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Postoperative breast cancer recurrence is tricky due to the limited therapeutic options. Transforming growth factors-ß (TGF-ß) is vital in promoting postoperative tumor recurrence. However, conventional blocking strategies fail to satisfy both bio-safety and sufficient relapse correction. Neutrophil extracellular traps (NETs) are essential for the spatiotemporal dynamics of TGF-ß at tumor-resection sites, whose unique mechanism for local TGF-ß amplification could remarkably increase the risk of relapse after surgery. Herein, the principle of NETs formation is ingeniously utilized to construct a surgical residual cavity hydrogel that mimics NETs formation. The hydrogel is prepared based on the electrostatic interaction between histidine (His) and sodium alginate (Alg). Then, arginine deiminase 4 (PAD4) protein is released during NETs formation. Simultaneously, the electrical property of His in hydrogel changes automatically, which further lead to promising localized release of anti-TGF-ß. The hydrogel system can realize specific and selective drug release at targeted NETs site over a prolonged period while exhibiting excellent biocompatibility. Superior breast cancer recurrence inhibition is achieved by suppressing TGF-ß and related indicators, impeding epithelial-mesenchymal transition (EMT) progression, and rectifying the locally exacerbated immunosuppressive environment within NETs. The novel NETs local microenvironment drug release functional hydrogel will provide inspiration for postoperative recurrence correction strategies.
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Polysaccharides have gained attention as valuable supplements and natural medicinal resources, particularly for their anti-tumor properties. Their low toxicity and potent anti-tumor effects make them promising candidates for cancer prevention and treatment. The tumor microenvironment is crucial in tumor development and offers potential avenues for novel cancer therapies. Research indicates that polysaccharides can positively influence the tumor microenvironment. However, the structural complexity of most anti-tumor polysaccharides, often heteropolysaccharides, poses challenges for structural analysis. To enhance their pharmacological activity, researchers have modified the structure and properties of natural polysaccharides based on structure-activity relationships, and they have discovered that many polysaccharides exhibit significantly enhanced anti-tumor activity after chemical modification. This article reviews recent strategies for targeting the tumor microenvironment with polysaccharides and briefly discusses the structure-activity relationships of anti-tumor polysaccharides. It also summarises the main chemical modification methods of polysaccharides and discusses the impact of chemical modifications on the anti-tumor activity of polysaccharides. The review aims to lay a theoretical foundation for the development of anti-tumor polysaccharides and their derivatives.
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Neoplasias , Polisacáridos , Microambiente Tumoral , Polisacáridos/química , Polisacáridos/farmacología , Polisacáridos/uso terapéutico , Microambiente Tumoral/efectos de los fármacos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Animales , Relación Estructura-Actividad , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/uso terapéutico , Productos Biológicos/farmacología , Productos Biológicos/química , Productos Biológicos/uso terapéuticoRESUMEN
Inflammation has been confirmed to be closely related to the development of tumors, while peroxynitrite (ONOO-) is one of the most powerful oxidative pro-inflammatory factors. Although ONOO- can kill bacteria through oxidation, it will activate matrix metalloproteinases (MMPs), accelerate the degradation of the extracellular matrix (ECM), and subsequently lead to the activation and release of other tumor promotion factors existing in the ECM, promoting tumor metastasis and invasion. Herein, we report a simple aggregation-induced emission (AIE) nanoprobe (NP), TPE-4NMB, that can simultaneously visualize and deplete ONOO-. The probe can light up the endogenous and exogenous ONOO- in cells and selectively inhibit the proliferation and migration of 4T1 cells by inducing an intracellular redox homeostasis imbalance through ONOO- depletion. After being modified with DSPE-PEG2000, the TPE-4NMB NPs can be used to image ONOO- induced by various models in vivo; especially, it can monitor the dynamic changes of ONOO- level in the residual tumor after surgery, which can provide evidence for clarifying the association between surgery, ONOO-, and cancer metastasis. Excitingly, inhibited tumor volume growth and decreased counts of lung metastases were observed in the TPE-4NMB NPs group, which can be attributed to the downregulated expression of MMP-9 and transforming growth factor-ß (TGF-ß), increased cell apoptosis, and inhibited epithelial-mesenchymal transition (EMT) mediated by ONOO-. The results will provide new evidence for clarifying the relationship between surgery, ONOO-, and tumor metastasis and serve as a new intervention strategy for preventing tumor metastasis after tumor resection.
