RESUMO
Emerging data have shown that previously defined noncoding genomes might encode peptides that bind human leukocyte antigen (HLA) as cryptic antigens to stimulate adaptive immunity1,2. However, the significance and mechanisms of action of cryptic antigens in anti-tumour immunity remain unclear. Here mass spectrometry of the HLA class I (HLA-I) peptidome coupled with ribosome sequencing of human breast cancer samples identified HLA-I-binding cryptic antigenic peptides that were noncanonically translated by a tumour-specific circular RNA (circRNA): circFAM53B. The cryptic peptides efficiently primed naive CD4+ and CD8+ T cells in an antigen-specific manner and induced anti-tumour immunity. Clinically, the expression of circFAM53B and its encoded peptides was associated with substantial infiltration of antigen-specific CD8+ T cells and better survival in patients with breast cancer and patients with melanoma. Mechanistically, circFAM53B-encoded peptides had strong binding affinity to both HLA-I and HLA-II molecules. In vivo, administration of vaccines consisting of tumour-specific circRNA or its encoded peptides in mice bearing breast cancer tumours or melanoma induced enhanced infiltration of tumour-antigen-specific cytotoxic T cells, which led to effective tumour control. Overall, our findings reveal that noncanonical translation of circRNAs can drive efficient anti-tumour immunity, which suggests that vaccination exploiting tumour-specific circRNAs may serve as an immunotherapeutic strategy against malignant tumours.
Assuntos
Neoplasias da Mama , Melanoma , Peptídeos , Biossíntese de Proteínas , RNA Circular , Animais , Feminino , Humanos , Camundongos , Antígenos de Neoplasias/imunologia , Neoplasias da Mama/genética , Neoplasias da Mama/imunologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , Espectrometria de Massas , Melanoma/genética , Melanoma/imunologia , Melanoma/mortalidade , Melanoma/patologia , Peptídeos/genética , Peptídeos/imunologia , Perfil de Ribossomos , RNA Circular/genética , RNA Circular/metabolismo , Análise de SobrevidaRESUMO
A high-fat diet (HFD) is a high-risk factor for the malignant progression of cancers through the disruption of the intestinal microbiota. However, the role of the HFD-related gut microbiota in cancer development remains unclear. This study found that obesity and obesity-related gut microbiota were associated with poor prognosis and advanced clinicopathological status in female patients with breast cancer. To investigate the impact of HFD-associated gut microbiota on cancer progression, we established various models, including HFD feeding, fecal microbiota transplantation, antibiotic feeding, and bacterial gavage, in tumor-bearing mice. HFD-related microbiota promotes cancer progression by generating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, the HFD microbiota released abundant leucine, which activated the mTORC1 signaling pathway in myeloid progenitors for PMN-MDSC differentiation. Clinically, the elevated leucine level in the peripheral blood induced by the HFD microbiota was correlated with abundant tumoral PMN-MDSC infiltration and poor clinical outcomes in female patients with breast cancer. These findings revealed that the "gut-bone marrow-tumor" axis is involved in HFD-mediated cancer progression and opens a broad avenue for anticancer therapeutic strategies by targeting the aberrant metabolism of the gut microbiota.
Assuntos
Neoplasias da Mama , Diferenciação Celular , Dieta Hiperlipídica , Progressão da Doença , Microbioma Gastrointestinal , Leucina , Células Supressoras Mieloides , Animais , Dieta Hiperlipídica/efeitos adversos , Leucina/metabolismo , Feminino , Humanos , Camundongos , Células Supressoras Mieloides/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/microbiologia , Neoplasias da Mama/metabolismo , Obesidade/microbiologia , Obesidade/metabolismo , Obesidade/patologia , Linhagem Celular TumoralRESUMO
Immune checkpoint blockade (ICB) therapies have achieved clinical benefit, but most 'immune-cold' solid tumors are not responsive. The diversity of immune evasion mechanisms remains a key obstacle in turning nonresponsive 'cold' tumors into responsive 'hot' ones. Therefore, exploring the mechanisms of such transitions and tumor immunotyping can provide significant insights into designing effective therapeutic strategies against cancer. Here, we focus on the latest advances regarding local and systemic regulatory mechanisms of immune responses in cold and hot tumors. We also highlight the necessity for tumor immunotyping through the assessment of multiple immunological variables using various diagnostic techniques and biomarkers. Finally, we discuss the challenges and potential clinical applications of immunophenotyping to turn cold tumors hot, which may further guide combined immunotherapies.
