RESUMEN
In different types of cancer treatments, cancer-specific T cells are required for effective anticancer immunity, which has a central role in cancer immunotherapy. However, due to the multiple inhibitions of CD8+ T cells by tumor-related immune cells, CD8+ T-cell mediated antitumor immunotherapy has not achieved breakthrough progress in the treatment of solid tumors. Receptors for sialic acid (SA) are highly expressed in tumor-associated immune cells, so SA-modified nanoparticles are a drug delivery nanoplatform using tumor-associated immune cells as vehicles. To relieve the multiple inhibitions of CD8+ T cells by tumor-associated immune cells, we prepared SA-modified doxorubicin liposomes (SL-DOX, Scheme 1A). In our study, free SA decreased the toxicity of SL-DOX to tumor-associated immune cells. Compared with common liposomes, SL-DOX could inhibit tumor growth more effectively. It is worth noting that SL-DOX could not only kill tumor-related neutrophils and monocytes to relieve the multiple inhibitions of CD8+ T cells but also induce immunogenic death of tumor cells to promote the infiltration and differentiation of CD8+ T cells (Scheme 1B). Therefore, SL-DOX has potential value for the clinical therapeutic effect of CD8+ T cells mediating anti-tumor immunotherapy.
Asunto(s)
Linfocitos T CD8-positivos , Doxorrubicina , Liposomas , Ácido N-Acetilneuramínico , Doxorrubicina/farmacología , Doxorrubicina/química , Doxorrubicina/análogos & derivados , Linfocitos T CD8-positivos/inmunología , Animales , Ratones , Ácido N-Acetilneuramínico/química , Liposomas/química , Humanos , Inmunoterapia/métodos , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Línea Celular Tumoral , Ratones Endogámicos C57BL , Tamaño de la Partícula , Femenino , PolietilenglicolesRESUMEN
DOX liposomes have better therapeutic effects and lower toxic side effects. The targeting ability of liposomes is one of the key factors affecting the therapeutic effect of DOX liposomes. This study developed two types of targeted liposomes. Sialic acid (SA)-modified liposomes were designed to target the highly expressed Siglec-1 receptor on tumor-associated macrophages surface. Phosphatidylserine (PS)-modified liposomes were designed to promote phagocytosis by monocyte-derived macrophages through PS apoptotic signaling. In order to assess and compare the therapeutic potential of different targeted pathways in the context of anti-tumor treatment, we compared four phosphatidylserine membrane materials (DOPS, DSPS, DPPS and DMPS) and found that liposomes prepared using DOPS as material could significantly improve the uptake ability of RAW264.7 cells for DOX liposomes. On this basis, normal DOX liposomes (CL-DOX) and SA-modified DOX liposomes (SAL-DOX), PS-modified DOX liposomes (PS-CL-DOX), SA and PS co-modified DOX liposomes (PS-SAL-DOX) were prepared. The anti-tumor cells function of each liposome on S180 and RAW264.7 in vitro was investigated, and it was found that SA on the surface of liposomes can increase the inhibitory effect. In vivo efficacy results exhibited that SAL-DOX and PS-CL-DOX were superior to other groups in terms of ability to inhibit tumor growth and tumor inhibition index, among which SAL-DOX had the best anti-tumor effect. Moreover, SAL-DOX group mice had high expression of IFN-γ as well as IL-12 factors, which could significantly inhibit mice tumor growth, improve the immune microenvironment of the tumor site, and have excellent targeted delivery potential.
