RESUMEN
The development of in situ tumor vaccines offers promising prospects for cancer treatment. Nonetheless, the generation of plenary autologous antigens in vivo and their codelivery to DC cells along with adjuvants remains a significant challenge. Herein, we developed an in situ tumor vaccine using a supramolecular nanoparticle/hydrogel composite (ANPMTO/ALCD) and a deformable nanoadjuvant (PPER848). The ANPMTO/ALCD composite consisted of ß-cyclodextrin-decorated alginate (Alg-g-CD) and MTO-encapsulated adamantane-decorated nanoparticles (ANPMTO) through supramolecular interaction, facilitating the long-term and sustained production of plenary autologous antigens, particularly under a 660 nm laser. Simultaneously, the produced autologous antigens were effectively captured by nanoadjuvant PPER848 and subsequently transported to lymph nodes and DC cells, benefiting from its optimized size and deformability. This in situ tumor vaccine can trigger a robust antitumor immune response and demonstrate significant therapeutic efficacy in inhibiting tumor growth, suppressing tumor metastasis, and preventing postoperative recurrence, offering a straightforward approach to programming in situ tumor vaccines.
Asunto(s)
Adyuvantes Inmunológicos , Vacunas contra el Cáncer , Inmunoterapia , Nanopartículas , Vacunas contra el Cáncer/química , Vacunas contra el Cáncer/administración & dosificación , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/uso terapéutico , Animales , Ratones , Inmunoterapia/métodos , Nanopartículas/química , Adyuvantes Inmunológicos/química , Adyuvantes Inmunológicos/administración & dosificación , Adyuvantes Inmunológicos/uso terapéutico , Adyuvantes Inmunológicos/farmacología , Hidrogeles/química , Humanos , Línea Celular Tumoral , Células Dendríticas/inmunología , beta-Ciclodextrinas/química , Neoplasias/terapia , Neoplasias/inmunología , Alginatos/química , Adamantano/química , Adamantano/uso terapéuticoRESUMEN
T-cell acute lymphoblastic leukemia (T-ALL), a heterogeneous hematological malignancy, is caused by the developmental arrest of normal T-cell progenitors. The development of targeted therapeutic regimens is impeded by poor knowledge of the stage-specific aberrances in this disease. In this study, we performed multi-omics integration analysis, which included mRNA expression, chromatin accessibility, and gene-dependency database analyses, to identify potential stage-specific druggable targets and repositioned drugs for this disease. This multi-omics integration helped identify 29 potential pathological genes for T-ALL. These genes exhibited tissue-specific expression profiles and were enriched in the cell cycle, hematopoietic stem cell differentiation, and the AMPK signaling pathway. Of these, four known druggable targets (CDK6, TUBA1A, TUBB, and TYMS) showed dysregulated and stage-specific expression in malignant T cells and may serve as stage-specific targets in T-ALL. The TUBA1A expression level was higher in the early T cell precursor (ETP)-ALL cells, while TUBB and TYMS were mainly highly expressed in malignant T cells arrested at the CD4 and CD8 double-positive or single-positive stage. CDK6 exhibited a U-shaped expression pattern in malignant T cells along the naïve to maturation stages. Furthermore, mebendazole and gemcitabine, which target TUBA1A and TYMS, respectively, exerted stage-specific inhibitory effects on T-ALL cell lines, indicating their potential stage-specific antileukemic role in T-ALL. Collectively, our findings might aid in identifying potential stage-specific druggable targets and are promising for achieving more precise therapeutic strategies for T-ALL.
RESUMEN
In some cancers mutant p53 promotes the occurrence, development, metastasis and drug resistance of tumours, with targeted protein degradation seen as an effective therapeutic strategy. However, a lack of specific autophagy receptors limits this. Here, we propose the synthesis of biomimetic nanoreceptors (NRs) that mimic selective autophagy receptors. The NRs have both a component for targeting the desired protein, mutant-p53-binding peptide, and a component for enhancing degradation, cationic lipid. The peptide can bind to mutant p53 while the cationic lipid simultaneously targets autophagosomes and elevates the levels of autophagosome formation, increasing mutant p53 degradation. The NRs are demonstrated in vitro and in a patient-derived xenograft ovarian cancer model in vivo. The work highlights a possible direction for treating diseases by protein degradation.
