RESUMEN
PURPOSE: The aim of this research was to design dexamethasone palmitate (DP) loaded sialic acid modified liposomes, with the eventual goal of using peripheral blood neutrophils (PBNs) that carried drug-loaded liposomes to improve the therapeutic capacity for rheumatoid arthritis (RA). METHODS: A sialic acid - cholesterol conjugate (SA-CH) was synthesized and anchored on the surface of liposomal dexamethasone palmitate (DP-SAL). The physicochemical characteristics and in vitro cytotoxicity of liposomes were evaluated. Flow cytometry and confocal laser scanning microscopy were utilized to investigate the accumulation of liposomes in PBNs. The adjuvant-induced arthritis was adopted to investigate the targeting ability and anti-inflammatory effect of DP loaded liposomes. RESULTS: Both DP-CL and DP-SAL existed an average size less than 200 nm with remarkably high encapsulation efficiencies more than 90%. In vitro and in vivo experiments manifested SA-modified liposomes provided a reinforced accumulation of DP in PBNs. As well, DP-SAL displayed a greater degree of accumulation in the joints and a stronger anti-inflammatory effect in terms of RA suppression. CONCLUSIONS: SA-modified liposomal DP was a promising candidate for RA-targeting treatment through the neutrophil-mediated drug delivery system.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Dexametasona/farmacocinética , Liposomas/química , Ácido N-Acetilneuramínico/química , Neutrófilos/metabolismo , Animales , Antiinflamatorios/administración & dosificación , Antiinflamatorios/farmacocinética , Antiinflamatorios/toxicidad , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/patología , Artritis Reumatoide/patología , Colesterol/química , Dexametasona/administración & dosificación , Dexametasona/toxicidad , Liberación de Fármacos , Articulaciones/efectos de los fármacos , Articulaciones/patología , Selectina L/metabolismo , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/patología , Masculino , Neutrófilos/patología , Palmitatos/química , Ratas Wistar , Distribución TisularRESUMEN
In our previous study, polysialic acid-octadecyl dimethyl betaine (PSA-BS18) was synthesized and modified to liposomal EPI. Preliminary experiments revealed that the PSA-BS18 was a potential material for targeting tumor site with superior curative effects. In this study, PSA-BS18 and Pluronic F127 (F127) mixed polymeric micelles encapsulated docetaxel (DTX) (FP/DTX) were prepared by a self-assembly method. The FP/DTX was found to have a diameter of 34.83 ± 0.50 nm with a narrow polydispersity, the entrapment efficiency was 99.12 ± 1.17%, and the drug loading efficiency of 1.40 ± 0.01%. The storage and dilution stability of FP/DTX was fine. In vitro release studies demonstrated that FP/DTX had delayed the drug release from the micelles. In vitro cytotoxicity assay on B16 cells presented that FP/DTX led to a stronger cytotoxic activity in comparison to F127 micelles based DTX (F127/DTX) and Tween80-based DTX (Taxotere®). The in vivo imaging study showed that the accumulation of FP/DTX at tumor sites was more than F127/DTX. The in vivo antitumor activity of FP/DTX against B16 tumor xenograft model showed a significant higher inhibition and a lower toxicity compared with F127/DTX and Taxotere®. Taken together, the results obtained above showed that PSA-BS18 and F127 mixed polymeric micelles may be a promising strategy for antitumor delivery of DTX.