Asunto(s)
Doxorrubicina , Liposomas , Ácido N-Acetilneuramínico , Fosfatidilserinas , Macrófagos Asociados a Tumores , Animales , Ratones , Ácido N-Acetilneuramínico/química , Células RAW 264.7 , Fosfatidilserinas/metabolismo , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/metabolismo , Línea Celular Tumoral , Antineoplásicos/farmacología , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Fagocitosis/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Apoptosis/efectos de los fármacosRESUMEN
Doxorubicin (DOX) has a cytotoxic effect on many tumor cells; however, its clinical application is limited owing to its strong side effects. Although Doxil® reduces the cardiotoxicity of free DOX, it has also introduced a new dose-limiting toxicity. In a previous study, a sialic acid-cholesterol conjugate (SA-CH) was synthesized and modified onto the surface of DOX-loaded liposomes to target tumor-associated macrophages (TAMs), further improving the efficacy of DOX-loaded liposomes over that of Doxil®. Meanwhile, the good retention characteristics and promising antitumor ability of sphingomyelin/cholesterol (SM/CH) system for water-soluble drugs have attracted wide attention. Therefore, we aimed to use SA-CH as the target and hydrogenated soybean phosphatidylcholine (HSPC) or egg sphingomyelin (ESM) as the membrane material to develop a more stable DOX-loaded liposome with stronger antitumor activity. The liposomes were evaluated for particle size, polydispersity index, zeta potential, entrapment efficiency, in vitro release, long-term storage, cytotoxicity, cellular uptake, pharmacokinetics, tumor targetability, and in vivo antitumor activity. In the liposomes prepared using HSPC/CH, sialic acid (SA) modification considerably increased the accumulation of DOX-loaded liposomes in the tumor, thus exerting a better antitumor effect. However, SA modification in DOX-ESL (SA-CH-modified DOX-loaded liposomes prepared by ESM/CH) destroyed the strong retention effect of the ESM/CH system on DOX, resulting in a reduced antitumor effect. Notably, DOX-ECL (DOX-loaded liposome prepared by ESM/CH) had the optimal storage stability, lowest toxicity, and optimal antitumor effect due to better drug retention properties. Thus, the ESM/CH liposome of DOX is a potential drug delivery system. Sketch of the effect of two DOX-loaded liposomes with hydrogenated soybean phospholipid (HSPC) and egg sphingomyelin (ESM) as lipid membrane material and surface-modified SA derivative on tumor growth inhibition.
Asunto(s)
Liposomas , Neoplasias , Humanos , Esfingomielinas , Ácido N-Acetilneuramínico , Doxorrubicina/uso terapéutico , Neoplasias/tratamiento farmacológico , Colesterol , Línea Celular TumoralRESUMEN
Breast cancer metastasis is an important cause of death in patients with breast cancer and is closely related to circulating tumor cells (CTCs) and the metastatic microenvironment. As the most infiltrating immune cells in the tumor microenvironment (TME), tumor-associated macrophages (TAMs), which highly express sialic acid (SA) receptor (Siglec-1), are closely linked to tumor progression and metastasis. Furthermore, the surface of CTCs also highly expressed receptor (Selectin) for SA. A targeting ligand (SA-CH), composed of SA and cholesterol, was synthesized and modified on the surface of epirubicin (EPI)-loaded liposomes (EPI-SL) as an effective targeting delivery system. Liposomes were evaluated for characteristics, stability, in vitro release, cytotoxicity, cellular uptake, pharmacokinetics, tumor targeting, and pharmacodynamics. In vivo and in vitro experiments showed that EPI-SL enhanced EPI uptake by TAMs. In addition, cellular experiments showed that EPI-SL could also enhance the uptake of EPI by 4T1 cells, resulting in cytotoxicity second only to that of EPI solution. Pharmacodynamic experiments have shown that EPI-SL has optimal tumor inhibition with minimal toxicity, which can be ascribed to the fact that EPI-SL can deliver drugs to tumor based on TAMs and regulate TME through the depletion of TAMs. Our study demonstrated the significant potential of SA-modified liposomes in antitumor metastasis. Schematic diagram of the role of SA-CH modified EPI-loaded liposomes in the model of breast cancer metastasis.