Asunto(s)
Autofagia , Proteína p53 Supresora de Tumor , Humanos , Proteína p53 Supresora de Tumor/genética , Proteína p53 Supresora de Tumor/metabolismo , Proteolisis , Proteínas Mutantes/metabolismo , Proteínas Mutantes/farmacología , Línea Celular Tumoral , Péptidos/metabolismo , Lípidos/farmacologíaRESUMEN
BACKGROUND: Newborn screening (NBS) aims to detect congenital anomalies, and next-generation sequencing (NGS) has shown promise in this aspect. However, the NBS strategy for monogenic inherited diseases in China remains insufficient. METHODS: We developed a NeoEXOME panel comprising 601 genes that are relevant to the Chinese population found through extensive research on available databases. An interpretation system to grade the results into positive (high-risk, moderate-risk, and low-risk genotypes), negative, and carrier according to the American College of Medical Genetics (ACMG) guidelines was also developed. We validated the panel to evaluate its efficacy by using data from the "1000 Genomes Project" and conducted a pilot multicenter study involving 3423 neonates. RESULTS: The NGS positive rate in the 1000 Genomes Project was 7.6% (23/301), whereas the rate was 12.0% in the multicenter study, including 3249 recruited neonates. Notably, in 200 neonates, positive per conventional NBS, 58.5% (69/118) showed results consistent with NGS. In the remaining 3049 neonates showing negative results in conventional NBS, 271 (8.9%) were positive per NGS, and nine of them were clinically diagnosed with diseases in the follow-up. CONCLUSION: We successfully designed a NeoEXOME panel for targeted sequencing of monogenic inherited diseases in NBS. The panel demonstrated high performance in the Chinese population, particularly for the early detection of diseases with no biochemical markers.
Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Tamizaje Neonatal , Humanos , Recién Nacido , Proyectos Piloto , Secuenciación del Exoma , Tamizaje Neonatal/métodos , Genotipo , Secuenciación de Nucleótidos de Alto Rendimiento/métodosRESUMEN
Efficiently reawakening immune cells, including T cells and macrophages, to eliminate tumor cells is a promising strategy for cancer treatment, but remains a huge challenge nowadays. Herein, a nanoassembly formed by doxorubicin (DOX)-conjugated polyphosphoester (PP-(hDOX)) and CD47-targeting siRNA (siCD47) via electrostatic and π-π stacking interactions, termed as PP-(hDOX&siCD47), was developed to reawaken the T cell and macrophage-mediated anticancer activity. The PP-(hDOX&siCD47) could efficiently blockade antiphagocytic signal by downregulation of CD47 expression to reactive macrophage-mediated anticancer immunotherapy. Moreover, the conjugated DOX of PP-(hDOX&siCD47) can perform the chemotherapy towards tumor cells and also elicit the T cell-mediated anticancer immune response via immunogenic cell death (ICD) effect. Therefore, the PP-(hDOX&siCD47) treatment could significantly increase M1-like macrophages proportion and tumor infiltration of CD8+ T cells, while the proportions of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSC) were considerably reduced in tumor tissue, eventually achieving significantly tumor growth inhibition. Overall, this study provides a simple siRNA and DOX codelivery approach to simultaneously elicit the macrophage- and T cell-mediated anticancer immune response for cancer therapy.
Asunto(s)
Antígeno CD47 , Neoplasias , ARN Interferente Pequeño/metabolismo , Linfocitos T CD8-positivos/metabolismo , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Inmunoterapia , Macrófagos/metabolismo , Inmunidad , Línea Celular Tumoral , Neoplasias/tratamiento farmacológicoRESUMEN
TAL1+ T-cell acute lymphoblastic leukemia (T-ALL) is a distinct subtype of leukemia with poor outcomes. Through the cooperation of co-activators, including RUNX1, GATA3, and MYB, the TAL1 oncoprotein extends the immature thymocytes with autonomy and plays an important role in the development of T-ALL. However, this process is not yet well understood. Here, by investigating the transcriptome and prognosis of T-ALL from multiple cohorts, we found that S1PR3 was highly expressed in a subset of TAL1+ T-ALL (S1PR3hi TAL1+ T-ALL), which showed poor outcomes. Through pharmacological and genetic methods, we identified a specific survival-supporting role of S1P-S1PR3 in TAL1+ T-ALL cells. In T-ALL cells, TAL1-RUNX1 up-regulated the expression of S1PR3 by binding to the enhancer region of S1PR3 gene. With hyperactivated S1P-S1PR3, T-ALL cells grew rapidly, partly by activating the KRAS signal. Finally, we assessed S1PR3 inhibitor TY-52156 in T-ALL patient-derived xenografts (PDXs) mouse model. We found that TY-52156 attenuated leukemia progression efficiently and extended the lifespan of S1PR3hi TAL1+ T-ALL xenografts. Our findings demonstrate that S1PR3 plays an important oncogenic role in S1PR3hi TAL1+ T-ALL and may serve as a promising therapeutic target.