Assuntos
Neoplasias , Microambiente Tumoral , Humanos , Imunidade , Imunoterapia/métodos , Neoplasias/tratamento farmacológicoRESUMO
Acute ischemic stroke (AIS), one of the leading causes of mortality worldwide, is characterized by a rapid inflammatory cascade resulting in exacerbation of ischemic brain injury. Microglia are the first immune responders. However, the role of postischemic microglial activity in ischemic brain injury remains far from being fully understood. Here, using the transgenic mouse line CX3 CR1creER :R26iDTR to genetically ablate microglia, we showed that microglial deletion exaggerated ischemic brain injury. Associated with this worse outcome, there were increased neutrophil recruitment, microvessel blockade and blood flow stagnation in the acute phase, accompanied by transcriptional upregulation of chemokine (C-X-C motif) ligand 1 (CXCL1). Our study showed that microglial interleukin-1 receptor antagonist (IL-1RA) suppressed astrocytic CXCL1 expression induced by oxygen and glucose deprivation and inhibited neutrophil migration. Furthermore, neutralizing antibody therapy against CXCL1 or the administration of recombinant IL-1RA protein reduced brain infarct volume and improved motor coordination performance of mice after ischemic stroke. Our study suggests that microglia protect against acute ischemic brain injury by secreting IL-1RA to inhibit astrocytic CXCL1 expression, which reduces neutrophil recruitment and neutrophil-derived microvessel occlusion.
Assuntos
Lesões Encefálicas , Isquemia Encefálica , AVC Isquêmico , Acidente Vascular Cerebral , Camundongos , Animais , Proteína Antagonista do Receptor de Interleucina 1/metabolismo , Proteína Antagonista do Receptor de Interleucina 1/farmacologia , AVC Isquêmico/metabolismo , Quimiocina CXCL1/metabolismo , Quimiocina CXCL1/farmacologia , Microglia/metabolismo , Infiltração de Neutrófilos/fisiologia , Lesões Encefálicas/metabolismo , Camundongos Transgênicos , Isquemia Encefálica/metabolismo , Acidente Vascular Cerebral/metabolismoRESUMO
BACKGROUND: Extensive production and usage of commercially available products containing TiO2 NPs have led to accumulation in the human body. The deposition of TiO2 NPs has even been detected in the human placenta, which raises concerns regarding fetal health. Previous studies regarding developmental toxicity have frequently focused on TiO2 NPs < 50 nm, whereas the potential adverse effects of large-sized TiO2 NPs received less attention. Placental vasculature is essential for maternal-fetal circulatory exchange and ensuring fetal growth. This study explores the impacts of TiO2 NPs (100 nm in size) on the placenta and fetal development and elucidates the underlying mechanism from the perspective of placental vasculature. Pregnant C57BL/6 mice were exposed to TiO2 NPs by gavage at daily dosages of 10, 50, and 250 mg/kg from gestational day 0.5-16.5. RESULTS: TiO2 NPs penetrated the placenta and accumulated in the fetal mice. The fetuses in the TiO2 NP-exposed groups exhibited a dose-dependent decrease in body weight and length, as well as in placental weight and diameter. In vivo imaging showed an impaired placental barrier, and pathological examinations revealed a disrupted vascular network of the labyrinth upon TiO2 NP exposure. We also found an increase in gene expression related to the transforming growth factor-ß (TGF-ß) -SNAIL pathway and the upregulation of mesenchymal markers, accompanied by a reduction in endothelial markers. In addition, TiO2 NPs enhanced the gene expression responsible for the endothelial-to-mesenchymal transition (EndMT) in cultured human umbilical vein endothelial cells, whereas SNAIL knockdown attenuated the induction of EndMT phenotypes. CONCLUSION: Our study revealed that maternal exposure to 100 nm TiO2 NPs disrupts placental vascular development and fetal mice growth through aberrant activation of EndMT in the placental labyrinth. These data provide novel insight into the mechanisms of developmental toxicity posed by NPs.
