RESUMEN
Metastatic cancer accounts for 90% of all cancer-related deaths and continues to be one of the toughest challenges in cancer treatment. A growing body of data indicates that S100A9, a major regulator of inflammation, plays a central role in cancer progression and metastasis, particularly in the lungs, where S100A9 forms a premetastatic niche. Thus, we developed a vaccine against S100A9 derived from plant viruses and virus-like particles. Using multiple tumor mouse models, we demonstrate the effectiveness of the S100A9 vaccine candidates in preventing tumor seeding within the lungs and outgrowth of metastatic disease. The elicited antibodies showed high specificity toward S100A9 without cross-reactivity toward S100A8, another member of the S100A family. When tested in metastatic mouse models of breast cancer and melanoma, the vaccines significantly reduced lung tumor nodules after intravenous challenge or postsurgical removal of the primary tumor. Mechanistically, the vaccines reduce the levels of S100A9 within the lungs and sera, thereby increasing the expression of immunostimulatory cytokines with antitumor function [(interleukin) IL-12 and interferonγ] while reducing levels of immunosuppressive cytokines (IL-10 and transforming growth factorß). This also correlated with decreased myeloid-derived suppressor cell populations within the lungs. This work has wide-ranging impact, as S100A9 is overexpressed in multiple cancers and linked with poor prognosis in cancer patients. The data presented lay the foundation for the development of therapies and vaccines targeting S100A9 to prevent metastasis.
Asunto(s)
Neoplasias Pulmonares , Vacunas Virales , Humanos , Ratones , Animales , Calgranulina B/metabolismo , Neoplasias Pulmonares/prevención & control , Calgranulina A/metabolismo , Pulmón/patología , Citocinas/metabolismoRESUMEN
Immune checkpoint therapy (ICT) for cancer can yield dramatic clinical responses; however, these may only be observed in a minority of patients. These responses can be further limited by subsequent disease recurrence and resistance. Combination immunotherapy strategies are being developed to overcome these limitations. We have previously reported enhanced efficacy of combined intratumoral cowpea mosaic virus immunotherapy (CPMV IIT) and ICT approaches. Lymphocyte-activation gene-3 (LAG-3) is a next-generation inhibitory immune checkpoint with broad expression across multiple immune cell subsets. Its expression increases on activated T cells and contributes to T cell exhaustion. We observed heightened efficacy of a combined CPMV IIT and anti-LAG-3 treatment in a mouse model of melanoma. Further, LAG-3 expression was found to be increased within the TME following intratumoral CPMV administration. The integration of CPMV IIT with LAG-3 inhibition holds significant potential to improve treatment outcomes by concurrently inducing a comprehensive anti-tumor immune response, enhancing local immune activation, and mitigating T cell exhaustion.
Asunto(s)
Comovirus , Melanoma , Humanos , Animales , Ratones , Terapia Combinada , Inmunoterapia , Modelos Animales de Enfermedad , Melanoma/terapiaRESUMEN
Toll-like receptors (TLRs) are promising targets in cancer immunotherapy due to their role in activating the immune system; therefore, various small-molecule TLR agonists have been tested in clinical applications. However, the clinical use of TLR agonists is hindered by their non-specific side effects and poor pharmacokinetics. To overcome these limitations, we used plant virus nanoparticles (VNPs) and bacteriophage virus-like particles (VLPs) as drug delivery systems. We conjugated TLR3 or TLR7 agonists to cowpea mosaic virus (CPMV) VNPs, cowpea chlorotic mottle virus (CCMV) VNPs, and bacteriophage Qß VLPs. The conjugation of TLR7 agonist, 2-methoxyethoxy-8-oxo-9-(4-carboxybenzyl)adenine (1V209), resulted in the potent activation of immune cells and promoted the production of pro-inflammatory cytokine interleukin 6. We found that 1V209 conjugated to CPMV, CCMV, and Qß reduced tumor growth in vivo and prolonged the survival of mice compared to those treated with free 1V209 or a simple admixture of 1V209 and viral particles. Nucleic acid-based TLR3 agonist, polyinosinic acid with polycytidylic acid (poly(I:C)), was also delivered by CPMV VNPs, resulting in enhanced mice survival. All our data suggest that coupling and co-delivery are required to enhance the anti-tumor efficacy of TLR agonists and simple mixing of the VLPs with the agonists does not confer a survival benefit. The delivery of 1V209 or poly(I:C) conjugated to VNPs/VLPs probably enhances their efficacy due to the multivalent presentation, prolongation of tumor residence time, and targeting of the innate immune cells mediated by the VNP/VLP carrier.