Asunto(s)
Leucemia-Linfoma Linfoblástico de Células T Precursoras , Humanos , Animales , Ratones , Leucemia-Linfoma Linfoblástico de Células T Precursoras/tratamiento farmacológico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/genética , Subunidad alfa 2 del Factor de Unión al Sitio Principal/genética , Proteína 1 de la Leucemia Linfocítica T Aguda/genética , Proteína 1 de la Leucemia Linfocítica T Aguda/metabolismo , Timocitos/metabolismo , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genéticaRESUMEN
The abnormal activation of epidermal growth factor receptor (EGFR) drives the development of non-small cell lung cancer (NSCLC). The EGFR-targeting tyrosine kinase inhibitor osimertinib is frequently used to clinically treat NSCLC and exhibits marked efficacy in patients with NSCLC who have an EGFR mutation. However, free osimertinib administration exhibits an inadequate response in vivo, with only â¼3% patients demonstrating a complete clinical response. Consequently, we designed a biomimetic nanoparticle (CMNP@Osi) comprising a polymeric nanoparticle core and tumor cell-derived membrane-coated shell that combines membrane-mediated homologous and molecular targeting for targeted drug delivery, thereby supporting a dual-target strategy for enhancing osimertinib efficacy. After intravenous injection, CMNP@Osi accumulates at tumor sites and displays enhanced uptake into cancer cells based on homologous targeting. Osimertinib is subsequently released into the cytoplasm, where it suppresses the phosphorylation of upstream EGFR and the downstream AKT signaling pathway and inhibits the proliferation of NSCLC cells. Thus, this dual-targeting strategy using a biomimetic nanocarrier can enhance molecular-targeted drug delivery and improve clinical efficacy.
RESUMEN
Cancer nanomedicine treatment aims to achieve highly specific targeting and localization to cancer cells. Coating of nanoparticles with cell membranes endows them with homologous cellular mimicry, enabling nanoparticles to acquire new functions and properties, including homologous targeting and long circulation in vivo, and can enhance internalization by homologous cancer cells. Herein, we fused a human-derived HCT116 colon cancer cell membrane (cM) with a red blood cell membrane (rM) to fabricate an erythrocyte-cancer cell hybrid membrane (hM). Oxaliplatin and chlorin e6 (Ce6) co-encapsulated reactive oxygen species-responsive nanoparticles (NPOC) were camouflaged by hM and obtained a hybrid biomimetic nanomedicine (denoted as hNPOC) for colon cancer therapy. hNPOC exhibited prolonged circulation time and recognized homologous targeting ability in vivo since both rM and HCT116 cM proteins were maintained on the hNPOC surface. hNPOC showed enhanced homologous cell uptake in vitro and considerable homologous self-localization in vivo, producing effective synergistic chemophotodynamic therapy efficacy under irradiation with a homologous HCT116 tumor compared to that with a heterologous tumor. Together, the biomimetic hNPOC nanoparticles showed prolonged blood circulation and preferential cancer cell-targeted function in vivo to provide a bioinspired strategy for chemophotodynamic synergistic therapy of colon cancer.
Asunto(s)
Neoplasias del Colon , Nanopartículas , Humanos , Biónica , Membrana Eritrocítica/metabolismo , Fototerapia , Neoplasias del Colon/tratamiento farmacológico , Especies Reactivas de Oxígeno/metabolismo , Línea Celular TumoralRESUMEN
The passive diffusion performance of nanocarriers results in inefficient drug transport across multiple biological barriers and consequently cancer therapy failure. Here, a magnetically driven amoeba-like nanorobot (amNR) is presented for whole-process active drug transport. The amNR is actively extravasated from blood vessels and penetrated into deep tumor tissue through a magnetically driven deformation effect. Moreover, the acidic microenvironment of deep tumor tissue uncovers the masked targeting ligand of amNR to achieve active tumor cell uptake. Furthermore, the amNR rapidly releases the encapsulated doxorubicin (DOX) after alternating magnetic field application. The amNRs eventually deliver DOX into ≈92.3% of tumor cells and completely delay tumor growth with an inhibition rate of 96.1%. The deformable amNRs, with the assistance of magnetic field application, provide a facile strategy for whole-process active drug transport.
