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The fibrillation of amyloid-ß (Aß) is the critical causal factor in Alzheimer's disease (AD), the dissolution and clearance of which are promising for AD therapy. Although many Aß inhibitors are developed, their low Aß-binding affinity results in unsatisfactory effect. To solve this challenge, the Aß sequence-matching strategy is proposed to tail-design dissociable nanosystem (B6-PNi NPs). Herein, B6-PNi NPs aim to improve Aß-binding affinity for effective dissolution of amyloid fibrils, as well as to interfere with the in vivo fate of amyloid for Aß clearance. Results show that B6-PNi NPs decompose into small nanostructures and expose Aß-binding sites in response to AD microenvironment, and then capture Aß via multiple interactions, including covalent linkage formed by nucleophilic substitution reaction. Such high Aß-binding affinity disassembles Aß fibrils into Aß monomers, and induces the reassembly of Aß&nanostructure composite, thereby promoting microglial Aß phogocytosis/clearance via Aß receptor-mediated endocytosis. After B6-PNi NPs treatment, the Aß burden, neuroinflammation and cognitive impairments are relieved in AD transgenic mice. This work provides the Aß sequence-matching strategy for Aß inhibitor design in AD treatment, showing meaningful insight in biomedicine.
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Breast cancer with bone metastasis accounts for serious cancer-associated pain which significantly reduces the quality of life of affected patients and promotes cancer progression. However, effective treatment using nanomedicine remains a formidable challenge owing to poor drug delivery efficiency to multiple cancer lesions and inappropriate management of cancer-associated pain. In this study, using engineered macrophage membrane (EMM) and drugs loaded nanoparticle, we constructed a biomimetic nanoplatform (EMM@DJHAD) for the concurrent therapy of bone metastatic breast cancer and associated pain. Tumor tropism inherited from EMM provided the targeting ability for both primary and metastatic lesions. Subsequently, the synergistic combination of decitabine and JTC801 boosted the lytic and inflammatory responses accompanied by a tumoricidal effect, which transformed the tumor into an ideal decoy for EMM, resulting in prolonged troop migration toward tumors. EMM@DJHAD exerted significant effects on tumor suppression and a pronounced analgesic effect by inhibiting µ-opioid receptors in bone metastasis mouse models. Moreover, the nanoplatform significantly reduced the severe toxicity induced by chemotherapy agents. Overall, this biomimetic nanoplatform with good biocompatibility may be used for the effective treatment of breast cancer with bone metastasis.
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Activating humoral and cellular immunity in lymph nodes (LNs) of nanoparticle-based vaccines is critical to controlling tumors. However, how the physical properties of nanovaccine carriers orchestrate antigen capture, lymphatic delivery, antigen presentation and immune response in LNs is largely unclear. Here, we manufactured gold nanoparticles (AuNPs) with the same size but different shapes (cages, rods, and stars), and loaded tumor antigen as nanovaccines to explore their disparate characters on above four areas. Results revealed that star-shaped AuNPs captured and retained more repetitive antigen epitopes. On lymphatic delivery, both rods and star-shaped nanovaccines mainly drain into the LN follicles region while cage-shaped showed stronger paracortex retention. A surprising finding is that the star-shaped nanovaccines elicited potent humoral immunity, which is mediated by CD4+ T helper cell and follicle B cell cooperation significantly preventing tumor growth in the prophylactic study. Interestingly, cage-shaped nanovaccines preferentially presented peptide-MHC I complexes to evoke robust CD8+ T cell immunity and showed the strongest therapeutic efficacy when combined with the PD-1 checkpoint inhibitor in established tumor study. These results highlight the importance of nanoparticle shape on antigen delivery and presentation for immune response in LNs, and our findings support the notion that different design strategies are required for prophylactic and therapeutic vaccines.