Asunto(s)
Bacteriófagos , Bromovirus , Neoplasias , Virus de Plantas , Animales , Ratones , Receptor Toll-Like 3 , Receptor Toll-Like 7 , Adyuvantes Inmunológicos , Inmunoterapia , Neoplasias/tratamiento farmacológicoRESUMEN
Plant virus nanoparticles can be used as drug carriers, imaging reagents, vaccine carriers, and immune adjuvants in the formulation of intratumoral in situ cancer vaccines. One example is the cowpea mosaic virus (CPMV), a nonenveloped virus with a bipartite positive-strand RNA genome with each RNA packaged separately into identical protein capsids. Based on differences in their densities, the components carrying RNA-1 (6 kb) denoted as the bottom (B) component or carrying RNA-2 (3.5 kb) denoted as the middle (M) component can be separated from each other and from a top (T) component, which is devoid of any RNA. Previous preclinical mouse studies and canine cancer trials used mixed populations of CPMV (containing B, M, and T components), so it is unclear whether the particle types differ in their efficacies. It is known that the CPMV RNA genome contributes to immunostimulation by activation of TLR7. To determine whether the two RNA genomes that have different sizes and unrelated sequences cause different immune stimulation, we compared the therapeutic efficacies of B and M components and unfractionated CPMV in vitro and in mouse cancer models. We found that separated B and M particles behaved similarly to the mixed CPMV, activating innate immune cells to induce the secretion of pro-inflammatory cytokines such as IFNα, IFNγ, IL-6, and IL-12, while inhibiting immunosuppressive cytokines such as TGF-ß and IL-10. In murine models of melanoma and colon cancer, the mixed and separated CPMV particles all significantly reduced tumor growth and prolonged survival with no significant difference. This shows that the specific RNA genomes similarly stimulate the immune system even though B particles have 40% more RNA than M particles; each CPMV particle type can be used as an effective adjuvant against cancer with the same efficacy as native mixed CPMV. From a translational point of view, the use of either B or M component vs the mixed CPMV formulation offers the advantage that separated B or M alone is noninfectious toward plants and thus provides agronomic safety.
Asunto(s)
Vacunas contra el Cáncer , Comovirus , Melanoma , Animales , Perros , Ratones , Comovirus/fisiología , ARN Viral/genética , Modelos Animales de Enfermedad , Citocinas , VacunaciónRESUMEN
Cowpea mosaic virus (CPMV) has been developed as a promising nanoplatform technology for cancer immunotherapy; when applied as in situ vaccine, CPMV exhibits potent, systemic, and durable efficacy. While CPMV is not infectious to mammals, it is infectious to legumes; therefore, agronomic safety needs to be addressed to broaden the translational application of CPMV. RNA-containing formulations are preferred over RNA-free virus-like particles because the RNA and protein, each, contribute to CPMV's potent antitumor efficacy. We have previously optimized inactivation methods to develop CPMV that contains RNA but is not infectious to plants. We established that inactivated CPMV has reduced efficacy compared to untreated, native CPMV. However, a systematic comparison between native CPMV and different inactivated forms of CPMV was not done. Therefore, in this study, we directly compared the therapeutic efficacies and mechanisms of immune activation of CPMV, ultraviolet- (UV-), and formalin (Form)-inactivated CPMV to explain the differential efficacies. In a B16F10 melanoma mouse tumor model, Form-CPMV suppressed the tumor growth with prolonged survival (there were no statistical differences comparing CPMV and Form-CPMV). In comparison, UV-CPMV inhibited tumor growth significantly but not as well as Form-CPMV or CPMV. The reduced therapeutic efficacy of UV-CPMV is explained by the degree of cross-linking and aggregated state of the RNA, which renders it inaccessible for sensing by Toll-like receptor (TLR) 7/8 to activate immune responses. The mechanistic studies showed that the highly aggregated state of UV-CPMV inhibited TLR7 signaling more so than for the Form-CPMV formulation, reducing the secretion of interleukin-6 (IL-6) and interferon-α (IFN-α), cytokines associated with TLR7 signaling. These findings support the translational development of Form-CPMV as a noninfectious immunotherapeutic agent.
