RESUMEN

Macrophages play a critical role in the body's defense against cancer by phagocytosing tumor cells, presenting antigens, and activating adaptive T cells. However, macrophages are intrinsically incapable of delivering targeted cancer immunotherapies. Engineered adoptive cell therapy introduces new targeting and antitumor capabilities by modifying macrophages to enhance the innate immune response of cells and improve clinical efficacy. In this study, we developed engineered macrophage cholesterol-AS1411-M1 (CAM1) for cellular immunotherapy. To target macrophages, cholesterol-AS1411 aptamers were anchored to the surface of M1 macrophages to produce CAM1 without genetic modification or cell damage. CAM1 induced significantly higher apoptosis/mortality than unmodified M1 macrophages in murine breast cancer cells. Anchoring AS1411 on the surface of macrophages provided a novel approach to construct engineered macrophages for tumor immunotherapy.

Asunto(s)

Aptámeros de Nucleótidos , Inmunoterapia Adoptiva , Macrófagos , Animales , Macrófagos/inmunología , Macrófagos/metabolismo , Inmunoterapia Adoptiva/métodos , Ratones , Línea Celular Tumoral , Colesterol/metabolismo , Femenino , Apoptosis , Ingeniería Celular/métodos , Membrana Celular/metabolismo , Humanos

RESUMEN

BACKGROUND: Triple-negative breast cancer (TNBC) is a recurrent, heterogeneous, and invasive form of breast cancer. The treatment of TNBC patients with paclitaxel and fluorouracil in a sequential manner has shown promising outcomes. However, it is challenging to deliver these chemotherapeutic agents sequentially to TNBC tumors. We aim to explore a precision therapy strategy for TNBC through the sequential delivery of paclitaxel and fluorouracil. METHODS: We developed a dual chemo-loaded aptamer with redox-sensitive caged paclitaxel for rapid release and non-cleavable caged fluorouracil for slow release. The binding affinity to the target protein was validated using Enzyme-linked oligonucleotide assays and Surface plasmon resonance assays. The targeting and internalization abilities into tumors were confirmed using Flow cytometry assays and Confocal microscopy assays. The inhibitory effects on TNBC progression were evaluated by pharmacological studies in vitro and in vivo. RESULTS: Various redox-responsive aptamer-paclitaxel conjugates were synthesized. Among them, AS1411-paclitaxel conjugate with a thioether linker (ASP) exhibited high anti-proliferation ability against TNBC cells, and its targeting ability was further improved through fluorouracil modification. The fluorouracil modified AS1411-paclitaxel conjugate with a thioether linker (FASP) exhibited effective targeting of TNBC cells and significantly improved the inhibitory effects on TNBC progression in vitro and in vivo. CONCLUSIONS: This study successfully developed fluorouracil-modified AS1411-paclitaxel conjugates with a thioether linker for targeted combination chemotherapy in TNBC. These conjugates demonstrated efficient recognition of TNBC cells, enabling targeted delivery and controlled release of paclitaxel and fluorouracil. This approach resulted in synergistic antitumor effects and reduced toxicity in vivo. However, challenges related to stability, immunogenicity, and scalability need to be further investigated for future translational applications.

Asunto(s)

Aptámeros de Nucleótidos , Preparaciones de Acción Retardada , Liberación de Fármacos , Fluorouracilo , Nucleolina , Paclitaxel , Fosfoproteínas , Proteínas de Unión al ARN , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Aptámeros de Nucleótidos/farmacología , Aptámeros de Nucleótidos/química , Humanos , Paclitaxel/uso terapéutico , Paclitaxel/farmacología , Línea Celular Tumoral , Animales , Femenino , Fluorouracilo/farmacología , Fluorouracilo/uso terapéutico , Proteínas de Unión al ARN/metabolismo , Fosfoproteínas/metabolismo , Oligodesoxirribonucleótidos/farmacología , Oligodesoxirribonucleótidos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ratones Desnudos , Ensayos Antitumor por Modelo de Xenoinjerto , Proliferación Celular/efectos de los fármacos , Oxidación-Reducción/efectos de los fármacos , Ratones Endogámicos BALB C

RESUMEN

5-Fluorouracil (5-FU) is a conventional nucleotide analogue used for cancer treatment. However, its clinical application faces challenges such as low stability and non-specific toxicity. With the remarkable advancements in DNA nanotechnology, DNA-based self-assembled nanocarriers have emerged as powerful tools for delivering nucleotide drugs. In this study, we have designed a non-linear hybrid chain reaction involving a fuel strand with AS1411 aptamer sequence to construct a dendritic structure capable of carrying 5-FU. This structure specifically targets cancer cells with overexpressed nucleolin on their surface, allowing the 5-FU to exert its anticancer effects and achieve therapeutic outcomes. Furthermore, we have also investigated the mechanistic action of this drug delivery system, aiming to establish a novel therapeutic platform for 5-FU treatment.

