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1.
J Am Chem Soc ; 145(40): 21991-22008, 2023 10 11.
Artigo em Inglês | MEDLINE | ID: mdl-37664981

RESUMO

Senolytics, which eliminate senescent cells from tissues, represent an emerging therapeutic strategy for various age-related diseases. Most senolytics target antiapoptotic proteins, which are overexpressed in senescent cells, limiting specificity and inducing severe side effects. To overcome these limitations, we constructed self-assembling senolytics targeting senescent cells with an intracellular oligomerization system. Intracellular aryl-dithiol-containing peptide oligomerization occurred only inside the mitochondria of senescent cells due to selective localization of the peptides by RGD-mediated cellular uptake into integrin αvß3-overexpressed senescent cells and elevated levels of reactive oxygen species, which can be used as a chemical fuel for disulfide formation. This oligomerization results in an artificial protein-like nanoassembly with a stable α-helix secondary structure, which can disrupt the mitochondrial membrane via multivalent interactions because the mitochondrial membrane of senescent cells has weaker integrity than that of normal cells. These three specificities (integrin αvß3, high ROS, and weak mitochondrial membrane integrity) of senescent cells work in combination; therefore, this intramitochondrial oligomerization system can selectively induce apoptosis of senescent cells without side effects on normal cells. Significant reductions in key senescence markers and amelioration of retinal degeneration were observed after elimination of the senescent retinal pigment epithelium by this peptide senolytic in an age-related macular degeneration mouse model and in aged mice, and this effect was accompanied by improved visual function. This system provides a strategy for the treatment of age-related diseases using supramolecular senolytics.


Assuntos
Senescência Celular , Senoterapia , Camundongos , Animais , Espécies Reativas de Oxigênio , Peptídeos/farmacologia , Integrinas
2.
J Am Chem Soc ; 144(12): 5503-5516, 2022 03 30.
Artigo em Inglês | MEDLINE | ID: mdl-35235326

RESUMO

Biological nanomachines, including proteins and nucleic acids whose function is activated by conformational changes, are involved in every biological process, in which their dynamic and responsive behaviors are controlled by supramolecular recognition. The development of artificial nanomachines that mimic the biological functions for potential application as therapeutics is emerging; however, it is still limited to the lower hierarchical level of the molecular components. In this work, we report a synthetic machinery nanostructure in which actuatable molecular components are integrated into a hierarchical nanomaterial in response to external stimuli to regulate biological functions. Two nanometers core-sized gold nanoparticles are covered with ligand layers as actuatable components, whose folding/unfolding motional response to the cellular environment enables the direct penetration of the nanoparticles across the cellular membrane to disrupt intracellular organelles. Furthermore, the pH-responsive conformational movements of the molecular components can induce the apoptosis of cancer cells. This strategy based on the mechanical motion of molecular components on a hierarchical nanocluster would be useful to design biomimetic nanotoxins.


Assuntos
Fenômenos Biológicos , Nanopartículas Metálicas , Nanoestruturas , Membrana Celular , Ouro , Nanoestruturas/toxicidade
3.
Chembiochem ; 22(24): 3391-3397, 2021 12 10.
Artigo em Inglês | MEDLINE | ID: mdl-34580971

RESUMO

Cellular senescence, a stable form of cell cycle arrest, facilitates protection from tumorigenesis and aids in tissue repair as they accumulate in the body at an early age. However, long-term retention of senescent cells causes inflammation, aging of the tissue, and progression of deadly diseases such as obesity, diabetes, and atherosclerosis. Various attempts have been made to achieve selective elimination of senescent cells from the body, yet little has been explored in designing the mitochondria-targeted senolytic agent. Many characteristics of senescence are associated with mitochondria. Here we have designed a library of alkyl-monoquaternary ammonium-triphenyl phosphine (TPP) and alkyl-diquaternary ammonium-TPP of varying alkyl chain lengths, which target the mitochondria; we also studied their senolytic properties. It was observed that the alkyl-diquaternary ammonium-TPP with the longest chain length induced apoptosis in senescent cells selectively via an increase of reactive oxygen species (ROS) and mitochondrial membrane disruption. This study demonstrates that mitochondria could be a potential target for designing new small molecules as senolytic agents for the treatment of a variety of dysfunctions associated with pathological aging.