Asunto(s)
Comovirus , Melanoma , Animales , Ratones , Receptor Toll-Like 7 , Modelos Animales de Enfermedad , Vacunación/métodos , MamíferosRESUMEN
PURPOSE: To test the hypothesis that cryoablation combined with intratumoral immunomodulating nanoparticles from cowpea mosaic virus (CPMV) as an in situ vaccination approach induces systemic antitumoral immunity in a murine model of hepatocellular carcinoma (HCC). MATERIALS AND METHODS: Mice with bilateral, subcutaneous RIL-175 cell-derived HCCs were randomized to 4 groups: (a) phosphate-buffered saline (control), (b) cryoablation only (Cryo), (c) CPMV-treated only (CPMV), and (d) cryoablation plus CPMV-treated (Cryo + CPMV) (N = 11-14 per group). Intratumoral CPMV was administered every 3 days for 4 doses, with cryoablation performed on the third day. Contralateral tumors were monitored. Tumor growth and systemic chemokine/cytokine levels were measured. A subset of tumors and spleens were harvested for immunohistochemistry (IHC) and flow cytometry. One- or 2-way analysis of variance was performed for statistical comparisons. A P value of <.05 was used as the threshold for statistical significance. RESULTS: At 2 weeks after treatment, the Cryo and CPMV groups, alone or combined, outperformed the control group in the treated tumor; however, the Cryo + CPMV group showed the strongest reduction and lowest variance (1.6-fold ± 0.9 vs 6.3-fold ± 0.5, P < .0001). For the untreated tumor, only Cryo + CPMV significantly reduced tumor growth compared with control (9.2-fold ± 0.9 vs 17.8-fold ± 2.1, P = .01). The Cryo + CPMV group exhibited a transient increase in interleukin-10 and persistently decreased CXCL1. Flow cytometry revealed natural killer cell enrichment in the untreated tumor and increased PD-1 expression in the spleen. Tumor-infiltrating lymphocytes increased in Cryo + CPMV-treated tumors by IHC. CONCLUSIONS: Cryoablation and intratumoral CPMV, alone or combined, demonstrated potent efficacy against treated HCC tumors; however, only cryoablation combined with CPMV slowed the growth of untreated tumors, consistent with an abscopal effect.
Asunto(s)
Carcinoma Hepatocelular , Comovirus , Criocirugía , Neoplasias Hepáticas , Animales , Ratones , Adyuvantes Inmunológicos , Carcinoma Hepatocelular/cirugía , Criocirugía/efectos adversos , Neoplasias Hepáticas/cirugía , VacunaciónRESUMEN
Cancer cells are more vulnerable to reactive oxygen species (ROS)-mediated oxidative stress than normal cells due to disturbed redox balance. It can be postulated that ROS-generating drug carriers exert anticancer actions, leading to combination anticancer therapy with drug payloads. Here, we report a ROS-generating polyprodrug of cinnamaldehyde (CA) that not only serves as a drug carrier but also synergizes with drug payloads. The polyprodrug of CA (pCA) incorporates ROS-generating CA in the backbone of an amphiphilic polymer through an acid-cleavable acetal linkage. pCA could self-assemble with tumor-targeting lipopeptide (DSPE-PEG-RGD) and encapsulate doxorubicin (DOX) to form T-pCAD micelles. At acidic pH, T-pCAD micelles release both CA and DOX to exert synergistic anticancer actions. Animal studies using mouse xenograft models revealed that T-pCAD micelles accumulate in tumors preferentially and suppress the tumor growth significantly. Based on the oxidative stress amplification and acid-responsiveness, ROS-generating pCAD micelles hold tremendous potential as drug carriers for combination anticancer therapy.
Asunto(s)
Micelas , Neoplasias , Animales , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Portadores de Fármacos/uso terapéutico , Liberación de Fármacos , Humanos , Concentración de Iones de Hidrógeno , Ratones , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Estrés Oxidativo , Especies Reactivas de OxígenoRESUMEN
Curcumin, a primary active element of turmeric, has potent antioxidant and anti-inflammatory activity, but its low bioavailability is a major hurdle in its pharmaceutical applications. To enhance the therapeutic efficacy of curcumin, we exploited polymeric prodrug strategy. Here, we report rationally designed acid-activatable curcumin polymer (ACP), as a therapeutic prodrug of curcumin, in which curcumin was covalently incorporated in the backbone of amphiphilic polymer. ACP could self-assemble to form micelles that rapidly release curcumin under the acidic condition. The potential of ACP micelles as therapeutics for osteoarthritis was evaluated using a mouse model of monoidoacetic acid (MIA)-induced knee osteoarthritis. ACP micelles drastically protected the articular structures from arthritis through the suppression of tumor necrosis factor-alpha (TNF-α) and interleukin 1ß (IL-1ß). Given their pathological stimulus-responsiveness and potent antioxidant and anti-inflammatory activities, ACP micelles hold remarkable potential as a therapeutic agent for not only osteoarthritis but also various inflammatory diseases.