Asunto(s)

Aptámeros de Nucleótidos , Fluorouracilo , Fluorouracilo/administración & dosificación , Fluorouracilo/química , Aptámeros de Nucleótidos/administración & dosificación , Aptámeros de Nucleótidos/química , Humanos , Antimetabolitos Antineoplásicos/administración & dosificación , Antimetabolitos Antineoplásicos/química , Animales , Sistemas de Liberación de Medicamentos/métodos , Oligodesoxirribonucleótidos/administración & dosificación , Oligodesoxirribonucleótidos/química , Proteínas de Unión al ARN/metabolismo , Fosfoproteínas/metabolismo , Línea Celular Tumoral , Nucleolina , Neoplasias/tratamiento farmacológico , Portadores de Fármacos/química , Ratones Desnudos , Ratones Endogámicos BALB C

RESUMEN

Breast cancer treatment can be challenging, but a targeted drug delivery system (DDS) has the potential to make it more effective and reduce side effects. This study presents a novel nanotherapeutic targeted DDS developed through the self-assembly of an amphiphilic di-block copolymer to deliver the chemotherapy drug SN38 specifically to breast cancer cells. The vehicle was constructed from the PHPMA-b-PEAMA diblock copolymer synthesized via RAFT polymerization. A single emulsion method was then used to encapsulate SN38 within nanoparticles (NPs) formed from the PHPMA-b-PEAMA copolymer. The AS1411 DNA aptamer was covalently bonded to the surface of the micellar NPs, producing a targeted DDS. Molecular dynamics (MD) simulation studies were also performed on the di block polymeric system, demonstrating that SN38 interacted well with the di block. The in vitro results demonstrated that AS1411- decorated SN38-loaded HPMA NPs were highly toxic to breast cancer cells while having a minimal effect on non-cancerous cells. Remarkably, in vivo studies elucidated the ability of the targeted DDS to enhance the antitumor effect of SN38, suppressing tumor growth and improving survival rates compared to free SN38.

Asunto(s)

Aptámeros de Nucleótidos , Neoplasias de la Mama , Portadores de Fármacos , Irinotecán , Micelas , Oligodesoxirribonucleótidos , Polímeros , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/administración & dosificación , Femenino , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Humanos , Animales , Portadores de Fármacos/química , Polímeros/química , Irinotecán/administración & dosificación , Irinotecán/química , Oligodesoxirribonucleótidos/administración & dosificación , Oligodesoxirribonucleótidos/química , Línea Celular Tumoral , Nanopartículas/química , Sistemas de Liberación de Medicamentos/métodos , Ratones Endogámicos BALB C , Ratones , Simulación de Dinámica Molecular , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Antineoplásicos/farmacología , Supervivencia Celular/efectos de los fármacos , Células MCF-7

RESUMEN

The interaction between glioma cells and astrocytes promotes the proliferation of gliomas. Micro-RNAs (miRNAs) carried by astrocyte exosomes (exos) may be involved in this process, but the mechanism remains unclear. The oligonucleotide AS1411, which consists of 26 bases and has a G-quadruplex structure, is an aptamer that targets nucleolin. In this study, we demonstrate exosome-miRNA-27a-mediated cross-activation between astrocytes and glioblastoma and show that AS1411 reduces astrocytes' pro-glioma activity. The enhanced affinity of AS1411 toward nucleolin is attributed to its G-quadruplex structure. After binding to nucleolin, AS1411 inhibits the entry of the NF-κB pathway transcription factor P65 into the nucleus, then downregulates the expression of miRNA-27a in astrocytes surrounding gliomas. Then, AS1411 downregulates astrocyte exosome-miRNA-27a and upregulates the expression of INPP4B, the target gene of miRNA-27a in gliomas, thereby inhibiting the PI3K/AKT pathway and inhibiting glioma proliferation. These results were verified in mouse orthotopic glioma xenografts and human glioma samples. In conclusion, the parallel structure of AS1411 allows it to bind to nucleolin and disrupt the exosome-miRNA-27a-mediated reciprocal activation loop between glioma cells and astrocytes. Our results may help in the development of a novel approach to therapeutic modulation of the glioma microenvironment.