Asunto(s)
Amoeba , Transporte Biológico , Doxorrubicina , Campos MagnéticosRESUMEN
Background: Neuroblastoma is the most common extracranial solid tumor of childhood, arising from the sympathetic nervous system. High-risk neuroblastoma (HRNB) remains a major therapeutic challenge with low survival rates despite the intensification of therapy. This study aimed to develop a malignant-cell marker gene signature (MMGS) that might serve as a prognostic indicator in HRNB patients. Methods: Multi-omics datasets, including mRNA expression (single-cell and bulk), DNA methylation, and clinical information of HRNB patients, were used to identify prognostic malignant cell marker genes. MMGS was established by univariate Cox analysis, LASSO, and stepwise multivariable Cox regression analysis. Kaplan-Meier (KM) curve and time-dependent receiver operating characteristic curve (tROC) were used to evaluate the prognostic value and performance of MMGS, respectively. MMGS further verified its reliability and accuracy in the independent validation set. Finally, the characteristics of functional enrichment, tumor immune features, and inflammatory activity between different MMGS risk groups were also investigated. Results: We constructed a prognostic model consisting of six malignant cell maker genes (MAPT, C1QTNF4, MEG3, NPW, RAMP1, and CDT1), which stratified patients into ultra-high-risk (UHR) and common-high-risk (CHR) group. Patients in the UHR group had significantly worse overall survival (OS) than those in the CHR group. MMGS was verified as an independent predictor for the OS of HRNB patients. The area under the curve (AUC) values of MMGS at 1-, 3-, and 5-year were 0.78, 0.693, and 0.618, respectively. Notably, functional enrichment, tumor immune features, and inflammatory activity analyses preliminarily indicated that the poor prognosis in the UHR group might result from the dysregulation of the metabolic process and immunosuppressive microenvironment. Conclusion: This study established a novel six-malignant cell maker gene prognostic model that can be used to predict the prognosis of HRNB patients, which may provide new insight for the treatment and personalized monitoring of HRNB patients.
RESUMEN
Nonalcoholic fatty liver disease (NAFLD) is characterized by excessive hepatic lipid accumulation, which can progress to nonalcoholic steatohepatitis (NASH). Histone deacetylase Sirtuin 6 (SIRT6) regulates NAFLD by regulating metabolism-related gene expression, but an extrachromosomal role for SIRT6 in NAFLD development remains elusive. We investigated whether SIRT6 functions on NAFLD in the cytoplasm. We found that SIRT6 binds saturated fatty acids, especially palmitic acid. This binding leads to its nuclear export, where it deacetylates long-chain acyl-CoA synthase 5 (ACSL5), thereby facilitating fatty acid oxidation. High-fat diet-induced NAFLD is suppressed by ACSL5 hepatic overexpression but is exacerbated by its depletion. As confirmation, overexpression of a deacetylated ACSL5 mimic attenuated NAFLD in Sirt6 liver-specific knockout mice. Moreover, NASH-hepatic tissues from both patients and diet-fed mice exhibited significantly reduced cytoplasmic SIRT6 levels and increased ACSL5 acetylation. The SIRT6/ACSL5 signaling pathway has a critical role in NAFLD progression and might constitute an avenue for therapeutic intervention.
Asunto(s)
Enfermedad del Hígado Graso no Alcohólico , Sirtuinas , Ratones , Animales , Enfermedad del Hígado Graso no Alcohólico/genética , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Acilcoenzima A/metabolismo , Ratones Endogámicos C57BL , Hígado/metabolismo , Metabolismo de los Lípidos , Ratones Noqueados , Ácidos Grasos/metabolismo , Sirtuinas/genética , Sirtuinas/metabolismo , Citoplasma/metabolismoRESUMEN
Acute myeloid leukemia (AML) is a malignant hematological tumor with disordered oncogenes/tumor suppressor genes and limited treatments. The potent anti-cancer effects of bromodomain and extra-terminal domain (BET) inhibitors, targeting the key component of super enhancers, in early clinical trials on AML patients, implies the critical role of super enhancers in AML. Here, we review the concept and characteristic of super enhancer, and then summarize the current researches about super enhancers in AML pathogenesis, diagnosis and classification, followed by illustrate the potential super enhancer-related targets and drugs, and propose the future directions of super enhancers in AML. This information provides integrated insight into the roles of super enhancers in this disease.