Asunto(s)
Antiinflamatorios , Curcumina , Nanopartículas , Osteoartritis de la Rodilla/tratamiento farmacológico , Animales , Antiinflamatorios/química , Antiinflamatorios/farmacología , Curcumina/química , Curcumina/farmacología , Preparaciones de Acción Retardada/química , Preparaciones de Acción Retardada/farmacología , Modelos Animales de Enfermedad , Concentración de Iones de Hidrógeno , Interleucina-1beta/inmunología , Ratones , Micelas , Nanopartículas/química , Nanopartículas/uso terapéutico , Osteoartritis de la Rodilla/inducido químicamente , Osteoartritis de la Rodilla/inmunología , Osteoartritis de la Rodilla/patología , Células RAW 264.7 , Factor de Necrosis Tumoral alfa/inmunologíaRESUMEN
Asthma is a common airway inflammatory disorder, characterized by increased infiltration of leukocytes and bronchoconstriction. Dexamethasone (DEX) has been widely used in the treatment of allergic asthma. However, long-term and frequent use of DEX has side effects. We therefore reasoned that if drug carriers have intrinsic anti-inflammatory and anti-asthmatic activity and synergize with drug payloads, a low dose of DEX could exert sufficient therapeutic effects. In this study, we developed DEX-loaded H2O2-activatable boronate maltodextrin (DEX-BM) nanoparticles. DEX-BM nanoparticles released DEX in a H2O2-triggered manner and remarkably suppressed the expression of pro-inflammatory cytokines in activated macrophages and lung epithelial cells. In the studies of a murine allergic asthma model, DEX-BM nanoparticles (5 mg/kg) effectively inhibited the inflammatory cell infiltration and airway inflammation than equivalent DEX and BM nanoparticles without noticeable side effects. We anticipate that DEX-BM nanoparticles hold great potential as therapeutic agents for various airway inflammatory diseases.
Asunto(s)
Antiinflamatorios/uso terapéutico , Asma/tratamiento farmacológico , Dexametasona/uso terapéutico , Peróxido de Hidrógeno/química , Hipersensibilidad/tratamiento farmacológico , Nanopartículas/administración & dosificación , Animales , Asma/etiología , Dexametasona/química , Modelos Animales de Enfermedad , Portadores de Fármacos , Hipersensibilidad/complicaciones , Ratones , Ratones Endogámicos BALB C , Nanopartículas/toxicidad , Ovalbúmina/administración & dosificaciónRESUMEN
Cancer cells have a large amount of ROS (reactive oxygen species) because of disturbed ROS homeostasis. Cancer cells therefore undertake redox adaptation to drive proliferation in tumor environments and even survive during anticancer treatment by upregulating endogenous antioxidants. As one of antioxidant defense systems, heme oxygenase-1 (HO-1) acts as an essential role in tumor development by offering antioxidant bilirubin to protect cancer cells under stress conditions. It can be therefore reasoned that the combination of ROS generation and HO-1 inhibition would exert synergistic anticancer effects through the amplification of oxidative stress and provide a new opportunity for targeted anticancer therapy. To establish targeted anticancer therapy based on amplified oxidative stress, we developed molecularly engineered polymer, termed CZP, which incorporates ROS generating CA (cinnamaldehyde) and HO-1 inhibiting ZnPP (zinc protoporphyrin) in its backbone and could form stable micelles in aqueous solutions. CZP micelles not only elevated oxidative stress but also suppressed the expression of antioxidant HO-1, leading to apoptotic cell death. CZP micelles could also significantly suppress the tumor growth without body weight loss, tumor recurrence, and noticeable toxicity in organs. This study demonstrates that a combination of ROS generation and HO-1inhibition synergistically magnifies oxidative stress to kill cancer cells and oxidative stress amplifying CZP micelles may provide a promising strategy in anticancer treatment.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Hemo-Oxigenasa 1/antagonistas & inhibidores , Estrés Oxidativo/efectos de los fármacos , Polímeros/química , Especies Reactivas de Oxígeno/metabolismo , Células A549 , Animales , Antioxidantes/metabolismo , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos/métodos , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Micelas , Oxidación-Reducción/efectos de los fármacos , Protoporfirinas/metabolismoRESUMEN