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Neoplasias de la Mama , Neoplasias Pulmonares , Humanos , Femenino , Ácido Peroxinitroso , Neoplasias Pulmonares/prevención & control , Factor de Crecimiento Transformador beta , Metaloproteinasas de la Matriz/metabolismo , Colorantes FluorescentesRESUMEN
Photodynamic therapy (PDT) is an emerging clinical treatment that is expected to become an important adjuvant strategy for the immunotherapeutic cancer treatment. Recently, numerous works have reported combination strategies. However, clinical data showed that the anti-tumor immune response of PDT was not lasting though existing. The immune activation effect will eventually turn to immunosuppressive effect and get aggravated at the late stage post-PDT. So far, the mechanism is still unclear, which limits the design of specific correction strategies and further development of PDT. Several lines of evidence suggest a role for TGF-ß1 in the immunosuppression associated with PDT. Herein, this study systematically illustrated the dynamic changes of immune states post-PDT within the tumor microenvironment. The results clearly demonstrated that high-light-dose PDT, as a therapeutic dose, induced early immune activation followed by late immunosuppression, which was mediated by the activated TGF-ß1 upregulation. Then, the mechanism of PDT-induced TGF-ß1 accumulation and immunosuppression was elucidated, including the ROS/TGF-ß1/MMP-9 positive feedback loop and CD44-mediated local amplification, which was further confirmed by spatial transcriptomics, as well as by the extensive immune inhibitory effect of local high concentration of TGF-ß1. Finally, a TGF-ß blockade treatment strategy was presented as a promising combinational strategy to reverse high-light-dose PDT-associated immunosuppression. The results of this study provide new insights for the biology mechanism and smart improvement approaches to enhance tumor photodynamic immunotherapy.
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Neoplasias , Fotoquimioterapia , Humanos , Factor de Crecimiento Transformador beta1 , Fotoquimioterapia/métodos , Terapia de Inmunosupresión , Neoplasias/tratamiento farmacológico , Factor de Crecimiento Transformador beta , Línea Celular Tumoral , Microambiente TumoralRESUMEN
New drug delivery systems have rarely been used in the formulation of traditional Chinese medicine, especially those that are crude active Chinese medicinal ingredients. In the present study, hyaluronic acid decorated lipid-polymer hybrid nanoparticles were used to prepare a targeted drug delivery system (TDDS) for total alkaloid extract from Picrasma quassioides (TAPQ) to improve its targeting property and anti-inflammatory activity. Picrasma quassioides, a common-used traditional Chinese medicine (TCM), containing a series of hydrophobic total alkaloids including ß-carboline and canthin-6-one alkaloids show great anti-inflammatory activity. However, its high toxicity (IC50= 8.088±0.903 µg/ml), poor water solubility (need to dissolve with 0.8% Tween-80) and poor targeting property severely limits its clinical application. Herein, hyaluronic acid (HA) decorated lipid-polymer hybrid nanoparticles loaded with TAPQ (TAPQ-NPs) were designed to overcome above mentioned deficiencies. TAPQ-NPs have good water solubility, strong anti-inflammatory activity and great joint targeting property. The in vitro anti-inflammatory activity assay showed that the efficacy of TAPQ-NPs was significantly higher than TAPQ(P<0.001). Animal experiments showed that the nanoparticles had good joint targeting property and had strong inhibitory activity against collagen-induced arthritis (CIA). These results indicate that the application of this novel targeted drug delivery system in the formulation of traditional Chinese medicine is feasible.
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Alcaloides , Antineoplásicos , Artritis Experimental , Picrasma , Ratas , Animales , Picrasma/química , Estructura Molecular , Artritis Experimental/tratamiento farmacológico , Ácido Hialurónico , Alcaloides/química , Alcaloides/farmacología , Sistemas de Liberación de Medicamentos , Antiinflamatorios/química , Lípidos , AguaRESUMEN
The aim of this study is to overcome the obstacle of the blood-brain barrier (BBB) in therapeutic drugs of Parkinson's disease (PD), like rhynchophylline (RIN) entry by intranasal administration and to solve the problem of short residence time of drugs in the nasal cavity by the dosage form design of thermosensitive gel. We first conducted a study of the screening of absorption enhancers and 3% hydroxypropyl-ß-cyclodextrin (HP-ß-CD) was effective to improve the nasal mucosal permeability of RIN. By adjusting the ratio of different components in order to make the gel with adhesion and rapid gelation which were determined to be Poloxamer 407 (P407) 20%, Poloxamer 188 (P188) 1%, polyethylene glycol 6000 (PEG-6000) 1% and HP-ß-CD 3%. In addition, the characterization showed that the thermosensitive gel was network cross-linked, rapidly gelation upon entry into the nasal cavity and was stable as semi-solid state with adhesion as well as sustained release properties. Moreover, pharmacokinetic study was performed to evaluate the bioavailability and brain targeting of RIN thermosensitive gel and which were 1.6 times and 2.1 times higher than those of oral administration. We also evaluated the anti-PD effects of RIN thermosensitive gel in-vitro as well as in-vivo. The results showed that RIN thermosensitive gel was effective in repairing the motor function impairment, dysregulated expression levels of oxidative stress factors, and positive neuronal damage within the substantia nigra and dopamine caused by PD. The constructed intranasal drug administration strategy through thermosensitive gel provided a new choice for targeted treatment of PD together with other central nervous system diseases.
