RESUMO
Mild photothermal therapy (PTT) shows the potential for chemosensitization by tumor-localized P-glycoprotein (P-gp) modulation. However, conventional mild PTT struggles with real-time uniform temperature control, obscuring the temperature-performance relationship and resulting in thermal damage. Besides, the time-performance relationship and the underlying mechanism of mild PTT-mediated P-gp reversal remains elusive. Herein, we developed a temperature self-limiting lipid nanosystem (RFE@PD) that integrated a reversible organic heat generator (metal-phenolic complexes) and metal chelator (deferiprone, DFP) encapsulated phase change material. Upon NIR irradiation, RFE@PD released DFP for blocking ligand-metal charge transfer to self-limit temperature below 45 °C, and rapidly reduced P-gp within 3 h via Ubiquitin-proteasome degradation. Consequently, the DOX·HCl-loaded thermo-chemotherapeutic lipid nanosystem (RFE@PD-DOX) led to dramatically improved drug accumulation and 5-fold chemosensitization in MCF-7/ADR tumor models by synchronizing P-gp reversal and drug pulse liberation, achieving a tumor inhibition ratio of 82.42%. This lipid nanosystem integrated with "intrinsic temperature-control" and "temperature-responsive pulse release" casts new light on MDR tumor therapy.
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Immune cells stand as a critical component of the immune system to maintain the internal environment homeostasis. The dysfunction of immune cells can result in various life-threatening diseases, including refractory infection, diabetes, cardiovascular disease, and cancer. Therefore, strategies to standardize or even enhance the function of immune cells are critical. Recently, nanotechnology has been highly researched and extensively applied for enhancing the cytoplasmic delivery of bioactive molecules to immune cells, providing efficient approaches to correct in vivo and in vitro dysfunction of immune cells. This review focuses on the technologies and challenges involved in improving endo-lysosomal escape, cytoplasmic release and organelle targeted delivery of different bioactive molecules in immune cells. Furthermore, it will elaborate on the broader vision of applying nanotechnology for treating immune cell-related diseases and constructing immune therapies and cytopharmaceuticals as potential treatments for diseases.
Assuntos
Nanotecnologia , Neoplasias , Citoplasma , Citosol , Sistemas de Liberação de Medicamentos , Humanos , Neoplasias/tratamento farmacológico , OrganelasRESUMO
ABSTRACT: Cardiovascular disease is responsible for the largest number of deaths worldwide, and atherosclerosis is the primary cause. Apoptotic cell accumulation in atherosclerotic plaques leads to necrotic core formation and plaque rupture. Emerging findings show that the progression of atherosclerosis appears to suppress the elimination of apoptotic cells. Mechanistically, the reduced edibility of apoptotic cells, insufficient phagocytic capacity of phagocytes, downregulation of bridging molecules, and dysfunction in the polarization of macrophages lead to impaired efferocytosis in atherosclerotic plaques. This review focuses on the characteristics of efferocytosis in plaques and the therapeutic strategies aimed at promoting efferocytosis in atherosclerosis, which would provide novel insights for the development of antiatherosclerotic drugs based on efferocytosis.
Assuntos
Aterosclerose , Placa Aterosclerótica , Apoptose/fisiologia , Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Humanos , Macrófagos/metabolismo , Fagocitose/fisiologia , Placa Aterosclerótica/metabolismoRESUMO
Cholesterol crystals (CCs), originally accumulating in the lysosome of cholesterol-laden cells, can aggravate the progression of atherosclerosis. ß-cyclodextrin (CD) is a potent cholesterol acceptor or CC solubilizer. However, the random extraction of cholesterol impedes the in vivo application of CD for removing lysosomal CCs. Here, we exploit poly-ß-cyclodextrin (pCD) as a lysosomal CC solubilizer and dextran sulfate grafted with benzimidazole (BM) as a pH-sensitive switch (pBM) to self-assemble into a supramolecular nanoassembly (pCD/pBM-SNA). The CD cavity in pCD/pBM-SNA can be efficiently sealed by hydrophobic BM at pH 7.4 (OFF). After it enters the lysosome, pCD/pBM-SNA disassembles, recovers the CD cavity to dissolve CCs into free cholesterol due to the protonation of BM (ON), and reduces CCs, finally enhancing the cholesterol efflux and promoting atherosclerosis regression. Our findings provide an "OFF-ON" tactic to remove lysosomal CCs for antiatherosclerosis as well as other diseases such as Niemann-Pick type C diseases with excessive cholesterol accumulation in the lysosome.