Curcumin is a major active phenolic component of turmeric and has gained great attention in pharmaceutics due to its potent antioxidant, anti-inflammatory and anticancer activity. Here, we developed poly(oxalate-co-curcumin) (POC) as a hydrogen peroxide (H2O2)-activatable polymeric prodrug of curcumin by incorporating curcumin in the backbone of H2O2-responsive polyoxalate. POC particles effectively scavenged H2O2 and released curcumin in a H2O2-triggered manner. POC particles exhibited excellent antioxidant and anti-inflammatory activity in activated cells. POC particles intravenously administrated into acetaminophen-intoxicated mice remarkably suppressed the level of alanine transaminase and inhibited apoptotic cell death in liver. Interestingly, POC particles could also enhance the ultrasound contrast in the intoxicated liver due to CO2 bubble generation through H2O2-triggered oxidation of peroxalate esters. Given their H2O2-responsiveness and highly potent antioxidant activity, POC particles hold great translational potential as theranostic agents for H2O2-associated diseases.
Asunto(s)
Curcumina/uso terapéutico , Peróxido de Hidrógeno/química , Fallo Hepático Agudo/diagnóstico por imagen , Fallo Hepático Agudo/tratamiento farmacológico , Polímeros/química , Profármacos/uso terapéutico , Ultrasonografía/métodos , Animales , Antiinflamatorios/química , Antiinflamatorios/uso terapéutico , Antioxidantes/química , Antioxidantes/uso terapéutico , Curcumina/química , Masculino , Ratones , Ratones Endogámicos ICR , Profármacos/química , Células RAW 264.7RESUMEN
The key challenge in cancer treatment is prevention of metastatic disease which is therapeutically resistant and carries poor prognoses necessitating efficacious prophylactic approaches that prevent metastasis and recurrence. It is previously demonstrated that cowpea mosaic virus (CPMV) induces durable antitumor responses when used in situ, i.e., intratumoral injection. As a new direction, it is showed that CPMV demonstrates widespread effectiveness as an immunoprophylactic agent - potent efficacy is demonstrated in four metastatic models of colon, ovarian, melanoma, and breast cancer. Systemic administration of CPMV stimulates the innate immune system, enabling attack of cancer cells; processing of the cancer cells and associated antigens leads to systemic, durable, and adaptive antitumor immunity. Overall, CPMV demonstrated broad efficacy as an immunoprophylactic agent in the rejection of metastatic cancer.
Asunto(s)
Comovirus , Animales , Ratones , Femenino , Metástasis de la Neoplasia/prevención & control , Humanos , Línea Celular Tumoral , Modelos Animales de EnfermedadRESUMEN
Our lab demonstrated that intratumoral Cowpea mosaic virus (CPMV) is a potent antitumor immunotherapy when used as in situ vaccine. As we pave the way for human clinical translation, formulation chemistry needs to be optimized for long-term storage of the drug candidate. In this work, CPMV was nanoengineered with Pluronic F127 to realize liquid and gel formulations which mitigate structural changes and RNA release during long-term storage. We evaluated the CPMV-F127 formulations for their stability and biological activity through a combination of in vitro assays and efficacy in vivo using a B16F10 murine melanoma model. Results demonstrate that both F127 liquid and gel formulations preserve CPMV structure and function following extended periods of thermal incubation at 4°C, 25°C, and 37°C. Heat-incubated CPMV without formulation resulted in structural changes and inferior in vivo efficacy. In stark contrast, in vivo efficacy was preserved when CPMV was formulated and protected with the F127 "nanoarmor."
