RESUMEN
The marketed paclitaxel (PTX) formulation Taxol relies on the application of Cremophor EL as a solubilizer. The major drawback of Taxol is its hypersensitivity reactions and a pretreatment of anti-allergic drugs is a necessity. Therefore, developing an efficient and safe delivery vehicle is a solution to increase PTX treatment outcomes with minimal adverse effects. In this work, we prepared the amphiphilic peptides (termed AmP) from soybean proteins using a facile two-step method. AmP could efficiently solubilize PTX by self-assembling into mixed micelles with D-α-tocopherol polyethylene glycol succinate (TPGS), a common pharmaceutical expedient (PTX@TPGS-AmP). The intravenously administrated PTX@TPGS-AmP exhibited a slow clearance (0.24 mL·(min·kg)-1) and an enhanced AUC (41.4 µg.h/mL), manifesting a 3.6-fold increase compared to Taxol. In a murine 4T1 tumor model, PTX@TPGS-AmP displayed a superior antitumor effect over Taxol. Importantly, safety assessment showed a high biocompatibility of AmP and an i.v. dose up to 2500 mg/kg led to no observable abnormalities in the mice. In summary, the AmP presents a new green and easily-prepared amphiphilic biomaterial, with promising potential as a pharmaceutical excipient for drug delivery.
Asunto(s)
Neoplasias , Paclitaxel , Ratones , Animales , Paclitaxel/uso terapéutico , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos , Micelas , alfa-Tocoferol , PéptidosRESUMEN
BACKGROUND: Acute lung injury (ALI) is a fatal respiratory disease caused by overreactive immune reactions (e.g., SARS-CoV-2 infection), with a high mortality rate. Its treatment is often compromised by inefficient drug delivery barriers and insufficient potency of the currently used drugs. Therefore, developing a highly effective lung-targeted drug delivery strategy is a pressing clinical need. RESULTS: In this study, the micro-sized inclusion cocrystal of asiatic acid/γ-cyclodextrin (AA/γCD, with a stoichiometry molar ratio of 2:3 and a mean size of 1.8 µm) was prepared for ALI treatment. The dissolution behavior of the AA/γCD inclusion cocrystals followed a "spring-and-hover" model, which meaned that AA/γCD could dissolve from the cocrystal in an inclusion complex form, thereby promoting a significantly improved water solubility (nine times higher than free AA). This made the cyclodextrin-based inclusion cocrystals an effective solid form for enhanced drug absorption and delivery efficiency. The biodistribution experiments demonstrated AA/γCD accumulated predominantly in the lung (Cmax = 50 µg/g) after systemic administration due to the micron size-mediated passive targeting effect. The AA/γCD group showed an enhanced anti-inflammatory therapeutic effect, as evidenced by reduced levels of pro-inflammatory cytokines in the lung and bronchoalveolar lavage fluids (BALF). Histological examination confirmed that AA/γCD effectively inhibited inflammation reactions. CONCLUSION: The micro-sized inclusion cocrystals AA/γCD were successfully delivered into the lungs by pulmonary administration and had a significant therapeutic effect on ALI.
Asunto(s)
Lesión Pulmonar Aguda , Ciclodextrinas , Triterpenos Pentacíclicos , Humanos , Ciclodextrinas/química , Distribución Tisular , Sistemas de Liberación de Medicamentos , Lesión Pulmonar Aguda/tratamiento farmacológico , SolubilidadRESUMEN
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with high mortality. The Food and Drug Administration-approved drugs, nintedanib and pirfenidone, could delay progressive fibrosis by inhibiting the overactivation of fibroblast, however, there was no significant improvement in patient survival due to low levels of drug accumulation and remodeling of honeycomb cyst and interstitium surrounding the alveoli. Herein, we constructed a dual drug (verteporfin and pirfenidone)-loaded nanoparticle (Lip@VP) with the function of inhibiting airway epithelium fluidization and fibroblast overactivation to prevent honeycomb cyst and interstitium remodeling. Specifically, Lip@VP extensively accumulated in lung tissues via atomized inhalation. Released verteporfin inhibited the fluidization of airway epithelium and the formation of honeycomb cyst, and pirfenidone inhibited fibroblast overactivation and reduced cytokine secretion that promoted the fluidization of airway epithelium. Our results indicated that Lip@VP successfully rescued lung function through inhibiting honeycomb cyst and interstitium remodeling. This study provided a promising strategy to improve the therapeutic efficacy for IPF.
