RESUMEN
Low response rate of immune checkpoint blockade (ICB) has limited its clinical application. A promising strategy to overcome this limitation is the use of therapeutic cancer vaccines, which aim to induce robust immune responses that synergize with ICB through immune enhancement and immune normalization strategies. Herein, we developed a combination immunotherapy by combining nano-vaccines consisting of whole tumor cell lysates/CpG liposomes (LCLs) with an anti-PD-L1 loaded lipid gel (aPD-L1@LG). The LCLs were fabricated using cationic liposomes, while the lipid gels (LGs) were prepared by using soybean phosphatidylcholine (SPC) and glycerol dioleate (GDO). Subcutaneous administration of LCLs successfully activated dendritic cells (DCs), and intratumoral administration of anti-PD-L1@LG ensured sustained ICB activity. These results demonstrated that this combination immunotherapy enhanced anti-tumor efficacy and prolonged the survival time in melanoma by activating systemic anti-tumor immune responses. These findings highlight the potential of this rational design as a promising strategy for tumor treatment.
Asunto(s)
Liposomas , Melanoma , Humanos , Liposomas/farmacología , Inmunoterapia/métodos , Melanoma/tratamiento farmacológico , Inhibidores de Puntos de Control Inmunológico/farmacología , Lípidos/farmacología , Microambiente TumoralRESUMEN
A reversibly disulfide-crosslinked pullulan nanoparticle with folic acid (FA) decoration (FA-Pull-LA CLNPs) was fabricated for dual-targeted and reduction-responsive anti-tumoral liver drug delivery based on the specific affinity of pullulan and FA to overexpress asialoglycoprtein receptors (ASGPR) and folate receptors (FR), respectively. Paclitaxel (PTX)-loaded FA-Pull-LA nanoparticles (NPs) with satisfactory size, polydispersity index (PDI), and zeta potential exhibited much faster PTX release in the presence of 10mM glutathione (GSH) rather than physiological conditions. In vitro cellular assays confirmed the dual targetability and endosomal accumulation of FA-Pull-LA NPs. In SMMC-7721 tumor-bearing mice, FA-Pull-LA-PTX CLNPs showed the strongest anti-tumor efficiency as well as the lowest toxicity among all three groups. Conclusively, the present study implied that reversibly crosslinked FA-Pull-LA NPs with dual-targeting capacity provided a stable and intelligent platform for efficient liver cancer therapy, which should be further studied for a wide range of anti-cancer applications.
Asunto(s)
Sistemas de Liberación de Medicamentos , Ácido Fólico/química , Glucanos/química , Neoplasias Hepáticas/tratamiento farmacológico , Nanopartículas/administración & dosificación , Paclitaxel/farmacología , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Receptor de Asialoglicoproteína/metabolismo , Receptor 1 de Folato/metabolismo , Humanos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Paclitaxel/administración & dosificación , Paclitaxel/química , Ratas , Ratas Sprague-Dawley , Células Tumorales Cultivadas , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Nanotechnology-based chemotherapy is efficient in cancer treatment due to the targeted delivery of small molecules via nano-carriers, which are usually regarded as "inert". However, nano-materials are more preferred as carriers since many cause synergistic anti-tumor effects along with the drug cargo. In this study, a "bioactive" tocopherol succinate (TOS) was grafted to hyaluronic acid (HA) via of disulfide bonds to obtain HA-ss-TOS conjugates which can assemble into nano-micelles but dissociate when exposed to reducing environments in vitro and in vivo. Moreover, paclitaxel-loaded HA-ss-TOS micelles (HA-ss-TOS-PTX) can be efficiently taken up by B16F10 cells overexpressing CD 44, thereafter exhibiting enhanced cytotoxicity. The in vivo imaging study here revealed much greater tumor accumulation of Dir-labeled HA-ss-TOS compared to the free Dir group. In vivo antitumor activities further ensured that the PTX-loaded HA-ss-TOS micelles provided superior antineoplastic responses versus PTX-loaded HA-TOS micelles and Taxol. Moreover, the subcellular dissociated TOS from HA-ss-TOS showed synergistic effects with PTX. These experimental results revealed that reduction-responsive PTX-loaded polymeric nano-micelles with multi-functional properties hold great potential for anti-tumor treatment and, thus, should be further studied.
