RESUMO
Preparation of materials that possess highly strong and tough properties simultaneously is a great challenge. Thermosetting resins as a type of widely used polymeric materials without synergistic strength and toughness limit their applications in some special fields. In this report, an effective strategy to prepare thermosetting resins with synergistic strength and toughness, is presented. In this method, the soft and rigid microspheres with dynamic hemiaminal bonds are fabricated first, followed by hot-pressing to crosslink at the interfaces. Specifically, the rigid or soft microspheres are prepared via precipitation polymerization. After hot-pressing, the resulting rigid-soft blending materials exhibit superior strength and toughness, simultaneously. As compared with the precursor rigid or soft materials, the toughness of the rigid-soft blending films (RSBFs) is improved to 240% and 2100%, respectively, while the strength is comparable to the rigid precursor. As compared with the traditional crushing, blending, and hot-pressing of rigid or soft materials to get the nonuniform materials, the strength and toughness of the RSBFs are improved to 168% and 255%, respectively. This approach holds significant promise for the fabrication of polymer thermosets with a unique combination of strength and toughness.
Assuntos
Polimerização , Resinas Sintéticas/química , Microesferas , Polímeros/química , Temperatura , Teste de Materiais , Propriedades de Superfície , Tamanho da PartículaRESUMO
The multi-drug resistance (MDR) of cancers is one of the main barriers for the success of diverse chemotherapeutic methods and is responsible for most cancer deaths. Developing efficient approaches to overcome MDR is still highly desirable for efficient chemotherapy of cancers. The delivery of targeted anticancer drugs that can interact with mitochondrial DNA is recognized as an effective strategy to reverse the MDR of cancers due to the relatively weak DNA-repairing capability in the mitochondria. Herein, we report on a polyprodrug that can sequentially target cancer cells and mitochondria using folic acid (FA) and tetraphenylphosphonium (TPP) targeting moieties, respectively. They were conjugated to the terminal groups of the amphiphilic block copolymer prodrugs composed of poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA) and copolymerized monomers containing cinnamaldehyde (CNM) and doxorubicin (DOX). After self-assembly into micelles with the suitable size (â¼30 nm), which were termed as TF@CNM + DOX, and upon intravenous administration, the micelles can accumulate in tumor tissues. After FA-mediated endocytosis, the endosomal acidity (â¼pH 5) can trigger the release of CNM from TF@CNM + DOX micelles, followed by enhanced accumulation into the mitochondria via the TPP target. This promotes the overproduction of reactive oxygen species (ROS), which can subsequently enhance the intracellular oxidative stress and trigger ROS-responsive release of DOX into the mitochondria. TF@CNM + DOX shows great potential to inhibit the growth of DOX-resistant MCF-7 ADR tumors without observable side effects. Therefore, the tumor and mitochondria dual-targeting polyprodrug design represents an ideal strategy to treat MDR tumors through improvement of the intracellular oxidative level and ROS-responsive drug release.
Assuntos
Micelas , Neoplasias , Humanos , Liberação Controlada de Fármacos , Espécies Reativas de Oxigênio/metabolismo , Células MCF-7 , Doxorrubicina , Resistência a Múltiplos Medicamentos , Mitocôndrias/metabolismo , Resistencia a Medicamentos Antineoplásicos , Neoplasias/tratamento farmacológico , Neoplasias/metabolismoRESUMO
Polymersomes have been extensively investigated for drug delivery as nanocarriers for two decades due to a series of advantages including high stability under physiological conditions, simultaneous encapsulation of hydrophilic and hydrophobic drugs inside inner cavities and membranes, respectively, and facile adjustment of membrane and surface properties, as well as controlled drug release through incorporation of stimuli-responsive components. Despite these features, polymersome nanocarriers frequently suffer from nontargeting delivery and poor membrane permeability. In recent years, polymersomes have been functionalized for more efficient drug delivery. The surface shells were explored to be modified with diverse active targeting groups to improve disease-targeting delivery. The membrane permeability of the polymersomes was adjusted by incorporation of the stimuli-responsive components for smart controlled transportation of the encapsulated drugs. Therefore, being the polymersome-biointerface, tailorable properties can be introduced by its carefully modulated engineering. This review elaborates on the role of polymersome membranes as a platform to incorporate versatile features. First, we discuss how surface functionalization facilitates the directional journey to the targeting sites toward specific diseases, cells, or intracellular organelles via active targeting. Moreover, recent advances in the past decade related to membrane permeability to control drug release are also summarized. We finally discuss future development to promote polymersomes as in vivo drug delivery nanocarriers.