Assuntos
Exposição Materna , Placenta , Gravidez , Camundongos , Feminino , Humanos , Animais , Placenta/metabolismo , Exposição Materna/efeitos adversos , Células Endoteliais , Camundongos Endogâmicos C57BL , Desenvolvimento Fetal , Troca Materno-Fetal , Titânio/toxicidade , Titânio/metabolismoRESUMO
The programmed cell death 1 (PD-1) receptor on the surface of immune cells is an immune checkpoint molecule that mediates the immune escape of tumor cells. Consequently, antibodies targeting PD-1 have shown efficacy in enhancing the antitumor activity of T cells in some types of cancers. However, the potential effects of PD-1 on tumor cells remain largely unknown. Here, we show that PD-1 is expressed across a broad range of tumor cells. The silencing of PD-1 or its ligand, PD-1 ligand 1 (PD-L1), promotes cell proliferation and colony formation in vitro and tumor growth in vivo. Conversely, overexpression of PD-1 or PD-L1 inhibits tumor cell proliferation and colony formation. Moreover, blocking antibodies targeting PD-1 or PD-L1 promote tumor growth in cell cultures and xenografts. Mechanistically, the coordination of PD-1 and PD-L1 activates its major downstream signaling pathways including the AKT and ERK1/2 pathways, thus enhancing tumor cell growth. This study demonstrates that PD-1/PD-L1 is a potential tumor suppressor and potentially regulates the response to anti-PD-1/PD-L1 treatments, thus representing a potential biomarker for the optimal cancer immunotherapeutic treatment.
Assuntos
Anticorpos Monoclonais/farmacologia , Antígeno B7-H1/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Neoplasias Pulmonares/tratamento farmacológico , Receptor de Morte Celular Programada 1/metabolismo , Animais , Apoptose , Biomarcadores Tumorais , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Humanos , Neoplasias Pulmonares/metabolismo , Neoplasias Pulmonares/patologia , Camundongos , Camundongos Endogâmicos NOD , Camundongos SCID , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Transdução de Sinais , Linfócitos T/efeitos dos fármacos , Linfócitos T/imunologia , Linfócitos T/metabolismo , Células Tumorais Cultivadas , Microambiente Tumoral , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Most therapeutic peptides available on the market today are naturally occurring hormones or protein fragments that were serendipitously discovered to possess therapeutic effects. However, the limited repertoire of available natural resources presents difficulties for the development of new peptide drug candidates. Traditional peptides possess several shortcomings that must be addressed for biomedical applications, including relatively low affinity or specificity toward biological targets compared to antibody- and protein scaffold-based affinity molecules, poor in vivo stability owing to rapid enzymatic degradation, and rapid clearance from circulation owing to their small size. Going forward, it will be increasingly important for scientists to develop novel classes of high-affinity and -specificity peptides against desired targets that mitigate these limitations while remaining compatible with pharmaceutical manufacturing processes. Recently, several highly constrained, artificial cyclic peptides have emerged as platforms capable of generating high-affinity peptide binders against various disease-associated protein targets by combining with phage or mRNA display method, some of which have entered clinical trials. In contrast, although linear peptides are relatively easy to synthesize cost-effectively and modify site-specifically at either N- or C-termini compared to cyclic peptides, there have been few linear peptide-based platforms that can provide high-affinity and -specificity peptide binders.In this Account, we describe the creation and development of a novel class of high-affinity peptides, termed "aptide"-from the Latin word "aptus" meaning "to fit" and "peptide"-and summarize their biomedical applications. In the first part, we consider the design and creation of aptides, with a focus on their unique structural features and binding mode, and address screening and identification of target protein-specific aptides. We also discuss advantages of the aptide platform over ordinary linear peptides lacking preorganized structures in terms of the affinity and specificity of identified peptide binders against target molecules. In the second part, we describe the potential biomedical applications of various target-specific aptides, ranging from imaging and therapy to theranostics, according to the types of aptides and diseases. We show that certain aptides can not only bind to a target protein but also inhibit its biological function, thereby showing potential as therapeutics per se. Further, aptides specific for cancer-associated protein antigens can be used as escort molecules or targeting ligands for delivery of chemotherapeutics, cytokine proteins, and nanomedicines, such as liposomes and magnetic particles, to tumors, thereby substantially improving therapeutic effects. Finally, we present a strategy capable of overcoming the critical issue of short blood circulation time associated with most peptides by constructing a hybrid system between an aptide and a hapten cotinine-specific antibody.
