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1.
ACS Appl Mater Interfaces ; 15(35): 41817-41827, 2023 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-37622994

RESUMO

To achieve efficient gene delivery in vitro or in vivo, nonviral vectors should have excellent biostability across cellular and tissue barriers and also smart stimuli responsiveness toward controlled release of therapeutic genes into the cell nucleus. However, it remains a key challenge to effectively combine the biostability of covalent polymers with the stimuli responsiveness of noncovalent polymers into one nonviral vehicle. In this work, we report the construction of a kind of cationic supramolecular block copolymers (SBCs) through noncovalent polymerization of ß-cyclodextrin/azobenzene-terminated pentaethylenehexamine (DMA-Azo-PEHA-ß-CD) in aqueous media using ß-CD-monosubstituted poly(ethylene glycol) (PEG-ß-CD) as a supramolecular initiator. The resultant SBC exhibits superior biostability, biocompatibility, and light/pH dual-responsive characteristics, and it also demonstrates efficient plasmid DNA condensation capacity and the ability to rapidly release plasmid DNA into cells driven by visible light (450 nm). Eventually, this SBC-based delivery system demonstrates visible light-induced enhancement of gene delivery in both COS-7 and HeLa cells. We anticipate that this work provides a facile and robust strategy to enhance gene delivery in vitro or in vivo via visible light-guided manipulation of genes, further achieving safe, highly efficient, targeting gene therapy for cancer.


Assuntos
Técnicas de Transferência de Genes , Luz , Polímeros , Células HeLa , Humanos , Polietilenoglicóis , Células COS , Animais , Chlorocebus aethiops , Células MCF-7
2.
Biomater Sci ; 11(8): 2809-2817, 2023 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-36826224

RESUMO

Specific cancer diagnosis at an early stage plays a significant role in preventing cancer metastasis and reducing cancer mortality. Thus, exploring specific and sensitive fluorescent probes to realize early cancer diagnosis is an urgent need in clinic. Aminopeptidase N (APN/CD13), overexpressed in numerous malignant tumors, is an important tumor biomarker associated with cancer progression, invasion, and metastasis. In this study, a novel fluorescent molecule APN-SUB, capable of monitoring APN in real time, is encapsulated in a pH-responsive block copolymer (termed APN-SUB nanoprobe) for cancer diagnosis. APN-SUB contains a fluorophore center and a trigger moiety (leucine group), which is covalently conjugated on the fluorophore with an amide bond. The hydrolysis of the amide bond in APN-SUB activated by APN leads to a red shift of maximum fluorescence emission wavelength from 495 nm to 600 nm, realizing dual-color transformation from green to red. Moreover, the APN-SUB nanoprobe with pH-responsiveness is prepared to improve the accumulation and the release rate in the tumor region. It is worth noting that the APN-SUB nanoprobe exhibits good performance for APN imaging, namely, superior limit of detection (0.14 nU mL-1), excellent selectivity and strong photostability. More importantly, the APN-SUB nanoprobe can be successfully employed as a color-convertible fluorescent probe for cancer diagnosis by tracking the activity of APN with high specificity and sensitivity in vivo, demonstrating its potential value for cancer diagnosis.


Assuntos
Corantes Fluorescentes , Neoplasias , Humanos , Corantes Fluorescentes/química , Antígenos CD13
3.
J Mater Chem B ; 8(36): 8219-8231, 2020 09 23.
Artigo em Inglês | MEDLINE | ID: mdl-32803207

RESUMO

Supramolecular block copolymers (SBCs) have received considerable interest in polymer chemistry, materials science, biomedical engineering and nanotechnology owing to their unique structural and functional advantages, such as low cytotoxicity, outstanding biodegradability, smart environmental responsiveness, and so forth. SBCs comprise two or more different homopolymer subunits linked by noncovalent bonds, and these polymers, in particular, combine the dynamically reversible nature of supramolecular polymers with the hierarchical microphase-separated structures of block polymers. A rapidly increasing number of publications on the synthesis and applications of SBCs have been reported in recent years; however, a systematic summary of the design, synthesis, properties and applications of SBCs has not been published. To this end, this review provides a brief overview of the recent advances in SBCs and describes the synthesis strategies, properties and functions, and their widespread applications in drug delivery, gene delivery, protein delivery, bioimaging and so on. In this review, we aim to elucidate the general concepts and structure-property relationships of SBCs, as well as their practical bioapplications, shedding further valuable insights into this emerging research field.


