RESUMEN

Intracellular bacteria can multiply inside host cells and manipulate their biology, and the efficacy of traditional antibiotic drug therapy for intracellular bacteria is limited by inadequate drug accumulation. Fighting against these stealthy bacteria has been a long-standing challenge. Here, a system of stimuli-responsive lactoferrin (Lf) nanoparticles is prepared using protein self-assembly technology to deliver broad-spectrum antibiotic rifampicin (Rif) (Rif@Lf NPs) for enhanced infection therapy through targeted elimination of intracellular bacteria. Compared to Rif@BSA NPs, the Rif@Lf NPs can specifically target macrophages infected by bacteria, thus increasing the accumulation of Rif within macrophages. Subsequently, Rif@Lf NPs with positive surface charge further displayed targeted adherence to the bacteria within macrophages and released Rif rapidly in a redox-responsive manner. Combined with the antibacterial activities of Lf and Rif, the Rif@Lf NPs showed broad-spectrum antibiotic abilities to intracellular bacteria and biofilms. As a result, the Rif@Lf NPs with high safety exhibited excellent therapeutic efficacy in the disease models of subcutaneous infection, sepsis, and bacterial keratitis. Taken together, the antibiotic-loaded Lf nanoparticles present a promising platform to combat pathogen infections through targeted elimination of intracellular bacteria.

RESUMEN

Stimulus-responsive materials hold significant promise for antitumor applications due to their variable structures and physical properties. In this paper, a series of peptides with a responsive viologen derivative, Pep-CnV (n = 1, 2, 3) were designed and synthesized. The process and mechanism of the interaction were studied and discussed. An ultraviolet-visible (UV) spectrophotometer and fluorescence spectrophotometer were used to study their redox responsiveness. Additionally, their secondary structures were measured by Circular Dichroism (CD) in the presence or absence of the reductant, Na2SO3. DPPC and DPPG liposomes were prepared to mimic normal and tumor cell membranes. The interaction between Pep-CnV and biomembranes was investigated by the measurements of surface tension and cargo leakage. Results proved Pep-CnV was more likely to interact with the DPPG liposome and destroy its biomembrane under the stimulus of the reductant. And the destruction increased with the length of the hydrophobic tail chain. Pep-CnV showed its potential as an intelligent antitumor agent.

Asunto(s)

Interacciones Hidrofóbicas e Hidrofílicas , Liposomas , Liposomas/química , Sustancias Reductoras/química , Oxidación-Reducción , Péptidos/química , Membrana Celular/química , Membrana Celular/metabolismo , Antineoplásicos/química , Antineoplásicos/farmacología , Fosfatidilgliceroles/química , Dicroismo Circular

RESUMEN

Based on the modified cross-linking of the degradable natural polymers chitosan oligosaccharides (COS) and gelatin (GEL) via introduction of a functional bridge 3,3'-dithiodipropionic acid, this study constructed an environmentally responsive dinotefuran (DNF) delivery system (DNF@COS-SS-GEL). The introduction of the disulfide bond (-S-S-) endowed DNF@COS-SS-GEL with redox-responsive properties, allowing for the rapid release of pesticides when stimulated by glutathione (GSH) in the simulated insect. Compared with commercial DNF suspension concentrate (DNF-SC), DNF@COS-SS-GEL showed superior wet spreading and retention performance on cabbage leaves with a reduced contact angle (57°) at 180 s and 4-fold increased retention capacity after rainfall washout. Nanoencapsulation effectively improved the UV-photostability with only a 31.4% decomposition rate of DNF@COS-SS-GEL at 96 h. The small scale and large specific surface area resulted in excellent uptake and transportation properties in plants as well as higher bioactivity against Plutella xylostella larvae. This study will help promote sustainable agricultural development by reducing environmental pollution through improved pesticide utilization.