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The biological barriers have seriously restricted the efficacious responses of oral delivery system in diseases treatment. Utilizing a carrier based on the single construction means is hard to overcome these obstacles simultaneously because the complex gastrointestinal tract environment requires carrier to have different or even contradictory properties. Interestingly, spore capsid (SC) integrates many unique biological characteristics, such as high resistance, good stability etc. This fact offers a boundless source of inspiration for the construction of multi-functional oral nanoplatform based on SC without further modification. Herein, we develop a type of biomimetic spore nanoplatform (SC@DS NPs) to successively overcome oral biological barriers. Firstly, doxorubicin (DOX) and sorafenib (SOR) are self-assembled to form carrier-free nanoparticles (DS NPs). Subsequently, SC is effectively separated from probiotic spores and served as a functional vehicle for delivering DS NPs. As expect, SC@DS NPs can efficaciously pass through the rugged stomach environment after oral administration and further be transported to the intestine. Surprisingly, we find that SC@DS NPs exhibit a significant improvement in the aspects of mucus penetration and transepithelial transport, which is related to the protein species of SC. This study demonstrates that SC@DS NPs can efficiently overcome multiple biological barriers and improve the therapeutic effect.
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Biomimética , Proteínas de la Cápside , Esporas , Tracto Gastrointestinal , Administración OralRESUMEN
The typical hallmark of tumor evolution is metabolic dysregulation. In addition to secreting immunoregulatory metabolites, tumor cells and various immune cells display different metabolic pathways and plasticity. Harnessing the metabolic differences to reduce the tumor and immunosuppressive cells while enhancing the activity of positive immunoregulatory cells is a promising strategy. We develop a nanoplatform (CLCeMOF) based on cerium metal-organic framework (CeMOF) by lactate oxidase (LOX) modification and glutaminase inhibitor (CB839) loading. The cascade catalytic reactions induced by CLCeMOF generate reactive oxygen species "storm" to elicit immune responses. Meanwhile, LOX-mediated metabolite lactate exhaustion relieves the immunosuppressive tumor microenvironment, preparing the ground for intracellular regulation. Most noticeably, the immunometabolic checkpoint blockade therapy, as a result of glutamine antagonism, is exploited for overall cell mobilization. It is found that CLCeMOF inhibited glutamine metabolism-dependent cells (tumor cells, immunosuppressive cells, etc.), increased infiltration of dendritic cells, and especially reprogrammed CD8+ T lymphocytes with considerable metabolic flexibility toward a highly activated, long-lived, and memory-like phenotype. Such an idea intervenes both metabolite (lactate) and cellular metabolic pathway, which essentially alters overall cell fates toward the desired situation. Collectively, the metabolic intervention strategy is bound to break the evolutionary adaptability of tumors for reinforced immunotherapy.
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Constant oxidative stress and lactate accumulation are two main causes of tumor immunosuppression, their concurrent reduction plays a dominant role in effective antitumor immunity, but remains challenging. Herein, reactive oxygen species (ROS) responsive prodrug nanoparticles (designed as DHCRJ) are constructed for metabolic amplified chemo-immunotherapy against triple-negative breast cancer (TNBC) by modulating oxidative state and hyperglycolysis. Specifically, DHCRJ is prepared by the self-assembly of DOX prodrug-tethered ROS consuming bond-bridged copolymers with the loading of bromodomain-containing protein 4 inhibitor (BRD4i) JQ1. Interestingly, the nanoparticle polymer network could reduce ROS to relieve tumor hypoxia and realize the dense-to-loose structure inversion arising from ROS-triggered network collapse, which favors JQ1 release and hyaluronidase (Hyal)-activatable DOX prodrugs generation. More importantly, disruption of oxidative stress decreases glucose uptake and assists JQ1 to down-regulate oncogene c-Myc driven tumor glycolysis for blocking the source of lactate and reshaping immunosuppressive tumor microenvironment (ITME). Meanwhile, benefiting from the synergistic effect of DOX prodrugs and JQ1, DHCRJ is able to facilitate tumor immunogenicity and potentiate systemic immune responses through antigen processing and presentation pathway. In this manner, DHCRJ significantly suppresses tumor growth and metastasis with prolonged survival. Collectively, this study represents a proof of concept antioxidant-enhanced chemo-immunometabolic therapy strategy using ROS-reducing nanoparticles for efficient synergistic therapeutic modality of TNBC.