RESUMEN
Cancer cells are equipped with abundant antioxidants such as glutathione (GSH) that eliminate reactive oxygen species (ROS) to deteriorate the therapeutic efficacy of photodynamic therapy (PDT). Another challenge in PDT is circumventing PDT-induced hypoxic condition that provokes upregulation of pro-angiogenic factor such as vascular endothelial growth factor (VEGF). It is therefore reasonable to expect that therapeutic outcomes of PDT could be maximized by concurrent delivery of photosensitizers with GSH depleting agents and VEGF suppressors. To achieve cooperative therapeutic actions of PDT with in situ GSH depletion and VEGF suppression, we developed tumor targeted redox-regulating and antiangiogenic phototherapeutic nanoassemblies (tRAPs) composed of self-assembling disulfide-bridged borylbenzyl carbonate (ssBR), photosensitizer (IR780) and tumor targeting gelatin. As a framework of tRAPs, ssBR was rationally designed to form nanoconstructs that serve as photosensitizer carriers with intrinsic GSH depleting- and VEGF suppressing ability. tRAPs effectively depleted intracellular GSH to render cancer cells more vulnerable to ROS and also provoked immunogenic cell death (ICD) of cancer cells upon near infrared (NIR) laser irradiation. In mouse xenograft models, tRAPs preferentially accumulated in tumors and dramatically eradicated tumors with laser irradiation. The design rationale of tRAPs provides a simple and versatile strategy to develop self-boosting phototherapeutic agents with great potential in targeted cancer therapy.
Asunto(s)
Nanopartículas , Neoplasias , Fotoquimioterapia , Animales , Ratones , Humanos , Fármacos Fotosensibilizantes/farmacología , Fármacos Fotosensibilizantes/uso terapéutico , Factor A de Crecimiento Endotelial Vascular/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Línea Celular Tumoral , Nanopartículas/uso terapéutico , Fototerapia , Neoplasias/tratamiento farmacológico , Glutatión/metabolismo , Oxidación-ReducciónRESUMEN
Compared to normal cells, cancer cells are more susceptible to insults of prooxidants that generate ROS (reactive oxygen species) or scavenge antioxidants such as glutathione (GSH). Cancer cells undergo immunogenic cell death (ICD) by elevated oxidative stress. Herein, we report rationally designed F-ssPBCA nanoparticles as a tumor-targeting prooxidant, which generates ROS and scavenges GSH simultaneously to cooperatively amplify oxidative stress, leading to ICD. Prooxidant F-ssPBCA nanoparticles are composed of a disulfide-bridged GSH scavenging dimeric prodrug (ssPB) that self-assembles to form nanoconstructs and encapsulates ROS-generating BCA (benzoyloxy cinnamaldehyde). F-ssPBCA nanoparticles significantly elevate oxidative stress to kill cancer cells and also evoke ICD featured by the release of CRT (calreticulin), HMGB-1 (high mobility group box-1), and adenosine triphosphate (ATP). Animal studies revealed that F-ssPBCA nanoparticles accumulate in tumors preferentially and suppress tumor growth effectively. The results of this study demonstrate that prooxidant-mediated oxidative stress elevation is a highly effective strategy to kill cancer cells selectively and even evoke abundant ICD. We anticipate that oxidative stress amplifying F-ssPBCA nanoparticles hold tremendous translational potential as a tumor targeted ICD-inducing anticancer nanomedicine.
Asunto(s)
Antineoplásicos , Nanopartículas , Neoplasias , Profármacos , Animales , Especies Reactivas de Oxígeno/metabolismo , Calreticulina/farmacología , Antioxidantes/farmacología , Profármacos/farmacología , Nanomedicina , Antineoplásicos/farmacología , Estrés Oxidativo , Neoplasias/tratamiento farmacológico , Glutatión/metabolismo , Disulfuros/metabolismo , Adenosina Trifosfato/metabolismo , Proteínas HMGB/metabolismo , Proteínas HMGB/farmacología , Línea Celular TumoralRESUMEN
Self-assembling prodrugs are able to form stable nanoparticles without additional excipients and therefore have gained increasing interest in the field of drug delivery. As a natural derivative of vitamin A, all-trans retinoic acid (atRA) exerts antioxidant, anti-inflammatory, and immunostimulatory effects. However, the clinical translation of atRA has been hampered by its insufficient therapeutic efficacy. In this work, to fully maximize the therapeutic potential of atRA, we developed delicately designed self-assembling RABA (atRA-based hybrid prodrug) as a hybrid prodrug of atRA and hydroxybenzyl alcohol (HBA). RABA could form nanoassemblies and decompose to release atRA and HBA simultaneously in response to hydrogen peroxide (H2O2). In a mouse model of hepatic ischemia/reperfusion (IR) injury, RABA nanoassemblies accumulated in liver preferentially and exerted highly potent antioxidant, anti-inflammatory, and antiapoptotic effects, leading to effective protection of liver from IR injury. RABA nanoassemblies exhibited significantly higher therapeutic efficacy than the combination of equivalent atRA and HBA. Given its H2O2-responsiveness, self-assembling and self-immolating behaviors, and cooperative therapeutic actions, RABA nanoassemblies have great potential as a pure nanodrug for hepatic IR injury. This study also provides a new valuable addition in the development of prodrug self-assemblies that will emerge as next generation of drugs.