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Enfermedad de Parkinson , Humanos , 2-Hidroxipropil-beta-Ciclodextrina , Enfermedad de Parkinson/tratamiento farmacológico , Geles/metabolismo , Temperatura , Encéfalo/metabolismo , Administración Intranasal , Poloxámero , Sistemas de Liberación de Medicamentos/métodosRESUMEN
Breast cancer (BC) is a serious threat to women's health and metastasis is the major cause of BC-associated mortality. Various techniques are currently used to preoperatively describe the metastatic status of tumors, based on which a comprehensive treatment protocol was determined. However, accurately staging a tumor before surgery remains a challenge, which may lead to the miss of optimal treatment options. More severely, the failure to detect and remove occult micrometastases often causes tumor recurrences. There is an urgent need to develop a more precise and non-invasive strategy for the detection of the tumor metastasis in lymph nodes and distant organs. Based on the facts that tumor metastasis is closely related to the primary tumor microenvironment (TME) evolutions and that metabolomics profiling of the circulatory system can precisely reflect subtle changes within TME, we suppose whether metabolomic technology can be used to achieve non-invasive and real-time monitoring of BC metastatic status. In this study, the metastasis status of BC mouse models with different tumor-bearing times was firstly depicted to mimic clinical anatomic TNM staging system. Metabolomic profiling together with metastasis-related changes in TME among tumor-bearing mice with different metastatic status was conducted. A range of differential metabolites reflecting tumor metastatic states were screened and in vivo experiments proved that two main metastasis-driving factors in TME, TGF-ß and hypoxia, were closely related to the regular changes of these metabolites. The differential metabolites level changes were also preliminarily confirmed in a limited number of clinical BC samples. Metabolite lysoPC (16:0) was found to be useful for clinical N stage diagnosis and the possible cause of its changes was analyzed by bioinformatics techniques.
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The antitumor immune response induced by chemotherapy has attracted considerable attention. However, the immunosuppressive tumor microenvironment hinders the immune activation effect of cancer chemotherapy. TGF-ß plays a key role in driving tumor immunosuppression and can prevent effective antitumor immune response through multiple roles. In this study, a dual-responsive prodrug micelle (PAOL) is designed to co-deliver LY2109761 (a TGF-ß receptor I/II inhibitor) and oxaliplatin (OXA, a conventional chemotherapy) to remodel tumor microenvironment and trigger immunogenic cell death (ICD) to induce antitumor immunity response. Under hypoxia tumor environment, the polyethylene glycol shell of the micelle cleavages, along with the release of LY2109761 and OXA prodrug. Cytotoxic effect of OXA is then activated by glutathione-mediated reduction in tumor cells and the activated OXA significantly enhances tumor immunogenicity and promotes intratumoral accumulation of cytotoxic T lymphocytes. Meanwhile, TGF-ß blockade through LY2109761 reprograms tumor microenvironment by correcting the immunosuppressive state and regulating tumor extracellular matrix, which further maintaining OXA induced immune response. Therefore, due to the capability of boosting tumor-specific antitumor immunity, the bifunctional micelle presents markedly synergistic antitumor efficacies and provides a potent therapeutic strategy for chemoimmunotherapy of solid tumors.
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Profármacos , Inmunoterapia , Micelas , Profármacos/farmacología , Factor de Crecimiento Transformador beta , Microambiente TumoralRESUMEN
Short half-life is one of the main causes of drug attrition in clinical development, which also leads to the failure of many leading compounds and hits to become drug candidates. Nowadays, nanomaterials have been applied to drug development to address this problem. In fact, the clinical application of nanoparticles (NPs) is severely limited due to their rapid elimination by the reticuloendothelial system (RES) in vivo. In this paper, we aim to summarize representative strategies on prolonging the circulation time for bridging the gap between excellent pharmaceutics and proper half-life and encourage clinical translation.