Asunto(s)

Brassica , Quitosano , Oxidación-Reducción , Plaguicidas , Hojas de la Planta , Animales , Hojas de la Planta/química , Hojas de la Planta/metabolismo , Brassica/química , Brassica/metabolismo , Quitosano/química , Plaguicidas/química , Plaguicidas/farmacología , Plaguicidas/metabolismo , Mariposas Nocturnas/efectos de los fármacos , Mariposas Nocturnas/metabolismo , Mariposas Nocturnas/química , Larva/crecimiento & desarrollo , Larva/efectos de los fármacos , Polímeros/química , Sistemas de Liberación de Medicamentos/instrumentación , Neonicotinoides/química , Neonicotinoides/metabolismo , Neonicotinoides/farmacología , Insecticidas/química , Insecticidas/farmacología , Gelatina/química

RESUMEN

Conjugation of a therapeutic agent to a polymer for enhanced delivery into target cells followed by its intracellular triggered release has proved to be an effective drug delivery approach. This approach is applied to the delivery of the immune-stimulatory unmethylated cytosine-phosphate-guanine (CpG) oligonucleotide for an anti-tumour immune response after intratumoral administration. On average four CpG-1668 molecules were covalently linked to a 40-kDa amino-functionalised dextran polymer via either a non-reversible (CpG-dextran) or an intracellular redox-responsive disulfide linkage (CpG-SS-dextran). Dynamic light scattering analysis showed that both conjugates had a similar particle size and surface charge of 17 nm and -10 mV, respectively. Agarose gel electrophoresis analysis showed that CpG-SS-dextran was stable in the extracellular low glutathione (GSH) concentration range (i.e. 10-20 µM) and was cleaved at the higher intracellular GSH concentration (5 mM), while CpG-dextran was stable in both GSH concentrations. Uptake and activation assays on bone-marrow-derived dendritic cells showed no significant difference between free CpG, CpG-dextran and CpG-SS-dextran. In a mouse subcutaneous colorectal tumour model the CpG-SS-dextran showed a statistically significantly greater inhibition of tumour growth (p < 0.03) and prolonged survival (p < 0.001) compared to CpG-dextran or free CpG. These results demonstrate that the redox-triggered intracellular release of CpG from a dextran polymer carrier has promise for intratumoral therapeutic vaccination against cancer.

Asunto(s)

Dextranos , Oligodesoxirribonucleótidos , Oxidación-Reducción , Dextranos/química , Dextranos/administración & dosificación , Animales , Oligodesoxirribonucleótidos/administración & dosificación , Ratones , Glutatión/metabolismo , Células Dendríticas/inmunología , Células Dendríticas/efectos de los fármacos , Femenino , Ratones Endogámicos C57BL , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/inmunología , Línea Celular Tumoral , Sistemas de Liberación de Medicamentos/métodos , Inyecciones Intralesiones , Ratones Endogámicos BALB C

RESUMEN

A sodium alginate (Alg) based REDOX (reduction and oxidation)-responsive and fluorescent active microgel was prepared via water in oil (w/o) mini-emulsion polymerization technique. Here, we initially synthesized sodium alginate-based disulfide cross linked microgels and after that those microgels were tagged with rhodamine amine derivative (RhB-NH2) by ionic interaction to get the pH-responsive fluorescent property. Functionalized microgels were characterized using 1H NMR, FTIR, DLS, HRTEM, FESEM, UV-vis, and fluorescence spectroscopy analyses. Presence of the REDOX-responsive disulfide-containing crosslinkers in the microgels enhances the release of doxorubicin (DOX), an anti-cancer drug in the reducing environment of the cancer-cells (simulated). Existence of the rhodamine-amine derivative in the microgels triggers the pH-dependent fluorescence property by showing fluorescence emission at 560-580 nm at pH 5.5 (cancer cell pH). The cytotoxicity of the biopolymer based microgel was assessed over both cancerous HeLa (IC50 100 µg/mL) and non-cancerous MDCK (IC50 200 µg/mL) cells by MTT assay which showed the synthesized microgel is non-toxic whereas DOX-loaded microgels showed significant toxicity. FACS and cell uptake (in vitro) analyses were conducted to understand the cell apoptosis cycle and behavior of the cancer cells in presence of the DOX-loaded microgels. This pH-responsive fluorescent active alginate-based biomaterial could be a promising material for the anti-cancer drug delivery and other medical fields.