Asunto(s)
Neoplasias de la Mama , Liposomas , Humanos , Femenino , Epirrubicina/farmacocinética , Ácido N-Acetilneuramínico , Neoplasias de la Mama/tratamiento farmacológico , Macrófagos Asociados a Tumores , Lectina 1 Similar a Ig de Unión al Ácido Siálico , Ligandos , Línea Celular Tumoral , Inmunoterapia , Colesterol , Microambiente Tumoral , Melanoma Cutáneo MalignoRESUMEN
D-α-Tocopheryl polyethylene glycol 1000 succinate (TPGS) has shown potential applications in cancer therapy owing to its attractive properties, including reversal of multi-drug resistance and synergistic effects with antitumor drugs. However, its associated shortcomings cannot be underestimated, including activation of the body's immune response and acceleration of blood clearance of polyethylene glycolylated preparations. Polysialic acid (PSA) is a polysaccharide homopolymer, with the dual function of immune camouflage and tumor targeting. PSA and TPGS conjugates (PSA-TPGS) were synthesized to weaken the immune risks of TPGS. We developed PSA-TPGS and TPGS self-assembled mixed micelles and encapsulated the classical antineoplastic, docetaxel. The particle size of docetaxel-loaded mixed micelles was 16.3 ± 2.0 nm, with entrapment efficiency of 99.0 ± 0.9% and drug-loading efficiency of 3.20 ± 0.03%. Antitumor activity studies revealed that the mixed micelles showed better tumor inhibition than Tween 80 and TPGS micelles. Detection of the accelerated blood clearance (ABC) phenomenon demonstrated that insertion of PSA-TPGS into the micelles weakened the ABC phenomenon induced by TPGS. In summary, PSA-TPGS could be a potential nanocarrier to improve antitumor activity and weaken immune responses.
Asunto(s)
Antineoplásicos , Micelas , Antineoplásicos/farmacología , Inmunidad , Polietilenglicoles , Ácidos Siálicos , Succinatos , Vitamina ERESUMEN
Many anti-inflammatory therapies targeting neutrophils have been developed so far. A sialic acid (SA)-modified liposomal (SAL) formulation, based on the high expression of L-selectin in peripheral blood neutrophils (PBNs) and SA as its targeting ligand, has proved to be an effective neutrophil-mediated drug delivery system targeting rheumatoid arthritis (RA). The objective of this study was to investigate the influence of particle size of drug-carrying SALs transported and delivered by neutrophils on their anti-RA effect. Dexamethasone palmitate-loaded SALs (DP-SALs) of different particle sizes (300.2 ± 5.5 nm, 150.3 ± 4.3 nm, and 75.0 ± 3.9 nm) were prepared with DP as a model drug. Our study indicated that DP-SALs could efficiently target PBNs, with larger liposomes leading to higher drug accumulation in cells. However, a high intake of large DP-SALs by PBNs inhibited their migration ability and capacity to release the payload at the target site. In contrast, small DP-SALs (75.0 ± 3.9 nm) could maintain the drug delivery potential of PBNs, leading to their efficient accumulation at the inflammatory site, where PBNs would be excessively activated to form neutrophil extracellular traps along with efficient payload release (small DP-SALs) and finally to induce excellent anti-RA effect.
Asunto(s)
Antiinflamatorios/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Dexametasona/administración & dosificación , Liposomas/química , Neutrófilos/efectos de los fármacos , Ácidos Siálicos/química , Animales , Antiinflamatorios/uso terapéutico , Dexametasona/uso terapéutico , Sistemas de Liberación de Medicamentos , Humanos , Masculino , Ácido N-Acetilneuramínico/metabolismo , Ácido N-Acetilneuramínico/farmacología , Ácido N-Acetilneuramínico/uso terapéutico , Tamaño de la Partícula , Ratas , Ratas WistarRESUMEN
It is well known that neutrophil-mediated delivery of therapeutic agents is a promising method for treating tumors. However, owing to the limited number and limited uptake ability of neutrophils, determining a reasonable dose has become an urgent problem to be solved. Furthermore, the number of nanoparticles is far greater than the number of neutrophils at normal doses, which causes excessive nanoparticles to reach nontargeted organs or tissues, leading to serious adverse effects. To address these problems, a neutrophil-targeting delivery system (DiR-DADGC-L) based on DiR-labeled and butanedioic acid (DA)-linked 5-amino-3,5-dideoxy-D-Glycerol-D-galactonanulose-cholesterol conjugate (DADGC) was designed to improve the efficiency of hitchhiking neutrophils through the specific binding of sialic acid (SA) to L-selectin (SA-binding receptor, expressed on neutrophils). DiR-DADGC-L was prepared with favorable particle size and encapsulation efficiency (%EE) to deliver DiR into neutrophils. Subsequently, diverse doses of DiR-DADGC-L were injected intravenously into S180 tumor-bearing and cyclophosphamide-depleted (CTX-D) S180 tumor-bearing mice to evaluate the in vivo behavior of liposomes. The results verified the following: a) The content of DiR-DADGC-L in neutrophils accounts for approximately 14.5% of the content of DiR-DADGC-L in plasma, and the uptake capacity of neutrophils remains unchanged under different doses, and b) both neutrophils and the enhanced permeability and retention (EPR) effect might exert significant roles in tumor treatment. As for the neutrophil-mediated delivery system, higher doses are not necessarily appropriate, and a lower dose may achieve an unexpected effect. It will be wise to determine an optimum dose to improve delivery efficiency.