Assuntos
Nanomedicina , Peptídeos/metabolismo , Animais , Anticorpos/química , Anticorpos/metabolismo , Antineoplásicos/química , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Retinopatia Diabética/tratamento farmacológico , Humanos , Cinética , Magnetismo , Camundongos , Nanopartículas/química , Neoplasias/tratamento farmacológico , Peptídeos/química , Peptídeos/uso terapêutico , Estrutura Terciária de Proteína , Fator de Transcrição STAT3/química , Transplante Heterólogo , Fator A de Crescimento do Endotélio Vascular/químicaRESUMO
Selective amplification of reactive oxygen species (ROS) generation in tumor cells has been recognized as an effective strategy for cancer therapy. However, an abnormal tumor metabolism, especially the mitochondrial glutaminolysis, could promote tumor cells to generate high levels of antioxidants (e.g., glutathione) to evade ROS-induced damage. Here, we developed a tumor-targeted nanoparticle (NP) platform for effective breast cancer therapy via combining inhibition of mitochondrial glutaminolysis and chemodynamic therapy (CDT). This NP platform is composed of bovine serum albumin (BSA), ferrocene, and purpurin. After surface decoration with a tumor-targeting aptamer and then intravenous administration, this NP platform could target tumor cells and release ferrocene to catalyze hydrogen peroxide (H2O2) into the hydroxyl radical (·OH) for CDT. More importantly, purpurin could inhibit mitochondrial glutaminolysis to concurrently prevent the nutrient supply for tumor cells and disrupt intracellular redox homeostasis for enhanced CDT, ultimately leading to the combinational inhibition of tumor growth.
Assuntos
Nanopartículas , Neoplasias , Animais , Linhagem Celular Tumoral , Glutationa/metabolismo , Humanos , Peróxido de Hidrogênio , Camundongos , Neoplasias/tratamento farmacológico , Estresse Oxidativo , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
As a hallmark of solid tumors, hypoxia promotes tumor growth, metastasis, and therapeutic resistance by regulating the expression of hypoxia-related genes. Hypoxia also represents a tumor-specific stimulus that has been exploited for the development of bioreductive prodrugs and advanced drug delivery systems. Cell division cycle 20 (CDC20) functions as an oncogene in tumorigenesis, and we demonstrated the significant upregulation of CDC20 mRNA in the tumor vs paratumor tissues of breast cancer patients and its positive correlation with tumor hypoxia. Herein, a hypoxia-responsive nanoparticle (HRNP) was developed by self-assembly of the 2-nitroimidazole-modified polypeptide and cationic lipid-like compound for delivery of siRNA to specifically target CDC20, a hypoxia-related protumorigenic gene, in breast cancer therapy. The delivery of siCDC20 by HRNPs sufficiently silenced the expression of CDC20 and exhibited potent antitumor efficacy. We expect that this strategy of targeting hypoxia-correlated protumorigenic genes by hypoxia-responsive RNAi nanoparticles may provide a promising approach in cancer therapy.