Assuntos
Antineoplásicos/farmacologia , Membranas Mitocondriais/efeitos dos fármacos , Compostos de Amônio/química , Compostos de Amônio/farmacologia , Animais , Antineoplásicos/química , Apoptose/efeitos dos fármacos , Derivados de Benzeno/química , Derivados de Benzeno/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Senescência Celular/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Células HEK293 , Humanos , Camundongos , Estrutura Molecular , Células NIH 3T3 , Fosfinas/química , Fosfinas/farmacologia
4.
Chemistry ; 26(47): 10695-10701, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32428292

RESUMO

The development of photosensitizers for cancer photodynamic therapy has been challenging due to their low photostability and therapeutic inefficacy in hypoxic tumor microenvironments. To overcome these issues, we have developed a mitochondria-targeted photosensitizer consisting of an indocyanine moiety with triphenylphosphonium arms, which can self-assemble into spherical micelles directed to mitochondria. Self-assembly of the photosensitizer resulted in a higher photostability by preventing free rotation of the indoline ring of the indocyanine moiety. The mitochondria targeting capability of the photosensitizer allowed it to utilize intramitochondrial oxygen. We found that the mitochondria-targeted photosensitizer localized to mitochondria and induced apoptosis of cancer cells both normoxic and hypoxic conditions through generation of ROS. The micellar self-assemblies of the photosensitizer were further confirmed to selectively localize to tumor tissues in a xenograft tumor mouse model through passive targeting and showed efficient tumor growth inhibition.


Assuntos
Hipóxia Celular/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Fotoquimioterapia , Fármacos Fotossensibilizantes/síntese química , Fármacos Fotossensibilizantes/uso terapêutico , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Fármacos Fotossensibilizantes/farmacocinética , Fármacos Fotossensibilizantes/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
5.
Biomacromolecules ; 19(7): 3030-3039, 2018 07 09.
Artigo em Inglês | MEDLINE | ID: mdl-29883544

RESUMO

Current drug delivery systems are hampered by poor delivery to tumors, in part reflecting poor encapsulation stability of nanocarriers. Although nanocarriers such as polymeric micelles have high colloidal stability and do not aggregate or precipitate in bulk solution, nanocarriers with low encapsulation stability can lose their cargo during circulation in blood due to interactions with blood cells, cellular membranes, serum proteins, and other biomacromolecules. The resulting premature drug release from carriers limits the therapeutic efficacy at target sites. Herein, we report a simple and robust technique to improve encapsulation stability of drug delivery systems. Specifically, we show that installation of disulfide cross-linked noncovalent polymer gatekeepers onto mesoporous silica nanoparticles with a high loading capacity for hydrophobic drugs enhances in vivo therapeutic efficacy by preventing premature release of cargo. Subsequent release of drug cargos was triggered by cleavage of disulfide cross-linking by glutathione, leading to improved antitumor activity of doxoroubicin in mice. These findings provide novel insights into the development of nanocarriers with high encapsulation stability and improved in vivo therapeutic efficacy.


Assuntos
Nanocápsulas/química , Animais , Antineoplásicos/administração & dosagem , Coloides/química , Reagentes de Ligações Cruzadas/química , Doxorrubicina/administração & dosagem , Feminino , Células HeLa , Humanos , Camundongos , Camundongos Nus , Micelas , Nanocápsulas/efeitos adversos , Nanocápsulas/normas , Dióxido de Silício/química
6.
Org Biomol Chem ; 13(8): 2474-2479, 2015 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-25569869

RESUMO

Prolonged retention of internalized nanoparticulate systems inside cells improves their efficacy in imaging, drug delivery, and theranostic applications. Especially, regulating exocytosis of the nanoparticles is a key factor in the fabrication of effective nanocarriers for chemotherapeutic treatments but orthogonal control of exocytosis in the cellular environment is a major challenge. Herein, we present the first example of regulating exocytosis of gold nanoparticles (AuNPs), a model drug carrier, by using a simple host-guest supramolecular system. AuNPs featuring quaternary amine head groups were internalized into the cells through endocytosis. Subsequent in situ treatment of a complementary cucurbit[7]uril (CB[7]) to the amine head groups resulted in the AuNP-CB[7] complexation inside cells, rendering particle assembly. This complexation induced larger particle assemblies that remained sequestered in the endosomes, inhibiting exocytosis of the particles without any observed cytotoxicity.