Assuntos
beta-Ciclodextrinas , 2-Hidroxipropil-beta-Ciclodextrina , Colesterol , Concentração de Íons de Hidrogênio , Lisossomos , beta-Ciclodextrinas/farmacologiaRESUMO
A multimodal cancer therapeutic nanoplatform is reported. It demonstrates a promising approach to synergistically regulating the tumor microenvironment. The combination of intracellular reactive oxygen species (ROS) generated by irradiation of photosensitizer and endoplasmic reticulum (ER) stress induced by 2-deoxy-glucose (2-DG) has a profound effect on necrotic or apoptotic cell death. Especially, targeting metabolic pathway by 2-DG is a promising strategy to promote the effect of photodynamic therapy and chemotherapy. The nanoplatform can readily release its cargoes inside cancer cells and combines the advantages of ROS-sensitive releasing chemotherapeutic drugs, upregulating apoptosis pathways under ER stress, light-induced generation of cytotoxic ROS, achieving tumor accumulation, and in vivo fluorescence imaging capability. This work highlights the importance of considering multiple intracellular stresses as design parameters for nanoscale functional materials in cell biology, immune response, as well as medical treatments of cancer, Alzheimer's disease, etc.
Assuntos
Antineoplásicos/farmacologia , Desoxiglucose/farmacologia , Estresse do Retículo Endoplasmático , Luz , Microambiente Tumoral/efeitos dos fármacos , Apoptose , Terapia Combinada , Humanos , Cinética , Células MCF-7 , Nanomedicina , Necrose , Fagocitose , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Espécies Reativas de OxigênioRESUMO
Given the multiple interactions between neutrophils (NEs) and atherosclerosis (AS), in this study, we exploited NEs as cellular vehicles loaded with cationic liposomes for actively targeting atherosclerotic sites. The cellular vehicles based on NEs possess efficient internalization of cationic liposomes and sensitive response to the chemotaxis of atherosclerotic inflammatory cells, which ultimately realize the targeted delivery of the cargos into the target cells in vitro. Moreover, these effects also translated to significant enhancement of the accumulation of NEs' cargos into the atherosclerotic plaque in vivo after administering NE vehicles to the AS animal model. Consequently, cellular vehicles based on NEs could be a novel strategy for targeted delivery of payloads into atherosclerotic plaque, which would facilitate theranostics for AS and the development of anti-AS drugs to manage the disease.
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Aterosclerose/tratamento farmacológico , Aterosclerose/metabolismo , Sistemas de Liberação de Medicamentos/métodos , Neutrófilos/metabolismo , Placa Aterosclerótica/tratamento farmacológico , Animais , Aorta/metabolismo , Apolipoproteínas E/genética , Linhagem Celular , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Estabilidade de Medicamentos , Lipossomos/farmacocinética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Nanomedicina/métodos , Tamanho da Partícula , Distribuição TecidualRESUMO
Mitoxantrone (MTO) is a potent drug used to treat breast cancer; however, efforts to expand its clinical applicability have been restricted because of its high risk for cardiotoxicity. In this study, we successfully conjugated MTO or folic acid (FA) to a synthesized D-α-tocopheryl polyethylene glycol 2000 succinate (TPGS2k), herein, shortened to MCT and FCT, respectively. The two produced conjugates could self-assemble to form MCT micelles or MCT/FCT mixed micelles (FMCT) aiming to lower systemic toxicity, enhance entrapment efficiency, and provide a platform for targeted delivery. Moreover, these micellar materials showed a significantly low CMC and could be used to load MTO. The diameters of MTO-loaded micelles (MTO-MCT and MTO-FMCT) were less than 100 nm with a negative zeta potential. We further characterized the pH-responsive drug release of MTO-MCT and MTO-FMCT and then assessed their cellular uptake and antitumor efficacy in human breast cancer cell lines (MCF-7) via confocal microscopy, flow cytometry, and cytotoxicity studies. All the results revealed that both MTO-MCT and MTO-FMCT increased drug loading and entrapment efficiency and possessed sufficient pH-sensitive release. Additionally, MTO-FMCT displayed an improved uptake through folate-mediated endocytosis, resulting in a higher cytotoxic effect on MCF-7 cells compared with that of MTO-MCT. Meanwhile, both MTO-MCT and MTO-FMCT exhibited a low toxicity on hCMEC/D3 normal cells. More importantly, pharmacokinetic study demonstrated that, in comparison with free MTO injection, MTO-MCT and MTO-FMCT, respectively, achieved half-lives 11.5 and 13 times longer and a 9.7- and 5.8-fold increase in AUC. In vivo, both MTO-MCT and MTO-FMCT formulations significantly prolonged the survival time of MCF-7 tumor-bearing mice and had a better efficacy/toxicity ratio. Promisingly, MTO-FMCT micelles remarkably increased MTO accumulation in tumors in vivo, induced higher tumor cell apoptosis, and showed lower toxicity toward major organs. These results imply that MTO-FMCT may be used as a potential drug delivery system for breast cancer targeted therapy.
