pH in terms of morphology and drug release. Compared with free DOX, HA-ionic-TPP-DOX produced much greater intracellular DOX accumulation and mitochondrial localization, leading to increased ROS production, slightly decreased mitochondrial membrane potential, increased cytotoxicity in MCF-7/ADR cells and enhanced tumor targeting in vivo. In xenotransplant zebrafish model with the MCF-7/ADR cell line, both TPP-DOX and HA-ionic-TPP-DOX inhibited tumor cell proliferation without inducing significant side effects compared with free DOX. In addition, we observed a better anti-tumor effect of HA-ionic-TPP-DOX on MCF-7/ADR cells in zebrafish than that of TPP-DOX treatment. Furthermore, HA-ionic-DOX-TPP exhibited favorable biocompatibility and anti-tumor effects in MCF-7/ADR tumor-bearing nude mice in comparison with the effects of TPP-DOX and DOX, suggesting the potential of HA-ionic-TPP-DOX for the targeted delivery and controlled release of TPP-DOX, which can lead to the sensitization of resistant breast tumors.
Asunto(s)
Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Doxorrubicina/uso terapéutico , Portadores de Fármacos/química , Ácido Hialurónico/química , Mitocondrias/metabolismo , Animales , Antineoplásicos/química , Apoptosis/efectos de los fármacos , Doxorrubicina/química , Liberación de Fármacos , Resistencia a Antineoplásicos/efectos de los fármacos , Femenino , Humanos , Células MCF-7 , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Ratones Endogámicos BALB C , Ratones Desnudos , Compuestos Onio/química , Compuestos Organofosforados/química , Pez CebraRESUMEN
Mitochondrion is one of the most vital organelles in cells of human body, and it is involved in many metabolic processes. Mitochondrion dysfunction is closely related to many diseases such as cancers, neurodegenerative diseases, obesity and ischemia reperfusion injury. As a result, mitochondrial drug delivery has gained more and more attention in the drug discovery against these diseases. This review gives a brief introduction to the relationship between mitochondria and human diseases(e.g., cancer), and summarizes the latest trend of mitochondrial targeting drug delivery system(MTDDS).
Asunto(s)
Sistemas de Liberación de Medicamentos , Mitocondrias/efectos de los fármacos , Humanos , Neoplasias/tratamiento farmacológico , Enfermedades Neurodegenerativas/tratamiento farmacológico , Obesidad/tratamiento farmacológico , Daño por Reperfusión/tratamiento farmacológicoRESUMEN
An increasing percentage of people in China are suffering from osteoporosis, particularly postmenopausal osteoporosis (PMOP), as the country rapidly evolves into an aging culture. Patients with osteoporosis are inclined to endure fractures, as well as deformities and impairments, which drastically decrease people's quality of life. The benefits of Traditional Chinese medicine (TCM) treatment have continued to become increasingly apparent as reports of adverse responses to Western medications increased. The main advantage of traditional Chinese medicine treatment is that pharmacological interactions may be employed to lessen adverse effects while increasing therapeutic efficacy. In addition, there are various exercise therapies created by medical doctors in the past generations, such as: Wuqinxi, Taijiquan, Baduanjin, Yijinjing, etc. Chinese medicine and exercise treatment for postmenopausal osteoporosis have garnered a lot of attention recently both domestically and internationally, and investigations demonstrate that these therapies have considerable therapeutic effects. The pathophysiology of postmenopausal osteoporosis, advancements of herbal therapy options, and exercise treatment options are all thoroughly addressed in this article.