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/uso terapéutico , Nanopartículas/administración & dosificación , Neoplasias/tratamiento farmacológico , Neutrófilos/metabolismo , Animales , Antineoplásicos/farmacocinética , Ciclofosfamida/administración & dosificación , Ciclofosfamida/farmacocinética , Ciclofosfamida/uso terapéutico , Sistemas de Liberación de Medicamentos , Selectina L/metabolismo , Liposomas , Masculino , Ratones , Ácido N-Acetilneuramínico/metabolismo , Tamaño de la Partícula , Sarcoma 180/tratamiento farmacológico , Distribución TisularRESUMEN
Various types of nanocarriers modified with poly(ethylene glycol) (PEG) exhibit the accelerated blood clearance (ABC) phenomenon, resulting in reduced circulation time and abnormal increase in hepatic and splenic accumulations. Based on the abundance of esterases in the serum of rats, we developed cleavable methoxy PEG-cholesteryl methyl carbonate (mPEG-CHMC) with a carbonate linkage and noncleavable N-(carbonyl-methoxy PEG-n)-1,2-distearoyl-sn-glycero-3-phos-phoethanolamine (mPEG-DSPE) with a carbamate linkage on the surface of the nanoemulsions (CHMCE and PE, respectively). Both PEG derivatives possessed PEG with six different molecular weights (n = 350, 550, 750, 1000, 2000, and 5000). The pharmacokinetic behaviors and biodistributions of single and repeated injection of the two types of PEGylated nanoemulsions were determined to investigate the influence of cleavable linkages and PEG molecular weights on the ABC phenomenon in an attempt to find a potential strategy to eliminate the ABC phenomenon. CHMCEns (n = 1000, 2000, and 5000) exhibited the same pharmacokinetic behaviors as PE550 and PE750 and only alleviated the ABC phenomenon to a certain extent at the expense of shortened cycle time, indicating that the cleavable carbonate linkage was not an ideal strategy to eliminate the ABC phenomenon. As the molecular weights of PEG increased, the ABC phenomenon became more severe. Surprisingly, PE5000 induced a lower anti-PEG IgM level and a weaker ABC phenomenon compared with PE2000 while possessing a similar long circulation time. The results suggested that increasing the molecular weight of PEG in the PEG derivatives could be a potential strategy for eliminating the ABC phenomenon while simultaneously guaranteeing longer circulation time.
Asunto(s)
Colesterol/metabolismo , Emulsiones/metabolismo , Lípidos/química , Nanopartículas/metabolismo , Fosfolípidos/metabolismo , Polietilenglicoles/metabolismo , Animales , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Emulsiones/química , Inmunoglobulina M/metabolismo , Cinética , Masculino , Tasa de Depuración Metabólica/fisiología , Peso Molecular , Nanopartículas/química , Polietilenglicoles/química , Ratas , Ratas Wistar , Bazo/metabolismoRESUMEN
To investigate the effect of polyethylene glycol (PEG) molecular weights on circulation time of PEGylated emulsions and the second injection of injected PEGylated emulsions, we studied the effect of molecular weights on the pharmacokinetic behavior of PEG-DSPE (modified emulsions with 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-n-[methoxy (polyethyleneglycol)]) and PEG-CHMC (modified emulsions with poly(ethyleneglycol)-cholesteryl carbonate) emulsions in beagle dogs. The "accelerated blood clearance" (ABC) phenomenon was induced. Through this study, the contribution of PEG molecular weights on the ABC phenomenon was further clarified, and the results provided guidance for lessening or eliminating the ABC phenomenon. We injected different PEG-modified emulsions with 10% PEG-modified density into beagle dogs at 2 µmol phospholipids kg-1 and the blood samples were drawn after 1 min, 3 min, 5 min, 10 min, 15 min, 30 min, 60 min, 120 min, 240 min, 360 min, 600 min, and 24 h. Then, concentrations of the drug were assayed using high-performance liquid chromatography (HPLC). The results showed that the circulation times of PEG-DSPE-modified emulsions were significantly different because of the difference in molecular weights, whereas those of the PEG-CHMC modified emulsions were not. The spatial conformation of PEG with small molecular weights (PEG400, PEG600, and PEG800) was more likely to induce a strong ABC phenomenon. The results of our work suggest the interaction of circulation time and PEG molecular weights on the ABC phenomenon, implying that the spatial conformation of PEG has advantages that alleviate the ABC phenomenon. Importantly, the results have implications for the choice of molecular weights of PEG for PEGylated formulations.