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Nanopartículas , SemividaRESUMEN
Photodynamic therapy (PDT) has been widely used in cancer therapy, but its therapeutic effect is reduced by the aggravating hypoxic microenvironment via upregulating hypoxia-associated proteins and promoting tumor metastasis. To mitigate these issues, we designed an albumin-binding and light-triggered core-shell dimeric prodrug nanoparticle to inhibit hypoxia-induced tumor metastasis and enhance the PDT efficacy. The prodrug nanoparticles, Ce6&DHA-S-DHA@CMN NPs (CDC NPs), were prepared using a single thioether-linked dihydroartemisinin (DHA) dimer co-encapsulated with Chlorin e6 (Ce6) and stabilized by albumin-capturing maleimide- and hypoxia-sensitive 2-nitroimidazole-modified carboxymethyl chitosan (CMCTS-MAL&NI, CMN for short). Upon laser irradiation, Ce6 could generate reactive oxygen species (ROS), which not only exerted the effect of the PDT but also broke the ROS-sensitive single thioether bridge in the dimeric prodrug DHA-S-DHA, thus accelerating the disassembly of the nanoparticles. DHA-S-DHA served as both an ROS-responsive carrier for Ce6 and a chemotherapeutic drug, synergizing with PDT and inhibiting tumor metastasis by downregulating hypoxia-inducible factor-1α (HIF-1α)/vascular endothelial growth factor (VEGF). Polyethylene glycol (PEG) modification has been widely used to stabilize hydrophobic prodrug nanoparticles and prolong the circulation time, but the PEGylated nanoparticles always suffer from accelerated blood clearance (ABC), a phenomenon which restricts their application severely. In this study, PEG was replaced by an amphipathic micelle, CMN, which could specifically capture albumin in the blood, conferring the nanoparticles long circulation and no ABC phenomenon. Under the aggravating hypoxic condition during PDT, the conversion of 2-nitroimidazole groups to 2-aminoimidazole groups in CMN could destabilize the structure of the shell and accelerate drug release. Results showed that the novel CDC NPs exhibited unique advantages in chemo-photodynamic combination therapy, such as long systemic circulation, high tumor accumulation, light-triggered drug release, HIF-1α/VEGF downregulation, and anti-metastasis efficacy, which provided a new route to overcome the ABC phenomenon of the PEGylated prodrug nanoparticles and reverse the hypoxia-induced metastasis simultaneously.
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Neoplasias Pulmonares , Nanopartículas , Fotoquimioterapia , Porfirinas , Profármacos , Albúminas , Línea Celular Tumoral , Liberación de Fármacos , Humanos , Hipoxia , Neoplasias Pulmonares/tratamiento farmacológico , Fármacos Fotosensibilizantes , Microambiente Tumoral , Factor A de Crecimiento Endotelial VascularRESUMEN
Intelligent systems that offer traceable cancer therapy are highly desirable for precision medicine. Although photodynamic therapy (PDT) has been approved in the clinic for decades, determining where the tumor is, when to irradiate, and how long to expose to light still confuse the clinicians. Patients are always suffering from the phototoxicity of the photosensitizer in nonmalignant tissues. Herein, an activatable theranostic agent, ZnPc@TPCB nanoparticles (NPs), is prepared by doping a photosensitizer, ZnPc, with an aggregation-induced emission probe, TPCB. The assembled or disassembled ZnPc@TPCB NPs in various phases have behaved differently in fluorescence intensity, photoacoustic (PA) signals, and PDT efficiency. The intact nanoparticles are non-emissive in aqueous media while showing strong PA signals and low PDT efficiency, which can eliminate the phototoxicity and self-monitor their distribution and image the tumors' location. Disassembling of the NPs leads to the release of ZnPc and its red fluorescence turn-on to self-report the photosensitizer's activation. Upon light irradiation, the reactive oxygen species (ROS) generated by ZnPc can induce cell apoptosis and activate the ROS sensor, TPCB, which will yield intense orange-red fluorescence and instantly predict the therapeutic effect. Moreover, enhanced PDT efficacy is achieved via the GSH-depleting adjuvant quinone methide produced by the activated TPCB. The well-designed ZnPc@TPCB NPs have shown promising potential for finely controlled PDT with good biosafety and broad application prospects in individual therapy, which may inspire the development of precision medicine.