Asunto(s)

Alginatos , Doxorrubicina , Sistemas de Liberación de Medicamentos , Liberación de Fármacos , Microgeles , Oxidación-Reducción , Alginatos/química , Concentración de Iones de Hidrógeno , Doxorrubicina/administración & dosificación , Doxorrubicina/farmacología , Doxorrubicina/química , Humanos , Células HeLa , Animales , Microgeles/química , Sistemas de Liberación de Medicamentos/métodos , Perros , Antineoplásicos/química , Antineoplásicos/administración & dosificación , Antineoplásicos/farmacología , Rodaminas/química , Supervivencia Celular/efectos de los fármacos , Portadores de Fármacos/química , Colorantes Fluorescentes/química

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

In this paper, a novel mono-methacrylated ß-cyclodextrin (ß-CD) monomer mediated by disulfide bond was synthesized, and then thermal copolymerized with HEMA monomer in the presence of a little crosslinker to prepare redox-responsive hydrogel for regulated drug delivery. The structure of the monomer was confirmed by FTIR, 1H NMR, 13C NMR spectroscopy. The substitution degree of polymerizable methacrylated group grafted onto ß-CD was about 1 by calculating by1H NMR (0.987) and element analysis (0.937). The mono-methacrylated ß-CD monomer can well copolymerize with 2-hydroxyethyl methacrylate (HEMA) monomer with gel fraction over 80%. The hydrogel shows low cytotoxicity, and copolymerization of the mono-methacrylated ß-CD monomer in the hydrogels increases its equilibrium swelling degree (ESD) and tensile strength, while its transmittance slightly decreases. Drug loading and release rate are dependent on the ß-CD content. The hydrogel with high ß-CD content of 13.83 wt% shows 1.8 and 8.5 folds puerarin (PUE) and curcumin (CUR) loading than pure pHEMA hydrogel, respectively. The incorporation of ß-CD sustained drug release, especially CUR release was prolonged more than 24 h from 5 h of pure pHEMA hydrogel (80% release). The hydrogels are highly sensitive to reduced glutathione (GSH), and low concentration of GSH of 3 mM can significantly accelerate drug release rate. The higher of ß-CD content, the more sensitive the hydrogels to GSH, resulting in rapider drug release rate.

RESUMEN

Multidrug resistance (MDR) is frequently induced after long-term exposure to reduce the therapeutic effect of chemotherapeutic drugs, which is always associated with the overexpression of efflux proteins, such as P-glycoprotein (P-gp). Nano-delivery technology can be used as an efficient strategy to overcome tumor MDR. In this study, mesoporous silica nanoparticles (MSNs) were synthesized and linked with a disulfide bond and then coated with lipid bilayers. The functionalized shell/core delivery systems (HT-LMSNs-SS@DOX) were developed by loading drugs inside the pores of MSNs and conjugating with D-α-tocopherol polyethylene glycol 1000 succinate (TPGS) and hyaluronic acid (HA) on the outer lipid surface. HT-LMSNs-SS and other carriers were characterized and assessed in terms of various characteristics. HT-LMSNs-SS@DOX exhibited a dual pH/reduction responsive drug release. The results also showed that modified LMSNs had good dispersity, biocompatibility, and drug-loading capacity. In vitro experiment results demonstrated that HT-LMSNs-SS were internalized by cells and mainly by clathrin-mediated endocytosis, with higher uptake efficiency than other carriers. Furthermore, HT-LMSNs-SS@DOX could effectively inhibit the expression of P-gp, increase the apoptosis ratios of MCF-7/ADR cells, and arrest cell cycle at the G0/G1 phase, with enhanced ability to induce excessive reactive oxygen species (ROS) production in cells. In tumor-bearing model mice, HT-LMSNs-SS@DOX similarly exhibited the highest inhibition activity against tumor growth, with good biosafety, among all of the treatment groups. Therefore, the nano-delivery systems developed herein achieve enhanced efficacy towards resistant tumors through targeted delivery and redox-responsive drug release, with broad application prospects.