Assuntos
Portadores de Fármacos/química , Portadores de Fármacos/metabolismo , Exocitose , Nanopartículas Metálicas/química , Aminas/química , Hidrocarbonetos Aromáticos com Pontes/química , Endossomos/metabolismo , Ouro/química , Ouro/metabolismo , Humanos , Imidazóis/química , Células MCF-7
7.
Acc Chem Res ; 46(3): 681-91, 2013 Mar 19.
Artigo em Inglês | MEDLINE | ID: mdl-23294365

RESUMO

Surface properties dictate the behavior of nanomaterials in vitro, in vivo, and in the environment. Such properties include surface charge and hydrophobicity. Also key are more complex supramolecular interactions such as aromatic stacking and hydrogen bonding, and even surface topology from the structural to the atomic level. Surface functionalization of nanoparticles (NPs) provides an effective way to control the interface between nanomaterials and the biological systems they are designed to interact with. In medicine, for instance, proper control of surface properties can maximize therapeutic or imaging efficacy while minimizing unfavorable side effects. Meanwhile, in environmental science, thoughtful choice of particle coating can minimize the impact of manufactured nanomaterials on the environment. A thorough knowledge of how NP surfaces with various properties affect biological systems is essential for creating NPs with such useful therapeutic and imaging properties as low toxicity, stability, biocompatibility, favorable distribution throughout cells or tissues, and favorable pharmacokinetic profiles--and for reducing the potential environmental impact of manufactured nanomaterials, which are becoming increasingly prominent in the marketplace. In this Account, we discuss our research and that of others into how NP surface properties control interactions with biomolecules and cells at many scales, including the role the particle surface plays in determining in vivo behavior of nanomaterials. These interactions can be benign, beneficial, or lead to dysfunction in proteins, genes and cells, resulting in cytotoxic and genotoxic responses. Understanding these interactions and their consequences helps us to design minimally invasive imaging and delivery agents. We also highlight in this Account how we have fabricated nanoparticles to act as therapeutic agents via tailored interactions with biomacromolecules. These particles offer new therapeutic directions from traditional small molecule therapies, and with potentially greater versatility than is possible with proteins and nucleic acids.


Assuntos
Nanopartículas/toxicidade , Animais , Sobrevivência Celular/efeitos dos fármacos , DNA/química , Ouro/química , Bicamadas Lipídicas/intoxicação , Modelos Biológicos , Nanopartículas/química , Nanoestruturas , Propriedades de Superfície
8.
Commun Biol ; 5(1): 722, 2022 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-35859009

RESUMO

Cellular senescence of the retinal pigment epithelium (RPE) is thought to play an important role in vision-threatening retinal degenerative diseases, such as age-related macular degeneration (AMD). However, the single-cell RNA profiles of control RPE tissue and RPE tissue exhibiting cellular senescence are not well known. We have analyzed the single-cell transcriptomes of control mice and mice with low-dose doxorubicin (Dox)-induced RPE senescence (Dox-RPE). Our results have identified 4 main subpopulations in the control RPE that exhibit heterogeneous biological activities and play roles in ATP synthesis, cell mobility/differentiation, mRNA processing, and catalytic activity. In Dox-RPE mice, cellular senescence mainly occurs in the specific cluster, which has been characterized by catalytic activity in the control RPE. Furthermore, in the Dox-RPE mice, 6 genes that have not previously been associated with senescence also show altered expression in 4 clusters. Our results might serve as a useful reference for the study of control and senescent RPE.


Assuntos
Degeneração Macular , Epitélio Pigmentado da Retina , Animais , Senescência Celular/genética , Doxorrubicina/farmacologia , Degeneração Macular/metabolismo , Camundongos , Epitélio Pigmentado da Retina/metabolismo , Transcriptoma
9.
ACS Nano ; 15(9): 14492-14508, 2021 09 28.
Artigo em Inglês | MEDLINE | ID: mdl-34478266

RESUMO

Recent advances in supramolecular chemistry research have led to the development of artificial chemical systems that can form self-assembled structures that imitate proteins involved in the regulation of cellular function. However, intracellular polymerization systems that operate inside living cells have been seldom reported. In this study, we developed an intramitochondrial polymerization-induced self-assembly system for regulating the cellular fate of cancer cells. It showed that polymeric disulfide formation inside cells occurred due to the high reactive oxygen species (ROS) concentration of cancer mitochondria. This polymerization barely occurs elsewhere in the cell owing to the reductive intracellular environment. The polymerization of the thiol-containing monomers further increases the ROS level inside the mitochondria, thereby autocatalyzing the polymerization process and creating fibrous polymeric structures. This process induces dysfunction of the mitochondria, which in turn activates cell necroptosis. Thus, this in situ polymerization system shows great potential for cancer treatment, including that of drug-resistant cancers.