Asunto(s)
Emulsiones , Polietilenglicoles/química , Animales , Perros , Cinética , Liposomas/química , Masculino , Peso Molecular , Fosfatidiletanolaminas/química , Ratas WistarRESUMEN
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
Mannose receptor (CD206) and E-selectin are selectively expressed in M2-like tumor-associated macrophages (M2-TAMs) and activated endothelial cells of vessels surrounding tumor tissues. With the knowledge that D-mannose is the natural ligand of mannose receptors and L-fucose is the key calcium chelator for tumor-associated carbohydrate antigens (TACAs) binding to E-selectin, herein, we firstly reported D-mannose polyethylene glycol (PEG) conjugates (Man-PEG) and L-fucose PEG conjugates (Fuc-PEG) co-modified liposomal doxorubicin (DOX-MFPL) to improve tumor-targeting ability. The dual-ligand modified PEGylated liposomes (DOX-MFPL) were assessed by both in vitro and in vivo trials. Compared with the single-ligand D-mannose- or L-fucose-modified liposomes (DOX-MPL or DOX-FPL), DOX-MFPL achieved an increased distribution of DOX in tumor tissues. The antitumor study based on S180 tumor-bearing mice was conducted and the superior tumor inhibitory rate was shown with DOX-MFPL, probably owing to the superior tumor-targeting effect of DOX-MFPL and the modulation of the tumor microenvironment with the exhaustion of TAMs. In general, the dual-ligand drug delivery systems are expected to be promising in the development of specific and efficient methods for tumor treatment.
Asunto(s)
Doxorrubicina/análogos & derivados , Sistemas de Liberación de Medicamentos , Fucosa/química , Manosa/química , Polietilenglicoles/química , Animales , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Humanos , Ligandos , Masculino , Ratones , Polietilenglicoles/administración & dosificación , Células RAW 264.7RESUMEN
The accelerated blood clearance (ABC) phenomenon is an immune response against the first injection of PEGylated colloidal drug delivery systems (CDDSs), which causes the accelerated clearance of the second dose. The enhanced complement-mediated phagocytic activity of Kupffer cells is responsible for accelerated second-dose clearance. Nevertheless, few studies have focused on the role of Kupffer cells in the induction phase of the ABC phenomenon. In this study, the intrinsic phagocytic activity of Kupffer cells was significantly enhanced at 6 days after the initial injected PEGylated emulsions (PEs) using the carbon clearance test and single-pass liver perfusion experiment. Furthermore, PE could stimulate Kupffer cells activation, leading to enhanced cell viability of Kupffer cells and opsonization-independent cellular uptake. It was also found that the response ability of Kupffer cells to the antigen-antibody complexes was augmented by the first injection of PE. Conclusively, we proposed that, besides anti-PEG IgM and complement activation-mediated hepatic uptake, enhanced opsonization-independent phagocytosis of Kupffer cells and the high response ability to opsonized antigen-antibody complexes contribute to the accelerated clearance of the second administration. The results indicated that Kupffer cells play an indispensable role in the ABC phenomenon and provided novel insights into the current view on the mechanism of the ABC effect.