Asunto(s)

Doxorrubicina , Resistencia a Antineoplásicos , Membrana Dobles de Lípidos , Nanopartículas , Oxidación-Reducción , Dióxido de Silicio , Dióxido de Silicio/química , Humanos , Animales , Resistencia a Antineoplásicos/efectos de los fármacos , Nanopartículas/química , Ratones , Doxorrubicina/farmacología , Doxorrubicina/química , Doxorrubicina/administración & dosificación , Membrana Dobles de Lípidos/química , Portadores de Fármacos/química , Liberación de Fármacos , Sistemas de Liberación de Medicamentos , Apoptosis/efectos de los fármacos , Porosidad , Femenino , Células MCF-7 , Ensayos Antitumor por Modelo de Xenoinjerto , Línea Celular Tumoral , Ácido Hialurónico/química , Resistencia a Múltiples Medicamentos/efectos de los fármacos , Ratones Desnudos

RESUMEN

Development of theranostic nanomedicines to tackle glioma remains to be challenging. Here, we present an advanced blood-brain barrier (BBB)-crossing nanovaccine based on cancer cell membrane-camouflaged poly(N-vinylcaprolactam) (PVCL) nanogels (NGs) incorporated with MnO2 and doxorubicin (DOX). We show that the disulfide bond-cross-linked redox-responsive PVCL NGs can be functionalized with dermorphin and imiquimod R837 through cell membrane functionalization. The formed functionalized PVCL NGs having a size of 220 nm are stable, can deplete glutathione, and responsively release both Mn2+ and DOX under the simulated tumor microenvironment to exert the chemo/chemodynamic therapy mediated by DOX and Mn2+, respectively. The combined therapy induces tumor immunogenic cell death to maturate dendritic cells (DCs) and activate tumor-killing T cells. Further, the nanovaccine composed of cancer cell membranes as tumor antigens, R837 as an adjuvant with abilities of DC maturation and macrophages M1 repolarization, and MnO2 with Mn2+-mediated stimulator of interferon gene activation of tumor cells can effectively act on both targets of tumor cells and immune cells. With the dermorphin-mediated BBB crossing, cell membrane-mediated homologous tumor targeting, and Mn2+-facilitated magnetic resonance (MR) imaging property, the designed NG-based theranostic nanovaccine enables MR imaging and combination chemo-, chemodynamic-, and imnune therapy of orthotopic glioma with a significantly decreased recurrence rate.

Asunto(s)

Glioma , Imagen por Resonancia Magnética , Compuestos de Manganeso , Nanomedicina Teranóstica , Glioma/diagnóstico por imagen , Glioma/tratamiento farmacológico , Glioma/terapia , Glioma/patología , Animales , Ratones , Humanos , Compuestos de Manganeso/química , Compuestos de Manganeso/farmacología , Doxorrubicina/química , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Vacunas contra el Cáncer/química , Inmunoterapia , Óxidos/química , Óxidos/farmacología , Línea Celular Tumoral , Neoplasias Encefálicas/diagnóstico por imagen , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/terapia , Neoplasias Encefálicas/patología , Materiales Biomiméticos/química , Materiales Biomiméticos/farmacología , Barrera Hematoencefálica/metabolismo , Nanogeles/química , Imiquimod/química , Imiquimod/farmacología , Nanovacunas

RESUMEN

Treatment for triple negative breast cancer (TNBC) remains a huge challenge due to the lack of targeted therapeutics and tumor heterogenicity. Cisplatin (Cis) have demonstrated favorable therapeutic response in TNBC and thus is used together with various kinase inhibitors to fight the heterogenicity of TNBC. The combination of Cis with SRC inhibitor dasatinib (DAS) has shown encouraging anti-TNBC efficacy although the additive toxicity was commonly observed. To overcome the severe side effects of this Cis involved therapy, here we co-encapsulated Cis and DAS into a self-assembled hyaluronan (HA) nanogel (designated as HA/Cis/DAS (HCD) nanogel) to afford the TNBC targeted delivery by using the 4T1 mouse model. The acquired HCD nanogel was around 181 nm in aqueous solution, demonstrating the pharmacological activities of both Cis and DAS. Taking advantages of HA's targeting capability towards CD44 that is overexpressed on many TNBC cells, the HCD could well maintain the anticancer efficacy of the Cis and DAS combination, significantly increase the maximum tolerated dose and relieve the renal toxicity in vivo. The current HCD nanogel provides a potent strategy to improve the therapeutic outcome of Cis and DAS combination and thus representing a new targeted treatment option for TNBC.