Assuntos
Nanopartículas , Neoplasias , Linhagem Celular Tumoral , Sistemas de Liberação de Medicamentos , Humanos , Hipóxia , Nanomedicina , Neoplasias/tratamento farmacológico , Neoplasias/genética , Interferência de RNA , RNA Interferente Pequeno/genéticaRESUMO
BACKGROUND: Although both circular RNAs (circRNAs) and autophagy are associated with the function of breast cancer (BC), whether circRNAs regulate BC progression via autophagy remains unknown. In this study, we aim to explore the regulatory mechanisms and the clinical significance of autophagy-associated circRNAs in BC. METHODS: Autophagy associated circRNAs were screened by circRNAs deep sequencing and validated by qRT-PCR in BC tissues with high- and low- autophagic level. The biological function of autophagy associated circRNAs were assessed by plate colony formation, cell viability, transwells, flow cytometry and orthotopic animal models. For mechanistic study, RNA immunoprecipitation, circRNAs pull-down, Dual luciferase report assay, Western Blot, Immunofluorescence and Immunohistochemical staining were performed. RESULTS: An autophagy associated circRNA circCDYL was elevated by 3.2 folds in BC tissues as compared with the adjacent non-cancerous tissues, and circCDYL promoted autophagic level in BC cells via the miR-1275-ATG7/ULK1 axis; Moreover, circCDYL enhanced the malignant progression of BC cells in vitro and in vivo. Clinically, increased circCDYL in the tumor tissues and serum of BC patients was associated with higher tumor burden, shorter survival and poorer clinical response to therapy. CONCLUSIONS: circCDYL promotes BC progression via the miR-1275-ATG7/ULK1-autophagic axis and circCDYL could act as a potential prognostic and predictive molecule for breast cancer patients.
Assuntos
Autofagia , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Proteínas Correpressoras/metabolismo , Hidroliases/metabolismo , MicroRNAs/genética , RNA Circular/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Apoptose , Proteína 7 Relacionada à Autofagia/genética , Proteína 7 Relacionada à Autofagia/metabolismo , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/genética , Proteína Homóloga à Proteína-1 Relacionada à Autofagia/metabolismo , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Proliferação de Células , Proteínas Correpressoras/genética , Progressão da Doença , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Hidroliases/genética , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Pessoa de Meia-Idade , Prognóstico , Taxa de Sobrevida , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Nanoparticles (NPs) formulated with cationic lipids and/or polymers have shown substantial potential for systemic delivery of RNA therapeutics such as small interfering RNA (siRNA) for the treatment of cancer and other diseases. While both cationic lipids and polymers have demonstrated the promise to facilitate siRNA encapsulation and endosomal escape, they could also hamper cytosolic siRNA release due to charge interaction and induce potential toxicities. Herein, a unique polymer-prodrug hybrid NP platform was developed for multistage siRNA delivery and combination cancer therapy. This NP system is composed of (i) a hydrophilic polyethylene glycol (PEG) shell, (ii) a hydrophobic NP core made with a tumor microenvironment (TME) pH-responsive polymer, and (iii) charge-mediated complexes of siRNA and amphiphilic cationic mitoxantrone (MTO)-based prodrug that are encapsulated in the NP core. After intravenous administration, the long-circulating NPs accumulate in tumor tissues and then rapidly release the siRNA-prodrug complexes via TME pH-mediated NP disassociation for subsequent tissue penetration and cytosolic transport. With the overexpressed esterase in tumor cells to hydrolyze the amphiphilic structure of the prodrug and thereby induce destabilization of the siRNA-prodrug complexes, the therapeutic siRNA and anticancer drug MTO can be efficiently released in the cytoplasm, ultimately leading to the combinational inhibition of tumor growth via concurrent RNAi-mediated gene silencing and MTO-mediated chemotherapy.