Asunto(s)
Quistes , Fibrosis Pulmonar Idiopática , Nanopartículas , Humanos , Verteporfina , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , PulmónRESUMEN
Inflammatory bowel disease (IBD) is a chronic, life quality-reducing disease with no cures available yet. To develop an effective medication suitable for long-term use is an urgent but unmet need. Quercetin (QT) is a natural dietary flavonoid with good safety and multifaceted pharmacological activities against inflammation. However, orally administrated quercetin yields unproductive outcomes for IBD treatment because of its poor solubility and extensive metabolism in the gastrointestinal tract. In this work, a colon-targeted QT delivery system (termed COS-CaP-QT) was developed, of which the pectin (PEC)/Ca2+ microspheres were prepared and then crosslinked by oligochitosan (COS). The drug release profile of COS-CaP-QT was pH-dependent and colon microenvironment-responsive, and COS-CaP-QT showed preferential distribution in the colon. The mechanism study showed that QT triggered the Notch pathway to regulate the proliferation of T helper 2 (Th2) cells and group 3 innate lymphoid cells (ILC3s) and the inflammatory microenvironment was remodeled. The in vivo therapeutic results revealed that COS-CaP-QT could relieve the colitis symptoms and maintain the colon length and intestinal barrier integrity.
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Sistemas de Liberación de Medicamentos , Enfermedades Inflamatorias del Intestino , Humanos , Sistemas de Liberación de Medicamentos/métodos , Quercetina/farmacología , Quercetina/uso terapéutico , Preparaciones de Acción Retardada/farmacología , Inmunidad Innata , Pectinas/farmacología , Microesferas , Linfocitos , Enfermedades Inflamatorias del Intestino/tratamiento farmacológico , Enfermedades Inflamatorias del Intestino/metabolismo , Colon/metabolismo , Quitina/farmacologíaRESUMEN
Alleviating immunosuppression of the tumor microenvironment is an important strategy to improve immune checkpoint therapy. It is an urgent but unmet need to develop adjuvant therapeutics for assisting the mainstay immunotherapies. Trichosanthin is an approved gynecology drug in China and its immunomodulatory effects have drawn much attention as an old drug for new applications in cancer. In this work, a recombinant cell-penetrating trichosanthin (rTCS-LMWP) was prepared via genetic fusion of a cell-penetrating peptide sequence (LMWP) to trichosanthin aiming to overcome the intratumoral penetration and intracellular delivery challenges. The potential of trichosanthin as an adjuvant therapy was explored, including its effects on tumor cells, antigen-presenting cells, tumor immune microenvironment, and the synergistic effect in combination with anti-PD-1. The results revealed that rTCS-LMWP can stimulate the maturation of dendritic cells via activating the STING-TBK1-IRF3 pathway, repolarize the protumor M2-type macrophages, and upregulate the pro-inflammatory cytokine expression. Moreover, rTCS-LMWP can enhance anti-PD-1 therapeutic efficacy in a CT26-bearing mouse model. The synergistic effect involved the induction of immunogenic cell death in the tumors, the proliferation and functionalization of cytotoxic T cells, and the suppression of the immunosuppressive regulatory T cells. These findings indicate that trichosanthin can be developed as an immunomodulator to facilitate cancer immunotherapy.
Asunto(s)
Neoplasias Colorrectales , Tricosantina , Animales , Ratones , Células Presentadoras de Antígenos , Línea Celular Tumoral , Neoplasias Colorrectales/tratamiento farmacológico , Citocinas , Tricosantina/farmacología , Tricosantina/uso terapéutico , Microambiente TumoralRESUMEN
Dysregulated mucosal immune responses and colonic fibrosis impose two formidable challenges for ulcerative colitis treatment. It indicates that monotherapy could not sufficiently deal with this complicated disease and combination therapy may provide a potential solution. A chitosan-modified poly(lactic-co-glycolic acid) nanoparticle (CS-PLGA NP) system was developed for co-delivering patchouli alcohol and simvastatin to the inflamed colonic epithelium to alleviate the symptoms of ulcerative colitis via remodeling immune microenvironment and anti-fibrosis, a so-called "two-birds-one-stone" nanotherapeutic strategy. The bioadhesive nanomedicine enhanced the intestinal epithelial cell uptake efficiency and improved the drug stability in the gastrointestinal tract. The nanomedicine effectively regulated the Akt/MAPK/NF-κB pathway and reshaped the immune microenvironment through repolarizing M2Φ, promoting regulatory T cells and G-MDSC, suppressing neutrophil and inflammatory monocyte infiltration, as well as inhibiting dendritic cell maturation. Additionally, the nanomedicine alleviated colonic fibrosis. Our work elucidates that the colon-targeted codelivery for combination therapy is promising for ulcerative colitis treatment and to address the unmet medical need.