Asunto(s)

Aptámeros de Nucleótidos , Astrocitos , Exosomas , Glioma , MicroARNs , Nucleolina , Oligodesoxirribonucleótidos , Fosfoproteínas , Proteínas de Unión al ARN , Proteínas de Unión al ARN/metabolismo , Proteínas de Unión al ARN/genética , Humanos , Astrocitos/metabolismo , Fosfoproteínas/metabolismo , Fosfoproteínas/genética , MicroARNs/genética , MicroARNs/metabolismo , Animales , Glioma/metabolismo , Glioma/patología , Glioma/genética , Ratones , Oligodesoxirribonucleótidos/genética , Oligodesoxirribonucleótidos/metabolismo , Oligodesoxirribonucleótidos/farmacología , Aptámeros de Nucleótidos/metabolismo , Aptámeros de Nucleótidos/genética , Exosomas/metabolismo , Exosomas/genética , Línea Celular Tumoral , Proliferación Celular , Regulación Neoplásica de la Expresión Génica , Ratones Desnudos , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/genética , Transducción de Señal

RESUMEN

Proteolysis-targeting chimeras (PROTACs) are heterobifunctional molecules consisting of two ligands joined by a linker, enabling them to simultaneously bind with an E3 ligase and a protein of interest (POI) and trigger proteasomal degradation of the POI. Limitations of PROTAC include lack of potent E3 ligands, poor cell selectivity, and low permeability. AS1411 is an antitumor aptamer specifically recognizing a membrane-nucleus shuttling nucleolin (NCL). Here, we repurpose AS1411 as a ligand for an E3 ligase mouse double minute 2 homolog (MDM2) via anchoring the NCL-MDM2 complex. Then, we construct an AS1411-NCL-MDM2-based PROTAC (ANM-PROTAC) by conjugating AS1411 with large-molecular-weight ligands for "undruggable" oncogenic STAT3, c-Myc, p53-R175H, and AR-V7. We show that the ANM-PROTAC efficiently penetrates tumor cells, recruits MDM2 and degrades the POIs. The ANM-PROTAC achieves tumor-selective distribution and exhibits excellent antitumor activity with no systemic toxicity. This is a PROTAC with built-in tumor-targeting and cell-penetrating capacities.

Asunto(s)

Antineoplásicos , Aptámeros de Nucleótidos , Proteolisis , Proteínas Proto-Oncogénicas c-mdm2 , Humanos , Proteínas Proto-Oncogénicas c-mdm2/metabolismo , Proteínas Proto-Oncogénicas c-mdm2/antagonistas & inhibidores , Animales , Ratones , Proteolisis/efectos de los fármacos , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/farmacología , Aptámeros de Nucleótidos/metabolismo , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Ligandos , Nucleolina , Proteínas de Unión al ARN/metabolismo , Reposicionamiento de Medicamentos , Femenino , Ratones Desnudos , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Ratones Endogámicos BALB C , Fosfoproteínas/metabolismo , Fosfoproteínas/antagonistas & inhibidores , Fosfoproteínas/química , Ensayos de Selección de Medicamentos Antitumorales , Quimera Dirigida a la Proteólisis , Oligodesoxirribonucleótidos

RESUMEN

Post-operative chemotherapy is still required for the treatment of glioblastoma (GBM), for which nanocarrier-based drug delivery has been identified as one of the most effective methods. However, the blood-brain barrier (BBB) and non-specific delivery to non-tumor tissues can significantly limit drug accumulation in tumor tissues and cause damage to nearby normal tissues. This study describes a targeted cancer therapy approach that uses AS1411 aptamer-conjugated nanospheres (100-300 nm in size) loaded with doxorubicin (Dox) to selectively identify tumor cells overexpressing nucleolin (NCL) proteins. The study demonstrates that the active target model, which employs aptamer-mediated drug delivery, is more effective than non-specific enhanced permeability and maintenance (EPR)-mediated delivery and passive drug delivery in improving drug penetration and maintenance in tumor cells. Additionally, the study reveals the potential for anti-cancer effects through 3D spheroidal and in vivo GBM xenograft models. The DNA-protein hybrid nanospheres utilized in this study offer numerous benefits, such as efficient synthesis, structural stability, high drug loading, dye labeling, biocompatibility, and biodegradability. When combined with nanospheres, the 1411 aptamer has been shown to be an effective drug delivery carrier allowing for the precise targeting of tumors. This combination has the potential to produce anti-tumor effects in the active targeted therapy of GBM.