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Nanopartículas , Profármacos , Neoplasias de la Mama Triple Negativas , Humanos , Profármacos/uso terapéutico , Profármacos/química , Especies Reactivas de Oxígeno/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Nanopartículas/química , Polímeros/química , Estrés Oxidativo , Lactatos , Línea Celular Tumoral , Doxorrubicina/uso terapéutico , Doxorrubicina/farmacología , Microambiente TumoralRESUMEN
Chemotherapy and radiotherapy are first-line treatments in the management of advanced solid tumors. Whereas these treatments are directed at eliminating cancer cells, they cause significant adverse effects that can be detrimental to a patient's quality of life and even life-threatening. Diet is a modifiable risk factor that has been shown to affect cancer risk, recurrence, and treatment toxicity, but little information is known how diet interacts with cancer treatment modalities. Although dietary interventions, such as intermittent fasting and ketogenic diets, have shown promise in pre-clinical studies by reducing the toxicity and increasing the efficacy of chemotherapeutics, there remains a limited number of clinical studies in this space. This review surveys the impact of dietary interventions (caloric restriction, intermittent and short-term fasting, and ketogenic diet) on cancer treatment outcomes in both pre-clinical and clinical studies. Early studies support a complementary role for these dietary interventions in improving patient quality of life across multiple cancer types by reducing toxicity and perhaps a benefit in treatment efficacy. Larger, phase III, randomized clinical trials are ultimately necessary to evaluate the efficacy of these dietary interventions in improving oncologic or quality of life outcomes for patients that are undergoing chemotherapy or radiotherapy.
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The continuing challenges that limit effectiveness of tumor therapeutic vaccines were high heterogeneity of tumor immunogenicity, low bioactivity of antigens, as well as insufficient lymph nodes (LNs) drainage of antigens and adjuvants. Transportation of in situ neoantigens and adjuvants to LNs may be an effective approach to solve the abovementioned problems. Therefore, an FA-TSL/AuNCs/SV nanoplatform was constructed by integrating simvastatin (SV) adjuvant loaded Au nanocages (AuNCs) as cores (AuNCs/SV) and folic acid modified thermal-sensitive liposomes (FA-TSL) as shells to enhance de novo antitumor immunity. After accumulation in tumor guided by FA, AuNCs mediated photothermal therapy (PTT) induced the release of tumor-derived protein antigens (TDPAs) and the shedding of FA-TSL. Exposed AuNCs/SV soon captured TDPAs to form in situ recombinant vaccine (AuNCs/SV/TDPAs). Subsequently, AuNCs/SV/TDPAs could efficiently transport to draining LNs owing to the hyperthermia induced vasodilation effect and small particle size, achieving co-delivery of antigens and adjuvant for initiation of specific T cell response. In melanoma bearing mice, FA-TSL/AuNCs/SV and laser irradiation effectively ablated primary tumor, against metastatic tumors and induced immunological memory. This approach served a hyperthermia enhanced platform drainage to enable robust personalized cancer vaccination.
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The failure of any phase in continuous multi-link immune response process can cause unsatisfactory outcomes, which might be improved by all-cancer-immunity-cycle boosted strategy. Herein, a nanoplatform Mn/CaCO3@PL/SLC is developed, which is based on palmitoyl ascorbate (PA)-liposome (PL) loaded with Mn-doped CaCO3 nanoparticles (Mn/CaCO3 NPs) and carbonic anhydrase (CAIX) inhibitor SLC-0111. The nanoplatform comprehensively amplifies all immune stages including tumor-associated antigens (TAAs) release and presentation, T cells activation and infiltration, as well as tumor cells destruction. In detail, Mn-triggered lipid peroxidation facilitates TAAs release and subsequent T cells activation to initiate immunity cycle. Additionally, SLC-0111 and PA amplify the infiltration and tumor killing activity of these effector T cells. The former polarizes the immunosuppressive tumor microenvironment to an immune-active phenotype and the latter enhances the function of tumor-infiltrating T lymphocytes. Importantly, Mn augments the all-immunity-cycle by promoting cGAS-STING pathway activation. In summary, the Mn/CaCO3@PL/SLC nanoplatform is verified to boost anti-tumor immunity and achieve outstanding immunotherapeutic effects in eradicating tumor and preventing tumor metastasis. Such an all-cancer-immunity-cycle boosted strategy is meaningful for antitumor immunotherapy.