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Colitis Ulcerosa , Colitis , Nanopartículas , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/metabolismo , Colon/metabolismo , Humanos , NanomedicinaRESUMEN
There is a close connection between epigenetic regulation, cancer metabolism, and immunology. The combination of epigenetic therapy and immunotherapy provides a promising avenue for cancer management. As an epigenetic regulator of histone acetylation, panobinostat can induce histone acetylation and inhibit tumor cell proliferation, as well as regulate aerobic glycolysis and reprogram intratumoral immune cells. JQ1 is a BRD4 inhibitor that can suppress PD-L1 expression. Herein, we proposed a chemo-free, epigenetic-based combination therapy of panobinostat/JQ1 for metastatic colorectal cancer. A novel targeted binary-drug liposome was developed based on lactoferrin-mediated binding with the LRP-1 receptor. It was found that the tumor-targeted delivery was further enhanced by in situ formation of albumin corona. The lactoferrin modification and endogenous albumin adsorption contribute a dual-targeting effect on the receptors of both LRP-1 and SPARC that were overexpressed in tumor cells and immune cells (e.g., tumor-associated macrophages). The targeted liposomal therapy was effective to suppress the crosstalk between tumor metabolism and immune evasion via glycolysis inhibition and immune normalization. Consequently, lactic acid production was reduced and angiogenesis inhibited; TAM switched to an anti-tumor phenotype, and the anti-tumor function of the effector CD8+ T cells was reinforced. The strategy provides a potential method for remodeling the tumor immune microenvironment (TIME).
RESUMEN
Cell-penetrating peptides (CPPs) can aid in intracellular and in vivo drug delivery. However, the mechanisms of CPP-mediated penetration remain unclear, limiting the development and further application of CPPs. Flow cytometry and laser confocal fluorescence microscopy were performed to detect the effects of different endocytosis inhibitors on the internalization of CC12 and penetratin in ARPE-19 cells. The co-localization of CPPs with the lysosome and macropinosome was detected via an endocytosis tracing experiment. The flow cytometry results showed that chlorpromazine, wortmannin, cytochalasin D, and the ATP inhibitor oligomycin had dose-dependent endocytosis-inhibitory effects on CC12. The laser confocal fluorescence results showed that oligomycin had the most significant inhibitory effect on CC12 uptake; CC12 was co-located with the lysosome, but not with the macropinosome. For penetratin, cytochalasin D and oligomycin had obvious inhibitory effects. The laser confocal fluorescence results indicated that oligomycin had the most significant inhibitory effect on penetratin uptake; the co-localization of penetratin with the lysosome was higher than that with the macropinosome. Cation-independent CC12 and cationic penetratin may be internalized into cells primarily through caveolae and clathrin-mediated endocytosis, and they are typically dependent on ATP. The transport of penetratin could be partly achieved through the direct transmembrane pathway, as the positive charge of penetratin interacts with the negative charge of the cell membrane, and partly through the endocytic pathway.
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Péptidos de Penetración Celular , Adenosina Trifosfato/metabolismo , Proteínas Portadoras/metabolismo , Cationes/farmacología , Péptidos de Penetración Celular/metabolismo , Péptidos de Penetración Celular/farmacología , Citocalasina D/metabolismo , Citocalasina D/farmacología , Endocitosis , Oligomicinas/farmacología , TranscitosisRESUMEN
Sepsis is a dysregulated immune response to infection and potentially leads to life-threatening organ dysfunction, which is often seen in serious Covid-19 patients. Disulfiram (DSF), an old drug that has been used to treat alcohol addiction for decades, has recently been identified as a potent inhibitor of the gasdermin D (GSDMD)-induced pore formation that causes pyroptosis and inflammatory cytokine release. Therefore, DSF represents a promising therapeutic for the treatment of inflammatory disorders. Lactoferrin (LF) is a multifunctional glycoprotein with potent antibacterial and anti-inflammatory activities that acts by neutralizing circulating endotoxins and activating cellular responses. In addition, LF has been well exploited as a drug nanocarrier and targeting ligands. In this study, we developed a DSF-LF nanoparticulate system (DSF-LF NP) for combining the immunosuppressive activities of both DSF and LF. DSF-LF NPs could effectively block pyroptosis and inflammatory cytokine release from macrophages. Treatment with DSF-LF NPs showed remarkable therapeutic effects on lipopolysaccharide (LPS)-induced sepsis. In addition, this therapeutic strategy was also applied to treat ulcerative colitis (UC), and substantial treatment efficacy was achieved in a murine colitis model. The underlying mode of action of these DSF-LF-NPs may contribute to efficiently suppressing macrophage-mediated inflammatory responses and ameliorating the complications caused by sepsis and UC. As macrophage pyroptosis plays a pivotal role in inflammation, this safe and effective biomimetic nanomedicine may offer a versatile therapeutic strategy for treating various inflammatory diseases by repurposing DSF.