Asunto(s)

Cisplatino , Dasatinib , Ácido Hialurónico , Nanogeles , Neoplasias de la Mama Triple Negativas , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Ácido Hialurónico/química , Animales , Dasatinib/farmacología , Dasatinib/química , Ratones , Cisplatino/farmacología , Cisplatino/química , Femenino , Nanogeles/química , Línea Celular Tumoral , Humanos , Antineoplásicos/farmacología , Antineoplásicos/química , Polietileneimina/química , Ratones Endogámicos BALB C , Receptores de Hialuranos/metabolismo

RESUMEN

With a number of outstanding properties, gelatin is an ideal candidate for assembling nanoplatforms in biomedical applications. Generally, gelatin nanocarriers are cross-linked by aldehydes to improve their stability in water solution. However, aldehydes could cause multiple toxicities and their cross-linking products are uncontrollable. Here, we first used a self-immolative cross-linker to assemble gelatin nanocarriers for the controlled release of drugs and targeted cancer therapy. The cross-linker contains a disulphide bridge and two symmetrical succinimidyl-esters, endowing it with multiple functions: 1) to cross-link the gelatin nanocarriers and thus improve their stability in water; 2) to conjugate the drug and tumor-targeting ligands with nanocarriers through covalent linkage; 3) to redox-responsively degrade the nanocarriers through hydrolysis of disulphide bridge; and 4) to produce traceless drug molecules through self-immolative reaction. Good biocompatibility and controllable drug release were demonstrated by in vitro experiments. Both qualitative and quantitative analyses confirmed the intracellular uptake of the nanocarriers by using doxorubicin (DOX) as a drug model and phenylboronic acid (PBA) as the targeting ligand. In vivo results demonstrated high therapeutic efficiency and low toxic side effects of the DOX loaded nanocarriers against artificial liver tumors.

Asunto(s)

Doxorrubicina , Portadores de Fármacos , Liberación de Fármacos , Gelatina , Nanopartículas , Portadores de Fármacos/química , Doxorrubicina/química , Doxorrubicina/farmacología , Gelatina/química , Humanos , Animales , Nanopartículas/química , Ratones , Reactivos de Enlaces Cruzados/química , Antineoplásicos/química , Antineoplásicos/farmacología , Ácidos Borónicos/química , Línea Celular Tumoral

RESUMEN

A pH and redox dual responsive amphiphilic viologen is synthesized, which can be reversibly transformed among the zwitterionic (SVa), monovalent anionic (SV+), and divalent anionic (SVH2+) forms upon pH variation, exhibiting pH-controllable redox responsive properties. Switchable Pickering emulsions with different droplet size and viscosity are prepared by the mixture of hydrophilic silica nanoparticles and the viologens (SV+ or SVH2+) at acidic conditions, while such combination yielded an oil-in-dispersion emulsion at neutral pH value. Not only can rapid reversible demulsification/stabilization of the Pickering emulsions be achieved by redox reactions, but the rate of redox-demulsification can also be controlled by pH trigger. The dual-responsive amphiphilic viologens have potential applications in developing intelligent colloid materials and molecular logic systems.

RESUMEN

Controlling the drug release and restricting its presence in healthy organs is extremely valuable. In this study, mesoporous silica nanoparticles (MSN) as the core, loaded with paclitaxel (PTX), were coated with a non-porous silica shell functionalized with disulfide bonds. The nanoparticles were further coated with polyethylene glycol (PEG) via disulfide linkages. We analyzed the physicochemical properties of nanoparticles, including hydrodynamic size via Dynamic Light Scattering (DLS), zeta potential, X-ray Diffraction (XRD) patterns, Fourier-Transform Infrared (FTIR) spectra, and imaging through Transmission Electron Microscopy (TEM) and Scanning Electron Microscopy (SEM). The drug release profile in two distinct glutathione (GSH) concentrations of 2 µM and 10 µM was measured. The cellular uptake of nanoparticles by MCF-7 cell line was determined using Confocal Laser Scanning Microscopy (CLSM) images and flow cytometry. Furthermore, the cell viability and the capability of nanoparticles to induce apoptosis in MCF-7 cell line were studied using the MTT assay and flow cytometry, respectively. Our investigations revealed that the release of PTX from the drug delivery system was redox-responsive. Also, results indicated an elevated level of cellular uptake and efficient induction of apoptosis, underscoring the promising potential of this redox-responsive drug delivery system for breast cancer therapy.