Asunto(s)
Disulfuros/química , Sistemas de Liberación de Medicamentos , Ácido Hialurónico/química , Melanoma Experimental/tratamiento farmacológico , Micelas , Paclitaxel/farmacología , alfa-Tocoferol/química , Animales , Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacología , Femenino , Ratones , Ratones Endogámicos C57BL , Nanopartículas/administración & dosificación , Nanopartículas/química , Oxidación-Reducción , Paclitaxel/administración & dosificación , Paclitaxel/química , Microambiente TumoralRESUMEN
As the essential components in formulations, pharmaceutical excipients directly affect the safety, efficacy, and stability of drugs. Recently, safety incidents of pharmaceutical excipients posing seriously threats to the patients highlight the necessity of controlling the potential risks. Hence, it is indispensable for the industry to establish an effective risk assessment system of supply chain. In this study, an AHP-fuzzy comprehensive evaluation model was developed based on the analytic hierarchy process and fuzzy mathematical theory, which quantitatively assessed the risks of supply chain. Taking polysorbate 80 as the example for model analysis, it was concluded that polysorbate 80 for injection use is a high-risk ingredient in the supply chain compared to that for oral use to achieve safety application in clinic, thus measures should be taken to control and minimize those risks.
Asunto(s)
Industria Farmacéutica/normas , Excipientes/química , Excipientes/normas , Lógica Difusa , Polisorbatos/química , Polisorbatos/normas , Evaluación Preclínica de Medicamentos/métodos , Excipientes/efectos adversos , Polisorbatos/efectos adversos , Medición de RiesgoRESUMEN
As the essential components in formulations, pharmaceutical excipients directly affect the safety, efficacy, and stability of drugs. Recently, safety incidents of pharmaceutical excipients posing seriously threats to the patients highlight the necessity of controlling the potential risks. Hence, it is indispensable for the industry to establish an effective risk assessment system of supply chain. In this study, an AHP-fuzzy comprehensive evaluation model was developed based on the analytic hierarchy process and fuzzy mathematical theory, which quantitatively assessed the risks of supply chain. Taking polysorbate 80 as the example for model analysis, it was concluded that polysorbate 80 for injection use is a high-risk ingredient in the supply chain compared to that for oral use to achieve safety application in clinic, thus measures should be taken to control and minimize those risks.
Asunto(s)
Excipientes/efectos adversos , Polisorbatos/efectos adversos , Medición de Riesgo/métodos , Administración Oral , Excipientes/administración & dosificación , Excipientes/toxicidad , Lógica Difusa , Humanos , Inyecciones , Polisorbatos/administración & dosificación , Polisorbatos/toxicidadRESUMEN
Oxidative stress is a distinguishing feature in atherosclerosis disease. Reactive oxygen species (ROS) can increase the oxidized low density lipoprotein (ox-LDL) and oxidative damage to macrophages in the plaque. Although antioxidant agents such as N-acetylcysteine are used to treat atherosclerosis, but provide a poor clinical benefit to the majority of patients with atherosclerosis. Here we have designed hyaluronic acid-guided assemblies of ceria nanozymes (HA-CeO2 NPs) as novel plaque-targeting ROS scavengers. The introduction of hyaluronic acid not only provide the stability and biocompatibility, but also surprisingly enhance SOD-mimic activities of ceria nanozymes compared to bare CeO2 precipitates, dextran or poly-aspartic acid coated ceria nanozymes. Interestingly, we find HA-CeO2 NPs not only actively target plaque-associated macrophages in atherosclerosis to remove superfluous ROS and protect macrophages from ROS-caused damages, but also effectively inhibit endocytosis of ox-LDL by activated macrophages. We believe HA-CeO2 nanozymes can serve as a simple and promising platform for anti-atherosclerotic therapy.
Asunto(s)
Aterosclerosis , Ácido Hialurónico , Antioxidantes/metabolismo , Antioxidantes/farmacología , Aterosclerosis/tratamiento farmacológico , Humanos , Estrés Oxidativo , Especies Reactivas de OxígenoRESUMEN
Receptor-mediated active targeting and tumor microenvironment responsive systems from polymeric micelles have been studied for rapid cellular internalization and triggered drug release. Previously we have constructed redox-responsive polymeric micelles composed of vitamin E succinate conjugated hyaluronic acid (HA-ss-TOS), which are able to actively target CD44 proteins and quickly release loaded drugs upon exposure to high levels of glutathione (GSH) in tumor cells. In the present study, we found that despite different cellular internalization mechanisms, micelles showed strong antineoplastic effects on 4T1 and B16F10 cells due to redox responsiveness. HA-ss-TOS-PTX micelles exhibited an excellent tumor targeting ability and prolonged retention time compared to Taxol in vivo. In addition, a superior antitumor effect was achieved compared to PTX-loaded insensitive micelles (HA-TOS-PTX) and Taxol. Our results revealed that PTX-loaded HA-ss-TOS micelles could enhance the antineoplastic efficacy of PTX for breast cancer and melanoma treatment and, thus, deserve further attention.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Antineoplásicos Fitogénicos/farmacología , Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel/administración & dosificación , Paclitaxel/farmacología , Línea Celular Tumoral , Supervivencia Celular , Liberación de Fármacos , Humanos , Receptores de Hialuranos/efectos de los fármacos , Ácido Hialurónico/química , Micelas , Oxidación-Reducción , Células Oxífilas/efectos de los fármacos , Tamaño de la Partícula , alfa-Tocoferol/químicaRESUMEN
One of the main challenges for immune checkpoint blockade antibodies lies in malignancies with limited T-cell responses or immunologically "cold" tumors. Inspired by the capability of fever-like heat in inducing an immune-favorable tumor microenvironment, mild photothermal therapy (PTT) is proposed to sensitize tumors to immune checkpoint inhibition and turn "cold" tumors "hot." Here we present a combined all-in-one and all-in-control strategy to realize a local symbiotic mild photothermal-assisted immunotherapy (SMPAI). We load both a near-infrared (NIR) photothermal agent IR820 and a programmed death-ligand 1 antibody (aPD-L1) into a lipid gel depot with a favorable property of thermally reversible gel-to-sol phase transition. Manually controlled NIR irradiation regulates the release of aPD-L1 and, more importantly, increases the recruitment of tumor-infiltrating lymphocytes and boosts T-cell activity against tumors. In vivo antitumor studies on 4T1 and B16F10 models demonstrate that SMPAI is an effective and promising strategy for treating "cold" tumors.