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Nanopartículas , Fotoquimioterapia , Línea Celular Tumoral , Humanos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Medicina de Precisión , Nanomedicina TeranósticaRESUMEN
The pan-cancer detection and precise visualization of tiny tumors in surgery still face great challenges. As tumors grow aggressively, hypoxia is a common feature of solid tumors and has supplied a general way for detecting tumors. Herein, we report a simple aggregation-induced emission nanoprobe-TPE-4NE-O that can specifically switch on their fluorescence in the presence of cytochrome P450 reductase, a reductase which is overexpressed under hypoxia conditions. The probe can selectively light up the hypoxia cells and has shown enhanced deep tumor penetration via charge conversion both in vitro and in vivo. After being modified with FA-DSPE-PEG, higher tumor uptake can be seen and FA-DSPE/TPE-4NE-O showed specific visualization to the hypoxia cancer cells. Excitingly, much brighter fluorescence was accumulated at the tumors in the FA-DSPE/TPE-4NE-O group, even though the tumor was as small as 2.66 mm. The excellent performance of FA-DSPE/TPE-4NE-O in detecting tiny tumors has made it possible for imaging-guided tumor resection. More importantly, the probe exhibited good biocompatibility with negligible organ damage and eliminated a hemolysis risk. The simple but promising probe has supplied a new strategy for pan-cancer detection and tiny tumor visualization, which have shown great potential in clinical translation.
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Carcinoma Hepatocelular/diagnóstico por imagen , Hipoxia de la Célula , Colorantes Fluorescentes/química , Neoplasias Hepáticas/diagnóstico por imagen , Imagen Óptica , Animales , Línea Celular Tumoral , Sistema Enzimático del Citocromo P-450/análisis , Sistema Enzimático del Citocromo P-450/metabolismo , Colorantes Fluorescentes/síntesis química , Humanos , Neoplasias Hepáticas Experimentales/diagnóstico por imagen , Masculino , Ratones , Ratones Endogámicos C57BLRESUMEN
Photodynamic therapy (PDT) and chemotherapy of cancer both meet respective challenges. Tumor hypoxia, low penetration and high glutathione (GSH) level bear the brunt. Herein, a core-shell nanoparticle, with multi-function of hypoxia-responsiveness, specific oxygen supply and deep tumor penetration, was constructed for smart mutual-promotion between the both to overcome the respective restrictions. The nano platform (GC@MCS NPs) was composed of hypoxia-responsive hyaluronic acid-nitroimidazole (HA-NI) as shells, MnO2 NPs as oxygen modulators and reduction-responsive functionalized poly (l-glutamic acid) derivatives (γ-PFGA) as cores to deliver gambogic acid (GA) and Chlorine6 (Ce6). After endocytosis, the approximately 100 nm of GC@MCS NPs achieved hypoxia-responsive shell degradation and MnO2 release, followed by reduction-activated charge conversion to form positively charged cores. With the damage effect of superficial tumor cells by the partially released GA, GA&Ce6-loadedγ-PFGA penetrated deep inside through electronic interaction step by step. Upon irradiated with 638 nm of laser, widely permeated Ce6 was activated for enhanced PDT under the high oxygenation by MnO2 NPs. The generated reactive oxygen species (ROS) in return facilitated the GA-induced paraptosis by clearing high level of GSH. As a result, this mutual promotion strategy contributed to 92.41% of 4T1 tumor inhibition rate, exhibiting outstanding advantages. Our GC@MCS NPs provided a smart combination of chemo-photodynamic therapy and focused on addressing the tumor hypoxia and low penetration issues.
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Nanopartículas , Fotoquimioterapia , Línea Celular Tumoral , Compuestos de Manganeso , Óxidos , Oxígeno , Fármacos Fotosensibilizantes , XantonasRESUMEN
Photodynamic therapy (PDT), a clinically approved cancer treatment, has faced many drawbacks that restricted its applications. For example, the hypoxia-induced elevated hypoxia-inducible factor-1α (HIF-1α) may desensitize tumors to PDT, and the high concentration of glutathione (GSH) in cancer cells can also neutralize the generated reactive oxygen species (ROS) during PDT, resulting in insufficient therapy. Moreover, extra probes for imaging-guided visualization therapy are always needed to track drug release or distribution, while it may decrease the drug loading of the drug delivery system (DDS). In the present study, we have designed and prepared a novel multifunctional combined therapy nanoparticle (ZnPc@Cur-S-OA NPs), in which curcumin (Cur) was not only used as a chemotherapy drug to achieve a combination therapy with PDT via downregulating HIF-1α and depleting GSH in B16F10 cells but also designed as a small-molecule ROS-triggered release prodrug to deliver the photosensitizer (PS). The red fluorescence of PS in the nanoparticles (NPs) can be used to track the NPs distribution, while the green fluorescence of Cur showed an "OFF-ON" activation, which enables additional imaging and real-time self-monitoring capabilities. These results proved that the prepared combined therapy NPs were more effective to inhibit the growth of B16F10 mouse melanoma tumor than was monotherapy without eliciting systemic toxicity either in vitro or in vivo, which indicated the combined therapy NPs as an effective way to improve the PDT efficacy via downregulation of HIF-1α and depletion of GSH. Thus, the strategy of using a multifunctional natural product as the stimuli-responsive carrier as well as the synergist with PDT for enhancing antitumor efficacy via multiple pathways may open an alternative avenue to fabricate new self-delivery combination therapy nanodrugs. Besides, the fluorescence emitted from the drug can be used for real-time self-monitoring of drug release and distribution, which has great potential in clinic to adjust the administration dose and irradiation time for different tumor types and stages for individual therapy.