Asunto(s)

Neoplasias de la Mama , Nanopartículas , Humanos , Femenino , Paclitaxel/farmacología , Paclitaxel/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Dióxido de Silicio/química , Sistemas de Liberación de Medicamentos , Nanopartículas/química , Polietilenglicoles/química , Glutatión/química , Oxidación-Reducción , Disulfuros , Portadores de Fármacos/química , Porosidad

RESUMEN

In the current study, a combination of precipitation polymerization and modified sol-gel methods were developed to prepare the novel hyaluronic acid-decorated pH and redox dual-stimuli responsive poly(methacrylic acid)/mesoporous organosilica nanoparticles with a core-shell structure for controlled drug release. The nanocarriers have a proper particle size of <200 nm, high negative zeta potential greater than -30 mV, controllable diameter, and tunable shell thickness. The prepared nanoparticles were able to entrap over 70 % of quercetin with a drug loading of >10 %, due to the mesoporous shell. In vitro drug release profiles indicated that the systems had good stability under normal physiological media, while the cumulative release was significantly accelerated at the simulated tumor tissue condition, which shows pH and redox-dependent drug release. In vitro cell viability and apoptosis assay proved that the obtained nanomaterials possess relatively good biocompatibility, and drug-loaded targeted nanoparticles exhibited greater cytotoxicity on MCF-7 human breast cancer cells than free drug and non-targeted nanocarriers due to the enhanced cellular uptake of nanoparticles via CD44 receptors overexpressed. All these findings demonstrated that proposed nanocarriers might be promising as a smart drug delivery system to improve the antitumor efficacy of chemotherapeutic drugs.

Asunto(s)

Neoplasias de la Mama , Metacrilatos , Nanopartículas , Humanos , Femenino , Ácido Hialurónico/química , Quercetina/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Nanopartículas/química , Sistemas de Liberación de Medicamentos/métodos , Oxidación-Reducción , Concentración de Iones de Hidrógeno , Doxorrubicina/química , Portadores de Fármacos/química , Liberación de Fármacos

RESUMEN

This study focuses on the design and evaluation of redox-responsive nanoparticles (NPs) by synthesizing disulfide-containing N-phthaloyl chitosan-SS-methoxy poly(ethylene glycol) (NPC-SS-mPEG) and incorporating the anti-cancer drug doxorubicin into the NPs. The structural features of NPC-SS-mPEG were investigated using FTIR, NMR, XRD, and TGA/DTA analysis. DLS and TEM analysis confirmed the particle size and morphology of the NPs. The stability of the NPs was measured with the presence and absence of glutathione (GSH) in buffers pH 5 and 7.4. Furthermore, the release of DOX from the NPs was studied in GSH (10 mM) containing/absent medium at pH 5 and pH 7.4 which mimics the intracellular environment with redox potential. The results indicated a significantly increased release of DOX in the GSH containing medium pH 5 (82.9 ± 2.1 %) and pH 7.4 (67.37 ± 0.88 %) compared to the GSH free pH 7.4 (29.99 ± 1.01 %) and pH 5 medium (56.56 ± 1.7 %) at 60 h. The cytotoxicity study in the MDA-MB-231 breast cancer cell line by MTT assay indicated higher toxicity of redox-responsive NPs to cancer cells than free DOX. In concurrence with the cytotoxicity assay, in-vitro fluorescence staining assays (AO/EB, Hoechst, ROS generation) also confirmed that NPs loaded with DOX induce higher toxicity to cancer cells than free DOX. Taken together, the overall results confirmed the superiority of the redox response-mediated release of DOX in effectively controlling cancer progression.