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Inmunoterapia , Neoplasias , Humanos , Activación de Linfocitos , Linfocitos Infiltrantes de Tumor , Neoplasias/terapia , Microambiente TumoralRESUMEN
Our previous work has shown that monoamine oxidase A (MAO A) is overexpressed in glioma and prostate cancer. Near-infrared dye conjugate MAO A Inhibitor (NMI) inhibited the growth of these cancers. This study investigated the effects of NMI on other cancers by NCI60 screening. Our results showed that 48 out of 59 screened cell lines from nine types of cancer had 100% growth inhibition at 10 µM NMI treatment. The in vitro efficacy of NMI determined by growth inhibition (GI50 and TGI) and lethal doses (LC50) has been further studied in various cell lines of CNS cancer, prostate cancer, and non-small cell lung cancer (NSCLC), these three cancers showed increased MAO A expression in tumors compared to normal tissues. Based on the waterfall plots and the 3D scatter plot of GI50, TGI, and LC50 data, NMI showed higher potency to several CNS cancer and NSCLC cell lines than prostate cancer cell lines. In vitro efficacy of NMI outperformed FDA-approved drugs for CNS cancer, prostate cancer, and NSCLC, respectively. The Pairwise Pearson Correlation Coefficient (PCC) showed that NMI has a unique mechanism compared to the existing anticancer drugs. This study shows that NMI is a novel theragnostic drug with high potency and unique mechanisms for brain, prostate, NSCLC, and other cancers.
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Intracellular ions played prominent part in cell function and behavior. Disrupting intracellular ions homeostasis might switch ions signal from "regulating" to "destroying". Inspired by this, we introduced the ions interference strategy for tumor therapy. Herein, curcumin (CUR) and transferrin (Tf) co-loaded calcium peroxide nanoparticles (CaO2 NPs) were formulated. With tumor targeting ability, CaO2/Tf/CUR pinpointed tumor cells and then instantaneously decomposed in acidic lysosomes, concurrently accompanying with the release of Ca2+ and CUR, as well as the production of H2O2. Then H2O2 not only damaged structure of Tf to release Fe3+, but also was converted to hydroxyl radicals via ferric ions mediated Fenton reaction for ferroptosis. In addition, the released Ca2+ and CUR induced Ca2+ overload via exogenous and endogenous calcium ions accumulation, respectively, further activating mitochondria apoptosis signaling pathway for cell injury. Therefore, based on calcium and ferric ions interference strategy, the cascade catalytic CaO2/Tf/CUR offered synergistic combination of ferroptosis, Ca2+ overload therapy and chemotherapy, which held a great promise in cancer treatment.
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Curcumina , Ferroptosis , Nanopartículas , Calcio , Línea Celular Tumoral , Peróxido de Hidrógeno , HierroRESUMEN
Intracellular Ca2+ ions as second messenger played key role in cell behaviour, which was often overlooked in traditional antitumor treatment. Disrupting Ca2+ ion homeostasis by Ca2+ overload might switch ions signal from 'regulating' to 'destroying'. Inspired by this, a biomimetic Ca2+ nanogenerator was constructed. Briefly, the curcumin (CUR) was loaded into mesoporous calcium carbonate nanoparticles (MCC NPs), and then coated with platelet (PLT) membrane. Upon reaching tumour cells by PLT membrane-mediated tumour targeting effect, PLT@MCC/CUR would instantaneously decompose in acidic lysosomes, concurrently accompanying with Ca2+ generation and CUR release. The CUR could further facilitate Ca2+ release from endoplasmic reticulum (ER) and inhibit Ca2+ efflux, aggravating Ca2+ overload to disrupt mitochondrial Ca2+ homeostasis for mitochondria apoptosis signalling pathway activation. Interestingly, such effect was ineffective in normal cells, realising the tumour-specific therapeutic therapy. Based on ions interference strategy, PLT@MCC/CUR herein offered synergistic combination of Ca2+ overload therapy and chemotherapy, which would pave the way towards more effective nanotherapeutics.