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , COVID-19 , Colitis Ulcerosa , Disulfiram/farmacocinética , Lactoferrina , Síndrome de Respuesta Inflamatoria Sistémica , Inhibidores del Acetaldehído Deshidrogenasa/farmacología , Animales , Antiinflamatorios/farmacología , Materiales Biomiméticos/farmacología , COVID-19/inmunología , Colitis Ulcerosa/tratamiento farmacológico , Colitis Ulcerosa/inmunología , Modelos Animales de Enfermedad , Disulfiram/farmacología , Portadores de Fármacos/farmacología , Humanos , Inmunosupresores/farmacología , Lactoferrina/metabolismo , Lactoferrina/farmacología , Lipopolisacáridos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Nanopartículas/uso terapéutico , Piroptosis/efectos de los fármacos , SARS-CoV-2 , Síndrome de Respuesta Inflamatoria Sistémica/tratamiento farmacológico , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/metabolismo , Resultado del TratamientoRESUMEN
Background: Immunotherapy has profoundly changed the landscape of cancer management and represented the most significant breakthrough. Yet, it is a formidable challenge that the majority of cancers - the so-called "cold" tumors - poorly respond to immunotherapy. To find a general immunoregulatory modality that can be applied to a broad spectrum of cancers is an urgent need. Methods: Magnetic hyperthermia (MHT) possesses promise in cancer therapy. We develop a safe and effective therapeutic strategy by using magnetism-mediated targeting MHT-immunotherapy in "cold" colon cancer. A magnetic liposomal system modified with cell-penetrating TAT peptide was developed for targeted delivery of a CSF1R inhibitor (BLZ945), which can block the CSF1-CSF1R pathway and reduce M2 macrophages. The targeted delivery strategy is characterized by its magnetic navigation and TAT-promoting intratumoral penetration. Results: The liposomes (termed TAT-BLZmlips) can induce ICD and cause excessive CRT exposure on the cell surface, which transmits an "eat-me" signal to DCs to elicit immunity. The combination of MHT and BLZ945 can repolarize M2 macrophages in the tumor microenvironment to relieve immunosuppression, normalize the tumor blood vessels, and promote T-lymphocyte infiltration. The antitumor effector CD8+ T cells were increased after treatment. Conclusion: This work demonstrated that TAT-BLZmlips with magnetic navigation and MHT can remodel tumor microenvironment and activate immune responses and memory, thus inhibiting tumor growth and recurrence.
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Neoplasias del Colon/terapia , Terapia Combinada/métodos , Hipertermia , Inmunoterapia/métodos , Liposomas/química , Magnetoterapia/métodos , Nanopartículas de Magnetita/química , Receptores de Factor Estimulante de Colonias de Granulocitos y Macrófagos/antagonistas & inhibidores , Animales , Apoptosis/efectos de los fármacos , Apoptosis/efectos de la radiación , Benzotiazoles/farmacocinética , Benzotiazoles/farmacología , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Línea Celular Tumoral , Neoplasias del Colon/diagnóstico por imagen , Neoplasias del Colon/inmunología , Femenino , Humanos , Liposomas/metabolismo , Liposomas/efectos de la radiación , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Recurrencia Local de Neoplasia/metabolismo , Recurrencia Local de Neoplasia/terapia , Ácidos Picolínicos/farmacocinética , Ácidos Picolínicos/farmacología , Ratas , Microambiente Tumoral/efectos de los fármacos , Macrófagos Asociados a Tumores/efectos de los fármacos , Macrófagos Asociados a Tumores/metabolismo , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Remodeling tumor immune microenvironment (TIME) is an important strategy to lift the immunosuppression and achieve immune normalization. In this work, a mannosylated lactoferrin nanoparticulate system (Man-LF NPs) is developed for dual-targeting biomimetic codelivery of shikonin and JQ1 via the mannose receptor and LRP-1 that are overexpressed in both cancer cells and tumor-associated macrophages. The Man-LF NPs can serve as multitarget therapy for inducing immune cell death in the cancer cells, repressing glucose metabolism and repolarizing tumor-associated macrophages, and consequently, lead to remodeling the TIME (e.g., promotion of dendritic cell maturation and CD8+ T cell infiltration, as well as suppression of Treg). Moreover, JQ1 is a suppressor of PD-L1, and the Man-LF NPs can also work on PD-L1 checkpoint blockage. The results reveal the synergistic combination of shikonin and JQ1 and the treatment potency of the Man-LF NPs. Importantly, it is demonstrated that the interaction between the tumor metabolism and immunity plays an essential role in immunotherapy, and the developed drug combination and nanoformulation can target the multiple components in the complicated network of TIME, providing a potential therapeutic strategy.