Asunto(s)
Complejo Antígeno-Anticuerpo/química , Complejo Antígeno-Anticuerpo/farmacología , Fagocitosis/efectos de los fármacos , Animales , Proliferación Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Emulsiones , Inmunoglobulina M/metabolismo , Macrófagos del Hígado/citología , Macrófagos del Hígado/efectos de los fármacos , Masculino , Polietilenglicoles/química , Ratas , Ratas WistarRESUMEN
The "accelerated blood clearance (ABC) phenomenon" is known to be involved in the adaptive immune system. Regretfully, the relationship between the ABC phenomenon and innate immune system, especially with respect to Kupffer cells (KCs) has been largely unexplored. In this study, the contribution of KCs to ABC was examined using the 4-aminophenyl-α-d-mannopyranoside (APM) lipid derivative DSPE-PEG2000-APM (DPM) and the 4-aminophenyl-ß-l-fucopyranoside (APF) lipid derivative DSPE-PEG2000-APF (DPF) as ligands for mannose/fucose receptors on KCs, which were synthesized and modified on the surface of liposomes. The results of cellular liposome uptake in vitro and biodistribution in vivo indicated that DPM and DPF comodified liposomes (MFPL5-5) present the strongest capability of KC-targeting among all preparations tested. In rats pretreated with MFPL5-5 instead of PEGylated liposomes (PL), the ABC phenomenon was significantly enhanced and the distribution of liposomes in the liver was increased. Cellular uptake of the second injection of PL in vivo demonstrated that KCs was responsible for the uptake. Furthermore, compared to pretreatment with PL, the uptake of second injection of PL was more enhanced when pretreated with MFPL5-5. These findings suggest that KCs, which are considered traditional members of the innate immune system, play a crucial role in the ABC phenomenon and act as a supplement to the phenomenon.
Asunto(s)
Inmunidad Adaptativa , Macrófagos del Hígado/metabolismo , Lectinas Tipo C/metabolismo , Hígado/metabolismo , Lectinas de Unión a Manosa/metabolismo , Receptores de Superficie Celular/metabolismo , Compuestos de Anilina/química , Compuestos de Anilina/farmacocinética , Animales , Línea Celular , Macrófagos del Hígado/inmunología , Ligandos , Liposomas , Hígado/citología , Hígado/inmunología , Masculino , Receptor de Manosa , Manósidos/química , Manósidos/farmacocinética , Tasa de Depuración Metabólica/inmunología , Modelos Animales , Fosfatidiletanolaminas/química , Fosfatidiletanolaminas/farmacocinética , Polietilenglicoles/química , Polietilenglicoles/farmacocinética , Ratas , Ratas Wistar , Distribución TisularRESUMEN
With increasing application of PEGylated products, drawbacks are beginning to emerge such as the "PEG dilemma". Other promising materials may need to be found in the current situation. Endogenous polysialic acid (PSA), which is highly expressed on mammalian, bacterial, and malignant surface, may be a promising material in oncology. In this study, a dual-responsive amphiphilic PSA cholesterol derivative (PSA-CS-CH) was synthesized to explore the opportunity of PSA in targeted drug delivery systems. PSA-CS-CH, F127 mixed micelles (PF-M), and pure F127 micelles (F-M) were prepared for comparative antitumor experiments. The in vitro experiments showed that modification of PSA-CS-CH significantly increased cytotoxicity and cellular uptake. PF-M had excellent tumor microenvironment response release behavior on acidic media with high GSH levels. The in vivo fluorescence imaging and antitumor experiments showed that PF-M had excellent tumor targeting ability and great tumor suppression ability. In summary, biodegradable PSA may contribute to cancer therapy.