RESUMEN

Conventional chemotherapy and poor targeted delivery in brain cancer resulting to poor treatment and develop resistance to anticancer drugs. Meanwhile, it is quite challenging to diagnose/detection of brain tumor at early stage of cancer which resulting in severity of the disease. Despite extensive research, effective treatment with real-time imaging still remains completely unavailable, yet. In this study, two brain cancer cell specific moieties i.e., AS1411 aptamer and RGD are decorated on the surface of chitosan-PLGA nanoparticles to improve targeted co-delivery of docetaxel (DTX) and upconversion nanoparticles (UCNP) for effective brain tumor therapy and real-time imaging. The nanoparticles were developed by a slightly modified emulsion/solvent evaporation method. This investigation also translates the successful synthesis of TPGS-chitosan, TPGS-RGD and TPGS-AS1411 aptamer conjugates for making PLGA nanoparticle as a potential tool of the targeted co-delivery of DTX and UCNP to the brain cancer cells. The developed nanoparticles have shown an average particle size <200 nm, spherical in shape, high encapsulation of DTX and UCNP in the core of nanoparticles, and sustained release of DTX up to 72 h in phosphate buffer saline (pH 7.4). AS1411 aptamer and RGD functionalized theranostic chitosan-PLGA nanoparticles containing DTX and UCNP (DUCPN-RGD-AS1411) have achieved greater cellular uptake, 89-fold improved cytotoxicity, enhanced cancer cell arrest even at lower drug conc., improved bioavailability with higher mean residence time of DTX in systemic circulation and brain tissues. Moreover, DUCPN-RGD-AS1411 have greatly facilitated cellular internalization and higher accumulation of UCNP in brain tissues. Additionally, DUCPN-RGD-AS1411 demonstrated a significant suppression in tumor growth in brain-tumor bearing xenograft BALB/c nude mice with no impressive sign of toxicities. DUCPN-RGD-AS1411 has great potential to be utilized as an effective and safe theranostic tool for brain cancer and other life-threatening cancer therapies.

Asunto(s)

Aptámeros de Nucleótidos , Neoplasias Encefálicas , Quitosano , Docetaxel , Oligodesoxirribonucleótidos , Copolímero de Ácido Poliláctico-Ácido Poliglicólico , Animales , Humanos , Ratones , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Antineoplásicos/farmacocinética , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Aptámeros de Nucleótidos/administración & dosificación , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/farmacocinética , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/patología , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/metabolismo , Línea Celular Tumoral , Quitosano/química , Docetaxel/farmacocinética , Docetaxel/administración & dosificación , Docetaxel/farmacología , Docetaxel/uso terapéutico , Nanopartículas/química , Oligopéptidos/química , Oligopéptidos/administración & dosificación , Oligopéptidos/farmacocinética , Copolímero de Ácido Poliláctico-Ácido Poliglicólico/química , Nanomedicina Teranóstica/métodos

RESUMEN

Herein, we constructed innovative reduction-sensitive and targeted gelatin-based micelles for doxorubicin (DOX) delivery in tumor therapy. AS1411 aptamer-modified gelatin-ss-tocopherol succinate (AGSST) and the control GSST without AS1411 modification were synthesized and characterized. Antitumor drug DOX-containing AGSST (AGSST-D) and GSST-D nanoparticles were prepared, and their shapes were almost spherical. Reduction-responsive characteristics of DOX release in vitro were revealed in AGSST-D and GSST-D. Compared with non-targeted GSST-D, AGSST-D demonstrated better intracellular uptake and stronger cytotoxicity against nucleolin-overexpressed A549 cells. Importantly, AGSST-D micelles showed more effective killing activity in A549-bearing mice than GSST-D and DOX⋅HCl. It was revealed that AGSST-D micelles had no obvious systemic toxicity. Overall, AGSST micelles would have the potential to be an effective drug carrier for targeted tumor therapy.

Asunto(s)

Aptámeros de Nucleótidos , Doxorrubicina , Sistemas de Liberación de Medicamentos , Gelatina , Micelas , Oligodesoxirribonucleótidos , Doxorrubicina/farmacología , Doxorrubicina/administración & dosificación , Animales , Humanos , Aptámeros de Nucleótidos/farmacología , Gelatina/química , Células A549 , Sistemas de Liberación de Medicamentos/métodos , Ratones , Oligodesoxirribonucleótidos/administración & dosificación , Oligodesoxirribonucleótidos/farmacología , Ratones Desnudos , Ratones Endogámicos BALB C , Portadores de Fármacos/química , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/administración & dosificación , Ensayos Antitumor por Modelo de Xenoinjerto , Liberación de Fármacos , Nanopartículas/química , Neoplasias/tratamiento farmacológico , Neoplasias/patología , Neoplasias/metabolismo