Assuntos
Sistemas de Liberação de Medicamentos , Polímeros , Polímeros/química , Liberação Controlada de Fármacos , PermeabilidadeRESUMO
Polymer alloys (PAs) are mixtures of two or more types of polymers to enhance the properties of polymeric materials. However, thermosets with crosslinked structures are immiscible and cannot be prepared PAs. Herein, two immiscible covalent adaptable networks containing phenoxy carbamate bonds are explored as the typical polymeric materials to prepare the hard-soft thermoset alloy (HSTA) by the interpenetrated dynamic crosslinked interface (IDCI) to enhance the toughness. Specifically, two types of polyurethane covalent adaptable networks with either high stiffness (thermoset) or extensibility (elastomer) are prepared, respectively. The granules of thermoset and elastomer are mixed and hot-pressed to prepare the HSTA. The HSTA shows improved mechanical properties with a toughness of 22.8 MJ m-3 which is 14 times higher than that of hard thermoset. In addition, the HSTA shows excellent impact-resistance property after 1000 punctures. Moreover, the obtained HSTA via addition of carbon nanotubes can significantly decrease the electric resistance over six orders of magnitudes as compared to the blending method, which is due to the distribution of the carbon nanotubes at the interfaces of the two networks.
Assuntos
Nanotubos de Carbono , Nanotubos de Carbono/química , Polímeros/química , Elastômeros , Condutividade ElétricaRESUMO
Poly(amic acid) (PAA) materials as the precursor of polyimide generally show remarkably poor mechanical properties, thus limiting their application as the engineering plastics. In this study, it is demonstrated that the mechanical properties of PAA materials can be improved significantly for tens of folds with breaking strength >50 MPa, Young's modulus >400 MPa, and elongation at break >300% by incorporation of 20% (mol%) poly(propylene glycol) (PPO) soft segments. The optimization for suitable hard-soft composition with 20% PPO and the existence of various hydrogen bonds with different binding energies can dissipate energies efficiently, which simultaneously improve the material strength and toughness. In addition, PAA82 films exhibit excellent tolerance toward cyclic stretch, and have the capability to resist various harsh conditions including solar radiation testing (1 sun), heat (85 °C), alkalinity (pH 10), and acidity (pH 4) over one month. Noted that PAA82 films can be laminated with Kapton films, which show excellent resistance to ultrahigh (200 °C) and ultralow temperature (-196 °C). The laminated film also exhibits bulletproof property with a thickness of 6 mm. The strategy via modulation of hard-soft compositions and hydrogen bonds in PAA materials shows great potentials to improve the mechanical properties of polymeric materials.
Assuntos
Plásticos , Polímeros , Ligação de Hidrogênio , Polímeros/química , Temperatura , Temperatura AltaRESUMO
Photodynamic therapy (PDT) of cancers is seriously restricted by tumor hypoxia. In addition to the intrinsic hypoxic microenvironment, continuous photoirradiation further aggravates intratumoral hypoxia, thereby reducing the PDT effect significantly. Oxygen-independent PDT is recognized as an efficient approach to overcome this issue. Herein, singlet oxygen (1 O2 )-stored covalent organic framework (COF) nanoparticles loading the near-infrared (NIR) dye cypate, which realize oxygen-independent 1 O2 production for concurrent photothermal therapy (PTT) and PDT under NIR irradiation, are presented. The cypate-loading COF nanoparticles are prepared by using the photosensitizers and 1 O2 -stored molecules via formation of Schiff base bonds, followed by coverage of poly(vinyl pyrrolidone). The COF nanoparticles significantly improve the photostability and photothermal conversion efficiency of cypate by protecting them from photodegradation under NIR irradiation. Upon 660 nm laser irradiation, 1 O2 is produced by the photosensitizer motifs and is successfully stored by the 1 O2 -stored moieties. After intravenous injection and tumor accumulation, the COF nanoparticles can generate heat quickly upon 808 nm irradiation which induces the efficient release of the stored 1 O2 to ablate tumors via O2 -independent concurrent PTT/PDT. Accordingly, the COF nanocarriers of 1 O2 provide a paradigm to develop O2 -independent concurrent PTT/PDT for precise cancer treatment upon NIR irradiation.