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Regulación hacia Abajo/efectos de los fármacos , Glutatión/metabolismo , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Nanopartículas/química , Fármacos Fotosensibilizantes/farmacología , Animales , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Curcumina/química , Curcumina/metabolismo , Portadores de Fármacos/química , Rayos Láser , Masculino , Melanoma Experimental/tratamiento farmacológico , Melanoma Experimental/patología , Ratones , Ratones Endogámicos BALB C , Compuestos Organometálicos/química , Fotoquimioterapia , Fármacos Fotosensibilizantes/química , Fármacos Fotosensibilizantes/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Nanomedicina Teranóstica , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Anaplastic lymphoma kinase (ALK) is a major target in treating non-small-cell lung cancer, and several ALK inhibitors have been developed to antagonize its kinase activity. However, patients treated with inhibitors ultimately develop drug resistance. Therefore, therapies with new mechanisms of action are needed. Proteolysis targeting chimeras (PROTACs) are molecules that comprise a ligand for binding a protein of interest (POI), a connecting linker and a ligand for recruiting E3 ligase, and cause degradation of the target POI. Here, the first multi-headed PROTAC, as a proof of concept, is developed as a gold nanoparticle (GNP)-based drug delivery system for delivering PROTACs to target ALK. Pegylated GNPs loaded with both ceritinib and pomalidomide molecules, termed Cer/Pom-PEG@GNPs, showed good stability in several media. The GNP conjugates potently decreased the levels of ALK fusion proteins in a dose- and time-dependent manner, and specifically inhibited the proliferation of NCI-H2228 cells. In comparison with small molecule PROTACs, the new multi-headed PROTAC promoted the formation of coacervates of POIs/multi-headed PROTAC/E3 ubiquitin ligases, and POI and E3 ubiquitin ligase interacted through multidirectional ligands and a flexible linker, thereby avoiding the need for complicated structure optimization of PROTACs. In conclusion, Cer/Pom-PEG@GNPs can degrade intracellular ALK fusion proteins with minor off-target toxicity and can be applied in patients resistant to ALK inhibitors. As a nano-based drug carrier, Cer/Pom-PEG@GNPs have the potential to enable prolonged circulation and specifically distribute drugs to tumor regions in vivo; thus, further investigation is warranted.
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Quinasa de Linfoma Anaplásico/antagonistas & inhibidores , Antineoplásicos/farmacología , Oro/metabolismo , Nanopartículas del Metal/química , Inhibidores de Proteínas Quinasas/farmacología , Talidomida/análogos & derivados , Quinasa de Linfoma Anaplásico/química , Quinasa de Linfoma Anaplásico/metabolismo , Antineoplásicos/síntesis química , Antineoplásicos/química , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Oro/química , Humanos , Estructura Molecular , Tamaño de la Partícula , Inhibidores de Proteínas Quinasas/síntesis química , Inhibidores de Proteínas Quinasas/química , Proteolisis , Propiedades de Superficie , Talidomida/síntesis química , Talidomida/química , Talidomida/farmacología , Células Tumorales CultivadasRESUMEN
Gambogic acid (GA) is a natural anti-tumor drug whose application is restricted by its poor aqueous solubility and inefficient bioavailability. Developing nanomaterials with excellent biocompatibility can amplify the therapeutic effects of GA. In this study, a tumor-targeted redox controllable self-assembled nano-system with magnetic enhanced EPR effects (mPEG-HA/CSO-SS-Hex/SPION/GA) was developed to improve the anticancer efficacy of GA. The nano-system is constituted by three layers: the outer layer is mono-aminated poly(ethylene glycol) grafted hyaluronic acid (mPEG-HA), which can target the CD44 receptor in breast cancer cells; the middle layer consists of disulfide linked hexadecanol (Hex) and chitosan oligosaccharide (CSO) to control the drug release by reduction response; the core layer is superparamagnetic iron oxide nanoparticles (SPION), which can enhance the EPR effect by magnetic guidance and contribute to GA entrapment. Different experiments were performed to characterize the complex self-assembly, and the cytotoxicity, pharmacokinetics, and in vivo antitumor activity of the self-assembly were investigated to evaluate its anti-tumor effects. The results revealed that mPEG-HA/CSO-SS-Hex/SPION/GA is an excellent nanosystem with appropriate size and sensitive responsiveness; it can accumulate in tumor sites and achieve excellent therapeutic effects on triple-negative breast cancer (TNBC). In summary, a CD44-targeted redox-triggered self-assembly nanosystem with magnetic enhanced EPR effects was developed for effective amplification of GA; it has potential to act as an effective carrier in drug delivery for chemotherapy of TNBC.