Assuntos
Polímeros/química , Animais , Sistemas de Liberação de Medicamentos/métodos , Técnicas de Transferência de Genes , Humanos , Polímeros/síntese química , Medicina de Precisão/métodos
4.
Biomater Sci ; 8(2): 694-701, 2020 Jan 21.
Artigo em Inglês | MEDLINE | ID: mdl-31777870

RESUMO

Despite the great advances achieved in hypoxia-associated tumor therapy, the efficacy of hypoxia-activated prodrugs alone is usually limited owing to the moderate oxygen supply at the tumor area. Herein, we develop a polymerized platinum(iv) compound-based nanogel (polyprodrug) containing a bioreductive and hypoxia-activated prodrug (tirapazamine, TPZ) as a prodrug combo (polyprodrug@TPZ) for synergistic chemotherapy. Upon exposure to the tumor microenvironment, platinum(iv) moieties in the polyprodrug are reduced to platinum(ii) species, which significantly upregulates the expression of NADPH oxidases (NOXs) to accelerate oxygen (O2) depletion and promote reactive oxygen species (ROS) production, as confirmed by reverse transcription-PCR (RT-PCR) and fluorescence probes. In the exaggerated hypoxia environment, highly cytotoxic radicals are generated due to TPZ activation, which serve as second antitumor agents working together with platinum(ii) species in synergistic chemotherapy. With the rational design of nanosized architecture, the platinum(iv)-based polyprodrug@TPZ complex exhibits the advantages of redox-responsive drug release, superior tumor accumulation, and long-term circulation during the synergistic antitumor treatment in a mouse model. These results indicate that combination of an oxygen depletion prodrug and hypoxia-activated antitumor agents would serve as a promising strategy to realize a better synergistic chemotherapy.


Assuntos
Antineoplásicos/farmacologia , Compostos Organoplatínicos/farmacologia , Pró-Fármacos/farmacologia , Tirapazamina/farmacologia , Hipóxia Tumoral/efeitos dos fármacos , Células A549 , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Quimioterapia Combinada , Humanos , Compostos Organoplatínicos/química , Oxigênio/metabolismo , Pró-Fármacos/química , Espécies Reativas de Oxigênio/metabolismo , Tirapazamina/química
5.
Chem Commun (Camb) ; 55(47): 6735-6738, 2019 Jun 06.
Artigo em Inglês | MEDLINE | ID: mdl-31119236

RESUMO

A near-infrared (NIR)-sensitive gated assembly of supramolecular conjugated unimicelles based on robust host-guest recognition between a ß-cyclodextrin-grafted hyperbranched conjugated polymer and azobenzene-functionalized poly(ethylene glycol) was constructed. Utilized as a drug carrier, these unimicelles exhibited controlled drug release through the NIR-triggered photoisomerization of azobenzene in cancer cells via a two-photon excited fluorescence resonance energy transfer (TP-FRET) approach, leading to efficient cancer therapy.


Assuntos
Doxorrubicina/metabolismo , Portadores de Fármacos/química , Raios Infravermelhos , Micelas , Compostos Azo/química , Doxorrubicina/química , Liberação Controlada de Fármacos , Transferência Ressonante de Energia de Fluorescência , Células HeLa , Humanos , Isomerismo , Microscopia Confocal , Fótons , Polietilenoglicóis/química , Polímeros/química , beta-Ciclodextrinas/química
6.
Biomater Sci ; 7(1): 336-346, 2018 Dec 18.
Artigo em Inglês | MEDLINE | ID: mdl-30474655