Assuntos
Antineoplásicos/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Ácido Fólico/administração & dosagem , Mitoxantrona/administração & dosagem , Vitamina E/administração & dosagem , Animais , Apoptose/efeitos dos fármacos , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Liberação Controlada de Fármacos/fisiologia , Feminino , Humanos , Células MCF-7 , Masculino , Camundongos , Camundongos Nus , Micelas , Ratos , Ratos Sprague-DawleyRESUMO
A novel "collaborative assembly" approach was reported for the synthesis of an siRNA delivery system via a combination of an electrostatically driven physical assembly and a facile click reaction-mediated chemical assembly, which showed various advantages of more safety, efficiency, and flexibility over the conventional approach that is only based on the physical assembly. This strategy remained a high cationic property of lipid-based complex for high siRNA loading capacity. The direct chemical modification of a model polyanion, hyaluronic acid (HA) on the cationic complex via click chemistry shielded the positive charge of complex without affecting the siRNA binding, which reduced the toxicity and enhanced the blood stability of the complex. In addition, the incorporated polyanion might be prefunctionalized, which endued the carrier with better biological characteristics such as long circulating or tumor targeting. We demonstrated that the obtained lipid-polymer hybrid nanoparticle (RSC-HA) using collaborative assembly presented greater in vivo stability in the blood for efficient tumor targeting than the physically assembled RSC/HA in which HA was physically adsorbed on the complex. After endocytosis into the cells, the protection of RSC-HA on siRNA turned off, while the release of siRNA induced by the intracellular signals for enhanced gene-silencing capacity. This combination of physical and chemical assemblies provides an efficient strategy for the exploitation of safe, stable, and functionalized siRNA delivery systems.
Assuntos
Técnicas de Transferência de Genes , Neoplasias Experimentais/genética , Neoplasias Experimentais/metabolismo , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/metabolismo , Animais , Linhagem Celular Tumoral , Inativação Gênica/efeitos dos fármacos , Humanos , Lipídeos/química , Camundongos , Estrutura Molecular , Nanopartículas/química , Neoplasias Experimentais/patologia , Polímeros/química , RNA Interferente Pequeno/química , RNA Interferente Pequeno/farmacologia , RatosRESUMO
In this study, a dual-targeting drug delivery system based on bovine serum albumin nanoparticles (BSA-NPs) modified with both lactoferrin (Lf) and mPEG2000 loading doxorubicin (DOX) was designed, and its blood-brain barrier (BBB) penetration and brain glioma cells targeting properties were explored. BSA-NPs were prepared by a desolvation technique, and mPEG2000 was incorporated onto the surface of BSA-NPs by reacting with the free amino-group of BSA to form mPEG2000-modified BSA-NPs (P2000-NPs). Finally, Lf-modified P2000-NPs (Lf-NPs) was obtained by absorbing Lf onto the surface of P2000-NPs via the positive and negative charges interaction at physiological pH. Three levels of mPEG2000 and Lf-modified NPs were prepared and characterized, respectively. The uptake and potential cytotoxicity of different DOX preparations in vitro by the primary brain capillary endothelial cells (BCECs) and glioma cells (C6) were investigated. The dual-targeting effects were studied on the BBB model in vitro, BCECs/C6 glioma coculture model in vitro, and C6 glioma-bearing rats in vivo, respectively. The results exhibited that, with the increase of the amount of both mPEG2000 and Lf, the particle size of NPs increased and its zeta potential decreased. The in vivo pharmacokinetics study in healthy rats exhibited that P2000-NPs with a high level of mPEG2000 (P2000H-NPs) had longer circulation time in vivo. Compared to other NPs, Lf-NPs with high level of both Lf and mPEG2000 (LfH-NPs) showed the strongest cytotoxicity and the highest effectiveness in the uptake both in BCECs and C6 as well as improved the dual-targeting effects. Body distribution of DOX in different formulations revealed that LfH-NPs could significantly increase the accumulation of DOX in the brain, especially at 2 h postinjection (P < 0.05). In conclusion, Lf-NPs were a prospective dual-targeting drug delivery system for effective targeting therapy of brain gliomas.
Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Portadores de Fármacos/administração & dosagem , Glioma/tratamento farmacológico , Lactoferrina/administração & dosagem , Nanopartículas/administração & dosagem , Polietilenoglicóis/administração & dosagem , Soroalbumina Bovina/administração & dosagem , Animais , Antibióticos Antineoplásicos/administração & dosagem , Barreira Hematoencefálica/metabolismo , Química Farmacêutica/métodos , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Células Endoteliais/metabolismo , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Distribuição Tecidual/fisiologiaRESUMO
Neutrophil extracellular traps (NETs) play a crucial role in the formation of vulnerable plaques and the development of atherosclerosis. Alleviating the pathological process of atherosclerosis by efficiently targeting neutrophils and inhibiting the activity of neutrophil elastase to inhibit NETs is relatively unexplored and is considered a novel therapeutic strategy with clinical significance. Sivelestat (SVT) is a second-generation competitive inhibitor of neutrophil elastase with high specificity. However, therapeutic effect of SVT on atherosclerosis is restricted because of the poor half-life and the lack of specific targeting. In this study, we construct a plaque-targeting and neutrophil-hitchhiking liposome (cRGD-SVT-Lipo) to improve the efficacy of SVT in vivo by modifying the cRGD peptide onto SVT loaded liposome, which was based on the interaction between cRGD peptide and integrin ανß3 on the surface of cells in blood and plaque, including epithelial cell, macrophage and neutrophils. The cRGD-SVT-Lipo could actively tend to or hitchhike neutrophils in situ to reach atherosclerotic plaque, which resulted in enhanced atherosclerotic plaque delivery. The cRGD-SVT-Lipo could also reduce plaque area, stabilize plaque, and ultimately alleviate atherosclerosis progression through efficiently inhibiting the activity of neutrophil elastase in atherosclerotic plaque. Therefore, this study provides a basis and targeting strategy for the treatment of neutrophil-related diseases. STATEMENT OF SIGNIFICANCE: Neutrophil extracellular traps (NETs)-inhibiting is a prospective therapeutic approach for atherosclerosis but has received little attention. The NETs can be inhibited by elastase-restraining. In this work, an intriguing system that delivers Sivelestat (SVT), a predominantly used neutrophil elastase inhibitor with poor targeting capability, is designed to provide the drug with plaque-targeting and neutrophil-hitchhiking capability. The result suggests that this system can effectively hinder the formation of NETs and delay the progression of atherosclerosis.
Assuntos
Aterosclerose , Placa Aterosclerótica , Humanos , Placa Aterosclerótica/tratamento farmacológico , Neutrófilos , Elastase de Leucócito , Lipossomos , Aterosclerose/tratamento farmacológico , Aterosclerose/patologiaRESUMO
Refractory leukemia remains the most common therapeutic problem in clinical treatment of leukemia. The key therapy of refractory leukemia is to kill, thoroughly, the minimal residual disease and leukemia stem cells in the highly vascularized red marrow areas. In this study, two new conjugates, alendronate-polyethylene glycol (100) monostearate and folate-polyethylene glycol (100) monostearate, were synthesized to develop a multistep targeting nanostructured lipid carriers by enhancing drug transport to the high bone turnover areas adjacent to the red marrow and targeting the minimal residual disease and leukemia stem cells. This dual targeting system demonstrated a great binding affinity to hydroxyapatite, a model component of bone minerals, and higher cell uptake (in the form of carriers but not drug) and cytotoxicity in the K562 cell line, a leukemia cell line with overexpressed folate receptors, were observed in vitro compared to unmodified carriers, especially when the cells were pretreated and the receptors were up-regulated by all-trans retinoic acid. The comodel test of K562 cells and HA showed that this dual targeting system could desorb from bone surface and be taken up by leukemia cells. For the in vivo study, this dual targeting system exhibited a significant increase in plasma half-life and could specifically accumulate in the bone tissue of rats or mice after intravenous injection. Ex vivo imaging of mice femurs and confocal laser scanning microscope imaging of mice femur slices further confirmed that this dual targeting system could favorably deposit to the osteoblast-enriched areas of high bone turnover in regions of trabecular bone surrounded by red marrow. In vivo antitumor activity in K562/BALB/c-nu leukemia mice showed that the treatment of this dual targeting system significantly reduced the white blood cell (WBC) number in peripheral blood and bone marrow to the normal level. In conclusion, this dual targeting system could precisely target to the regions where the minimal residual disease and leukemia stem cells are located and then be specifically uptaken in large amounts, which is a valuable target for refractory leukemia therapy.