Assuntos
Dissulfetos , Neoplasias , Neoplasias/tratamento farmacológico , Polimerização
10.
Geroscience ; 43(6): 2809-2833, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34601706

RESUMO

Although age-related macular degeneration (AMD) is a multifactorial disorder with angiogenic, immune, and inflammatory components, the most common clinical treatment strategies are antiangiogenic therapies. However, these strategies are only applicable to neovascular AMD, which accounts for less than 20% of all AMD cases, and there are no FDA-approved drugs for the treatment of dry AMD, which accounts for ~ 80% of AMD cases. Here, we report that the elimination of senescent cells is a potential novel therapeutic approach for the treatment of all types of AMD. We identified senescent retinal pigment epithelium (RPE) cells in animal models of AMD and determined their contributions to retinal degeneration. We further confirmed that the clearance of senescent RPE cells with the MDM2-p53 inhibitor Nutlin-3a ameliorated retinal degeneration. These findings provide new insights into the use of senescent cells as a therapeutic target for the treatment of AMD.


Assuntos
Epitélio Pigmentado da Retina , Degeneração Macular Exsudativa , Inibidores da Angiogênese , Animais , Células Epiteliais , Camundongos , Pigmentos da Retina , Acuidade Visual
11.
J Mater Chem B ; 9(14): 3143-3152, 2021 04 14.
Artigo em Inglês | MEDLINE | ID: mdl-33586760

RESUMO

Drug resistance is a major cause of treatment failure for small-molecule cancer chemotherapies, despite the advances in combination therapies, drug delivery systems, epigenetic drugs, and proteolysis-targeting chimeras. Herein, we report the use of a drug resistance-free cytotoxic nanodrug as an alternative to small-molecule drugs. The present nanodrugs comprise 2 nm core gold nanoparticles (AuNPs) covered completely with multivalent hydrocarbon chains to a final diameter of ∼10 nm as single drug molecules. This hydrophobic drug-platform was delivered in composite form (∼35 nm) with block-copolymer like other small-molecular drugs. Upon uptake by cells, the nanodrugs enhanced the intracellular levels of reactive oxygen species and induced apoptosis, presumably reflecting multivalent interactions between aliphatic chains and intracellular biomolecules. No resistance to our novel nanodrug was observed following multiple treatment passages and the potential for use in cancer therapy was verified in a breast cancer patient-derived xenograft mouse model. These findings provide insight into the use of nano-scaled compounds as agents that evade drug resistance to cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Bibliotecas de Moléculas Pequenas/farmacologia , Animais , Antineoplásicos/síntese química , Antineoplásicos/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaios de Seleção de Medicamentos Antitumorais , Feminino , Ouro/química , Ouro/farmacologia , Humanos , Hidrocarbonetos/química , Hidrocarbonetos/farmacologia , Neoplasias Mamárias Experimentais/tratamento farmacológico , Neoplasias Mamárias Experimentais/patologia , Nanopartículas Metálicas/química , Camundongos , Camundongos Nus , Tamanho da Partícula , Bibliotecas de Moléculas Pequenas/síntese química , Bibliotecas de Moléculas Pequenas/química
13.
ACS Omega ; 3(8): 9276-9281, 2018 Aug 31.
Artigo em Inglês | MEDLINE | ID: mdl-31459059

RESUMO

Protein detection and identification are important for the diagnosis of diseases; however, the development of facile sensing probes still remains challenging. Here, we present an array-based "turn on" protein-sensing platform capable of detecting and identifying proteins using aggregation-induced emission luminogens (AIEgens). The water-soluble AIEgens in which fluorescence was initially turned off showed strong fluorescence in the presence of nanomolar concentrations of proteins via restriction of the intramolecular rotation of the AIEgens. The binding affinities between the AIEgens and proteins were associated with various chemical functional groups on AIEgens, resulting in distinct fluorescent-signal outcomes for each protein. The combined fluorescence outputs provided sufficient information to detect and discriminate proteins of interest by linear discriminant analysis. Furthermore, the array-based sensor enabled classification of different concentrations of specific proteins. These results provide novel insight into the use of the AIEgens as a new type of sensing probe in array-based systems.

14.
Chem Sci ; 9(9): 2474-2479, 2018 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-29732123

RESUMO

The use of biomineralization that regulates cellular functions has emerged as a potential therapeutic tool. However, the lack of selectivity still limits its therapeutic efficacy. Here, we report a subcellular-targeting biomineralization system featuring a triphenylphosphonium cation (TPP) (the mitochondria-targeting moiety) and trialkoxysilane (the biomineralization moiety via silicification). The TPP-containing trialkoxysilane exhibited approximately seven times greater cellular uptake into cancer cells (SCC7) than into normal cells (HEK293T) due to the more negative mitochondrial membrane potentials of the cancer cells. In turn, its accumulation inside mitochondria (pH 8) induces specific silicification, leading to the formation of silica particles in the mitochondrial matrix and further activation of apoptosis. In vivo assessment confirmed that the biomineralization system efficiently inhibits tumor growth in a mouse xenograft cancer model. Exploiting both the subcellular specificity and the targeting strategy provides new insight into the use of intracellular biomineralization for targeted cancer therapy.