RESUMEN
Developing precise nanomedicines to improve the transport of anticancer drugs into tumor tissue and to the final action site remains a critical challenge. Here, we present a bioorthogonal in situ assembly strategy for prolonged retention of nanomedicines within tumor areas to act as drug depots. After extravasating into the tumor site, the slightly acidic microenvironment induces the exposure of cysteine on the nanoparticle surface, which subsequently undergoes a bioorthogonal reaction with the 2-cyanobenzothiazole group of another neighboring nanoparticle, enabling the formation of micro-sized drug depots to enhance drug retention and enrichment. This in situ nanoparticle assembly strategy remarkably improves the antimetastatic efficacy of extracellular-targeted drug batimastat, and also leads to the simultaneous enhanced retention and sustained release of multiple agents for combined cocktail chemoimmunotherapy to finally elicit a potent antitumor immune response. Such in situ assembly of nanomedicines represents a generalizable strategy towards extracellular drug delivery and cocktail chemoimmunotherapy.
Asunto(s)
Antineoplásicos , Nanopartículas , Neoplasias , Antineoplásicos/farmacología , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Humanos , Nanomedicina , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Preparaciones Farmacéuticas , Microambiente TumoralRESUMEN
OBJECTIVE: The prognostic value of tumor size in neuroblastoma (NB) patients has not been fully evaluated. Our purpose is to elucidate the prognostic significance of tumor size in surgery performed on neuroblastoma patients. METHODS: Neuroblastoma patients diagnosed from 2004 to 2015 were selected from the Surveillance, Epidemiology, and End Results Program (SEER) for the study. Univariate and multivariate Cox proportional hazard regression models were used to identify risk factors and the independent prognostic influences of tumor size on NB patients. Overall survival (OS) was analyzed through univariate Cox regression analysis. To determine the optimal cutoff value of tumor size, we first divided the cohort into three groups (≤5 cm, 5-10 cm, >10 cm). Subsequently, the patients were divided into two groups repeatedly, with tumor size at 1 cm intervals. The cutoff value that maximized prognostic outcome difference was selected. Furthermore, we performed the Kaplan-Meier methods to visually present differences in prognosis between the optimal tumor size cutoff value in different subgroups. RESULTS: A total of 591 NB patients who met the inclusion criteria were selected from the SEER database in this study. Cox analysis showed that age >1 year (HR = 2.42, p < 0.0001), originate from adrenal site (HR = 1.7, p = 0.014), distant stage (HR = 6.4, p < 0.0001), undifferentiated grade (HR = 1.94, p = 0.002), and large tumor size (HR = 1.5, p < 0.0001) independently predicted poor prognosis. For tumor size, there were significant differences in tumor size distribution in different ages, tumor grade, disease stage, and primary site subgroup but not in sex, race, and histology subgroup. Furthermore, both univariate (HR = 4.96, 95% CI 2.31-10.63, p < 0.0001) and multivariable analysis (HR = 2.8, 95% CI 1.29-6.08, p < 0.0001) indicated the optimal cutoff value of tumor size was 4 cm for overall survival of NB patients. Using a 4 cm of tumor size cutoff in subgroups, we found that it can identify poor prognosis patients whatever their age or primary site. Interestingly, tumor size of 4 cm cutoff can only identify unfavorable NB patients with diagnosis at distant-stage disease, or differentiated grade tumor, but not with regional and local or undifferentiated tumor. CONCLUSIONS: Tumor size is first to be recognized as a key prognostic factor of neuroblastoma patients and a cutoff value >4 cm might predict poor prognosis, which should be included in the evaluation of prognostic factors for NB.