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Leucemia/tratamento farmacológico , Neoplasia Residual/tratamento farmacológico , Células-Tronco Neoplásicas/efeitos dos fármacos , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/uso terapêutico , Medula Óssea/efeitos dos fármacos , Linhagem Celular Tumoral , Durapatita/química , Ácido Fólico/análogos & derivados , Ácido Fólico/química , Humanos , Leucócitos/efeitos dos fármacos , Camundongos , Mitoxantrona/administração & dosagem , Mitoxantrona/uso terapêutico , Polietilenoglicóis/química , RatosRESUMO
Checkpoint blockade immunotherapy (CBI) have exhibited remarkable benefits for cancer therapy. However, the low responsivity of CBI hinders its application in treatment of bladder cancer. Ferroptosis shows potential for increasing the responsivity of CBI by inducing immunogenic cell death (ICD) process. Herein, we developed a mitochondrial-targeted liposome loaded with brequinar (BQR) (BQR@MLipo) for enhancing the mitochondrial-related ferroptosis in bladder cancer in situ. It could be found that BQR@MLipo could selectively accumulate into mitochondria and inactivate dihydroorotate dehydrogenase (DHODH), which induced extensive mitochondrial lipid peroxidation and ROS, finally triggering ferroptosis of bladder cancer cells to boost the release of intracellular damage-associated molecular patterns (DAMPs) such as calreticulin (CRT), adenosine triphosphate (ATP), high mobility group box 1 (HMGB1). In addition, BQR@MLipo further promoted the release of mtDNA into the cytoplasm to activate the cGAS-STING pathway for the secretion of IFN-ß, which would increase the cross-presentation of antigens by dendritic cells and macrophage phagocytosis. Furthermore, the in vivo studies revealed that BQR@MLipo could remarkably accumulate into the bladder tumor and successfully initiate the infiltration of CD8+ T cells into tumor microenvironment for enabling efficient CBI to inhibit bladder tumor growth. Therefore, BQR@MLipo may represent a clinically promising modality for enhancing CBI in bladder tumor.
Assuntos
Ferroptose , Neoplasias da Bexiga Urinária , Humanos , Linfócitos T CD8-Positivos , Inibidores de Checkpoint Imunológico , Lipossomos , Imunoterapia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Mitocôndrias , Linhagem Celular Tumoral , Microambiente TumoralRESUMO
Atherosclerotic cardiovascular diseases remain the leading causes of morbidity and mortality worldwide. Cholesterol crystals in atherosclerotic plaques play an essential role in atherosclerosis progression. However, no clinical drugs have been used for removing cholesterol crystals from plaque to counter atherosclerosis. Previous studies identified the hydrophobic domain of lipid bilayer in liposomes acted as sinks for solubilizing hydrophobic cholesterol. Moreover, adjusting the composition of the lipid bilayer in liposomes can enhance its hydrophobic molecule loading capacity. Therefore, in this study, ginsenosides Rb1 (Rb1), one of main active components of ginseng which has a similar structure to cholesterol, is anchored into soy phospholipids bilayer with its hydrophobic region to prepare nano-sponge-like liposomes (Rb1-LPs), aiming to amplify the solubilization of cholesterol in lipid bilayer. For targeting delivery to atherosclerotic plaques, Annexin V (AnxV), a protein that can specifically recognize phosphatidylserine upregulated in atherosclerotic plaques, is applied to decorate the surface of Rb1-LPs by click reaction to obtain the final preparation of AnxV-Rb1-LPs. The in vitro studies showed that incorporating Rb1 into lipid bilayer remarkably increased the affinity of the lipid bilayer to free cholesterol and the solubilization of cholesterol crystals. Additionally, nano-sponge-like liposomes could efficiently reduce the accumulation of cholesterol crystals and improve cholesterol efflux, finally inhibiting inflammation and apoptosis in cholesterol-laden cells. Furthermore, AnxV-Rb1-LPs could efficiently accumulate in atherosclerotic plaques after intravenous injection, exert nano-sponge-like functions to remove intra- and extracellular cholesterol crystals, ultimately alleviating inflammation and apoptosis in atherosclerotic plaques for antiatherosclerosis. Therefore, AnxV-Rb1-LPs provide a potential strategy for removing cholesterol crystals in atherosclerotic plaques and can be further utilized in other diseases with excessive cholesterol accumulation.
