RESUMEN
The strategy of in vivo self-assembly has been developed for improved enrichment and long-term retention of anticancer drug in tumor tissues. However, most self-assemblies with non-covalent bonding interactions are susceptible to complex physiological environments, leading to weak stability and loss of biological function. Here, we develop a coupling-induced assembly (CIA) strategy to generate covalently crosslinked nanofibers, which is applied for in situ constructing artificial shell on mitochondria. The oxidation-responsive peptide-porphyrin conjugate P1 is synthesized, which self-assemble into nanoparticles. Under the oxidative microenvironment of mitochondria, the coupling of thiols in P1 causes the formation of dimers, which is further ordered and stacked into crosslinked nanofibers. As a result, the artificial shell is constructed on the mitochondria efficiently through multivalent cooperative interactions due to the increased binding sites. Under ultrasound (US) irradiation, the porphyrin molecules in the shell produce a large amount of reactive oxygen species (ROS) that act on the adjacent mitochondrial membrane, exhibiting ~2-fold higher antitumor activity than nanoparticles in vitro and in vivo. Therefore, the mitochondria-targeted CIA strategy provides a novel perspective on improved sonodynamic therapy (SDT) and shows potential applications in antitumor therapies.
RESUMEN
Metal oxide nanozymes have emerged as the most efficient and promising candidates to mimic antioxidant enzymes for treatment of oxidative stress-mediated pathophysiological disorders, but the current effectiveness is unsatisfactory due to insufficient catalytic performance. Here, we report for the first time an intrinsic strain-mediated ultrathin ceria nanoantioxidant. Surface strain in ceria with variable thicknesses and coordinatively unsaturated Ce sites was investigated by theoretical calculation analysis and then was validated by preparing â¼1.2 nm ultrathin nanoplates with â¼3.0% tensile strain in plane/â¼10.0% tensile strain out of plane. Compared with nanocubes, surface strain in ultrathin nanoplates could enhance the covalency of the Ce-O bond, leading to increasing superoxide dismutase (SOD)-mimetic activity by â¼2.6-fold (1533 U/mg, in close proximity to that of natural SOD) and total antioxidant activity by â¼2.5-fold. As a proof of concept, intrinsic strain-mediated ultrathin ceria nanoplates could boost antioxidation for improved ischemic stroke treatment in vivo, significantly better than edaravone, a commonly used clinical drug.
Asunto(s)
Antioxidantes , Accidente Cerebrovascular Isquémico , Humanos , Antioxidantes/farmacología , Catálisis , Óxidos , Superóxido DismutasaRESUMEN
The in situ construction of the nanoassembly has been demonstrated to improve the performance of bioactive molecules, but the control of the morphology of nanomaterials in vivo still remains a tremendous challenge. Herein, a photothermal-promoted morphology transformation (PMT) strategy is developed to accelerate the formation of nanomaterials for improving the biological performance of drug molecules. Compared with the spontaneous process, the rate of transformation increases by â¼4 times in the PMT process. Owing to increased assembly rate, the tumor accumulation of drugs is â¼2-fold than that without photo irradiation, which inhibits tumor growth effectively. More importantly, the chemical reassembly process in vitro and in vivo is monitored by the advanced ratiometric photoacoustic image, confirming the photoinduced transformation acceleration. Through the noninvasively artificial control on assembly dynamics in vivo, the PMT strategy provides a new insight for developing the intelligent theranostics.