RESUMEN

Here, a novel targeted nanostructure complex was designed as an alternative to the traditional treatment approaches for breast cancer. A delivery system utilizing CuS nanoparticles (CuS NPs) was developed for the purpose of targeted administration of doxorubicin (Dox), an anticancer agent. To regulate Dox release, chitosan (CS), a biodegradable and hydrophilic polymer with biocompatible properties, was applied to coat the Dox-loaded CuS NPs. Furthermore, AS1411 aptamer, served as a targeting agent for breast cancer cells (MCF-7 and 4T1 cells), was conjugated with CS-Dox-CuS NPs effectively. To assess the effectiveness of APT-CS-CuS NPs, various methods such as flow cytometry analysis, MTT assay, fluorescence imaging, and in vivo antitumor efficacy were employed. The hollow core and porous surface of CuS NPs improved the Dox loading capacity and entrapment efficiency (almost 100%). The rate of drug release at the tumor site (citrate buffer with pH 5.6) exhibited a marked increase in comparison to that observed within the physiological environment (phosphate buffer with pH 7.4). The targeted formulation (APT-CS-Dox-CuS NPs) significantly increased cytotoxicity of the Dox payload in target cells, including 4T1 (p ≤ 0.0001 (****)) and MCF7 (p ≤ 0.01 (**)) cells compared to CHO cells. Moreover, the ability of tumor growth inhibition of the targeted system was significantly (p ≤ 0.05 (*)) more than free Dox in tumor-bearing mice. The findings indicate that the targeted formulation augmented effectiveness and specificity while minimizing harm to non-targeted cells, signifying its potential as a sophisticated cancer drug delivery system.

Asunto(s)

Aptámeros de Nucleótidos , Quitosano , Doxorrubicina , Nanopartículas , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Doxorrubicina/farmacocinética , Doxorrubicina/química , Quitosano/química , Animales , Humanos , Aptámeros de Nucleótidos/química , Aptámeros de Nucleótidos/administración & dosificación , Femenino , Nanopartículas/química , Ratones , Células MCF-7 , Línea Celular Tumoral , Antibióticos Antineoplásicos/administración & dosificación , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacología , Antibióticos Antineoplásicos/química , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Sistemas de Liberación de Medicamentos/métodos , Ratones Endogámicos BALB C , Liberación de Fármacos , Portadores de Fármacos/química , Cricetulus , Células CHO , Cobre , Oligodesoxirribonucleótidos

RESUMEN

Triple-negative breast cancer (TNBC) is the most malignant breast cancer, with high rates of relapse and metastasis. Because of the nonspecific targeting of chemotherapy and insurmountable aggressiveness, TNBC therapy lacks an effective strategy. Exosomes have been reported as an efficient drug delivery system (DDS). CD82 is a tumor metastasis inhibitory molecule that is enriched in exosomes. Aptamer AS1411 specifically targets TNBC cells due to its high expression of nucleolin. We generated a "triple-punch" cell membrane-derived exosome-mimetic nanovesicle system that integrated with CD82 overexpression, AS1411 conjugation, and doxorubicin (DOX) delivery. CD82 enrichment effectively inhibits the migration of TNBC cells. AS1411 conjugation specifically targets TNBC cells. DOX loading effectively inhibits proliferation and induces apoptosis of TNBC cells. Our results demonstrate a system of exosome-mimetic nanovesicles with "triple-punch" that may facilitate TNBC therapeutics.

RESUMEN

Improving the selective delivery and uptake efficiency of chemotherapeutic drugs remains a challenge for cancer-targeted therapy. In this work, a DNA tetrahedron is constructed as a targeted drug delivery system for efficient delivery of doxorubicin (Dox) into cancer cells. The DNA tetrahedron is composed of a tetrahedral DNA nanostructure (TDN) with two strands of AS1411 aptamer as recognition elements which can target the nucleolin protein on the cell membrane of cancer cells. The prepared DNA tetrahedron has a high drug-loading capacity and demonstrates pH-responsive Dox release properties. This enables efficient delivery of Dox into targeted cancer cells while reducing side effects on nontarget cells. The proposed drug delivery system exhibits significant therapeutic efficacy in vitro compared to free Dox. Accordingly, this work provides a good paradigm for developing a targeted drug delivery system for cancer therapy based on DNA tetrahedrons.

Asunto(s)

Aptámeros de Nucleótidos , Nanoestructuras , Neoplasias , Humanos , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , ADN/química , Nanoestructuras/química , Doxorrubicina , Neoplasias/tratamiento farmacológico , Aptámeros de Nucleótidos/farmacología , Aptámeros de Nucleótidos/química , Línea Celular Tumoral