Assuntos
Aterosclerose , Ginsenosídeos , Placa Aterosclerótica , Anexina A5 , Aterosclerose/tratamento farmacológico , Colesterol/química , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Humanos , Inflamação , Bicamadas Lipídicas , Lipopolissacarídeos , Lipossomos/uso terapêutico , Fosfatidilserinas , Placa Aterosclerótica/tratamento farmacológicoRESUMO
Tumor metastasis is directly correlated to poor prognosis and high mortality. Circulating tumor cells (CTCs) play a pivotal role in metastatic cascades, of which CTC clusters is highly metastatic compared to single CTCs. Although platelets and neutrophils within the bloodstream could further exacerbate the pro-metastatic effect of single CTCs, the influence of platelets and neutrophils on CTC clusters mediated metastasis remains unclear. In this study, a pro-metastatic complex composed of CTC clusters, platelets and neutrophils, namely circulating tumor microemboli (CTM), was identified in vivo among different metastatic tumor, which was demonstrated with highly upregulation of hypoxia-inducible factor-1α (HIF-1α). While knock-out of HIF-1α or therapeutically downregulating of HIF-1α via HIF-1α inhibitor (BAY87-2243)-loaded neutrophil cyto-pharmaceuticals (PNEs) could efficiently restrain CTM mediated lung metastasis. The underlying mechanism of metastasis inhibition was attributed to the downregulation of HIF-1α-associated PD-L1, which would enhance immune response for inhibiting metastatic cells. Thus, our work here illustrates that hypoxia was an essential factor in promoting CTM colonization in lung. More importantly, we provide a promising strategy by targeted downregulation of HIF-1α in CTM via neutrophil cyto-pharmaceuticals for treatment of CTM mediated metastasis.
Assuntos
Embolia , Neoplasias Pulmonares , Células Neoplásicas Circulantes , Linhagem Celular Tumoral , Regulação para Baixo , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Neoplasias Pulmonares/patologia , Metástase Neoplásica , Células Neoplásicas Circulantes/patologia , Preparações FarmacêuticasRESUMO
A new conjugate, octreotide-polyethylene glycol(100) monostearate (OPMS), was developed for the enhancement of targeting delivery of hydroxycamptothecine (HCPT) loaded in nanostructured lipid carrier (NLC). 2 × 10(-3) and 5 × 10(-3) mmol of OPMS were respectively used to modify NLC so that the targeted nanocarriers with low and high ligand density were obtained. For comparison, the pegylated NLCs without octreotide were prepared by adding equal molar amounts of polyethylene glycol(100) monostearate (PGMS). The relation between the modification levels and properties of various NLCs were studied in vivo and in vitro. At a high modification level, a slower release rate of HCPT and the more stable nanocarriers was achieved. At the same time, the fixed aqueous layer thickness (FALT) and average surface density of PEG chains (SD(PEG)) was increased, but the distance (D) between two neighboring PEG grafting sites became narrower. The in vivo pharmacokinetic study in healthy rat indicated that the modified NLCs had a longer circulation than NLC (P < 0.05) due to pegylation effect and OPMS modified NLCs had larger MRT and AUC(0-t) than that of PGMS modified NLCs at the same modification level. Furthermore, the florescence microscopy observation also showed the targeting effect of octreotide modification on somatostatin receptors (SSTRs) of tumor cell (SMMC-7721). The uptake of SMMC-7721 was much more than that of normal liver cell (L02) for OPMS modified NLC, and the highest uptake was observed for 5 × 10(-3) mmol of OPMS modified one. No obvious difference was found among the L02 uptake of OPMS modified NLCs and NLC, but their uptake was higher than that of PGMS modified NLCs. All the results indicated that the OPMS highly modified NLCs would improve the effect of antitumor therapy by inhibiting the degradation, evading RES and enhancing the drug uptake of tumor cells.