Assuntos
Estruturas Metalorgânicas , Nanopartículas , Neoplasias , Fotoquimioterapia , Linhagem Celular Tumoral , Humanos , Hipóxia/tratamento farmacológico , Indóis , Estruturas Metalorgânicas/química , Nanopartículas/química , Neoplasias/tratamento farmacológico , Oxigênio/química , Fármacos Fotossensibilizantes/química , Terapia Fototérmica , Propionatos , Oxigênio Singlete , Microambiente TumoralRESUMO
The hypoxia environment inside tumors is tightly associated with tumor growth, metastasis, and drug resistance. However, the heterogonous distribution of hypoxic areas limits the efficacy of hypoxia-activatable drug delivery systems. Herein, we report the hypoxia-activable block copolymer polyprodrugs, which are composed of poly(ethylene glycol) (PEG) and copolymerized segments of ortho-nitrobenzyl-linked camptothecin (CPT) methacrylate and 2-(piperidin-1-yl)ethyl methacrylate (PEMA) monomers. After self-assembly in aqueous solution, indocyanine green (ICG) photosensitizers were encapsulated to formulate ICG-loaded micellar nanoparticles (ICG@CPTNB) for near-infrared (NIR) light-boosted photodynamic therapy (PDT), tumor hypoxia aggravation, and responsive drug activation. Through intravenous injection and prolonged blood circulation, the nanoparticles can accumulate into tumor efficiently. Tumor acidity-triggered charge transition of PEMA units remarkably promotes cellular internalization of the nanoparticles. Upon exposure to NIR laser irradiation, ICG inside the nanoparticles produced reactive oxygen species (ROS) along with local hypothermia. Simultaneously, the oxygen consumption during ROS production aggravated the intratumoral hypoxia, which amplified hypoxia-responsive self-immolative CPT release from the nanoparticles. The combined photodynamic chemotherapy using hypoxia-responsive polyprodrug nanoparticles, ICG@CPTNB, overcomes the limitations of single therapy of hypoxia-activable prodrugs or PDT, which remarkably improves the efficiency of tumor growth suppression.
Assuntos
Fotoquimioterapia , Sistemas de Liberação de Medicamentos , Humanos , Hipóxia/tratamento farmacológico , Raios Infravermelhos , Fármacos Fotossensibilizantes/uso terapêuticoRESUMO
A remarkable hallmark of cancer cells is the heterogeneous coexistence of overproduced intracellular glutathione (GSH) and a high level of reactive oxygen species (ROS) compared with those in normal cells, which have been frequently used as the stimuli to trigger drug release from the nanocarriers. Most of the stimuli-responsive delivery vehicles have been designed to respond to only one redox stimulus (e.g., GSH or ROS). Herein, we develop a GSH and ROS dual-responsive amphiphilic diblock copolymer prodrug (BCP) (GR-BCP) consisting of poly(ethylene glycol) (PEG)- and camptothecin (CPT)-conjugated poly(methacrylate) in the side chains via thioether bonds. In comparison, GSH or ROS single-responsive BCPs (G-BCPs or R-BCPs) were prepared, where CPT drugs were linked by disulfide or thioketal bonds, respectively. The three BCPs can form well-defined spherical micellar nanoparticles in an aqueous solution with a diameter of â¼50 nm. Compared with G-BCP and R-BCP, GR-BCP realized the highest cytotoxicity against HeLa cells with the half-inhibitory concentration (IC50) of 6.3 µM, which is much lower than 17.8 µM for G-BCP and 28.9 µM for R-BCP. Moreover, for in vivo antitumor performance, G-BCP, R-BCP, and GR-BCP showed similar efficiencies in blood circulation and tumor accumulation after intravenous injection. However, GR-BCP realized the most efficient tumor suppression with few side effects. Our findings demonstrate that intracellular GSH and ROS dual-responsive BCPs show a more efficient responsive drug release inside tumor cells for boosting the antitumor efficacy as compared with GSH or ROS single-responsive BCPs, which provides novel strategies for designing redox-responsive BCPs.