RESUMEN

G-quadruplexes are important drug targets and get attention due to their existence in telomere, ribosomal DNA, promoter regions of some oncogenes, and the untranslated regions of mRNA. Due to the biological roles of G-quadruplexes, investigating of the G-quadruplex-small molecule interaction is essential. The primary motivation for these studies is the possibility of inhibiting cell functions associated with G-quadruplex sequences by binding with small molecules. Targeting the small molecules to desired tissue with the G-quadruplex vehicles is the second important goal of the G-quadruplex-small molecule interaction studies. In the present study, the new peripherally 2-mercaptopyridine octasubstituted copper(II) phthalocyanine and its quaternized derivative (CuPc) were synthesized and characterized by elemental analysis FT-IR, UV-Vis, and mass spectra. The excellent solubility of CuPc in water is essential for its transport in the organism. Because of this feature, its affinity toward G-quadruplex forming aptamers, AS1411, Tel21, and Tel45, was investigated. The UV-Vis spectrophotometric titration data confirmed the prevention of aggregation upon interaction with G-quadruplex, which is very important for biomedical applications. The CD spectroscopic analyses and binding stoichiometry confirmed the "end stacking" model for interaction of AS1411 with CuPc. The interaction of CuPc caused the equilibrium shift from hybrid conformation to antiparallel conformation for Tel21 and Tel45. The isothermal titration calorimeter (ITC) was used for the determination of thermodynamic parameters. The thermodynamic data of the interaction was fitted well with the one-site model. The negative values of Gibbs free energy change confirmed the spontaneous nature of the reactions. Besides, the negative values of enthalpy change and entropy change proved that the nature of processes was "enthalpy driven." The interaction stoichiometry was 2 for AS1411 and Tel21 and 1.5 for Tel45. The binding constants were 1.3(±0.3) × 105 , 3.2(±0.4) × 105 , and 1.1(±0.3) × 105 M-1 , which were at the level of ethidium bromide intercalation binding constant given in the literature. The DNA polymerase stop assay further supported the interaction of CuPc with G-quadruplex DNA. The experimental results confirm that the CuPc has a potential photosensitizer behaviour for photodynamic therapy.

Asunto(s)

G-Cuádruplex , Piridinas , Cobre , Sulfatos , Espectroscopía Infrarroja por Transformada de Fourier , Dicroismo Circular , Termodinámica , Telómero

RESUMEN

Metastasis is the most challenging health problem contributing to about 90 % of cancer-related deaths worldwide. Metastatic tumors are highly aggressive and resistant to the most available therapeutic options. Hence, innovative therapeutic approaches are required to target metastatic tumors selectively. In this study, we prepared AS1411 functionalized Withaferin A loaded PEGylated nanoliposomes (ALW) and investigated its therapeutic effect in B16F10 induced in pulmonary metastasis mice models. The prepared formulations' size and morphological properties were evaluated using dynamic light scattering system and Transmission electron microscope. ALW had spherical-shaped nanosized particles with a size of 118 nm and an encapsulation efficacy of 82.5 %. TEM analysis data indicated that ALW has excellent dispersibility and uniform spherical nano-size particles. ALW inhibited cell viability, and induced cell apoptosis of B16F10. In vivo, the pulmonary metastasis study in C57BL/6 mice revealed that the ALW significantly (p < 0.01) improved the encapsulated WA anti-metastatic activity and survival rate compared to WA or LW treated groups. ALW significantly (p < 0.01) downregulated the levels of IL-6, TNF-α, and IL-1ß and significantly reduced the lung collagen hydroxyproline, hexosamine, and uronic acid content in metastatic tumor bearing animals compared to WA or LW. Gene expression levels of MMPs and NF-κB were downregulated in ALW treated metastatic pulmonary tumor-bearing mice. These findings demonstrate that the AS1411 functionalized Withaferin A loaded PEGylated nanoliposomes could be a promising nanoliposomal formulation for targeting metastatic tumors.

Asunto(s)

Liposomas , Neoplasias Pulmonares , Ratones , Animales , Ratones Endogámicos C57BL , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/metabolismo , Polietilenglicoles

RESUMEN

Targeted therapy is highly desirable, as it allows for selective cytotoxicity on diseased cells without off-target side effects. Nucleolin is a remarkable target for cancer therapy given its high abundance, selective presence on the plasma membrane, and multifaceted influence on the initiation and progression of cancer. Nucleolin is a protein overexpressed on the cell membrane in many tumors and serves as a binding protein for several ligands implicated in angiogenesis and tumorigenesis. Nucleolin is present in the cytoplasm, nucleoplasm, and nucleolus and is used by selected pathogens for cell entry. AS1411 is a guanosine-rich oligonucleotide aptamer that binds nucleolin and is internalized in the tumor cells. AS1411 is well tolerated at therapeutic doses and localizes to tumor cells overexpressing nucleolin. AS1411 has a good safety profile with efficacy in relapsed acute myeloid leukemia and renal cell carcinoma producing mild or moderate side effects. The promising potential of AS1411 is its ability to be conjugated to drugs and nanoparticles. When a drug is bound to AS1411, the drug will localize to tumor cells leading to targeted therapy with fewer systemic side effects than traditional practices. AS1411 can also be bound to nanoparticles capable of detecting nucleolin at concentrations far lower than lab techniques used today for cancer diagnosis. AS1411 has a promising potential to change cancer diagnoses and treatment.