Asunto(s)

Quitosano , Nanopartículas , Humanos , Doxorrubicina/farmacología , Doxorrubicina/química , Quitosano/farmacología , Quitosano/química , Células MDA-MB-231 , Polietilenglicoles/química , Oxidación-Reducción , Nanopartículas/química , Concentración de Iones de Hidrógeno , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos/métodos

RESUMEN

The efficacy of injectable micellar carriers is hindered due to the disassembly of micelles into free surfactants in the body, resulting in their dilution below the critical micelle concentration (CMC). Copolymer micelles were developed to address this issue, containing a superhydrophilic zwitterionic block and a superhydrophobic block with a disulfide bond, which exhibited a CMC lower than conventional micellar carriers. Cleavable copolymers composed of 2-methacryloyloxyethyl phosphorylcholine (MPC) zwitterion and polycaprolactone CHLZW as the shell, with gold nanoparticles as their core, were studied to deliver doxorubicin to tumor cells while reducing the side effect of the free cytotoxic agent. The research focused on the impact of gold nanoparticles present in targeted TMT-micelles core on stability and in vivo bioavailability and sonotoxicity of the nanoparticles, as well as their synergistic effect on targeted chemotherapy. The nanomicelles prepared in this study demonstrated excellent biocompatibility and responsiveness to stimuli. PCL-SS-MPC nanomicelles displayed drug release in response to GSH and pH, resulting in high DOX release at GSH 10 mM and pH 5. Our findings, supported by MTT, flow cytometry, and confocal laser scanning microscopy, demonstrated that AuS-PM-TMTM-DOX micelles effectively induced apoptosis and enhanced cellular uptake in MCF7 and MDA-MB231 cell lines. The cytotoxic effects of AuS-PM-DOX/US on cancer cells were approximately 38 % higher compared to AuS-PM-DOX samples at a concentration of IC50 0.68 nM. This increase in cellular toxicity was primarily attributed to the promotion of apoptosis. The introduction of disulfide linkages in AuSNPs resulted in increased ROS production when exposed to ultrasound stimulation, due to a reduction in GSH levels. Compared to other commercially available nanosensitizers such as titanium dioxide, exposure of AuS-PM to ultrasound radiation (1.0 W/cm, 2 min) significantly enhanced cavitation effects and resulted in 3 to 5 times higher ROS production. Furthermore, laboratory experiments using human breast cancer cells (MDA-MB-231, MCF7) demonstrated that the toxicity of AuS-PM in response to ultrasound waves is dose-dependent. The findings of this study suggest that this formulated nanocarrier holds great potential as a viable treatment option for breast cancer. It can induce apoptosis in cancer cells, reduce tumor size, and display notable therapeutic efficacy.

Asunto(s)

Antineoplásicos , Neoplasias de la Mama , Nanopartículas del Metal , Humanos , Femenino , Micelas , Neoplasias de la Mama/tratamiento farmacológico , Oro , Especies Reactivas de Oxígeno , Doxorrubicina/farmacología , Doxorrubicina/uso terapéutico , Antineoplásicos/farmacología , Polímeros , Oxidación-Reducción , Concentración de Iones de Hidrógeno , Disulfuros

RESUMEN

Cancer development and progression of cancer are closely associated with the activation of oncogenes and loss of tumor suppressor genes. Nucleic acid drugs (e.g., siRNA, mRNA, and DNA) are widely used for cancer therapy due to their specific ability to regulate the expression of any cancer-associated genes. However, nucleic acid drugs are negatively charged biomacromolecules that are susceptible to serum nucleases and cannot cross cell membrane. Therefore, specific delivery tools are required to facilitate the intracellular delivery of nucleic acid drugs. In the past few decades, a variety of nanoparticles (NPs) are designed and developed for nucleic acid delivery and cancer therapy. In particular, the polymeric NPs in response to the abnormal redox status in cancer cells have garnered much more attention as their potential in redox-triggered nanostructure dissociation and rapid intracellular release of nucleic acid drugs. In this review, the important genes or signaling pathways regulating the abnormal redox status in cancer cells are briefly introduced and the recent development of redox-responsive NPs for nucleic acid delivery and cancer therapy is systemically summarized. The future development of NPs-mediated nucleic acid delivery and their challenges in clinical translation are also discussed.