Asunto(s)
Nanopartículas , Profármacos , Daño por Reperfusión , Animales , Antiinflamatorios/uso terapéutico , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Peróxido de Hidrógeno/farmacología , Isquemia/tratamiento farmacológico , Hígado , Ratones , Nanopartículas/uso terapéutico , Profármacos/farmacología , Profármacos/uso terapéutico , Daño por Reperfusión/tratamiento farmacológico , Tretinoina/farmacologíaRESUMEN
Stimulus-responsive self-assembling prodrug-based nanomedicine has emerged as a novel paradigm in controlled drug delivery. All-trans retinoic acid (RA), one of vitamin A metabolites, induces apoptotic cancer cell death, but its clinical applications are limited by weak anticancer efficacy. To fully maximize the therapeutic potential of RA, we exploited the unique chemistry of arylboronic acid which undergoes hydrogen peroxide (H2O2)-triggered degradation to release quinone methide (QM) that alkylates glutathione (GSH) to disrupt redox homeostasis and is also converted into hydroxybenzyl alcohol (HBA) to suppress the expression of vascular endothelial growth factor (VEGF). Here, we report that boronated retinoic acid prodrug (RABA) can be formulated into self-deliverable nanoassemblies which release both RA and QM in a H2O2-triggered self-immolative manner to exert cooperative anticancer activities. RABA nanoassemblies exert anticancer effects by inducing reactive oxygen species (ROS)-mediated apoptosis, eliciting immunogenic cell death (ICD) and suppressing angiogenic VEGF expression. The excellent anticancer efficacy of RABA nanoassemblies can be explained by benefits of self-assembling prodrug-based drug self-delivery and cooperative anticancer actions. The design strategy of RABA would provide a new insight into the rational design of self-deliverable and self-immolative boronated prodrug nanoassemblies for targeted cancer therapy.
RESUMEN
Phototherapy including photothermal therapy (PTT) and photodynamic therapy (PDT) uses photosensitizers and light to kill cancer cells and has become a promising therapeutic modality because of advantages such as minimal invasiveness and high cancer selectivity. However, PTT or PDT as a single treatment modality has insufficient therapeutic efficacy. Moreover, oxygen consumption by PDT activates angiogenic factors and leads to cancer recurrence and progression. Therefore, the therapeutic outcomes of phototherapy would be maximized by employing photosensitizers for concurrent PTT and PDT and suppressing angiogenic factors. Therefore, integrating photosensitive agents and antiangiogenic agents in a single nanoplatform would be a promising strategy to maximize the therapeutic efficacy of phototherapy. In this study, we developed hyaluronic acid-coated fluorescent boronated polysaccharide (HA-FBM) nanoparticles as a combination therapeutic agent for phototherapy and antiangiogenic therapy. Upon a single near-infrared laser irradiation, HA-FBM nanoparticles generated heat and singlet oxygen simultaneously to kill cancer cells and also induced immunogenic cancer cell death. Beside their fundamental roles as photosensitizers, HA-FBM nanoparticles exerted antiangiogenic effects by suppressing the vascular endothelial growth factor (VEGF) and cancer cell migration. In a mouse xenograft model, intravenously injected HA-FBM nanoparticles targeted tumors by binding CD44-overexpressing cancer cells and suppressed angiogenic VEGF expression. Upon laser irradiation, HA-FBM nanoparticles remarkably eradicated tumors and increased anticancer immunity. Given their synergistic effects of phototherapy and antiangiogenic therapy from tumor-targeting HA-FBM nanoparticles, we believe that integrating the photosensitizers and antiangiogenic agents into a single nanoplatform presents an attractive strategy to maximize the anticancer therapeutic efficacy of phototherapy.