Asunto(s)
Antineoplásicos/farmacología , Diagnóstico por Imagen/métodos , Neoplasias/tratamiento farmacológico , Técnicas Fotoacústicas/métodos , Antineoplásicos/química , Línea Celular Tumoral , Humanos , Nanoestructuras/química , Fotoquimioterapia , Nanomedicina Teranóstica/tendenciasRESUMEN
The systemic use of pharmaceutical drugs for cancer patients is a compromise between desirable therapy and side effects because of the intrinsic shortage of organ-specific pharmaceutical drug. Design and construction of pharmaceutical drug to achieve the organ-specific delivery is thus desperately desirable. We herein regulate perylene skeleton to effect organ-specificity and present an example of lung-specific distribution on the basis of bay-twisted PDIC-NC. We further demonstrate that PDIC-NC can target into mitochondria to act as cellular respiration inhibitor, inducing insufficient production of adenosine triphosphate, promoting endogenous H2 O2 and . OH burst, elevating calcium overload, efficiently triggering the synergistic apoptosis, autophagy and endoplasmic reticulum stress of lung cancer cells. The antitumor performance of PDIC-NC is verified on in vivo xenografted, metastasis and orthotopic lung cancer, presenting overwhelming evidences for potentially clinical application. This study contributes a proof-of-concept demonstration of twisted perylene to well attain lung-specific distribution, and meanwhile achieves intensive lung cancer chemotherapy.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/farmacología , Perileno/química , Perileno/farmacología , Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Línea Celular Tumoral , Estrés del Retículo Endoplásmico/efectos de los fármacos , Humanos , Relación Estructura-ActividadRESUMEN
Therapeutic peptides have been widely concerned, but their efficacy is limited by the inability to penetrate cell membranes, which is a key bottleneck in peptide drugs delivery. Herein, an in vivo self-assembly strategy is developed to induce phase separation of cell membrane that improves the peptide drugs internalization. A phosphopeptide KYp is synthesized, containing an anticancer peptide [KLAKLAK]2 (K) and a responsive moiety phosphorylated Y (Yp). After interacting with alkaline phosphatase (ALP), KYp can be dephosphorylated and self-assembles in situ, which induces the aggregation of ALP and the protein-lipid phase separation on cell membrane. Consequently, KYp internalization is 2-fold enhanced compared to non-responsive peptide, and IC50 value of KYp is approximately 5 times lower than that of free peptide. Therefore, the in vivo self-assembly induced phase separation on cell membrane promises a new strategy to improve the drug delivery efficacy in cancer therapy.
Asunto(s)
Membrana Celular/química , Péptidos/aislamiento & purificación , Fosfatasa Alcalina/metabolismo , Membrana Celular/metabolismo , Humanos , Péptidos/química , Péptidos/metabolismo , Conformación ProteicaRESUMEN
The precise and highly efficient drug delivery of nanomedicines into lesions remains a critical challenge in clinical translational research. Here, an autocatalytic morphology transformation platform is presented for improving the tumor-specific accumulation of drugs by kinetic control. The in situ reorganization of prodrug from nanoparticle to ß-sheet fibrous structures for targeted accumulation is based on nucleation-based growth kinetics. During multiple administrations, the autocatalytic morphology transformation can be realized for skipping slow nucleating process and constructing the bulky nanoassembly instantaneously, which has been demonstrated to induce the cumulative effect of prodrug. Furthermore, the sustained drug release from fibrous prodrug depot in the tumor site inhibits the tumor growth efficiently. The autocatalytic morphology transformation strategy in vivo offers a novel perspective for targeted delivery strategy by introducing chemical kinetics and shows great potential in disease theranostics.
Asunto(s)
Antineoplásicos/farmacología , Camptotecina/farmacología , Portadores de Fármacos/química , Nanofibras/química , Péptidos/química , Animales , Antineoplásicos/metabolismo , Camptotecina/análogos & derivados , Camptotecina/metabolismo , Catepsina B/metabolismo , Preparaciones de Acción Retardada , Portadores de Fármacos/metabolismo , Liberación de Fármacos , Femenino , Células HeLa , Humanos , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Nanopartículas/metabolismo , Péptidos/metabolismo , Polietilenglicoles/química , Profármacos/química , Profármacos/metabolismo , Multimerización de Proteína , ProteolisisRESUMEN
The morphology controlled molecular assemblies play vital roles in biological systems. Here we present endogenous reactive oxygen species (ROS)-triggered morphology transformation of polymer-peptide conjugates (PPCs) for cooperative interaction with mitochondria, exhibiting high tumor therapeutic efficacy. The PPCs are composed of (i) a ß-sheet-forming peptide KLVFF conjugated with poly(ethylene glycol) through ROS-cleavable thioketal, (ii) a mitochondria-targeting cytotoxic peptide KLAK, and (iii) a poly(vinyl alcohol) backbone. The self-assembled PPCs nanoparticles can enter cells and target mitochondria. Because of overgenerated ROS around mitochondria in most cancer cells, the thioketal linker can be cleaved, leading to transformation from nanoparticles to fibrous nanostructures. As a result, the locational nanofibers with exposure of KLAK exhibit enhanced multivalent cooperative interactions with mitochondria, which causes selective cytotoxicity against cancer cells and powerful tumor suppression efficacy in vivo. As the first example of ROS-triggered intracellular transformation, the locational assembly strategy in vivo may provide a new insight for disease diagnosis and therapy through enhanced interaction with targeting site.