Asunto(s)

Nanopartículas , Neoplasias , Ácidos Nucleicos , Humanos , Ácidos Nucleicos/uso terapéutico , Polímeros/química , Sistemas de Liberación de Medicamentos , Neoplasias/tratamiento farmacológico , Neoplasias/genética , Nanopartículas/química , Oxidación-Reducción

RESUMEN

The importance of an adequate linking moiety design that allows controlled drug(s) release at the desired site of action is extensively studied for polymer-drug conjugates (PDCs). Redox-responsive self-immolative linkers bearing disulfide moieties (SS-SIL) represent a powerful strategy for intracellular drug delivery; however, the influence of drug structural features and linker-associated spacers on release kinetics remains relatively unexplored. The influence of drug/spacer chemical structure and the chemical group available for conjugation on drug release and the biological effect of resultant PDCs is evaluated. A "design of experiments" tool is implemented to develop a liquid chromatography-mass spectrometry method to perform the comprehensive characterization required for this systematic study. The obtained fit-for-purpose analytical protocol enables the quantification of low drug concentrations in drug release studies and the elucidation of metabolite presence. and provides the first data that clarifies how drug structural features influence the drug release from SS-SIL and demonstrates the non-universal nature of the SS-SIL. The importance of rigorous linker characterization in understanding structure-function correlations between linkers, drug chemical functionalities, and in vitro release kinetics from a rationally-designed polymer-drug nanoconjugate, a critical strategic crafting methodology that should remain under consideration when using a reductive environment as an endogenous drug release trigger.

Asunto(s)

Sistemas de Liberación de Medicamentos , Polímeros , Polímeros/química , Preparaciones Farmacéuticas , Liberación de Fármacos , Sistemas de Liberación de Medicamentos/métodos , Nanoconjugados

RESUMEN

We report the fabrication of optically clear underwater adhesives using polyplexes of oppositely charged partially-thiolated polyamide polyelectrolytes (TPEs). The thiol content of the constituent PEs was varied to assess its influence on the adhesive properties of the resulting glues. These catechol-free, redox-responsive TPE-adhesives were formulated in aquo and exhibited high optical transparency and strong adhesion even on submerged or moist surfaces of diverse polar substrates such as glass, aluminium, wood, and bone pieces. The adhesives could be cured under water through oxidative disulphide crosslinking of the constituent TPEs. The polyamide backbone provided multi-site H-bonding interactions with the substrates while the disulphide crosslinking provided the cohesive strength to the glue. Strong adhesion of mammalian bones (load bearing capacity upto 7 kg/cm2 ) was achieved using the adhesive containing 30 mol % thiol residues. Higher pH and use of oxidants such as povidone-iodine solution enhanced the curing rate of the adhesives, and so did the use of Tris buffer instead of Phosphate buffer. The porous architecture of the adhesive and its progressive degradation in aqueous medium over the course of three weeks bode well for diverse biomedical applications where temporary adhesion of tissues is required.

RESUMEN

Homodimeric prodrug nanoassemblies (HDPNs) hold promise for improving the delivery efficiency of chemo-drugs. However, the key challenge lies in designing rational chemical linkers that can simultaneously ensure the chemical stability, self-assembly stability, and site-specific activation of prodrugs. The "in series" increase in sulfur atoms, such as trisulfide bond, can improve the assembly stability of HDPNs to a certain extent, but limits the chemical stability of prodrugs. Herein, trithiocarbonate bond (─SC(S)S─), with a stable "satellite-type" distribution of sulfur atoms, is developed via the insertion of a central carbon atom in trisulfide bonds. ─SC(S)S─ bond effectively addresses the existing predicament of HDPNs by improving the chemical and self-assembly stability of homodimeric prodrugs while maintaining the on-demand bioactivation. Furthermore, ─SC(S)S─ bond inhibits antioxidant defense system, leading to up-regulation of the cellular ROS and apoptosis of tumor cells. These improvements of ─SC(S)S─ bond endow the HDPNs with in vivo longevity and tumor specificity, ultimately enhancing the therapeutic outcomes. ─SC(S)S─ bond is, therefore, promising for overcoming the bottleneck of HDPNs for efficient oncological therapy.

Asunto(s)

Antineoplásicos , Nanopartículas , Profármacos , Tionas , Profármacos/farmacología , Profármacos/química , Línea Celular Tumoral , Antineoplásicos/farmacología , Polímeros , Azufre , Nanopartículas/química , Liberación de Fármacos