Assuntos
Sistemas de Liberação de Medicamentos , Técnicas de Transferência de Genes , Neoplasias/genética , RNA Interferente Pequeno/farmacologia , Linhagem Celular Tumoral , Humanos , Interações Hidrofóbicas e Hidrofílicas , Lipídeos/química , Mitoxantrona/química , Mitoxantrona/farmacologia , Nanopartículas/química , Nanoestruturas/química , Neoplasias/terapia , Polietilenoglicóis/química , Polímeros/química , Polímeros/farmacologia , Pró-Fármacos/química , Pró-Fármacos/farmacologia , RNA Interferente Pequeno/genética , Microambiente Tumoral/efeitos dos fármacosRESUMO
Structural morphology is the key parameter for efficacy of nanomedicine. To date, lipid-based nanomaterial has been the most widely used material in nanomedicine and many other biomedical applications. However, to the best of our knowledge, there has not been an in-depth or systematic investigation of the structure-function relationship of lipid-based nanostructures. In this report, we investigated the formulation of novel lipid-based nanostructures via simple tuning of lipid combinations. To prove this concept, we used a combination of various ratios of simple and common phospholipids with different chain lengths (14-carbon chain DMPC: 6-carbon chain DHPC) to find out whether a myriad of novel lipid nanostructures could be obtained. Interestingly, many combinations resulted in distinct lipid nanostructures. Drug encapsulation tests confirmed that they are able to load large amounts of drugs for biological application. In vivo anti-tumor efficacy revealed that certain lipid nanostructures possessed superior tumor retardation effects.
Assuntos
Portadores de Fármacos/química , Engenharia , Nanoestruturas/química , Fosfolipídeos/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , CamundongosRESUMO
Biodegradable polymeric nanoparticles (NPs) have demonstrated significant potential to improve the systemic delivery of RNA interference (RNAi) therapeutics, such as small interfering RNA (siRNA), for cancer therapy. However, the slow and inefficient siRNA release inside tumor cells generally observed for most biodegradable polymeric NPs may result in compromised gene silencing efficacy. Herein, a biodegradable and redox-responsive NP platform, composed of a solid poly(disulfide amide) (PDSA)/cationic lipid core and a lipid-poly(ethylene glycol) (lipid-PEG) shell for systemic siRNA delivery to tumor cells, is developed. This newly generated NP platform can efficiently encapsulate siRNA under extracellular environments and can respond to the highly concentrated glutathione (GSH) in the cytoplasm to induce fast intracellular siRNA release. By screening a library of PDSA polymers with different structures and chain lengths, the optimized NP platform shows the unique features of i) long blood circulation, ii) high tumor accumulation, iii) fast GSH-triggered intracellular siRNA release, and iv) exceptionally effective gene silencing. Together with the facile polymer synthesis technique and robust NP formulation enabling scale-up, this new redox-responsive NP platform may become an effective tool for RNAi-based cancer therapy.
Assuntos
Nanopartículas/química , Citoplasma/metabolismo , Glutationa/química , Humanos , Oxirredução , Interferência de RNARESUMO
While RNA interference (RNAi) therapy has demonstrated significant potential for cancer treatment, the effective and safe systemic delivery of RNAi agents such as small interfering RNA (siRNA) into tumor cells in vivo remains challenging. We herein reported a unique multistaged siRNA delivery nanoparticle (NP) platform, which is comprised of (i) a polyethylene glycol (PEG) surface shell, (ii) a sharp tumor microenvironment (TME) pH-responsive polymer that forms the NP core, and (iii) charge-mediated complexes of siRNA and tumor cell-targeting- and penetrating-peptide-amphiphile (TCPA) that are encapsulated in the NP core. When the rationally designed, long circulating polymeric NPs accumulate in tumor tissues after intravenous administration, the targeted siRNA-TCPA complexes can be rapidly released via TME pH-mediated NP disassembly for subsequent specific targeting of tumor cells and cytosolic transport, thus achieving efficient gene silencing. In vivo results further demonstrate that the multistaged NP delivery of siRNA against bromodomain 4 (BRD4), a recently discovered target protein that regulates the development and progression of prostate cancer (PCa), can significantly inhibit PCa tumor growth.