Assuntos
Antineoplásicos/farmacocinética , Camptotecina/análogos & derivados , Portadores de Fármacos/farmacocinética , Lipídeos/química , Nanoestruturas/química , Octreotida/química , Polietilenoglicóis/química , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Antineoplásicos/metabolismo , Transporte Biológico , Camptotecina/administração & dosagem , Camptotecina/química , Camptotecina/metabolismo , Camptotecina/farmacocinética , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Linhagem Celular Tumoral , Fenômenos Químicos , Preparações de Ação Retardada , Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Meia-Vida , Humanos , Ligantes , Lipídeos/efeitos adversos , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Masculino , Nanoestruturas/efeitos adversos , Nanoestruturas/ultraestrutura , Proteínas de Neoplasias/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Somatostatina/metabolismoRESUMO
This study was done to prepare thymopentin (TP5)-loaded poly (butyl cyanoacrylate) nanoparticles (TP5-PBCA-NPs) and evaluate thier efficacy for oral delivery. TP5-PBCA-NPs were prepared by emulsion polymerization, and the formulation was optimized based on Box-Behnken experimental design. The physico-chemical characteristics of TP5-PBCA-NPs were evaluated using transmission electron microscopy (TEM), malvern zetasizer, Fourier transform infra-red spectroscopy (FT-IR) and differential scanning calorimetry (DSC). The encapsulation efficiency, enzymatic degradation and release behavior of TP5-PBCA-NPs in various media were evaluated using a high-performance liquid chromatography (HPLC) method. The pharmacodynamic studies on oral administration of TP5-PBCA-NPs were performed in FACScan flow cytometry. An optimum formulation consisted of 0.7% poloxamer 188 (Pol), 0.6% dextran-70 (Dex), 0.1% sodium metabisulfite (Sm), 0.1% TP5 and 1% (v/v) n-butyl cyanoacrylate. The particle size and zeta potential of optimized TP5-PBCA-NPs was 212 nm and -22.6 mV respectively with 82.45% encapsulation efficiency. TP5 was entrapped inside the nanoparticles in molecular dispersion form. The release of TP5 from PBCA-NPs was pH dependent; the cumulative release percentage in 0.1 M HCI for 4 hours was less than 16% while it was more than 80% in pH6.8 PBS. The PBCA-NPs could efficiently protect TP5 from enzymatic degradation; the remained percentage of TP5 encapsulated in PBCA-NPs was 58.40% after incubated with trypsin in pH6.8 PBS for 4 h while it was only 32.29% for free drug. In the oral administration study in vivo, the lowered T-lymphocyte subsets values were significantly increased and the raised CD4+/CD8+ ratio was evidently reduced compared with that of TP5 solution (p < 0.05), and the improvement of bioavailability was dose-dependent. These results indicated that the PBCA nanoparticles may be a promising carrier for oral delivery of TP5.
Assuntos
Adjuvantes Imunológicos/administração & dosagem , Adjuvantes Imunológicos/farmacocinética , Cianoacrilatos/química , Timopentina/administração & dosagem , Timopentina/farmacocinética , Adjuvantes Imunológicos/química , Animais , Disponibilidade Biológica , Varredura Diferencial de Calorimetria , Química Farmacêutica , Ciclofosfamida/antagonistas & inibidores , Portadores de Fármacos , Desenho de Fármacos , Eletroquímica , Feminino , Citometria de Fluxo , Hidrólise , Imunidade/efeitos dos fármacos , Imunossupressores/antagonistas & inibidores , Cinética , Nanopartículas , Tamanho da Partícula , Ratos , Ratos Sprague-Dawley , Solubilidade , Espectroscopia de Infravermelho com Transformada de Fourier , Subpopulações de Linfócitos T/efeitos dos fármacos , Timopentina/químicaRESUMO
Limb and CNS expressed 1 like (LIX1L) is over-expressed in several types of tumors. However, the function of LIX1L in glucose metabolism and hepatocellular carcinoma (HCC) progression remains elusive. Here we report that LIX1L is over-expressed in human HCC tissues, which predicts unfavorable prognosis. LIX1L deficiency in vivo significantly attenuated liver cancer initiation in mice. Functional studies indicated that LIX1L overexpression elevated proliferation, migratory, invasive capacities of HCC cells in vitro, and promoted liver cancer growth and metastasis in vivo. LIX1L knockdown up-regulated fructose-1,6-bisphosphatase (FBP1) expression to reduce glucose consumption as well as lactate production. Mechanistically, LIX1L increased miR-21-3p expression, which targeted and suppressed FBP1, thereby promoting HCC growth and metastasis. MiR-21-3p inhibitor could abrogate LIX1L induced enhancement of cell migration, invasion, and glucose metabolism. Inhibition of miR-21-3p suppressed tumor growth in an orthotopic tumor model. Our results establish LIX1L as a critical driver of hepatocarcinogenesis and HCC progression, with implications for prognosis and treatment.