RESUMO

Cationic gelatin nanoparticles ((+)nGNPs) were prepared by in situ polymerization upon the surfaces of monodispersed gelatin nanoparticles (GNPs) using N-(3-Aminopropyl)methacrylamide (APm) as monomer, which were then decorated with doxorubicin terminated poly(2-methylacryloyloxyethyl phosphorylcholine) (DOX-pMPC) via EDC/NHS conjugation to obtain core-shell nanoparticles ((+)nGNPs@DOX-pMPC) for cancer therapy. The non-fouling pMPC shell could effectively shield the positively charged surface of inner nanoparticle and prevent non-specific protein adsorption, thus endowing the materials with potential for long-acting cancer treatment. Furthermore, the acyl hydrazone bond connecting DOX and pMPC chain could be easily hydrolyzed in the weakly acidic tumor microenvironment. After decladding of the pMPC shell, electropositive (+)nGNPs carrying the drugs can be effectively internalized by cancer cells to induce apoptosis, avoiding undesirable hindrance caused by the superhydrophilic outer layer. On combining the above properties, this drug delivery system can be a promising candidate for long-acting, low-toxicity and high-efficiency cancer therapy.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Apoptose/efeitos dos fármacos , Preparações de Ação Retardada/química , Doxorrubicina/administração & dosagem , Gelatina/química , Nanopartículas/química , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Incrustação Biológica/prevenção & controle , Preparações de Ação Retardada/metabolismo , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Gelatina/metabolismo , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Hidrólise , Nanopartículas/metabolismo , Microambiente Tumoral/efeitos dos fármacos
7.
ACS Appl Mater Interfaces ; 10(31): 26005-26015, 2018 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-30001103

RESUMO

Glucose oxidase (GOx) has seen large-scale technological applications, and the determinations of its activity that is directly related to the enzymatic functions are extremely important. However, conventional methods to analyze the enzymatic activity involving high oxygen dependency and indirect redox reactions are usually tedious and restricted in complicated environments. For analyzing enzymatic activity by direct detection of the electron signals from the active centers, mediators are often used for facilitating the electron transfer. Differing from common methods of preparing electron mediators-contained GOx composites, a strategy aiming at remolding of the enzyme itself has been proposed in this work. Cofactor-like molecule 2'-diallyamino-ethyl flavin (DAA-flavin) derived from riboflavin is synthesized and incorporated as cross-linker into the polyacrylamide (PAAm) network around GOx surface by in situ polymerization to obtain enzyme nanocapsules termed as GOx@Fla-c-PAAm. The peripheral polymer shell confines the orientation of GOx and prevents it from denaturing, whereas incorporated DAA-flavin can replace the oxygen as an alternative electron acceptor to interact with the active centers of GOx in the presence of the substrate, thus giving the nanocapsules oxygen-independent characteristics. The introduced unlimited cofactor-like molecules endow the nanocapsules redox-related fluorescence, and the intensity variation is closely correlated with the enzymatic activity. There is a high goodness of fitting ( R2 ∼ 0.990) between the slope of linear fluorescence-time plots and enzymatic activity, thereby making the nanocapsules a reliable activity-reporting enzymatic nanosystem with oxygen-independent fluorescence variation for further extended potential application in biofuel cells and biosensors.


Assuntos
Nanocápsulas , Fontes de Energia Bioelétrica , Técnicas Biossensoriais , Enzimas Imobilizadas , Glucose , Glucose Oxidase , Oxigênio
8.
Biomaterials ; 177: 67-77, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29885587