Asunto(s)
Antineoplásicos Inmunológicos/farmacología , Antígeno B7-H1/antagonistas & inhibidores , Hipertermia Inducida/métodos , Melanoma Experimental/inmunología , Animales , Linfocitos B/efectos de los fármacos , Linfocitos B/inmunología , Línea Celular Tumoral , Terapia Combinada , Preparaciones de Acción Retardada , Geles , Humanos , Inmunoterapia , Verde de Indocianina/análogos & derivados , Verde de Indocianina/farmacología , Lípidos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Ratones , Células 3T3 NIH , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
In this study, we prepared paclitaxel (PTX) loaded bovine serum albumin (BSA) microparticles (MPs) of different sizes (0.5, 1.0, and 3.0⯵m) and converted them into dry powders (DPs) of a uniform size (â¼5.0⯵m) through spray-drying techniques. The aim of preparing different sized PTX-MPs is to investigate the size-based in vivo biodistribution and retention of PTX in the lungs after intratracheal administration. Following the in vitro characterizations, the anti-tumor efficacy of the DPs containing differently sized PTX-BSA-MPs administered through intratracheal insufflation was compared with intravenously administered PTX solution (Taxol). While the fastest drug release was found for the 0.5⯵m group, the 1.0 and 3.0⯵m groups showed the highest anti-tumor efficiency in vivo. Taken together, our results demonstrate that the initial particle size of the incorporated particles, i.e., MPs, is crucial for the anti-tumor efficacy of DPs administered by inhalation, and the initial particle size should be regarded as one of the key factors in the development and quality control of such preparations.
Asunto(s)
Antineoplásicos Fitogénicos/administración & dosificación , Portadores de Fármacos/administración & dosificación , Neoplasias Pulmonares/tratamiento farmacológico , Paclitaxel/administración & dosificación , Albúmina Sérica Bovina/administración & dosificación , Administración por Inhalación , Animales , Antineoplásicos Fitogénicos/química , Antineoplásicos Fitogénicos/farmacocinética , Antineoplásicos Fitogénicos/uso terapéutico , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/uso terapéutico , Liberación de Fármacos , Pulmón/efectos de los fármacos , Pulmón/metabolismo , Pulmón/patología , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patología , Masculino , Ratones Endogámicos BALB C , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/uso terapéutico , Tamaño de la Partícula , Polvos , Albúmina Sérica Bovina/química , Albúmina Sérica Bovina/farmacocinética , Albúmina Sérica Bovina/uso terapéutico , Distribución TisularRESUMEN
Core-crosslinked pullulan nanoparticles (Pull-LA-CLNPs) were synthesized by the reduction-sensitive strategy for paclitaxel (PTX) delivery. Pull-LA-CLNPs showed high stability against extensive dilution, high salt concentration and organic solvent. In vitro drug release study showed that PTX release from Pull-LA-NPs at pH 7.4 and 5.4 was significantly influenced by addition of DTT. In cytotoxicity assay, PTX loaded Pull-LA-CLNPs showed a low IC50 at 0.51µg/mL. Asialoglycoprotein receptor (ASGPR) competitive inhibition and intracellular distribution studies performed by flow cytometer, fluorescence microscope and confocal laser scanning microscopy (CLSM) showed that Pull-LA-NPs could be efficiently taken up by the cells via ASGPR-mediated endocytosis and mainly distributed in cytoplasm. From in vivo pharmacokinetics study, Pull-LA-CLNPs displayed the longest systemic retention time and slowest plasma elimination rate in comparison with Taxol and Pull-LA-NCLNPs. In conclusion, Pull-LA-CLNPs is a promisingly safe, biodegradable and cell-specific nano-carrier to deliver lipophilic anticancer drugs.