Asunto(s)
Antibióticos Antineoplásicos/administración & dosificación , Doxorrubicina/administración & dosificación , Portadores de Fármacos/química , Neoplasias/tratamiento farmacológico , Animales , Antibióticos Antineoplásicos/farmacocinética , Línea Celular Tumoral/trasplante , Colesterol/química , Modelos Animales de Enfermedad , Doxorrubicina/farmacocinética , Liberación de Fármacos , Ensayos de Selección de Medicamentos Antitumorales , Estabilidad de Medicamentos , Humanos , Concentración de Iones de Hidrógeno , Microscopía Intravital , Masculino , Ratones , Micelas , Microscopía Fluorescente , Neoplasias/diagnóstico por imagen , Neoplasias/patología , Oxidación-Reducción , Polietilenos/química , Polipropilenos/química , Ratas , Ratas Wistar , Ácidos Siálicos/químicaRESUMEN
The accelerated blood clearance (ABC) phenomenon is induced by repeated intravenous injection of stealth polyethylene glycol (PEG) nanocarriers and appears as the alteration of the pharmacokinetics and biodistribution of the second administration. Nevertheless, there is no any report about the ABC phenomenon induced by intraperitoneal administration of PEGylated nanocarriers. In this study, we firstly observed whether the ABC phenomenon is induced with PEGylated nanoemulsion at the dose of 0.5~100 µmol phospholipid·kg-1 by intraperitoneal/intravenous injections in rats. The PEG (molecule weight, 2000)-modified nanoemulsions PE-B and PE in which fluorescence indicator dialkylcarbocyanines (DiR) is encapsulated by PE-B were prepared for this work. The pharmacokinetics of the first injected PE via veins or peritoneal cavity features different variation trends. Moreover, the tissue distributions (in vivo or in vitro) of the first injected PE by intraperitoneal injection reveals that the PE gains access to the whole lymphatic circulatory system. Furthermore, our results demonstrate that the ABC phenomenon can be induced by intraperitoneal administration PE-B and present obvious changes with varying PE-B concentration 0.5~100 µmol phospholipid·kg-1. Moreover, an interesting point is that the ABC phenomenon induced by intraperitoneal injected PE-B can be significantly inhibited by intraperitoneal pre-injection of distilled water. For understanding this issue clear, we studied the production of anti-PEG IgM and the characteristic morphologies of immune cells. We observed that the mast cells in peritoneal cavity exhibit rapid depletion in response to the intraperitoneal pre-injection of distilled water, while the anti-PEG IgM secretes at the same level.
Asunto(s)
Polietilenglicoles/farmacocinética , Animales , Emulsiones , Inmunoglobulina M/sangre , Inyecciones Intraperitoneales , Masculino , Nanopartículas , Polietilenglicoles/administración & dosificación , Ratas , Ratas Wistar , Distribución TisularRESUMEN
As an anti-tumor drug, gemcitabine (Gem) is commonly used for the treatment of non-small cell lung cancer and pancreatic cancer. However, there are several clinical drawbacks to using Gem, including its extremely short plasma half-life and side effects. To prolong its half-life and reduce its side effects, we synthesized a derivative of Gem using cholesterol (Chol). This derivative, called gemcitabine-cholesterol (Gem-Chol), was entrapped into liposomes by a thin-film dispersion method. The particle size of the Gem-Chol liposomes was 112.57 ± 1.25 nm, the encapsulation efficiency was above 99%, and the drug loading efficiency was about 50%. In vitro studies revealed that the Gem-Chol liposomes showed delayed drug release and long-term stability at 4 °C for up to 2 months. In vivo studies also showed the superiority of the Gem-Chol liposomes, and compared with free Gem, the Gem-Chol liposomes had longer circulation time. Moreover, an anti-tumor study in H22 and S180 tumor models showed that liposomal entrapment of Gem-Chol improved the anti-tumor effect of Gem. This study reports a potential formulation of Gem for clinical application.
Asunto(s)
Antineoplásicos/administración & dosificación , Antineoplásicos/farmacocinética , Colesterol/química , Desoxicitidina/análogos & derivados , Liposomas/química , Antineoplásicos/química , Colesterol/farmacocinética , Desoxicitidina/administración & dosificación , Desoxicitidina/química , Desoxicitidina/farmacocinética , Desoxicitidina/farmacología , Liberación de Fármacos , Semivida , Humanos , GemcitabinaRESUMEN
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
Bone is among the most common sites of metastasis in cancer patients, so it is an urgent need to develop drug delivery systems targeting tumor bone metastasis with the feature of controlled release. This study aimed to delivery of thermosensitive liposomal doxorubicin to bone for tumor metastasis treatment. First, Brij78 (polyoxyethylene stearyl ether) was conjugated with Pamidronate (Pa). By incorporating Pa-Brij78 to DPPC/Chol liposomes, we developed Pa surface functionalized liposomes. The Pa-Brij78/DPPC/Chol liposomes (PB-liposomes) exhibited a stronger binding affinity to hydroxyapatite (HA), a major component of bone, than Brij78/DPPC/Chol liposomes (B-liposomes). Doxorubicin (Dox) was then encapsulated in PB-liposomes and the results demonstrated complete release of Dox from PB-liposomes or the complex of HA/PB-liposomes within 10 min at 42 °C. Next, human lung cancer A549 cells were treated with the thermosensitive complex of HA/PB-liposomes/Dox to mimic tumor bone metastasis treatment through bone targeted delivery of therapeutic agents. Pre-incubation of HA/PB-liposomes/Dox with mild heat at 42 °C induced subsequent higher cytotoxicity to A549 cells than incubation of the same complex at 37 °C, suggesting more active drug release triggered by heat. In conclusion, we synthesized a novel surfactant Pa-Brij78 and it has the potential to be used for development of a bone targeted thermosensitive liposome formulation for treatment of tumor bone metastasis.