Asunto(s)
Antineoplásicos/farmacología , Poloxámero/química , Polietilenglicoles/química , Ácidos Siálicos/química , Antineoplásicos/química , Docetaxel , Portadores de Fármacos , Sistemas de Liberación de Medicamentos , Liposomas , Micelas , TaxoidesRESUMEN
Polysialic acid (PSA) is a nonimmunogenic and biodegradable polysaccharide. In recent years, PSA has shown its potential applications to cancer treatment. In this study, PSA-polyethylene glycol (PEG) conjugate was synthesized for the decoration of epirubicin (EPI)-loaded liposomes. The study aimed to evaluate the PSA-PEG conjugated modified liposomes (EPI-PSL) in vitro and in vivo to investigate the role of PSA on physicochemical characteristics and antitumor activity in PEGylated liposomes. EPI-PSL showed a particle size of 116.9 ± 5.2 nm, zeta potential of - 40.3 ± 3.5 mV, and encapsulation efficiency of 99.1 ± 1.5%. The results of in vitro release experiments showed a delayed release of EPI from EPI-PSL. Greater cellular uptake of EPI-PSL was observed compared with PEGylated liposomes (EPI-PL) in B16 cells. Cytotoxicity studies suggested that EPI-PSL exhibited stronger cytotoxic activity than EPI-PL. Though EPI-PSL exhibited comparable blood plasma profiles with EPI-PL, biodistribution studies proved that the distribution of EPI-PSL in tumors was more than that of EPI-PL. The superior antitumor efficacy of EPI-PSL was also verified in the B16 xenograft mouse model with a reduction in systemic toxicity. In conclusion, these results therefore indicated that PSA-modified PEGylated liposomes may represent an excellent anticancer drug delivery system for targeted cancer therapy.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Epirrubicina/administración & dosificación , Polietilenglicoles/administración & dosificación , Ácidos Siálicos/administración & dosificación , Animales , Antibióticos Antineoplásicos/sangre , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Transporte Biológico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Estabilidad de Medicamentos , Epirrubicina/sangre , Epirrubicina/química , Epirrubicina/farmacocinética , Liposomas , Masculino , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Ratones Endogámicos C57BL , Fosfatidiletanolaminas/administración & dosificación , Fosfatidiletanolaminas/química , Polietilenglicoles/química , Ratas Wistar , Ácidos Siálicos/química , Carga Tumoral/efectos de los fármacosRESUMEN
Based on the knowledge that poly(sialic acid) is a critical element for tumour development and that the receptors for its monomer are expressed on neutrophils, which play important roles in the progression and invasion of tumours, a poly(sialic acid)-p-octadecylamine conjugate (PSA-p-ODA) was synthesised and used to modify the surface of liposomal pixantrone (Pix-PSL) to improve the delivery of Pix to peripheral blood neutrophils (PBNs). The liposomes were fabricated using a remote loading technology via a pH gradient, and were then assessed for particle size, encapsulation efficiency, in vitro release, in vitro cytotoxicity, and pharmacokinetics. Simultaneously, in vitro and in vivo cellular uptake studies demonstrated that Pix-PSL provided an enhanced accumulation of Pix in PBNs. An in vivo study showed that the anti-tumour activity of Pix-PSL was superior to that of other formulations, probably owing to the efficient targeting of PBNs by Pix-PSL, after which PBNs containing Pix-PSL (Pix-PSL/PBNs) in the circulatory system are recruited by the tumour microenvironment. These findings suggest that PSA-p-ODA-decorated liposomal Pix may provide a neutrophil-mediated drug delivery system (DDS) for the eradication of tumours, and thus represents a promising approach for the tumour targeting of chemotherapeutic treatments.