Asunto(s)
Antineoplásicos/metabolismo , Mitocondrias/metabolismo , Péptidos/metabolismo , Alcohol Polivinílico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Animales , Antineoplásicos/química , Antineoplásicos/farmacología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Ensayos de Selección de Medicamentos Antitumorales , Células HeLa , Humanos , Ratones , Mitocondrias/química , Neoplasias Experimentales/diagnóstico por imagen , Neoplasias Experimentales/tratamiento farmacológico , Imagen Óptica , Péptidos/química , Péptidos/farmacología , Alcohol Polivinílico/química , Alcohol Polivinílico/farmacología , Especies Reactivas de Oxígeno/químicaRESUMEN
Local tumor recurrence after surgical resection is a critical concern in cancer therapy, and the current treatments, such as postsurgical chemotherapy, still show undesired side effects. Here a nonimplant strategy (transformation induced localization, TIL) is presented to in situ construct long-term retentive drug depots, wherein the sustained drug release from fibrous drug depots results in highly efficient suppression of postsurgical local tumor relapse. The peptide-based prodrug nanoparticles show favorable tumor targeting and instantly reorganize into fibrous nanostructures under overexpressed enzyme, realizing the construction of long-term drug depot in the tumor site. After the resection surgery, the remnant cancer cells are still inhibited by the sustained drug release from the fibrous prodrug depot, effectively preventing postsurgical local recurrences. This TIL strategy shows great potential in cancer recurrence therapy and offers a novel perspective for constructing functional biomaterials in vivo.
Asunto(s)
Antineoplásicos/química , Antineoplásicos/uso terapéutico , Recurrencia Local de Neoplasia/prevención & control , Animales , Sistemas de Liberación de Medicamentos/métodos , Femenino , Células HeLa , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Nanopartículas/química , Nanoestructuras/química , Profármacos/química , Neoplasias del Cuello Uterino/tratamiento farmacológicoRESUMEN
Despite recent advances in tumor treatment through cancer immunotherapy, the efficacy of this approach remains to be improved. Looking forward to high rates of objective clinical response, cancer immunotherapy combined with chemotherapy has gained increasing attention recently. Here, we constructed liposomes with matrix metalloproteinases (MMPs) responsive moiety and PD-L1 inhibitor conjugate combine with low dose chemotherapy to achieve enhanced antitumor efficacy. Upon introduction of the pH-responsive polymer to LPDp, the coassembly could be almost stable in physiological conditions and tumor microenvironments and release the loaded cargos at the lysosome. MMP-2 enzyme extracellularly secreted by the B16F10 cells could cleave the cross-linker and liberate the PD-L1 inhibitor effectively disrupting the PD-1/PD-L1 interaction in vitro. Low dose DOX encapsulated in the LPDp was capable of sensitizing B16F10 cells to CTLs by inducing overexpression of M6PR on tumor cell membranes. In comparison with free PD-L1 inhibitor, LPDp improved the biodistribution and on-demand release of the peptide inhibitor in tumor regions following administration. LPDp achieved the optimal tumor suppression efficiency (â¼78.7%), which demonstrated the significantly enhanced antitumor effect ( P < 0.01) than that of LPp (â¼57.5%) as well as that of LD (<40%), attributing to synergistic contribution from the substantial increase in M6PR expression on tumor cells and the blockade of immune checkpoints. This strategy provides a strong rationale for combining standard-of-care chemotherapy with relative nontoxic and high specific immunotherapy.