Asunto(s)
Neuroblastoma , Estudios de Cohortes , Humanos , Neuroblastoma/patología , Pronóstico , Modelos de Riesgos Proporcionales , Factores de Riesgo , Programa de VERF , Tasa de SupervivenciaRESUMEN
In response to the new round of COVID-19 outbreaks since March 2022, universities with high outbreak rates around the country have taken quarantine measures to contain the epidemic. Evidence from previous coronavirus outbreaks has shown that people under quarantine are at risk for mental health disorders. To better understand the impacts of this round of COVID-19 quarantine on domestic college students and their responses, we conducted a systematic survey to assess the stress and anxiety, and to evaluate effective measurements in this population. We searched relevant documents and literature, and designed a questionnaire from six aspects, including psychological status, epidemic situation, study, daily life, sports, and interpersonal communication, with 51 items in total. We sent the questionnaire on the Wenjuanxing Web platform, from April 2 to 8, 2022. We evaluated the mental status according to parts of the Generalized Anxiety Disorder-7 (GAD-7) and Depression Anxiety Stress Scales-21 (DASS-21), and investigated the influencing risk factors and countermeasures. Statistical analysis was performed by using the Chi-square test and multi-variable logistic regression. In total, 508 college respondents were recruited in our survey, and the pooled prevalence of mild anxiety (GAD score â½ 5, or DASS-21 anxiety score â½ 8) or stress (DASS-21 pressure score â½ 14) caused by the new round of COVID-19 pandemic quarantine was 19.69% (100/508). The prevalence of the anxiety or stress in college students with COVID-19 quarantine between different genders, regions, and majors was not significantly different. Independent risk factors for the mild anxiety or stress of undergraduates by COVID-19 quarantine included learning efficiency or duration [OR = 1.36, 95%CI (1.14-1.62), P = 0.001], based on the combined analysis of Chi-square test analysis with multi-variable logistic regression analysis. Interestingly, the mental well-beings before COVID-19 epidemic quarantine [OR = 0.22, 95%CI (0.13-0.36), P < 0.0001], more low-intensity exercise [OR = 0.36, 95%CI (0.15-0.87), P = 0.02, high-intensity exercise as reference], and good sleep quality [OR = 0.14, 95%CI (0.07-0.30), P < 0.0001: OR = 0.42, 95%CI (0.30-0.59), P < 0.0001] are protective factors for alleviating the quarantine-caused anxiety or stress in Chinese college students for this round of COVID-19 epidemic quarantine. During the round of COVID-19 epidemic quarantine in 2022, a small number of college students have mild anxiety, affected by decreased learning efficiency or duration, which could be mitigated with low-intensity exercise and good sleep quality.
RESUMEN
Effectively activating macrophages that can engulf cancer cells is a promising immunotherapeutic strategy but remains a major challenge due to the expression of "self" signals (e.g., CD47 molecules) by tumor cells to prevent phagocytosis. Herein, we explored a siRNA-assisted assembly strategy for the simultaneous delivery of siRNA and mitoxantrone hydrochloride (MTO·2HCl) via PLGA-based nanoparticles. The siRNA suppressed a "self" signal by silencing the CD47 gene, while the MTO induced surface exposure of calreticulin (CRT) to provide an "eat-me" signal. The siRNA-assisted assembly strategy synergistically increased the phagocytosis of tumor cells by macrophages, promoted effective antigen presentation, and initiated T cell-mediated immune responses in two aggressive tumor animal models of melanoma and colon cancer, eventually achieving significantly improved antitumor activity. This study provides a straightforward codelivery strategy to simultaneously suppress "self" and upregulate "eat-me" signals to potentiate macrophage-mediated immunotherapy.
Asunto(s)
Neoplasias , Receptores Inmunológicos , Animales , Antígeno CD47 , Inmunoterapia , Neoplasias/tratamiento farmacológico , Fagocitosis , ARN Interferente PequeñoRESUMEN
Immunotherapy has revolutionized the therapeutic modalities of cancer treatment but is severely limited by a low objective response rate and the risk of immune-related side effects. Herein, an injectable supramolecular hydrogel is developed for local delivery of the DPPA-1 peptide (a d-peptide antagonist with a high binding affinity to programmed cell death-ligand 1 (PD-L1)) and doxorubicin (DOX). On the one hand, DOX could kill tumor cells directly and also induce immunogenic cell death to provoke the antitumor immune response. On the other hand, the DPPA-1 peptide could locoregionally block the PD-1/PD-L1 pathway to potentiate T-cell-mediated immune responses and minimize side effects. Eventually, by local injection of this supramolecular hydrogel, the synergistic cancer therapeutic effect was evaluated, showing promise in improving the objective response rate of immunotherapy and minimizing its systemic side effects.