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Neoplasias de la Mama/tratamiento farmacológico , Carbonato de Calcio/química , Curcumina/farmacología , Nanopartículas , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Apoptosis/efectos de los fármacos , Biomimética , Plaquetas/química , Calcio/metabolismo , Curcumina/administración & dosificación , Liberación de Fármacos , Femenino , Homeostasis , Humanos , Células MCF-7 , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Mitocondrias/efectos de los fármacos , Células RAW 264.7RESUMEN
The unique tumor microenvironment (TME) characteristics such as immunosuppression impeded traditional cancer treatments. In contrast, developing cascade catalytic nanoplatforms by fully making use of substances in TME for cancer therapy may deserve full credit. Herein, a cascade catalytic nanoplatform based on glucose oxidase (GOD) modified mesoporous iron oxide nanoparticles (IONP) loaded with Artemisinin (ART) is developed, which is designed as IONP-GOD@ART. GOD can catalyze the oxidization of glucose into gluconic acid and H2 O2 , which not only realizes tumor starvation therapy, but also provides H2 O2 for IONP mediated Fenton reaction. Simultaneously, mesoporous IONP releases Fe2+ and Fe3+ ions in acidic TME. On the one hand, iron ions undergo Fenton reaction to generate hydroxyl radicals for chemodynamic therapy. On the other hand, the endoperoxide bridge in ART is broken in presence of Fe2+ and further generates reactive oxygen species (ROS) to achieve therapeutic purpose. In this sense, IONP-GOD@ART manipulates TME characteristics and leads to "butterfly effect", which brings out a large amount of ROS for eliciting immunogenic cell death, inducing M1-TAMs polarization, and further reprogramming immunosuppressive TME for enhanced immunotherapy. By this delicate design, the cascade catalytic nanoplatform of IONP-GOD@ART realizes potent cancer immunotherapy for tumor regression and metastasis prevention.
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Mariposas Diurnas , Animales , Catálisis , Línea Celular Tumoral , Inmunoterapia , Microambiente TumoralRESUMEN
Although immunogenic cell death (ICD)-based chemoimmunotherapy elicits an immune response, it always focuses on eliminating "seeds" (tumor cells) but neglects "soil" (tumor microenvironment, TME), leading to tumor growth and metastasis. Herein, a type of detachable core-shell nanoplatform (DOX@HA-MMP-2-DEAP/CXB) is developed, which could swell in the acidic TME because of the protonation of the 3-diethylaminopropyl isothiocyanate (DEAP) inner core for celecoxib (CXB) release, while hyaluronic acid@doxorubicine (HA@DOX) prodrug in the outer shell could release by the cleavage of matrix metalloproteinase-2 (MMP-2) peptide. HA@DOX targets tumor cells precisely for triggering ICD. And CXB acts on multiple immune cells to remodulate TME, such as increasing the infiltration of dendritic cells (DCs) and T cells, decreasing the infiltration of the immunosuppressive cells, and eliminating the physical barriers between T cells and tumor cells. For comparison, HA-DOCA/DOX/CXB traditional nanoparticles are constructed. And DOX@HA-MMP-2-DEAP/CXB performs an impressive antitumor effect, which shows potential in enhancing the effect of chemoimmunotherapy.
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Metaloproteinasa 2 de la Matriz , Nanopartículas , Muerte Celular , Doxorrubicina , Inmunoterapia , Siembra Neoplásica , Neoplasias/terapia , Microambiente TumoralRESUMEN
Currently, cell membrane is always utilized for the construction of biomimetic nanoparticles. By contrast, mimicking the intracellular activity seems more meaningful. Inspired by the specific killing mechanism of deoxy-hemoglobin (Hb) dependent drug (RRx-001) in hypoxic red blood cells (RBC), this work aims to develop an inner and outer RBC-biomimetic antitumor nanoplatform that replicates both membrane surface properties and intracellularly certain therapeutic mechanisms of RRx-001 in hypoxic RBC. Herein, RRx-001 and Hb are introduced into RBC membrane camouflaged TiO2 nanoparticles. Upon arrival at hypoxic tumor microenvironment (TME), the biomimetic nanoplatform (R@HTR) is activated and triggers a series of reactions to generate reactive nitrogen species (RNS). More importantly, the potent antitumor immunity and immunomodulatory function of RNS in TME are demonstrated. Such an idea would transfer the battlefield of RRx-001 from hypoxic RBC to hypoxic TME, enhancing its combat capability. As a proof of concept, this biomimetic nanoreactor of RNS exhibits efficient tumor regression and metastasis prevention. The battlefield transfer strategy would not only present meaningful insights for immunotherapy, but also realize substantial breakthroughs in biomimetic nanotechnology.