Asunto(s)
Antineoplásicos/administración & dosificación , Antígeno B7-H1/antagonistas & inhibidores , Liposomas/química , Metaloproteinasas de la Matriz/metabolismo , Polímeros de Estímulo Receptivo/química , Microambiente Tumoral , Animales , Línea Celular Tumoral , Doxorrubicina/administración & dosificación , Liberación de Fármacos , Quimioterapia/métodos , Concentración de Iones de Hidrógeno , Inmunoterapia/métodos , RatonesRESUMEN
Nanotherapeutics have encountered some bottleneck problems in cancer therapy, such as poor penetration and inefficient accumulation in tumor site. We herein developed a novel strategy for deep tissue penetration in molecular level and near-infrared (NIR) laser guided in situ self-assembly to solve these challenges. For the proof-of-concept study, we synthesized the polymer-peptide conjugates (PPCs) composed of (i) poly(ß-thioester) as thermoresponsive backbone, (ii) functional peptides (cytotoxic peptide and cell-penetrating peptide), and (iii) the NIR molecule with photothermal property. The PPCs in the molecular level with small size (<10 nm) can penetrate deeply into the interior of the tumor at body temperature. Under the irradiation of NIR laser, the temperature rise induced by photothermal molecules led to the intratumoral self-assembly of thermoresponsive PPCs. The resultant spherical nanoparticles can accumulate in tumor and enter cells effectively, inducing cell apoptosis by destroying mitochondria membrane. Through the site-specific size control, a variety of merits of PPCs are realized including deep tumor penetration, enhanced accumulation, and cellular internalization in vivo. Taking advantage of the NIR guided in situ assembly strategy, numerous polymeric or nanoscaled therapeutics with high anticancer activity can be exploited.
Asunto(s)
Doxorrubicina/administración & dosificación , Sistemas de Liberación de Medicamentos , Nanopartículas/administración & dosificación , Neoplasias/tratamiento farmacológico , Línea Celular Tumoral , Doxorrubicina/química , Oro/química , Humanos , Hipertermia Inducida/métodos , Rayos Infrarrojos , Rayos Láser , Nanopartículas/química , Neoplasias/patología , Polímeros/químicaRESUMEN
In cancer treatment, the unsatisfactory solid-tumor penetration of nanomaterials limits their therapeutic efficacy. We employed an inâ vivo self-assembly strategy and designed polymer-peptide conjugates (PPCs) that underwent an acid-induced hydrophobicity increase with a narrow pH-response range (from 7.4 to 6.5). Inâ situ self-assembly in the tumor microenvironment at appropriate molecular concentrations (around the IC50 values of PPCs) enabled drug delivery deeper into the tumor. A cytotoxic peptide KLAK, decorated with the pH-sensitive moiety cis-aconitic anhydride (CAA), and a cell-penetrating peptide TAT were conjugated onto poly(ß-thioester) backbones to produce PT-K-CAA, which can penetrate deeply into solid tumors owing to its small size as a single chain. During penetration inâ vivo, CAA responds to the weak acid, leading to the self-assembly of PPCs and the recovery of therapeutic activity. Therefore, a deep-penetration ability for enhanced cancer therapy is provided by this inâ vivo assembly strategy.
Asunto(s)
Antineoplásicos/farmacología , Péptidos/farmacología , Polímeros/farmacología , Microambiente Tumoral/efectos de los fármacos , Ácido Aconítico/administración & dosificación , Ácido Aconítico/análogos & derivados , Ácido Aconítico/química , Ácido Aconítico/farmacología , Administración Intravenosa , Animales , Antineoplásicos/administración & dosificación , Antineoplásicos/química , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Ensayos de Selección de Medicamentos Antitumorales , Humanos , Concentración de Iones de Hidrógeno , Ratones , Tamaño de la Partícula , Péptidos/administración & dosificación , Péptidos/química , Polímeros/administración & dosificación , Polímeros/química , Propiedades de SuperficieRESUMEN
Nanoscaled polymer-peptide conjugates (PPCs) containing both functional peptides and synthetic polymer comprise a new family of biomaterials that can circumvent the limitation of peptides alone. Our previous work showed that PPCs with the therapeutic peptide KLAK, especially PPCs with shorter PEG spacers and a higher degree of polymerization, exhibit enhanced antitumor effects through disrupting mitochondrial membranes. However, as PPCs have a spherical nanostructure (45-60 nm), this may have other effects besides the conjugated therapeutic peptide KLAK itself when they enter cancer cells. In this research, we compared the proteome differences of U87 cells treated with KLAK, polymer, and their conjugates (P-KLAK) through quantitative proteomics technology. The result reveals that proteins involved in oxidative stress response and the Nrf2/ARE pathway were significantly up-regulated after P-KLAK treatment. Moreover, the overexpression of sequestosome 1, a protein substrate that is selectively incorporated into the formation of autophagosome and degraded by autophagy, is found in our study and has not been reported previously in the study of KLAK toxicity. Additional experiments suggest that upon endocytosis, P-KLAK causes lysosome impairment and results in autophagosomes accumulation. Hence, P-KLAK might induce U87 cell death by autophagy blockage due to lysosome impairment as well as mitochondria damage synergistically.