Asunto(s)
Doxorrubicina/uso terapéutico , Portadores de Fármacos/química , Hidrogeles/química , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Péptidos/uso terapéutico , Resinas Acrílicas/síntesis química , Resinas Acrílicas/química , Animales , Antígeno B7-H1/antagonistas & inhibidores , Línea Celular Tumoral , Portadores de Fármacos/síntesis química , Combinación de Medicamentos , Sinergismo Farmacológico , Femenino , Hidrogeles/síntesis química , Inmunidad/efectos de los fármacos , Muerte Celular Inmunogénica/efectos de los fármacos , Ratones Endogámicos BALB CRESUMEN
Local administration of therapeutic agents with long-term retention capabilities efficiently avoids nonspecific distribution in normal organs with an increased drug concentration in pathological tissue. Herein, we developed an injectable and degradable alginate-calcium (Ca2+) hydrogel for the local administration of corn-like Au/Ag nanorods (NRs) and doxorubicin hydrochloride (DOX·HCl). The immobilized Au/Ag NRs with strong absorbance in the near-infrared II (NIR-II) window efficiently ablated the majority of tumor cells after 1064 nm laser irradiation and triggered the release of DOX to kill residual tumor cells. As a result, injectable hydrogel-mediated NIR-II photothermal therapy (PTT) and chemotherapy efficiently inhibited tumor growth, resulting in the complete eradication of tumors in most of the treated mice. Furthermore, owing to the confinement of the Au/Ag NRs and DOX·HCl within the hydrogel, such treatment exhibited excellent biocompatibility.
Asunto(s)
Hipertermia Inducida , Neoplasias , Animales , Línea Celular Tumoral , Doxorrubicina , Oro , Hidrogeles , Hipertermia , Ratones , Neoplasias/terapiaRESUMEN
Reactive oxygen species (ROS)-responsive nanocarriers have aroused widespread interest in recent years. On the one hand, a high ROS level has been detected in many types of tumor cells. On the other hand, ROS generation is also induced during photodynamic, sonodynamic, or chemodynamic therapy. In addition, multiple types of polymers are sensitive to ROS. Therefore, numerous ROS-responsive polymeric nanocarriers with unique ROS-responsive characteristics have been developed. This review discusses ROS-sensitive polymeric nanocarriers to improve drug delivery efficacy. In particular, ROS-responsive nanocarriers for synergistic cancer therapy are highlighted. The development of novel ROS-sensitive nanocarriers holds great potential for combining ROS-mediated therapy, such as photodynamic therapy, and other therapies to achieve synergistic anticancer efficacy. STATEMENT OF SIGNIFICANCE: Reactive oxygen species (ROS)-responsive nanocarriers aroused widespread interest in recent years. On the one hand, a high level of ROS has been found in many types of tumor cells. On the other hand, the ROS generation can also be induced during the photodynamic, sonodynamic, or chemodynamic therapy. Besides, multiple types of polymers were sensitive to the ROS. Therefore, numerous ROS-responsive polymeric nanocarriers with unique ROS responsive characteristics have been developed. This review focuses on the ROS-sensitive polymeric nanocarriers to improve drug delivery efficacy for synergistic cancer therapy.
Asunto(s)
Nanopartículas , Neoplasias , Fotoquimioterapia , Línea Celular Tumoral , Portadores de Fármacos , Neoplasias/tratamiento farmacológico , Polímeros , Especies Reactivas de OxígenoRESUMEN
Simultaneously targeting tumor cells and nonmalignant cells represent a more efficient strategy for replacing the traditional method of targeting only tumor cells, and co-delivery nanocarriers have inherent advantages to achieve this goal. However, differential delivery of multiple agents to various types of cell with different spatial distribution patterns remains a large challenge. Herein, we developed a nanocarrier of platinum(IV) prodrug and BLZ-945, BLZ@S-NP/Pt, to differentially target tumor cells and tumor-associated macrophages (TAMs). The BLZ@S-NP/Pt undergoes shrinkage to small platinum(IV) prodrug-conjugating nanoparticles under 660 nm light, resulting in deep tumor penetration to kill more cancer cells. Meanwhile, such shrinkage also enables the rapid release of BLZ-945 in the perivascular regions of tumor to preferentially deplete TAMs (enriched in perivascular regions). Therefore, BLZ@S-NP/Pt differentially and precisely delivers agents to TAMs and tumor cells located in different spatial distribution, respectively, eventually having synergistic anticancer effects in multiple tumor models.