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Receptores de Hialuranos/antagonistas & inhibidores , Ácido Hialurónico/química , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Xantonas/administración & dosificación , Animales , Disponibilidad Biológica , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Portadores de Fármacos , Femenino , Humanos , Células MCF-7 , Nanopartículas de Magnetita , Ratones , Oxidación-Reducción , Polietilenglicoles , Células RAW 264.7 , Distribución Tisular , Neoplasias de la Mama Triple Negativas/metabolismo , Xantonas/química , Xantonas/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Precision medicine has increased the demand for stage-specific cancer chemotherapy. Drugs with different properties are needed for different stages of tumor development, which is, inducing rapid destruction in the early stage and facilitating deep penetration in the advanced stage. Herein, we report a novel reduction-activated charge-conversional core-shell nanoparticle (CS NP) formula based on ring-closing metathesis of the thiamine disulfide system (TDS) to deliver the chemotherapeutic agent-gambogic acid (GA). Methods: The shell consisted of hyaluronic acid-all-trans retinoid acid with a disulfide bond as the linker (HA-SS-ATRA). The core was selected from poly (γ-glutamic acid) with different grafting rates of the functional group (Fx%) of TDS. GA/CF100%S NPs, with the strongest reduction-responsive drug release, and GA/CF60%S NPs with the strongest penetration have been finally screened. On this basis, a stage-specific administration strategy against a two-stage hepatocellular carcinoma was proposed. Results: The developed CS NPs have been confirmed as inducing reduction-activated charge conversion from about -25 to +30 mV with up to 95% drug release within 48 h. The administration strategy, GA/CF100%S NPs for the early-stage tumor, and sequential administration of GA/CF60%S NPs followed by GA/CF100%S NPs for the advanced-stage tumor, achieved excellent tumor inhibition rates of 93.86±2.94% and 90.76±6.43%, respectively. Conclusions: Our CS NPs provide a novel platform for charge conversion activated by reduction. The stage-specific administration strategy showed great promise for cancer therapy.
Asunto(s)
Antineoplásicos/administración & dosificación , Sistemas de Liberación de Medicamentos/métodos , Nanopartículas/administración & dosificación , Nanopartículas/química , Xantonas/administración & dosificación , Animales , Antineoplásicos/farmacocinética , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/patología , Liberación de Fármacos , Células Hep G2 , Humanos , Ácido Hialurónico/química , Inyecciones Intravenosas , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Masculino , Ratones Endogámicos ICR , Oxidación-Reducción , Esferoides Celulares/efectos de los fármacos , Tiamina/análogos & derivados , Tiamina/química , Tretinoina/química , Xantonas/farmacocinética , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Rationale: Ferroptosis is a regulated process of cell death caused by iron-dependent accumulation of lipid hydroperoxides (LPO). It is sensitive to epithelial-to-mesenchymal transition (EMT) cells, a well-known therapy-resistant state of cancer. Previous studies on nanomaterials did not investigate the immense value of ferroptosis therapy (FT) in epithelial cell carcinoma during EMT. Herein, we describe an EMT-specific nanodevice for a comprehensive FT strategy involving LPO burst. Methods: Mitochondrial membrane anchored oxidation/reduction response and Fenton-Reaction-Accelerable magnetic nanophotosensitizer complex self-assemblies loading sorafenib (CSO-SS-Cy7-Hex/SPION/Srfn) were constructed in this study for LPO produced to overcome the therapy-resistant state of cancer. Both in vitro and in vivo experiments were performed using breast cancer cells to investigate the anti-tumor efficacy of the complex self-assemblies. Results: The nano-device enriched the tumor sites by magnetic targeting of enhanced permeability and retention effects (EPR), which were disassembled by the redox response under high levels of ROS and GSH in FT cells. Superparamagnetic iron oxide nanoparticles (SPION) released Fe2+ and Fe3+ in the acidic environment of lysosomes, and the NIR photosensitizer Cy7-Hex anchored to the mitochondrial membrane, combined sorafenib (Srfn) leading to LPO burst, which was accumulated ~18-fold of treatment group in breast cancer cells. In vivo pharmacodynamic test results showed that this nanodevice with small particle size and high cytotoxicity increased Srfn circulation and shortened the period of epithelial cancer treatment. Conclusion: Ferroptosis therapy had a successful effect on EMT cells. These findings have great potential in the treatment of therapy-resistant epithelial cell carcinomas.