Asunto(s)
Neoplasias/tratamiento farmacológico , Péptidos/química , Polímeros/química , Autofagosomas/metabolismo , Autofagia/efectos de los fármacos , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Lisosomas/efectos de los fármacos , Mitocondrias/patología , Factor 2 Relacionado con NF-E2 , Neoplasias/patología , Estrés Oxidativo , Péptidos/uso terapéutico , Polímeros/uso terapéutico , ProteómicaRESUMEN
The stimuli-responsive polymeric nanocarriers have been studied extensively, and their structural changes in cells are important for the controlled intracellular drug release. The present work reported RGD-dextran/purpurin 18 conjugates with pH-responsive phenylboronate as spacer for monitoring the structural change of nanovehicles through ratiometric photoacoustic (PA) signal. Phenylboronic acid modified purpurin 18 (NPBA-P18) could attach onto the RGD-decorated dextran (RGD-Dex), and the resulting RGD-Dex/NPBA-P18 (RDNP) conjugates with different molar ratios of RGD-Dex and NPBA-P18 were prepared. When the moles of NPBA-P18 were equivalent to more than triple of RGD-Dex, the single-stranded RDNP conjugates could self-assemble into nanoparticles in aqueous solution due to the fairly strong hydrophobicity of NPBA-P18. The pH-responsive aggregations of NPBA-P18 were investigated by UV-vis, fluorescence, and circular dichroism spectra, as well as transmission electron microscope. Based on distinct PA signals between monomeric and aggregated state, ratiometric PA signal of I750/I710 could be presented to trace the structural change progress. Compared with RDNP single chains, the nanoparticles exhibited effective cellular internalization through endocytosis pathway. Furthermore, the nanoparticles could form well-ordered aggregates responding to intracellular acidic environment, and the resulting structural change was also monitored by ratiometric PA signal. Therefore, the noninvasive PA approach could provide a deep insight into monitoring the intracellular structural change process of stimuli-responsive nanocarriers.
Asunto(s)
Ácidos Borónicos/química , Citoplasma/química , Dextranos/química , Oligopéptidos/química , Técnicas Fotoacústicas , Porfirinas/química , Portadores de Fármacos , Liberación de Fármacos , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Espectroscopía de Resonancia Magnética , Nanopartículas/química , Polímeros/químicaRESUMEN
In drug delivery systems, pH-sensitive polymers are commonly used as drug carriers, and significant efforts have been devoted to the aspects of controlled delivery and release of drugs. However, few studies address the possible autophagic effects on cells. Here, for the first time, using a fluorescent autophagy-reporting cell line, this study evaluates the autophagy-induced capabilities of four types of pH-sensitive polymeric nanoparticles (NPs) with different physical properties, including size, surface modification, and pH-sensitivity. Based on experimental results, this study concludes that pH-sensitivity is one of the most important factors in autophagy induction. In addition, this study finds that variation of concentration of NPs could cause different autophagic effect, i.e., low concentration of NPs induces autophagy in an mTOR-dependent manner, but high dose of NPs leads to autophagic cell death. Identification of this tunable autophagic effect offers a novel strategy for enhancing therapeutic effect in cancer therapy through modulation of autophagy.