RESUMO

A combinatorial therapy that utilizes two or more therapeutic modalities is more effective in overcoming the limitations than each individual method used alone. Despite great advances have been achieved, the combination of chemotherapy and photodynamic therapy (PDT) still cannot satisfy the clinic requirements as the antitumor efficacy could be severely affected by tumor-associated hypoxia. Herein, for the first time, we reported a platinum(IV) complex-based polyprodrug that can in situ generate the highly toxic platinum(II) species as chemotherapeutics and simultaneously induce a high level of reactive oxygen species (ROS) in a PDT-like process without the use of photosensitizer and consumption of oxygen. By in situ polymerizing the platinum(IV) complex-based prodrug monomer (PPM) and 2-methacryloyloxy ethyl phosphorylcholine (MPC), nanosized hydrogel-like polyprodrug could be synthesized. Upon being exposed to light, Pt(IV) moieties in this photoactivable polyprodrug were reduced to generate Pt(II) species. At the meantime, a high level of ROS was generated without the presence of endogenous oxygen, which was confirmed by electron spin resonance (ESR) and fluorescence probes. With the unique nanosized architecture and photoresponsive feature, the as-synthesized polyprodrug exhibited the advantages of sustained drug release, long-term circulation, preferable tumor accumulation, and reversing drug resistance by downregulating the expression of multidrug resistance-associated protein 1 (MRP1) in the anticancer treatment.


Assuntos
Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Compostos Organoplatínicos/uso terapêutico , Pró-Fármacos/uso terapêutico , Células A549 , Animais , Antineoplásicos/química , Antineoplásicos/farmacocinética , Humanos , Camundongos Endogâmicos BALB C , Neoplasias/metabolismo , Neoplasias/patologia , Compostos Organoplatínicos/química , Compostos Organoplatínicos/farmacocinética , Fotoquimioterapia , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Oxigênio Singlete/metabolismo , Hipóxia Tumoral/efeitos dos fármacos
9.
Chem Commun (Camb) ; 53(95): 12782-12785, 2017 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-29139491

RESUMO

A class of cationic supramolecular block copolymers with readily controlled charges has been exploited. Upon post-synthetic structural optimization, this copolymer exhibits comparable biocompatibility, greatly improved pDNA condensation capability and biostability, and further enhanced transfection efficiency in vitro. This work provides valuable insight into the creation of advanced nonviral vectors for gene delivery.


Assuntos
DNA/genética , Etilenodiaminas/química , Técnicas de Transferência de Genes , Polímeros/química , Animais , Células COS , Cátions/química , Cátions/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Chlorocebus aethiops , Etilenodiaminas/farmacologia , Vetores Genéticos/química , Células HeLa , Humanos , Células MCF-7 , Substâncias Macromoleculares/química , Substâncias Macromoleculares/farmacologia , Plasmídeos , Polímeros/farmacologia , Transfecção
10.
ACS Appl Mater Interfaces ; 9(10): 9006-9014, 2017 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-28233991

RESUMO

The design and fabrication of safe and highly efficient nonviral vectors is the key scientific issue for the achievement of clinical gene therapy. Supramolecular cationic polymers have unique structures and specific functions compared to covalent cationic polymers, such as low cytotoxicity, excellent biodegradability, and smart environmental responsiveness, thereby showing great application prospect for gene therapy. However, supramolecular gene vectors are facile to be degraded under physiological conditions, leading to a significant reduction of gene transfection efficiency. In order to achieve highly efficient gene expression, it is necessary for supramolecular gene vectors being provided with appropriate biostability to overcome various cell obstacles. To this end, a novel cationic supramolecular block copolymer composed of a conventional polymer and a noncovalent polymer was constructed through robust ß-cyclodextrin/ferrocene host-guest recognition. The resultant supramolecular block copolymer perfectly combines the advantages of both conventional polymers and supramolecular polymers ranging from structures to functions. This supramolecular copolymer not only has the ability to effectively condense pDNA for enhanced cell uptake, but also releases pDNA inside cancer cells triggered by H2O2, which can be utilized as a prospective nonviral delivery vehicle for gene delivery. The block polymer exhibited low cytotoxicity, good biostability, excellent biodegradability, and intelligent responsiveness, ascribing to the dynamic/reversible nature of noncovalent linkages. In vitro studies further illustrated that the supramolecular block polymer exhibited greatly improved gene transfection efficiency in cancer cells. This work offers an alternative platform for the exploitation of smart nonviral vehicles for specific cancer gene therapy in the future.


Assuntos
Técnicas de Transferência de Genes , Cátions , Peróxido de Hidrogênio , Polímeros , Transfecção
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