RESUMEN

Development of AS1411aptamer-conjugated liposomes for targeted delivery of arsenic trioxide is the primary goal of this study. AS1411aptamer was used as ligand to target nucleolin, which is highly expressed on the surface of melanoma cancer cells. The targeted liposomes were constructed by the thin film method, and arsenic trioxide was loaded as cobalt (II) hydrogen arsenite (CHA) to increase the loading efficiency and stability of the liposomes. The liposomal structure was characterized by Fourier Transform Infrared Spectroscopy (FT-IR) and field emission scanning electron microscopy (FESEM). In addition, particle sizes and zeta potential of the CHA-loaded liposomes (CHAL) and aptamer-functionalized CHA-loaded liposomes (AP-CHAL) were determined. In vitro cytotoxicity of CHAL and AP-CHAL were evaluated using MTT assay in murine melanoma (B16) and mouse embryonic fibroblast (MEF) cell lines. The encapsulation efficiency of CHAL and AP-CHAL was reported as 60.2 ± 6.5% and 58.7 ± 4.2%, respectively. In vivo antitumor activity of CHAL and AP-CHAL in the B16 tumor-xenograft mouse model was dramatically observed. All mice of both groups survived until the end of treatment and showed body weight gain. The tumor protrusion completely disappeared in 50% of the mice in these groups. Furthermore, histopathology studies demonstrated that CHAL and AP-CHAL did not induce significant toxicity in healthy mice tissues. However, unlike the CHAL group, which showed an initial increase in tumor volume, a specific antitumor effect was observed in the AP-CHAL group from the beginning of treatment. The results showed that AP-CHAL can be used as an effective drug delivery system with high potential in the treatment of solid tumors.

RESUMEN

OBJECTIVE: Herein, a dual-targeting delivery system using mesoporous silica nanoparticles with hollow structures (HMSNs) was developed for the specific delivery of epirubicin (EPI) to cancer cells and introducing a H+-triggered bubble generating nanosystem (BGNS). HMSNs containing EPI are covered by hyaluronic acid (HA) shell and AS1411 aptamer to create the BGNS-EPI-HA-Apt complex, which is highly selective against CD44 marker and nucleolin overexpressed on the surface of tumor cells. METHODS: MTT assay compared the cytotoxicity of different treatments in CHO (Chinese hamster ovary) cells as well as 4T1 (murine mammary carcinoma) and MCF-7 (human breast adenocarcinoma) cells. The internalization of Epi was assessed by flow cytometry along with fluorescence imaging. In vivo studies were conducted on BALB/c mice bearing a tumor from 4T1 cell line where monitoring included measuring tumor volume, mouse weight changes over time alongside mortality rate; accumulation levels for Epi within organs were also measured during this process. RESULTS: The collected data illustrated that BGNS-EPI-HA-Apt complex controlled the release of EPI in a sustained method. Afterward, receptor-mediated internalization via nucleolin and CD44 was verified in 4T1 and MCF-7 cells using fluorescence microscopy assay and flow cytometry analysis. The results of tumor inhibitory effect study exhibited that BGNS-EPI-HA-Apt complex decreased off-target effect and improved on-target effects because of its targeting ability. CONCLUSION: The data acquired substantiates that HA-surface modified HMSNs functionalized with aptamers possess significant potential as a focused platform for efficient transportation of anticancer agents to neoplastic tissues.

Asunto(s)

Neoplasias de la Mama , Nanopartículas , Cricetinae , Humanos , Animales , Ratones , Femenino , Ácido Hialurónico , Células CHO , Sistemas de Liberación de Medicamentos/métodos , Línea Celular Tumoral , Cricetulus , Dióxido de Silicio/química , Epirrubicina , Nanopartículas/química , Células MCF-7 , Neoplasias de la Mama/tratamiento farmacológico

RESUMEN

Brain tumors represent an aggressive form of cancer, posing significant challenges in achieving complete remission. Development of advanced therapies is crucial for improving clinical outcomes in cancer patients. This study aimed to create a novel treatment approach using dual-targeted transferrin (TF) and AS1411 conjugated micelles, designed to enhance therapeutic effectiveness of docetaxel (DTX) and facilitate gadolinium (Gd) based imaging in brain cancer. Micelles were prepared using a slightly modified solvent-casting method, and the dual-targeting ligands were attached to the micelle's surface through a physical adsorption process. Average particle size of micelles ranged from 117.49 ± 3.90-170.38 ± 3.39 nm, with a low polydispersity index. Zeta potential ranged from - 1.5 ± 0.02 to - 18.7 ± 0.04 mV. Encapsulation efficiency of DTX in micelles varied from 92.64 ± 4.22-79.77 ± 4.13 %. Simultaneously, encapsulation of Gd in micelles was found to be 48.27 ± 3.18-58.52 ± 3.17, respectively. In-vitro drug release studies showed a biphasic sustained release profile, with DTX and Gd release continuing up to 72 h with their t50 % at 4.95, 11.29, and 24.14 h for GDTP, GDTP-TF and GDTP-TF-AS1411 micelles, respectively. Cytotoxicity effect of GDTP-TF-AS1411 micelles has shown significant improvement (P < 0.001) and reduced IC50 value up to 0.19 ± 0.14 µg/ml compared to Taxotere® (2.73 ± 0.73 µg/ml). Theranostic study revealed higher accumulation of GDTP-TF and GDTP-TF-AS1411 micelles free GD treated animal brains. The AUC of GDTP-TF-AS1411 micelles exhibited 23.79 ± 17.82 µg.h/ml higher than Taxotere® (14.14 ± 10.59 µg.h/ml). These findings direct enhanced effectiveness in brain cancer therapy leading to improved therapeutics in brain cancer patients. The combined targeted ligands and therapeutic agents strategy can direct advancement in brain cancer therapy and offer improved therapy for patients.