Assuntos
Antineoplásicos/metabolismo , Liberação Controlada de Fármacos/fisiologia , Glutationa/metabolismo , Polímeros/metabolismo , Pró-Fármacos/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Células HeLa , Humanos , Camundongos , Camundongos Endogâmicos BALB C , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/química , Polietilenoglicóis/metabolismo , Polímeros/administração & dosagem , Polímeros/química , Polimetil Metacrilato/administração & dosagem , Polimetil Metacrilato/química , Polimetil Metacrilato/metabolismo , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Resultado do TratamentoRESUMO
Hydrophobic segments and amino moieties in polymeric nonviral gene vectors play important roles in overcoming a cascade of barriers for efficient gene delivery. However, it remains a great challenge to facilely construct well-defined multifunctional polymers through optimization of the amino and hydrophobic groups. Herein, we choose thiolactone chemistry to perform the ring opening reaction of varying hydrophobic groups-modified thiolactones by various amines to generate mercapto groups for further Michael addition reaction with poly[2-(acryloyloxy)ethyl methacrylate] (PAOEMA). Based on the combinatorial methodology, a series of multifunctional polymers were prepared and screened. The polymer (P3D) from tetraethylenepentamine and heptafluorobutyric acid-functionalized thiolactone is the most efficacious one with significantly higher gene transfection efficiency and lower cytotoxicity compared with polyethylenimine (PEI) (branched average Mw â¼ 25 000 Da) and Lipofectamine 2000. Cellular uptake and intracellular distribution studies indicate that P3D complexes show high-efficiency endocytosis and excellent endosomal escape. Accordingly, thiolactone chemistry-based combinatorial methodology allows for facile integration of multifunctional groups to prepare simultaneous efficacious and low-cytotoxic gene delivery vectors.
Assuntos
Técnicas de Química Combinatória/métodos , Lactonas/química , Polímeros/química , Compostos de Sulfidrila/química , Transfecção , Técnicas de Transferência de Genes , Vetores Genéticos/administração & dosagem , Células HeLa , Humanos , Lactonas/síntese química , Polímeros/síntese química , Compostos de Sulfidrila/síntese química , Transfecção/métodosRESUMO
Therapeutic nanoreactors have been proposed as nanoplatforms to treat diseases through in situ production of therapeutic agents. When this treatment strategy is applied in cancer therapy, it can efficiently produce highly toxic anticancer drugs in situ from low-toxic prodrugs or some biomolecules in tumor tissues, which can maximize the therapeutic efficacy with a significantly low systemic toxicity. An ideal therapeutic nanoreactor can provide the reaction space, protect the loaded fragile catalysts, target the desired pathological site, and be selectively activated. In this minireview, we highlight the recent advances concerning the applications of therapeutic nanoreactors as in vivo nanoplatforms particularly in cancer therapy. Herein, the therapeutic nanoreactors are discussed on the basis of treatment strategies and various nanoparticles. Specifically, the treatment strategies of nanoreactors including single enzyme, single enzyme with chemodrugs, and multienzymes, as well as varying types of engineered nanoparticle-loaded active catalysts, primarily including liposomes, polymersomes, polymeric micelles, inorganic nanoparticles, and metal-organic framework (MOF) architectures, are documented and briefly discussed. Finally, we elucidate the current challenges to be addressed toward further development and translation into clinical applications of these therapeutic nanoreactors in cancer therapy.
Assuntos
Antineoplásicos/química , Nanopartículas/química , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , Pró-Fármacos/química , Animais , Antineoplásicos/efeitos adversos , Antineoplásicos/uso terapêutico , Meios de Contraste/química , Portadores de Fármacos/química , Humanos , Lipossomos/química , Estruturas Metalorgânicas/química , Micelas , Tamanho da Partícula , Polímeros/química , Pró-Fármacos/efeitos adversos , Pró-Fármacos/uso terapêutico , Propriedades de SuperfícieRESUMO
Relative to normal cells, tumor cells lack adequate capability of reactive oxygen scavenging. Thus, tumor cells can be selectively killed by increasing the concentration of reactive oxygen species in tumor tissue. In this report, we construct an integrated multifunctional polymeric nanoparticle which can selectively improve hydrogen peroxide (H2O2) levels in tumor tissue and convert them into more active hydroxyl radicals by Fenton reaction. First, the diblock copolymers containing polyethylene glycol (PEG) and poly(glutamic acid) modified by ß-cyclodextrin (ß-CD) were synthesized. The block copolymer, ferrocenecarboxylic acid hexadecyl ester (DFc), and ascorbyl palmitate (PA) were coassembled in aqueous solution to obtain stable core-shell micelles through the inclusion complexation between ß-CD moieties in the block copolymer and ferrocene (Fc) groups from DFc. After intravenous injection, the particles achieved significant accumulation in tumor tissue where ascorbic acid at the pharmacological concentration promotes the production of H2O2, and subsequently Fenton reaction was catalyzed by Fc groups to produce hydroxyl radicals to efficiently kill cancer cells and suppress tumor growth. The micellar systems possess great potentials toward cancer therapy through synergistic H2O2 production and conversion into hydroxyl radicals specifically in tumor tissue.
Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Nanopartículas/química , Polímeros/química , Animais , Ácido Ascórbico/análogos & derivados , Ácido Ascórbico/química , Ácido Ascórbico/farmacocinética , Ácido Ascórbico/farmacologia , Feminino , Compostos Ferrosos/química , Humanos , Peróxido de Hidrogênio/química , Peróxido de Hidrogênio/metabolismo , Radical Hidroxila/química , Radical Hidroxila/metabolismo , Injeções Intravenosas , Ferro/química , Células MCF-7 , Metalocenos , Camundongos Endogâmicos BALB C , Micelas , Nanopartículas/administração & dosagem , Polietilenoglicóis/química , Ácido Poliglutâmico/química , Polímeros/farmacocinética , Polímeros/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto , beta-Ciclodextrinas/químicaRESUMO
Therapeutic nanoreactors have been proposed to treat cancers through in situ transformation of low-toxicity prodrugs into toxic therapeutics in the body. However, the in vivo applications are limited by low tissue-specificity and different tissue distributions between sequentially injected nanoreactors and prodrugs. Herein, we construct a block copolymer prodrug-based polymersome nanoreactor that can achieve novel orchestrated oxidation/chemotherapy of cancer via specific activation at tumor sites. The block copolymers composed of poly(ethylene glycol) (PEG) and copolymerized monomers of camptothecin (CPT) and piperidine-modified methacrylate [P(CPTMA-co-PEMA)] were optimized to self-assemble into polymersomes in aqueous solution for encapsulation of glucose oxidase (GOD) to obtain GOD-loaded polymersome nanoreactors (GOD@PCPT-NR). GOD@PCPT-NR maintained inactive in normal tissues upon systemic administration. After deposition in tumor tissues, tumor acidity-triggered protonation of PPEMA segments resulted in high permeability of the polymersome membranes and oxidation reaction of diffused glucose and O2 under the catalysis of GOD. The activation of the reaction generated H2O2, improving the oxidative stress in tumors. Simultaneously, a high level of H2O2 further activated PCPTMA prodrugs, releasing active CPT drugs. High tumor oxidative stress and released CPT drugs synergistically killed cancer cells and suppressed tumor growth via oxidation/chemotherapy. Our study provides a new strategy for engineering therapeutic nanoreactors in an orchestrated fashion for cancer therapy.
Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/farmacologia , Glucose Oxidase/farmacologia , Peróxido de Hidrogênio/metabolismo , Metacrilatos/farmacologia , Polietilenoglicóis/farmacologia , Pró-Fármacos/farmacologia , Células A549 , Antineoplásicos Fitogênicos/química , Camptotecina/química , Portadores de Fármacos/química , Portadores de Fármacos/farmacologia , Glucose Oxidase/química , Humanos , Concentração de Íons de Hidrogênio , Metacrilatos/química , Nanoestruturas/química , Neoplasias/tratamento farmacológico , Oxirredução/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Polietilenoglicóis/química , Pró-Fármacos/químicaRESUMO
The amphiphilic block copolymer anticancer drug nanocarriers clinically used or in the progress of clinical trials frequently suffer from modest final therapeutic efficacy due to a lack of intelligent features. For example, the biodegradable amphiphilic block copolymer, poly(ethylene glycol)-b-poly(d,l-lactide) (PEG-PDLLA) has been approved for clinical applications as a paclitaxel (PTX) nanocarrier (Genexol-PM) due to the optimized pharmacokinetics and biodistribution; however, a lack of intelligent features limits the intracellular delivery in tumor tissue. To endow the mediocre polymer with smart properties via a safe and facile method, we introduced a matrix metalloproteinase (MMP)-responsive peptide GPLGVRGDG into the block copolymer via efficient click chemistry and ring-opening polymerization to prepare PEG-GPLGVRGDG-PDLLA (P1). P1 was further self-assembled into micellar nanoparticles (NPs) to load PTX, which show MMP-2-triggered dePEGylation due to cleavage of the peptide linkage. Moreover, the residual VRGDG sequences are retained on the surface of the NPs after dePEGylation, which can serve as ligands to facilitate the cellular uptake. The cytotoxicity of PTX loaded in P1 NPs against 4T1 cells is significantly enhanced as compared with free PTX or PTX-loaded PEG-GPLGVRG-PDLLA (P2) and PEG-PDLLA (P3) NPs. In vivo studies confirmed that PTX-loaded P1 NPs show prolonged blood circulation, which are similar to P2 and P3 NPs but exhibit more-efficient accumulation in the tumor site. Ultimately, PTX-loaded P1 NPs display statistically significant improvement of antitumor activity against tumor-bearing mice via systemic administration. Therefore, the strategy by facile incorporation of a responsive peptide linkage between PEG and PDLLA is a promising approach to improving the therapeutic efficacy of anticancer-drug-loaded amphiphilic block copolymer micelles.
Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Interações Hidrofóbicas e Hidrofílicas , Metaloproteinases da Matriz/metabolismo , Peptídeos/química , Poliésteres/química , Polietilenoglicóis/química , Sequência de Aminoácidos , Animais , Antineoplásicos/metabolismo , Transporte Biológico , Linhagem Celular Tumoral , Portadores de Fármacos/farmacocinética , Humanos , Camundongos , Distribuição TecidualRESUMO
Polymeric nanoreactors (NRs) have distinct advantages to improve chemical reaction efficiency, but the inâ vivo applications are limited by lack of tissue-specificity. Herein, novel glucose oxidase (GOD)-loaded therapeutic vesicular NRs (theraNR) are constructed based on a diblock copolymer containing poly(ethylene glycol) (PEG) and copolymerized phenylboronic ester or piperidine-functionalized methacrylate (P(PBEM-co-PEM)). Upon systemic injection, theraNR are inactive in normal tissues. At a tumor site, theraNR are specifically activated by the tumor acidity via improved permeability of the membranes. Hydrogen peroxide (H2 O2 ) production by the catalysis of GOD in theraNR increases tumor oxidative stress significantly. Meanwhile, high levels of H2 O2 induce self-destruction of theraNR releasing quinone methide (QM) to deplete glutathione and suppress the antioxidant ability of cancer cells. Finally, theraNR efficiently kill cancer cells and ablate tumors via the synergistic effect.
Assuntos
Antineoplásicos/uso terapêutico , Morte Celular/efeitos dos fármacos , Portadores de Fármacos , Nanoestruturas , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Polietilenoglicóis/química , Antineoplásicos/administração & dosagem , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Antioxidantes/metabolismo , Ácidos Borônicos/química , Permeabilidade da Membrana Celular , Ésteres , Glucose Oxidase/metabolismo , Glutationa/metabolismo , Humanos , Peróxido de Hidrogênio/metabolismo , Concentração de Íons de Hidrogênio , Indolquinonas/química , Metacrilatos/química , Microscopia Eletrônica de Transmissão , Neoplasias/metabolismo , Piperidinas/química , Estudo de Prova de ConceitoRESUMO
Construction of efficient doxorubicin (DOX) delivery systems addressing a cascade of physiological barriers remains a great challenge for better therapeutic efficacy of tumors. Herein, we design well-defined enzyme-responsive peptide-linked block copolymer, PEG-GPLGVRGDG-P(BLA-co-Asp) [PEG and P(BLA-co-Asp) are poly(ethylene glycol) and partially hydrolyzed poly(ß-benzyl l-aspartate) (PBLA), respectively] (P3), with modular functionality for efficient delivery of DOX. The block copolymers were successfully obtained via click reaction to introduce peptide (alkynyl-GPLGVRGDG) into the end of PEG for initiating ring-opening polymerization of ß-benzyl l-aspartate N-carboxyanhydride (BLA-NCA) by terminal amino groups followed by partial hydrolysis of PBLA segments. P3 micelle was demonstrated to encapsulate DOX efficiently through synergistic effect of benzyl group-based hydrophobic and carboxyl moiety-based electrostatic interactions. Effective matrix metalloproteinase-2 (MMP-2)-triggered cleavage of peptide for dePEGylation of P3 micelles was confirmed and residual RGD ligands were retained on the surfaces. Against HT1080 cells overexpressing MMP-2, DOX-loaded P3 micelles showed approximately 4-fold increase of the cellular internalization amount as compared with free DOX and half maximal inhibitory concentration (IC50) value of DOX-loaded P3 micelles was determined to be 0.38 µg/mL compared with 0.66 µg/mL of free DOX due to MMP-triggered dePEGylation, RGD-mediated cellular uptake, and rapid drug release inside cells. Binding and penetration evaluation toward HT1080 multicellular tumor spheroids (MCTs) confirmed high affinity and deep penetration of P3 micelles in tumor tissues. This modular design of enzyme-responsive block copolymers represents an effective strategy to construct intelligent drug delivery vehicles for addressing a cascade of delivery barriers.