Assuntos
Técnicas de Transferência de Genes , Nanopartículas/química , Neoplasias/tratamento farmacológico , RNA Interferente Pequeno/química , Microambiente Tumoral/fisiologia , Animais , Azepinas/química , Proteínas de Ciclo Celular , Liberação Controlada de Fármacos , Células HeLa , Xenoenxertos , Humanos , Concentração de Íons de Hidrogênio , Metacrilatos/química , Camundongos Nus , Proteínas Nucleares/genética , Imagem Óptica , Tamanho da Partícula , Peptídeos/química , Peptídeos/metabolismo , Polietilenoglicóis/química , Polímeros/química , RNA Interferente Pequeno/administração & dosagem , Distribuição Tecidual , Fatores de Transcrição/genéticaRESUMO
A major problem with cancer chemotherapy begins when cells acquire resistance. Drug-resistant cancer cells typically upregulate multi-drug resistance proteins such as P-glycoprotein (P-gp). However, the lack of overexpressed surface biomarkers has limited the targeted therapy of drug-resistant cancers. Here we report a drug-delivery carrier decorated with a targeting ligand for a surface marker protein extra-domain B(EDB) specific to drug-resistant breast cancer cells as a new therapeutic option for the aggressive cancers. We constructed EDB-specific aptide (APTEDB)-conjugated liposome to simultaneously deliver siRNA(siMDR1) and Dox to drug-resistant breast cancer cells. APTEDB-LS(Dox,siMDR1) led to enhanced delivery of payloads into MCF7/ADR cells and showed significantly higher accumulation and retention in the tumors. While either APTEDB-LS(Dox) or APTEDB-LS(siMDR1) did not lead to appreciable tumor retardation in MCF7/ADR orthotropic model, APTEDB-LS(Dox,siMDR1) treatment resulted in significant reduction of the drug-resistant breast tumor. Taken together, this study provides a new strategy of drug delivery for drug-resistant cancer therapy.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Fibronectinas , Animais , Linhagem Celular Tumoral , Doxorrubicina , Humanos , Lipossomos , Camundongos , Camundongos Endogâmicos BALB C , Células Tumorais CultivadasRESUMO
Photothermal therapy (PTT) has shown significant potential for cancer therapy. However, developing nanomaterials (NMs)-based photothermal agents (PTAs) with satisfactory photothermal conversion efficacy (PTCE) and biocompatibility remains a key challenge. Herein, a new generation of PTAs based on two-dimensional (2D) antimonene quantum dots (AMQDs) was developed by a novel liquid exfoliation method. Surface modification of AMQDs with polyethylene glycol (PEG) significantly enhanced both biocompatibility and stability in physiological medium. The PEG-coated AMQDs showed a PTCE of 45.5 %, which is higher than many other NMs-based PTAs such as graphene, Au, MoS2 , and black phosphorus (BP). The AMQDs-based PTAs also exhibited a unique feature of NIR-induced rapid degradability. Through both inâ vitro and inâ vivo studies, the PEG-coated AMQDs demonstrated notable NIR-induced tumor ablation ability. This work is expected to expand the utility of 2D antimonene (AM) to biomedical applications through the development of an entirely novel PTA platform.
Assuntos
Raios Infravermelhos , Neoplasias/terapia , Fototerapia/métodos , Pontos Quânticos , Animais , Materiais Biocompatíveis , Linhagem Celular Tumoral , Dissulfetos/química , Ouro/química , Grafite/química , Humanos , Camundongos , Camundongos Nus , Molibdênio/química , Fósforo/química , Polietilenoglicóis/química , Análise Espectral/métodos , Propriedades de Superfície , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
RNA molecules have emerged as promising clinical therapeutics due to their ability to target "undruggable" proteins or molecules with high precision and minimal side effects. Nevertheless, the primary challenge in RNA therapeutics lies in rapid degradation and clearance from systemic circulation, the inability to traverse cell membranes, and the efficient intracellular delivery of bioactive RNA molecules. In this review, we explore the implications of RNAs in diseases and provide a chronological overview of the development of RNA therapeutics. Additionally, we summarize the technological advances in RNA-screening design, encompassing various RNA databases and design platforms. The paper then presents an update on FDA-approved RNA therapeutics and those currently undergoing clinical trials for various diseases, with a specific emphasis on RNA medicine and RNA vaccines.