Asunto(s)
Inhibidores de la Angiogénesis/farmacología , Antineoplásicos/farmacología , Materiales Biocompatibles/farmacología , Peróxido de Hidrógeno/metabolismo , Fotoquimioterapia , Fármacos Fotosensibilizantes/farmacología , Inhibidores de la Angiogénesis/síntesis química , Inhibidores de la Angiogénesis/química , Animales , Antineoplásicos/síntesis química , Antineoplásicos/química , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Movimiento Celular/efectos de los fármacos , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Ácido Hialurónico/química , Ácido Hialurónico/farmacología , Rayos Láser , Ensayo de Materiales , Ratones , Estructura Molecular , Nanopartículas/química , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/tratamiento farmacológico , Neoplasias Experimentales/metabolismo , Imagen Óptica , Tamaño de la Partícula , Fármacos Fotosensibilizantes/síntesis química , Fármacos Fotosensibilizantes/química , Polisacáridos/química , Polisacáridos/farmacología , Células Tumorales Cultivadas , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Ischemia/reperfusion (IR) injury is induced by the restoration of blood flow to the prolonged ischemic tissues and is considered as the paradoxical exacerbation of ischemic damages. A large amount of reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) produced immediately after reperfusion induces oxidative stress, which plays an essential role in the pathogenesis of IR injury. It is therefore critical to suppress oxidative stress for the prevention and treatment of IR injury. Ursodeoxycholic acid (UDCA), one of the tertiary bile acids, promotes the generation of antioxidant glutathione (GSH) and also exerts hepatoprotective, cytoprotective, and antiapoptotic effects. However, the clinical uses of UDCA are limited mainly by its poor water solubility and low bioavailability. In this study, by exploiting the concept of self-assembling disulfide-bridged dimeric prodrugs, we developed a disulfide-bridged UDCA dimer (ssUDCA) as a therapeutic agent of hepatic IR injury. ssUDCA could self-assemble into stable nanospheres under aqueous conditions, scavenge H2O2, and exert anti-inflammatory and antiapoptotic activities. In a mouse model of hepatic IR injury, ssUDCA (5 mg/kg) significantly alleviated the IR injury by suppressing ROS production and inhibiting proinflammatory cytokines. Therefore, our findings offer a promising strategy for the effective treatment of hepatic IR injury and also provide deep insights into the impact of disulfide-bridged UDCA nanoassemblies in pharmaceutical applications.
Asunto(s)
Ácidos y Sales Biliares/farmacología , Materiales Biocompatibles/farmacología , Disulfuros/farmacología , Hígado/efectos de los fármacos , Daño por Reperfusión/tratamiento farmacológico , Animales , Ácidos y Sales Biliares/química , Materiales Biocompatibles/síntesis química , Materiales Biocompatibles/química , Supervivencia Celular/efectos de los fármacos , Dimerización , Disulfuros/química , Peróxido de Hidrógeno/antagonistas & inhibidores , Peróxido de Hidrógeno/farmacología , Hígado/patología , Masculino , Ensayo de Materiales , Ratones , Nanopartículas , Estrés Oxidativo/efectos de los fármacos , Tamaño de la Partícula , Células RAW 264.7 , Daño por Reperfusión/patologíaRESUMEN
Prodrug-type polymer-drug conjugates based on highly biocompatible functional polyethers are developed through mechanochemical post-polymerization modification. Herein, we design functional epoxide monomers of ethoxyethyl glycidyl ether (EEGE) and azidohexyl glycidyl ether (AHGE) and synthesize diblock copolyethers of PEEGE-b-PAHGE via sequential anionic ring-opening polymerization. Subsequent conversion of the functional monomers to the corresponding hydroxyl and amine groups allows for the preparation of double hydrophilic block copolyethers. Most notably, mechanochemical modification allows for the conjugation of these polymers with a highly hydrophobic and potent anticancer agent, cinnamaldehyde, through an imine linkage. The self-assembly of the resulting polymer-drug conjugates into polymeric micelles is characterized by dynamic light scattering and atomic force microscopy. The pH-responsive cleavage of the imine linkages under acidic conditions leads to the release of cinnamaldehyde with a concomitant disassembly of the polymeric micelles. The superior biocompatibility coupled with the solvent-less mechanochemical conjugation approach provides a convenient means to introduce various therapeutics for smart drug delivery.