15.
ACS Biomater Sci Eng ; 4(5): 1716-1722, 2018 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-33445328

RESUMO

Systemic administration of mesoporous silica nanoparticles (MSNs) in biomedical applications has recently been questioned because of poor degradability, which is necessary for the successful development of new drug-delivery systems. Herein, we report the development of colloidal-state-degradable MSNs functionalized with versatile polymer-gatekeepers with a cancer-cell-targeted moiety. The polymer MSNs (PMSNs) were designed with disulfide cross-linking enabling safe encapsulation until cargos are delivered to target cancer cells. Selective targeting was achieved by decoration of CD44-receptor-targeting ligands, hyaluronic acid (HA), with HA-PMSNs. The selective cellular uptake mechanism of the fabricated targeted nanocarrier into CD44-overexpressed cancer cells was demonstrated through the clathrin- and macropinocytosis-mediated pathways. Upon internalization into cancer cells, doxorubicin loaded into the HA-PMSNs can be released by degradation of the polymer shells in the reducing intracellular microenvironment that consequentially induces cell death and further degradation of the MSNs. This study offers a simple technique to fabricate a versatile drug carrier with a high drug loading capacity.

16.
Nat Commun ; 9(1): 4548, 2018 10 31.
Artigo em Inglês | MEDLINE | ID: mdl-30382085

RESUMO

Targeted drug delivery using nanoparticles can minimize the side effects of conventional pharmaceutical agents and enhance their efficacy. However, translating nanoparticle-based agents into clinical applications still remains a challenge due to the difficulty in regulating interactions on the interfaces between nanoparticles and biological systems. Here, we present a targeting strategy for nanoparticles incorporated with a supramolecularly pre-coated recombinant fusion protein in which HER2-binding affibody combines with glutathione-S-transferase. Once thermodynamically stabilized in preferred orientations on the nanoparticles, the adsorbed fusion proteins as a corona minimize interactions with serum proteins to prevent the clearance of nanoparticles by macrophages, while ensuring systematic targeting functions in vitro and in vivo. This study provides insight into the use of the supramolecularly built protein corona shield as a targeting agent through regulating the interfaces between nanoparticles and biological systems.


Assuntos
Sistemas de Liberação de Medicamentos , Nanopartículas/química , Coroa de Proteína/química , Animais , Antineoplásicos/farmacologia , Proteínas Sanguíneas/química , Linhagem Celular Tumoral , Feminino , Células HEK293 , Humanos , Camundongos , Camundongos Nus , Ligação Proteica , Proteômica , Células RAW 264.7
17.
Chem Commun (Camb) ; (46): 4887-9, 2007 Dec 14.
Artigo em Inglês | MEDLINE | ID: mdl-18361358

RESUMO

We have synthesized a highly efficient organic dye for a dye-sensitized solar cell; the overall solar-to-energy conversion efficiency was 9.1% at AM 1.5 illumination (100 mW cm(-2)): short-circuit current density (J(sc)) = 18.1 mA cm(-2), open circuit photovoltage (V(oc)) = 743 mV and fill factor (ff) = 0.675.

19.
Sci Rep ; 7: 46540, 2017 04 24.
Artigo em Inglês | MEDLINE | ID: mdl-28436438

RESUMO

Combination chemotherapy has become the primary strategy against cancer multidrug resistance; however, accomplishing optimal pharmacokinetic delivery of multiple drugs is still challenging. Herein, we report a sequential combination drug delivery strategy exploiting a pH-triggerable and redox switch to release cargos from hollow silica nanoparticles in a spatiotemporal manner. This versatile system further enables a large loading efficiency for both hydrophobic and hydrophilic drugs inside the nanoparticles, followed by self-crosslinking with disulfide and diisopropylamine-functionalized polymers. In acidic tumour environments, the positive charge generated by the protonation of the diisopropylamine moiety facilitated the cellular uptake of the particles. Upon internalization, the acidic endosomal pH condition and intracellular glutathione regulated the sequential release of the drugs in a time-dependent manner, providing a promising therapeutic approach to overcoming drug resistance during cancer treatment.


Assuntos
Doxorrubicina , Nanopartículas , Dióxido de Silício , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Células MCF-7 , Nanopartículas/química , Nanopartículas/uso terapêutico , Porosidade , Dióxido de Silício/química , Dióxido de Silício/farmacocinética , Dióxido de Silício/farmacologia
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