Asunto(s)
Ferroptosis/efectos de los fármacos , Peróxidos Lipídicos/uso terapéutico , Neoplasias/tratamiento farmacológico , Fármacos Fotosensibilizantes/administración & dosificación , Sorafenib/administración & dosificación , Animales , Resistencia a Antineoplásicos , Transición Epitelial-Mesenquimal/efectos de los fármacos , Femenino , Membranas Mitocondriales/metabolismo , Nanopartículas/uso terapéutico , Oxidación-Reducción , Ratas , Ratas WistarRESUMEN
Ferroptosis is an iron-dependent cell death caused by accumulation of lipid peroxidation (LPO), which is a new strategy for cancer treatment. Th current ferroptosis therapy nanodevices have low efficiency and side effects generally. Hence, we developed a Black Hole Quencher (BHQ)-based fluorescence "off-on" nanophotosensitizer complex assembly (CSO-BHQ-IR780-Hex/MIONPs/Sor). CSO-connected BHQ-IR780-Hex and -loaded magnetic iron oxide nanoparticles (MIONPs) and sorafenib (Sor) formed a very concise functionalized delivery system. CSO-BHQ-IR780-Hex disassembled by GSH attack and released IR780-Hex, MIONPs, and sorafenib. IR780-Hex anchored to the mitochondrial membrane, which would contribute to amplifying the efficiency of the photosensitizer. When NIR irradiation was given to CSO-BHQ-IR780-Hex/MIONPs/Sor-treated cells, iron supply increased, the xCT/GSH/GPX-4 system was triggered, and a lot of LPO burst. A malondialdehyde test showed that LPO in complex assembly-treated cells was explosive and increased about 18-fold compared to the control. The accumulation process of particles was monitored by an IR780-Hex photosensitizer, which showed an excellent tumor target ability by magnetic of nanodevice in vivo. Interestingly, the half-life of sorafenib in a nanodevice was increased about 26-fold compared to the control group. Importantly, the complex assembly effectively inhibits tumor growth in the breast tumor mouse model. This work would provide ideas in designing nanomedicines for the ferroptosis treatment of cancer.
Asunto(s)
Alcanosulfonatos , Compuestos Azo , Neoplasias de la Mama , Ferroptosis/efectos de los fármacos , Peroxidación de Lípido/efectos de los fármacos , Nanopartículas de Magnetita , Sorafenib , Alcanosulfonatos/química , Alcanosulfonatos/farmacología , Animales , Compuestos Azo/química , Compuestos Azo/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Células MCF-7 , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapéutico , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Ratas , Ratas Sprague-Dawley , Sorafenib/química , Sorafenib/farmacología , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
Gambogic acid (GA) is a natural antitumor drug candidate with advantages of broad-spectrum activity, low toxicity and multiple mechanisms. Its clinical application is hindered, however, by low aqueous solubility, instability and poor pharmacokinetic properties. In this research, core-shell hybrid nanoparticles have been developed to improve the druggability of GA. The nanoparticles are composed of a benzylamidated poly(γ-glutamic acid) (BzPGA) derivative as a core material and an amphiphilic hyaluronic acid derivative grafted with all-trans retinoic acid (HA-C6-ATRA) as a shell material. Through π-π stacking interactions, GA is encapsulated into BzPGA to form the "core" of the hybrid nanoparticle and the "shell" is formed by HA-C6-ATRA with a π-π stacking mediated "molecular fence". The nanovehicle, with sub 100 nm size, provides almost 100% encapsulation efficiency, a good protective effect and a sustained release profile for GA. A series of evaluations suggest that the core-shell nanoparticles provide a stable aqueous injection formulation (I), improved stability (II), prolonged circulation time and conferred tumor targeting properties (III) for GA. As a result, the anti-tumor activity of GA is significantly enhanced without causing higher toxicity, indicating that the designed nanoplatform dramatically improves the druggability of GA. This study may also provide inspiration for drug development research.