Assuntos
RNA , Humanos , RNA/genética , RNA/uso terapêutico , RNA/metabolismo , Animais , Terapia Genética/métodosRESUMO
A potential reason for the failure of tumor therapies is treatment resistance. Resistance to chemotherapy, radiotherapy, and immunotherapy continues to be a major obstacle in clinic, resulting in tumor recurrence and metastasis. The major mechanisms of therapy resistance are inhibitions of cell deaths, like apoptosis and necrosis, through drug inactivation and excretion, repair of DNA damage, tumor heterogeneity, or changes in tumor microenvironment, etc. Recent studies have shown that ferroptosis play a major role in therapies resistance by inducing phospholipid peroxidation and iron-dependent cell death. Some ferroptosis inducers in combination with clinical treatment techniques have been used to enhance the effect in tumor therapy. Notably, versatile ferroptosis nanoinducers exhibit an extensive range of functions in reversing therapy resistance, including directly triggering ferroptosis and feedback regulation. Herein, we provide a detailed description of the design, mechanism, and therapeutic application of ferroptosis-mediated synergistic tumor therapeutics. We also discuss the prospect and challenge of nanomedicine in tumor therapy resistance by regulating ferroptosis and combination therapy.
Assuntos
Ferroptose , Neoplasias , Humanos , Resistencia a Medicamentos Antineoplásicos , Nanomedicina , Terapia Combinada , Neoplasias/tratamento farmacológico , Microambiente TumoralRESUMO
Cancer stem cells (CSCs) are heterogeneous, possess self-renewal attributes, and orchestrate important crosstalk in tumors. We propose that the CSC state represents "mimicry" by cancer cells that leads to phenotypic plasticity. CSC mimicry is suggested as CSCs can impersonate immune cells, vasculo-endothelia, or lymphangiogenic cells to support cancer growth. CSCs facilitate both paracrine and juxtracrine signaling to prime tumor-associated immune and stromal cells to adopt pro-tumoral phenotypes, driving therapeutic resistance. Here, we outline the ingenuity of CSCs' mimicry in their quest to evade immune detection, which leads to immunotherapeutic resistance, and highlight CSC-mimicry-targeted therapeutic strategies for robust immunotherapy.
Assuntos
Resistencia a Medicamentos Antineoplásicos , Evasão da Resposta Imune , Neoplasias , Células-Tronco Neoplásicas , Humanos , Células-Tronco Neoplásicas/imunologia , Células-Tronco Neoplásicas/patologia , Células-Tronco Neoplásicas/metabolismo , Neoplasias/imunologia , Neoplasias/terapia , Neoplasias/patologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Animais , Imunoterapia/métodosRESUMO
Burn injuries are prevalent and life-threatening forms that contribute significantly to mortality rates due to associated wound infections. The management of burn wounds presents substantial challenges. Hydrogel exhibits tremendous potential as an ideal alternative to traditional wound dressings such as gauze. This is primarily attributed to its three-dimensional (3D) crosslinked polymer network, which possesses a high water content, fostering a moist environment that supports effective burn wound healing. Additionally, hydrogel facilitates the penetration of loaded therapeutic agents throughout the wound surface, combating burn wound pathogens through the hydration effect and thereby enhancing the healing process. However, the presence of eschar formation on burn wounds obstructs the passive diffusion of therapeutics, impairing the efficacy of hydrogel as a wound dressing, particularly in cases of severe burns involving deeper tissue damage. This review focuses on exploring the potential of hydrogel as a carrier for transdermal drug delivery in burn wound treatment. Furthermore, strategies aimed at enhancing the transdermal delivery of therapeutic agents from hydrogel to optimize burn wound healing are also discussed.