Asunto(s)

Antineoplásicos , Neoplasias Encefálicas , Animales , Humanos , Docetaxel/farmacología , Micelas , Antineoplásicos/farmacología , Transferrina , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Línea Celular Tumoral

RESUMEN

Self-assembled multivalent DNA nanocages are an emerging class of molecules useful for biomedicine applications. Here, we investigated the molecular mechanisms of cytotoxicity induced by AS1411 free aptamer, AS1411-linked nanocages (Apt-NCs) and nanocages harboring both folate and AS1411 functionalization (Fol-Apt-NCs) in HeLa and MDA-MB-231 cancer cell lines. The three treatments showed different cytotoxic efficacy and Fol-Apt-NCs resulted the most effective in inhibiting cell proliferation and inducing apoptotic pathways and ROS activation in both HeLa and MDA-MB-231 cells. RNA-seq analysis allowed to identify biological functions and genes altered by the various treatments, depending on the AS1411 route of intracellular entry, highlighting the different behavior of the two cancer cell lines. Notably, Fol-Apt-NCs altered the expression of a subset of genes associated to cancer chemoresistance in MDA-MB-231, but not in HeLa cells, and this may explain the increased chemosensitivity to drugs delivered through DNA nanocages of the triple-negative breast cancer cells.

Asunto(s)

Antineoplásicos , Aptámeros de Nucleótidos , Neoplasias , Humanos , Células HeLa , Ácido Fólico , Antineoplásicos/farmacología , Antineoplásicos/metabolismo , Oligodesoxirribonucleótidos/farmacología , Aptámeros de Nucleótidos/farmacología , ADN , Línea Celular Tumoral

RESUMEN

Background: Combination therapy has attracted tremendous interest for its great potential in treating cancers. Materials & methods: Based on chitosan-coated silver nanotriangles, polyethylene glycol, AS1411 aptamer and doxorubicin, a multifunctional nanocomposite (AS1411-DOX-AgNTs) was constructed and characterized. Then the photothermal properties, ability to target breast cancer cells and anti-breast cancer effect of AS1411-DOX-AgNTs were evaluated. Results: AS1411-DOX-AgNTs were successfully fabricated and showed excellent photothermal conversion efficiency, breast cancer cell and tumor targeting ability. Compared with single treatments, the combination of AS1411-DOX-AgNTs with near-infrared irradiation possessed the strongest anti-breast cancer effect in vitro and in vivo. Conclusion: AS1411-DOX-AgNTs hold great potential in targeted DOX delivery and combined chemo-photothermal therapy for breast cancer.

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This article focuses on nanomaterials, nanomedicine and photothermal therapy (PTT) to treat breast cancer. Nanomaterials refer to materials with at least one dimension in nanometer size (1­100 nm) or materials composed as basic units in a 3D space. Nanomedicine is the application of nanomaterials in medicine. Nanoparticles can deliver drugs to areas that are difficult for the drugs themselves to reach. PTT is a noninvasive tumor therapy that uses photothermal conversion agents to convert light energy into heat energy to kill tumor cells under the irradiation of external near-infrared (NIR) light. In recent years, combination therapy for cancers has drawn more and more attention. In the current study, we investigated the in vitro and in vivo anticancer effects of silver nanocomposites combined with chemotherapy and PTT. The prepared silver nanocomposites showed excellent physicochemical properties and possessed good anti-breast cancer efficacy combined with PTT and chemotherapy drug in vitro and in vivo. The results of this study demonstrated that these prepared silver nanocomposites had exceptional anti-breast cancer effects in combination with PTT and could be promising drug-loaded photothermal conversion agents.

Asunto(s)

Aptámeros de Nucleótidos , Neoplasias de la Mama , Femenino , Humanos , Doxorrubicina/farmacología , Terapia Fototérmica , Plata