Asunto(s)
Autofagia/efectos de los fármacos , Lisosomas/química , Nanopartículas/química , Polímeros/química , Polímeros/farmacología , Supervivencia Celular/efectos de los fármacos , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Humanos , Concentración de Iones de Hidrógeno , Células MCF-7RESUMEN
One of the major challenges in current cancer therapy is to maximize therapeutic effect and evaluate tumor progression under the scheduled treatment protocol. To address these challenges, we synthesized the cytotoxic peptide (KLAKLAK)2 (named KLAK) conjugated amphiphilic poly(ß-thioester)s copolymers (H-P-K) composed of reactive oxygen species (ROS) sensitive backbones and hydrophilic polyethylene glycol (PEG) side chains. H-P-K could self-assemble into micelle-like nanoparticles by hydrophobic interaction with copolymer backbones as cores and PEG and KLAK as shells. The assembled polymer-peptide nanoparticles remarkably improved cellular internalization and accumulation of therapeutic KLAK in cells. Compared to free KLAK peptide, the antitumor activity of H-P-K was significantly enhanced up to â¼400 times, suggesting the effectiveness of the nanoscaled polymer-peptide conjugation as biopharmaceuticals. The higher antitumor activity of nanoparticles was attributed to the efficient disruption of mitochondrial membranes and subsequent excessive ROS production in cells. To realize the ROS monitoring and treatment evaluation, we encapsulated squaraine (SQ) dyes as built-in reporters in ROS-sensitive H-P-K micelles. The overgenerated ROS around mitochondria stimulated the swelling of nanoparticles and subsequent release of SQ, which formed H-aggregates and significantly increased the photoacoustic (PA) signal. We believed that this self-assembled polymer-peptide nanotherapeutics incorporating built-in reporters has great potential for high antitumor performance and in situ treatment evaluation.
Asunto(s)
Ciclobutanos/química , Neoplasias/tratamiento farmacológico , Fragmentos de Péptidos/uso terapéutico , Fenoles/química , Polímeros/uso terapéutico , Especies Reactivas de Oxígeno/metabolismo , Apoptosis/efectos de los fármacos , Portadores de Fármacos/química , Sistemas de Liberación de Medicamentos , Humanos , Micelas , Nanopartículas/administración & dosificación , Nanopartículas/química , Estrés Oxidativo/efectos de los fármacos , Fragmentos de Péptidos/química , Polietilenglicoles/química , Polímeros/química , Resultado del TratamientoRESUMEN
Various nanomaterials have been demonstrated as autophagy inducers owing to their endocytosis cell uptake pathway and impairment of lysosomes. pH-dependent nanomaterials as drug delivery systems that are capable of dissociating in weakly acidic lysosomal environment (pH 4-5) and consequently releasing the payloads into the cytoplasm have been paid extensive attention, but their autophagy-modulating effects are less reported so far. In this study, we report pH-sensitive micelle-like nanoparticles (NPs) that self-assembled from poly(ß-amino ester)s to induce cell autophagy. By encapsulation of gold(I) compounds (Au(I)) into hydrophobic domains of NPs, the resultant Au(I)-loaded NPs (Au(I)âNPs) shows synergistic cancer cell killing performance. The Au(I)âNPs enter cells through endocytosis pathway and accumulate into acidic lysosomes. Subsequently, the protonation of tertiary amines of poly(ß-amino ester)s triggers the dissociation of micelles, damages the lysosomes, and blocks formation of autolysosomes from fusion of lysosomes with autophagosomes. In addition, Au(I) preferentially inhibits thioredoxin reductase (TrxR) in MCF-7 human breast cancer cells that directly links to up-regulate reactive oxygen species (ROS) and consequently induce autophagy and apoptosis. The blockade of autophagy leads to excessive depletion of cellular organelles and essential proteins and ultimately results in cell death. Therefore, pH-sensitive polymeric nanoparticles with gold(I) compound payloads can synergistically induce cancer cell death through regulation of autophagy. Identification of the pH-sensitive nanomaterials for synergistically inducing cell death through regulation autophagy may open a new avenue for cancer therapy.
Asunto(s)
Apoptosis/efectos de los fármacos , Autofagia/efectos de los fármacos , Sistemas de Liberación de Medicamentos , Oro/química , Nanopartículas del Metal/química , Polímeros/química , Línea Celular Tumoral , Portadores de Fármacos/química , Humanos , Concentración de Iones de Hidrógeno , Interacciones Hidrofóbicas e Hidrofílicas , Lisosomas/metabolismo , Células MCF-7 , Micelas , Fagosomas/metabolismo , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Supramolecular self-assemblies with various nanostructures in organic and aqueous solutions have been prepared with desired functions. However, in situ construction of self-assembled superstructures in physiological conditions to achieve expected biological functions remains a challenge. Here, we report a supramolecular system to realize the in situ formation of nanoaggregates in living cells. The bis(pyrene) monomers were dispersed inside of hydrophobic domains of pH-sensitive polymeric micelles and delivered to the lysosomes of cells. In the acidic lysosomes, the bis(pyrene) monomers were released and self-aggregated with turn-on fluorescence. We envision this strategy for in situ construction of supramolecular nanostructures in living cells will pave the way for molecular diagnostics in the future.