RESUMO
Naringenin (NGN) can be used to inhibit the progression of nonalcoholic fatty liver disease (NAFLD) in mice, but its poor water solubility limits its applications. Nanostructured lipid carriers (NLCs) have recently attracted much attention in the field of nanodrug delivery systems because they increase the drug loading capacity and impressively enhance the solubility of indissolvable drugs. Herein, a thin-film dispersion method was used to prepare naringenin-loaded nanostructured lipid carriers (NGN-NLCs). These NGN-NLCs have a narrow size distribution of 171.9 ±2.0 nm, a high drug loading capacity of 23.7 ± 0.3%, a high encapsulation efficiency of 99.9 ± 0.0% and a drug release rate of 86.2 ± 0.4%. NGN- NLCs elevated the pharmacokinetic parameters (Cmax and AUC0ât) of NGN, accelerated NGN transepithelial transport in MDCK cells and intestinal absorption in the jejunum and ileum, and reduced hepatic lipid accumulation in an oleic acid (OA) plus lipopolysaccharide (LPS)-induced lipid deposition cell model in primary hepatocytes and in a methionine/choline deficient (MCD) diet-induced NAFLD mouse model. A detailed study of the mechanism showed that this NLC formulation elevated the drug release rate in simulated intestinal solutions in vitro, the transepithelial transport in MDCK cells, the oral absorption in mice and the ex vivo intestinal absorption of NGN. Thus, NGN-NLCs significantly enhanced the inhibitory effects of NGN on MCD diet induced mouse NAFLD.
Assuntos
Nanoestruturas , Hepatopatia Gordurosa não Alcoólica , Administração Oral , Animais , Portadores de Fármacos , Flavanonas , Lipídeos , Camundongos , Hepatopatia Gordurosa não Alcoólica/tratamento farmacológico , Tamanho da Partícula , Ratos , Ratos Sprague-DawleyRESUMO
Octreotide is believed to be the ligand of somatostatin receptors (SSTRs) which are widely used in tumor diagnosis and clinical therapy. In the present work, a new targeting conjugate, octreotide-polyethylene glycol-phosphatidylethanolamine (Oct-PEG-PE), was developed for the assembling of liposome, and the effect of octreotide-modification on the enhancement of the delivery and targeting of doxorubicin-loaded liposomes was investigated in vitro and in vivo. Oct-PEG-PE was synthesized by a three-step reaction involving two derivative intermediate formations of bis (p-nitrophenyl carbonate)-PEG ((pNP)(2)-PEG) and pNP-PEG-PE. The Oct-modified and unmodified liposomes (DOX-OL and DOX-CL) were prepared by the ammonium sulfate gradient method. Both drug uptake assay and cell apoptosis assay suggested that DOX-OL noticeably increased the uptake of DOX in SMMC-7721 cells and showed a more significant cytotoxicity, compared with DOX-CL. The effect of DOX-OL was remarkably inhibited by free octreotide. In contrast, no significant difference in drug cytotoxicity was found between DOX-OL and DOX-CL in CHO cells without obvious expression of SSTRs. The study of ex vivo fluorescence tissues imaging of BALB/c mice and in vivo tissue distribution of B16 tumor-bearing mice indicated that DOX-OL caused remarkable accumulation of DOX in melanoma tumors and the pancreas, in which the SSTRs are highly expressed.
Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Lipossomos/química , Neoplasias/tratamento farmacológico , Octreotida/química , Receptores de Somatostatina/metabolismo , Animais , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Células CHO , Linhagem Celular Tumoral , Cricetinae , Cricetulus , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Humanos , Lipossomos/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Octreotida/metabolismo , Fosfatidiletanolaminas/química , Polietilenoglicóis/químicaRESUMO
Cytopharmaceuticals, in which drugs/nanomedicines are loaded into/onto autologous patient- or allogeneic donor-derived living cells ex vivo, have displayed great promise for targeted drug delivery in terms of improved biocompatibility, superior targeting, and prolonged circulation. Despite certain impressive therapeutic benefits in preclinical studies, several obstacles retard their clinical application, such as the lack of facile and convenient methods of carrier cell acquisition, technologies for preparing cytopharmaceuticals at scale with undisturbed carrier cell viability, and modalities for monitoring the in vivo fate of cytopharmaceuticals. To comprehensively understand cytopharmaceuticals and thereby accelerate their clinical translation, this review covers the main sources of various cytopharmaceuticals, technologies for preparing cytopharmaceuticals, the in vivo fate of cytopharmaceuticals including carrier cells and loaded drugs/nanomedicines, and the application prospects of cytopharmaceuticals. It is our hope that this review will elucidate the bottlenecks associated with cytopharmaceutical preparation, leading to the acceleration of future industrialization of cell-based formulations.