Asunto(s)
Antineoplásicos/administración & dosificación , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Isoquinolinas/administración & dosificación , Aminas/química , Animales , Antineoplásicos/farmacocinética , Antineoplásicos/farmacología , Línea Celular Tumoral , Química Farmacéutica/métodos , Isoquinolinas/farmacocinética , Isoquinolinas/farmacología , Liposomas , Masculino , Ratones , Ácido N-Acetilneuramínico/química , Neutrófilos/metabolismo , Tamaño de la Partícula , Ratas , Ratas Wistar , Sarcoma 180/tratamiento farmacológico , Microambiente Tumoral , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
With the knowledge that the receptors of sialic acid are overexpressed on the surface of tumor-associated macrophages (TAMs), which play a crucial role in the tumor's progression and metastasis, a sialic acid-cholesterol conjugate (SA-CH) was synthesized and modified on the surface of epirubicin (EPI)-loaded liposomes (EPI-SAL) to improve the delivery of EPI to the TAMs. The liposomes were developed using remote loading technology via a pH gradient. The liposomes were evaluated for particle size, encapsulation efficiency, in vitro release, stability, in vitro cytotoxicity and pharmacokinetics. And the in vitro and in vivo cellular uptake studies demonstrated EPI-SAL achieved enhanced accumulation of EPI into TAMs. The antitumor studies indicated that EPI-SAL provided the strongest antitumor activity compared with the other formulations (EPI-S, EPI-CL and EPI-PL represent EPI solution, conventional liposomal EPI, PEGylated liposomal EPI, respectively), and the survival percent of tumor-bearing mice was 83.3%. The superior antitumor efficacy was probably attributed to the killing of TAMs by EPI-SAL, and modulating the tumor microenvironment with the depletion of TAMs. These findings suggested that SA-CH decorated EPI-loaded liposomes may present an effective strategy to eradicate TAMs, which may be a promising approach for cancer therapy.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Colesterol/química , Epirrubicina/administración & dosificación , Ácido N-Acetilneuramínico/química , Neoplasias/tratamiento farmacológico , Animales , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Liberación de Fármacos , Estabilidad de Medicamentos , Epirrubicina/química , Epirrubicina/farmacocinética , Epirrubicina/uso terapéutico , Liposomas , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Ratones , Miocardio/patología , Neoplasias/metabolismo , Neoplasias/patología , Células RAW 264.7 , Ratas Wistar , Bazo/efectos de los fármacos , Timo/efectos de los fármacos , Microambiente Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Dexamethasone palmitate has the potential to inhibit the activity of tumor-associated macrophages, which promote cancer proliferation, invasion, and metastasis; however, only very high and frequent doses are capable of inducing antitumor effects. With the aim to reduce the anticancer dose and decrease the nonspecific toxicity, we designed a liposomal system to co-deliver dexamethasone palmitate and doxorubicin. Furthermore, a ligand conjugate sialic acid-octadecylamine, with enhanced affinity towards the membrane receptors over-expressed in tumors, was anchored on the surface of the liposomes to increase drug distribution to the tumor tissue. Co-loaded liposomes were developed using lipid film hydration method to load dexamethasone palmitate and remote loading technology to load doxorubicin. The co-loaded liposomes modified with sialic acid-octadecylamine represented comparable physicochemical properties and blood plasma profiles with conventional co-loaded liposomes, but the biodistribution proved that sialic acid-octadecylamine modified liposomes accumulated more in tumor. The co-loaded liposomes showed higher tumor growth suppression than the single-drug loaded liposomes, while showing no additional drug toxicity in S180-bearing Kunming mice. The co-loaded liposomes modified with sialic acid-octadecylamine achieved a significantly better antitumor effect, and induced "shedding" of cancerous tissue in the mice. These finding suggested that co-loaded liposomes modified with sialic acid-octadecylamine provided a safe therapeutic strategy with outstanding anticancer activity.
Asunto(s)
Aminas/química , Dexametasona/administración & dosificación , Doxorrubicina/administración & dosificación , Liposomas , Ácido N-Acetilneuramínico/química , Animales , Línea Celular , RatonesRESUMEN
Polysialic acid (PSA) serves as a hydrophilic polymer and affords conjugated biologically active molecules a longer circulation time in vivo. Furthermore, PSA could potentially target tumor tissues and help achieve better curative effects. In this study, PSA was conjugated with octadecyl dimethyl betaine (BS18) to yield a PSA-BS18 conjugate. The PSA-BS18 modified liposomal epirubicin (EPI-SL), had a particle size of 133.63±0.92nm, a zeta potential of -26.23±1.50mV and an encapsulation efficiency (%EE) of 96.23±1.16%. In vitro release studies showed that PSA-BS18 could delay EPI release from the modified liposomes. The MTT assay suggested that EPI-SL led to stronger cytotoxic activity than that exhibited by common and PEGylated liposomes. The pharmacokinetic study showed that EPI-SL prolonged the residence time of the EPI in the blood compared with that observed from common liposomes. Bio-distribution results obtained from tumor-bearing mice clearly demonstrated that PSA-BS18 increased the accumulation of modified liposomes in tumors compared with that of common liposomes. In the antitumor efficacy study, EPI-SL showed the best antitumor and life-prolonging effects among all of the tested formulations. These findings strongly indicate EPI-SL might have great potential as an effective approach for anticancer therapy.