Asunto(s)
Técnicas Citológicas/métodos , Colorantes Fluorescentes/química , Nanoestructuras/química , Polímeros/química , Pirenos/química , Colorantes Fluorescentes/metabolismo , Células HeLa , Humanos , Concentración de Iones de Hidrógeno , Polímeros/metabolismo , Pirenos/metabolismoRESUMEN
For the purpose of near-infrared (NIR) fluorescence and photoacoustic (PA) tomography dual-modular imaging, self-assembly of squaraine (SQ) dyes is constructed in the hydrophobic phospholipid bilayers of liposomes (SQâL) with variable mixing ratios of SQ and phospholipids from 1:500 to 1:10 (w/w). When doping minimal amounts of SQ, molecularly dispersed SQ in bilayers shows remarkable fluorescence. Interesting, the PA signal is enhanced with increase of SQ in the nanoconfined bilayer region, which is attributed to the formation of SQ-based H-aggregates and enhanced thermal conversion efficiency (η). SQâL shows satisfactory chemical and thermal stabilities and photobleaching resistance. SQâL is well-distributed in the cytoplasm of MCF-7 cells and its fluorescence signal remains for 7 days without dramatic quenching owing to the good stability of SQâL. Furthermore, SQâL is subjected to in vivo NIR fluorescence imaging to evaluate the whole-body biodistribution in organ level. Particularly, PA imaging with deeper tissue penetration capability is utilized to investigate the heterogeneous distribution SQâL inside solid tumor. The majority of SQâL are enriched in the area where the blood vessels are generated, implying that the liposomal nanocarriers exhibit lower tumor tissue penetration capability after the vascular leakage. This result is validated by histological examination of tumor tissue in parallel.
Asunto(s)
Ciclobutanos/química , Rayos Infrarrojos , Nanoestructuras , Imagen Óptica/métodos , Fenoles/química , Técnicas Fotoacústicas/métodos , Animales , Ciclobutanos/farmacocinética , Femenino , Colorantes Fluorescentes/química , Colorantes Fluorescentes/farmacocinética , Humanos , Interacciones Hidrofóbicas e Hidrofílicas , Imagenología Tridimensional , Liposomas , Células MCF-7 , Neoplasias Mamarias Experimentales/diagnóstico , Ratones , Modelos Moleculares , Conformación Molecular , Fenómenos Ópticos , Fenoles/farmacocinética , Fosfolípidos/químicaRESUMEN
Cancer is a severe threat to humans, as it is the second leading cause of death after cardiovascular diseases and still poses the biggest challenge in the world of medicine. Due to its higher mortality rates and resistance, it requires a more focused and productive approach to provide the solution for it. Many therapies promising to deliver favorable results, such as chemotherapy and radiotherapy, have come up with more negatives than positives. Therefore, a new class of medicinal solutions and a more targeted approach is of the essence. This review highlights the alluring properties, configurations, and self-assembly of peptide molecules which benefit the traditional approach toward cancer therapy while sparing the healthy cells in the process. As targeted drug delivery systems, self-assembled peptides offer a wide spectrum of conjugation, biocompatibility, degradability-controlled responsiveness, and biomedical applications, including cancer treatment and cancer imaging.
Asunto(s)
Neoplasias , Péptidos , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/diagnóstico por imagen , Péptidos/uso terapéutico , Péptidos/química , Sistemas de Liberación de Medicamentos/métodos , Animales , Antineoplásicos/uso terapéutico , Antineoplásicos/química , Antineoplásicos/farmacologíaRESUMEN
Biomacromolecules, such as proteins, nucleic acids and polysaccharides, are widely distributed in the human body, and some of them have been recognized as the targets of drugs for disease theranostics. Drugs typically act on targets in two ways: non-covalent bond and covalent bond. Non-covalent bond-based drugs have some disadvantages, such as structural instability and environmental sensitivity. Covalent interactions between drugs and targets have a longer action time, higher affinity and controllability than non-covalent interactions of conventional drugs. With the development of artificial intelligence, covalent drugs have received more attention and have been developed rapidly in pharmaceutical research in recent years. From the perspective of covalent drugs, this review summarizes the design methods and the effects of covalent drugs. Finally, we discuss the application of covalent peptide drugs and expect to provide a new reference for cancer treatment.