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Biomimética , Nanopartículas , Membrana Eritrocítica , Inmunoterapia , Especies de Nitrógeno ReactivoRESUMEN
Spores, the dormant life forms of probiotics, can germinate to metabolically active vegetative cells with the disintegration of their hydrophobic protein coat in the intestinal microenvironment, which provides the possibility for the formation of nanoparticles (NPs) in vivo. Inspired by the natural physiological process of spores, herein, an oral autonomous NPs generator is developed to overcome the spatially variable gastrointestinal tract environment and multibiological barriers. Spores modified with deoxycholic acid (DA) and loaded with chemotherapeutic drugs (doxorubicin and sorafenib, DOX/SOR) serve as an autonomous production line of NPs, which can efficaciously protect the drugs passing through the rugged environment of the stomach and furthermore can be transported to the intestinal environment and colonized rapidly. Subsequently, the DOX/SOR/Spore-DA NPs are produced by the autonomous NPs generator in the intestinal regions based on the disintegrated hydrophobic protein and the hydrophilic DA, and they can efficiently penetrate the epithelial cells via the bile acid pathway, increasing basolateral drug release. In vitro and in vivo studies confirm that this biological nanogenerator can autonomously produce substantial NPs in the intestine, providing a promising strategy for cancer therapy.
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Neoplasias del Colon/tratamiento farmacológico , Sistemas de Liberación de Medicamentos/métodos , Nanomedicina/métodos , Nanopartículas/metabolismo , Nanopartículas/uso terapéutico , Probióticos/metabolismo , Esporas/metabolismo , Administración Oral , Animales , Bacillus/metabolismo , Transporte Biológico , Células CACO-2 , Línea Celular Tumoral , Neoplasias del Colon/patología , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacología , Humanos , Absorción Intestinal , Ratones , Sorafenib/química , Sorafenib/metabolismo , Sorafenib/farmacologíaRESUMEN
Autophagy was considered as a double-edged sword that might cooperate, aggravate, or antagonize apoptosis. We found that the sonodynamic therapy (SDT) in low dosage induced autophagy and might function as a survival pathway for breast cancer and exhibit resistance to SDT-mediated apoptosis. In this sense, it was highly desired to enhance SDT via autophagy regulation strategy. Herein, we reported a biomimetic nanoplatform based on hollow mesoporous titanium dioxide nanoparticles (HMTNPs) by autophagy inhibitor (hydroxychloroquine sulphate, HCQ) loading and cancer cell membrane (CCM) coating. Owing to the biomimetic surface functionalization, the CCM-HMTNPs/HCQ could escape from macrophage phagocytosis, actively recognize and home in on the tumor by homologous targeting ability. Afterward, the released HCQ in response to the ultrasound stimulus was capable of blocking the autophagic flux and cutting off the nutrients supply derived from the damaged organelles, which was anticipated to abrogate the cells' resistance to SDT. Meanwhile, the vessel normalization effect of HCQ alleviated the tumor hypoxia, which was bound to enhance the oxygen-dependent HMTNPs-mediated SDT treatment. Based on the above findings, it was undoubtedly logical that CCM-HMTNPs/HCQ would sensitize breast cancer cells to SDT via autophagy regulation strategy, which held a great promise in cancer treatment.
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Autofagia , Biomimética , Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Membrana Celular/metabolismo , Nanopartículas/química , Animales , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Membrana Celular/efectos de los fármacos , Femenino , Humanos , Hidroxicloroquina/química , Hidroxicloroquina/farmacología , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células 3T3 NIH , Nanopartículas/ultraestructura , Porosidad , Titanio/químicaRESUMEN
The hypoxic microenvironment induced by sonodynamic therapy (SDT) via sonochemical oxygen consumption usually triggered tumor resistance to SDT, impeding therapeutic efficacy. In this sense, it was highly desired to tackle the hypoxia-related negative issues. Here we provide the therapeutic agents delivery system, TPZ/HMTNPs-SNO, which was constructed by loading tirapazamine (TPZ) into hollow mesoporous titanium dioxide nanoparticles (HMTNPs) with modification of S-nitrosothiol (R-SNO). Upon encountering ultrasound waves, the HMTNPs as sonosensitizers would generate reactive oxygen species (ROS) for SDT. In a sequential manner, the followed SDT-induced hypoxia further activated the "hypoxic cytotoxin", TPZ, for hypoxia-specific killing effect. Meanwhile, the generated ROS could sensitize -SNO groups for on-demand nitric oxide (NO) release in an "anticancer therapeutic window", resulting in the NO sensitized SDT effect. This study confirmed that the TPZ/HMTNPs-SNO with multi-mechanisms exploited the merits of synergistic combination of the three therapeutic modes, consequently potentiating the anticancer efficacy of SDT. Moreover, the echogenic property of NO made the nanoplatform as an ultrasound contrast agent to enhance ultrasound imaging. In this sense, we developed a sequential strategy for ultrasound mediated all-in-one nanotheranostic platform of TPZ/HMTNPs-SNO, which highlighted new possibilities of advancing cancer theranostics in biomedical fields.