Asunto(s)
Conservadores de la Densidad Ósea/síntesis química , Difosfonatos/síntesis química , Doxorrubicina/análogos & derivados , Sistemas de Liberación de Medicamentos/métodos , Tensoactivos/síntesis química , Células A549 , Conservadores de la Densidad Ósea/administración & dosificación , Supervivencia Celular/efectos de los fármacos , Supervivencia Celular/fisiología , Química Farmacéutica , Difosfonatos/administración & dosificación , Relación Dosis-Respuesta a Droga , Doxorrubicina/administración & dosificación , Doxorrubicina/síntesis química , Humanos , Polietilenglicoles/administración & dosificación , Polietilenglicoles/síntesis química , Tensoactivos/administración & dosificación , TemperaturaRESUMEN
Tumors have always been a major public health concern worldwide, and attempts to look for effective treatments have never ceased. Sialic acid is known to be a crucial element for tumor development and its receptors are highly expressed on tumor-associated immune cells, which perform significant roles in establishing the immunosuppressive tumor microenvironment and further boosting tumorigenesis, progression, and metastasis. Obviously, it is essential to consider sophisticated crosstalk between tumors, the immune system, and preparations, and understand the links between pharmaceutics and immunology. Sialic acid-based chemoimmunotherapy enables active targeting drug delivery via mediating the recognition between the sialic acid-modified nano-drug delivery system represented by liposomes and sialic acid-binding receptors on tumor-associated immune cells, which inhibit their activity and utilize their homing ability to deliver drugs. Such a "Trojan horse" strategy has remarkably improved the shortcomings of traditional passive targeting treatments, unexpectedly promoted tumor shedding, and persistently induced robust immunological memory, thus highlighting its prospective application potential for targeting various tumors. Herein, we review recent advances in sialic acid-based active targeting chemoimmunotherapy to promote tumor shedding, summarize the current viewpoints on the tumor shedding mechanism, especially the formation of durable immunological memory, and analyze the challenges and opportunities of this attractive approach.
Asunto(s)
Inmunoterapia , Ácido N-Acetilneuramínico , Neoplasias , Humanos , Ácido N-Acetilneuramínico/química , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Neoplasias/metabolismo , Neoplasias/inmunología , Microambiente Tumoral/efectos de los fármacos , Animales , Liposomas/química , Sistemas de Liberación de MedicamentosRESUMEN
AIMS: Cancer-related thrombosis (CAT) is a common complication in cancer patients, significantly impacting their quality of life and survival prospects. Nattokinase (NK) has potent thrombolytic properties, however, its efficacy is limited by low oral bioavailability and the risk of severe allergic reactions with intravenous use. Heparin (HP) is a widely used anticoagulant in clinical settings. This study aimed to overcome the intravenous toxicity of NK and explore its effect on CAT in advanced tumors. MAIN METHODS: In this study, NK-HP electrostatic complexes were constructed, and their safety and thrombolytic efficacy were verified through guinea pig allergy tests, mouse tail vein tests, and both in vivo and in vitro thrombolysis experiments. Additionally, an S180 advanced tumor model was developed and combined with sialic acid-modified doxorubicin liposomes (DOX-SAL) to investigate the impact of NK-HP on CAT and its antitumor effects in advanced tumors. KEY FINDINGS: We observed that NK-HP can eliminate the intravenous injection toxicity of NK, has strong thrombolytic performance, and can prevent thrombosis formation. Intravenous injection of NK-HP can enhance the antitumor effect of DOX-SAL by reducing the fibrin content in advanced tumors and increasing the levels of the cross-linked protein degradation product D-dimer. SIGNIFICANCE: This study developed a method to eliminate the intravenous injection toxicity of NK, proposing a promising therapeutic strategy for CAT treatment, particularly for CAT in advanced tumors, and improving the efficacy of nano-formulations in anti-tumor therapy.