Asunto(s)
Medicamentos Herbarios Chinos , Medicina Tradicional China , Osteoporosis Posmenopáusica , Humanos , Osteoporosis Posmenopáusica/tratamiento farmacológico , Medicamentos Herbarios Chinos/uso terapéutico , Medicamentos Herbarios Chinos/farmacología , Medicamentos Herbarios Chinos/química , FemeninoRESUMEN
OBJECTIVE: To study the pharmacokinetics of injected cefozopran hydrochloride in healthy volunteers. METHODS: 24 healthy volunteers were enrolled to receive low (0.5 g), middle (1.0 g), high (2.0 g) doses of single injection and multiple doses (1.0 g) injection of cefozopran hydrochloride in an open randomized study. The plasma concentrations of cefozopran were determined by RP-HPLC. The DAS2.0 was used to fit the concentration-time data and to calculate the pharmacokinetic parameters. RESULTS: The main pharmaeokinetic parameters for a single injection of low, middle and high doses of cefozopran were as follows: Cmax (48.27 +/- 9.84), (77.99 +/- 15.08) and (171.59 +/- 18.27) mg/L; Tmax (0.50 +/- 0.00), (0.51 +/- 0.02) and (0.51 + 0.02) h; AUCo-t (92.43 +/- 24.02), (152.45 +/- 16.26) and (341.03 +/- 44.16) mg x h/L; t1/2beta (1.97 +/- 0.19), (2.44 +/- 0.24) and (2.18 +/- 0.31) h, respectively. The main pharmacokinetic parameters for a multiple doses injection of cefozopran were as follows: Cmax (80.39 +/- 11.86) mg/L; Tmax (0.51 +/- 0.02) h; AUCo-t (159.74 +/- 15.06) mg x h/L; t1/2beta (2.55 +/- 0.55) h. The accumulative rate of cefozopran through urine pathway within 24 h was (89.4 +/- 15.5)%. The statistical analysis showed that Cmax, AUCo-t, and AUCo-infinity increased significantly with increased doses of injection (P < 0.05). Those parameters were linearly correlated with the doses of injection (r = 0.9950, 0.9960, 0.9963). However, dosage did not have an impact on other pharmacokinetic parameters (P > 0.05). No gender differences in the parameters were found (P > 0.05). CONCLUSION: Cefozopran hydrochloride performs a linear kinetics in healthy volunteers. The main pharmacokinetic parameters have no significant gender differences, and there is no drug accumulated with multiple doses of injection.
Asunto(s)
Antibacterianos/farmacocinética , Cefalosporinas/farmacocinética , Adulto , Antibacterianos/administración & dosificación , Cefalosporinas/administración & dosificación , Cromatografía Líquida de Alta Presión/métodos , Femenino , Humanos , Infusiones Intravenosas , Masculino , Adulto Joven , CefozopránRESUMEN
Currently, the limited penetration of nanoparticles remains a major challenge for antitumor nanomedicine to penetrate into the tumor tissues. Herein, we propose a size-shrinkable drug delivery system based on a polysaccharide-modified dendrimer with tumor microenvironment responsiveness for the first time to our knowledge, which was formed by conjugating the terminal glucose of hyaluronic acid (HA) to the superficial amidogen of poly(amidoamine) (PAMAM), using a matrix metalloproteinase-2 (MMP-2)-cleavable peptide (PLGLAG) via click reaction. These nanoparticles had an initial size of â¼200 nm, but once deposited in the presence of MMP-2, they experienced a dramatic and fast size change and dissociated into their dendrimer building blocks (â¼10 nm in diameter) because of cleavage of PLGLAG. This rapid size-shrinking characteristic not only promoted nanoparticle extravasation and accumulation in tumors benefited from the enhanced permeability and retention effect but also achieved faster nanoparticle diffusion and penetration. We have further conducted comparative studies of MMP-2-sensitive macromolecules (HA-pep-PAMAM) and MMP-2-insensitive macromolecules (HA-PAMAM) synthesized with a similar particle size, surface charge, and chemical composition and evaluated in both monolayer cells and multicellular spheroids. The results confirmed that the enzyme-responsive size shrink is an implementable strategy to enhance drug penetration and to improve therapeutic efficacy. Meanwhile, macromolecule-based nanoparticles with size-variable characteristics not only promote drug penetration, but they can also be used as gene delivery systems, suggesting great potential as nano-delivery systems.
Asunto(s)
Dendrímeros/química , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Humanos , Ácido Hialurónico , Metaloproteinasa 2 de la Matriz , PoliaminasRESUMEN
Nano-gold (sub-5 nm)@mesoporous-silica (m-SiO2) core-shell nanospheres with controlled size and core number were prepared via a soft-templated method. The single-core Au@m-SiO2 particles showed great sintering-resistance at 750 °C and kept high catalytic activity for CO oxidation after the treatment.