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Antineoplásicos/administración & dosificación , Nanopartículas/administración & dosificación , Neoplasias/diagnóstico por imagen , Neoplasias/terapia , S-Nitrosotioles/administración & dosificación , Tirapazamina/administración & dosificación , Titanio/administración & dosificación , Animales , Humanos , Hipoxia , Células MCF-7 , Ratones Endogámicos BALB C , Ratones Desnudos , Neoplasias/patología , Nanomedicina Teranóstica , Carga Tumoral/efectos de los fármacos , UltrasonografíaRESUMEN
Herein, a pH/ultrasound dual-responsive gas generator is reported, which is based on mesoporous calcium carbonate (MCC) nanoparticles by loading sonosensitizer (hematoporphyrin monomethyl ether (HMME)) and modifying surface hyaluronic acid (HA). After pinpointing tumor regions with prominent targeting efficiency, HMME/MCC-HA decomposes instantaneously under the cotriggering of tumoral inherent acidic condition and ultrasound (US) irradiation, concurrently accompanying with CO2 generation and HMME release with spatial/temporal resolution. Afterward, the CO2 bubbling and bursting effect under US stimulus results in cavitation-mediated irreversible cell necrosis, as well as the blood vessel destruction to further occlude the blood supply, providing a "bystander effect." Meanwhile, reactive oxygen species generated from HMME can target the apoptotic pathways for effective sonodynamic therapy. Thus, the combination of apoptosis/necrosis with multimechanisms consequently results in a remarkable antitumor therapeutic efficacy, simultaneously minimizing the side effects on major organs. Moreover, the echogenic property of CO2 make the nanoplatform as a powerful ultrasound contrast agent to identify cancerous lesions. Based on the above findings, such all-in-one drug delivery platform of HMME/MCC-HA is utilized to provide the US imaging guidance for therapeutic inertial cavitation and sonodynamic therapy simultaneously, which highlights possibilities of advancing cancer theranostics in biomedical fields.
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Dióxido de Carbono , Sistemas de Liberación de Medicamentos/métodos , Hematoporfirinas/química , Neoplasias/terapia , Nanomedicina Teranóstica/métodos , Terapia por Ultrasonido/métodos , Ondas Ultrasónicas , Animales , Dióxido de Carbono/química , Dióxido de Carbono/farmacología , Humanos , Ácido Hialurónico/química , Concentración de Iones de Hidrógeno , Células MCF-7 , Ratones , Células 3T3 NIH , Neoplasias/metabolismo , Neoplasias/patologíaRESUMEN
The chelate copper-based anticancer drug bleomycin (BLM) is usually believed to bind metal ions especially Cu(ii) to generate the "activated BLM" for DNA cleavage. Herein, BLM and L-menthol (LM) co-loaded hollow mesoporous Cu2-xS nanoparticles (HMCu2-xS NPs) with surface folic acid (FA) modification were formulated to construct an intelligent NIR-responsive nanoplatform for synergistic tumor targeted chemo-phototherapy. With the tumor targeting ability of the folate receptor (FR)-positive, FA-HMCu2-xS/BLM/LM could pinpoint tumor cells efficiently. Under NIR irradiation, the versatile HMCu2-xS would be bound to exploit the merits of phototherapy (including PTT and PDT-like effects) for cancer treatment. Meanwhile, benefiting from the controllable "solid-liquid" (S-L) phase transition feature of LM as a gatekeeper, FA-HMCu2-xS/BLM/LM offered a platform for simultaneous NIR-mediated temperature-responsive BLM and copper ion release, which further initiated the generation of the "activated BLM". As a matter of course, the remarkable synergistic combination of Cu-dependent chemo-phototherapy in vitro and in vivo by such a smart all-in-one drug delivery nanoplatform developed here provided information for advancing nanotherapy in biomedical fields.