Assuntos
Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Neoplasias/tratamento farmacológico , Peptídeos/administração & dosagem , Linhagem Celular Tumoral , Doxorrubicina/química , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Interações Hidrofóbicas e Hidrofílicas , Metaloproteinase 2 da Matriz/biossíntese , Metaloproteinase 2 da Matriz/genética , Neoplasias/genética , Tamanho da Partícula , Peptídeos/química , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/químicaRESUMO
Near-infrared light (NIR) possesses great advantages for light-responsive controllable drug release, such as deep tissue penetration and low damage to healthy tissues. Herein, a NIR-responsive drug delivery system is developed based on a NIR dye, indocyanine green (ICG), and anticancer drug, doxorubicin (DOX)-loaded thermoresponsive block copolymer micelles, in which the drug release can be controlled via NIR irradiation. First, block copolymers, poly(oligo(ethylene glycol) methacrylate)-block-poly(furfuryl methacrylate) (POEGMA-b-PFMA), are synthesized by sequential reversible addition-fragmentation chain-transfer (RAFT) polymerization, followed by modification with N-octyl maleimide through Diels-Alder (DA) reaction to produce POEGMA-b-POMFMA. The self-assembly of POEGMA-b-POMFMA by nano-precipitation in aqueous solution affords the polymeric micelles which are used to simultaneously encapsulate ICG and DOX. Upon irradiation by NIR light (805 nm), the loaded DOX is released rapidly from the micelles due to partial retro DA reaction and local temperature increase-induced faster drug diffusion by the photothermal effect. Cytotoxicity evaluation and intracellular distribution observation demonstrate significant synergistic effects of NIR-triggered drug release, photothermal, and chemotherapy toward cancer cells under NIR irradiation.
Assuntos
Antineoplásicos/química , Doxorrubicina/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Química Farmacêutica , Reação de Cicloadição , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Ensaios de Seleção de Medicamentos Antitumorais , Células HeLa , Humanos , Raios Infravermelhos , Micelas , Peso Molecular , Tamanho da Partícula , Processos Fotoquímicos , Polietilenoglicóis/química , Polimerização , Ácidos Polimetacrílicos/química , TemperaturaRESUMO
Adequate retention in blood circulation is a prerequisite for construction of gene delivery carriers for systemic applications. The stability of gene carriers in the bloodstream requires them to effectively resist protein adsorption and maintain small size in the bloodstream avoiding dissociation, aggregation, and nuclease digestion under salty and proteinous medium. Herein, a mixture of two block catiomers consisting of the same cationic block, poly{N-[N-(2-aminoethyl)-2-aminoethyl]aspartamide} (PAsp(DET)), but varying shell-forming blocks, poly[2-(2-methoxyethoxy) ethyl methacrylate] (PMEO2MA), and poly[oligo(ethylene glycol) methyl ether methacrylate] (POEGMA), was used to complex with plasmid DNA (pDNA) to fabricate polyplex micelles with mixed shells (MPMs) at 20 °C. The thermoresponsive property of PMEO2MA allows distinct phase transition from hydrophilic to hydrophobic by increasing incubation temperature from 20 to 37 °C, which results in a distinct heterogeneous corona containing hydrophilic and hydrophobic regions at the surface of the MPMs. Subsequent study verified that this transition promoted further condensation of pDNA, thereby giving rise to improved complex and colloidal stability. The proposed system has shown remarkable stability in salty and proteinous solution and superior tolerance to nuclease degradation. As compared with polyplex micelles formed from single POEGMA-b-PAsp(DET) block copolymer, in vivo circulation experiments in the bloodstream further confirmed that the retention time of MPMs was prolonged significantly. Moreover, the proposed system exhibited remarkably high cell transfection activity especially at low N/P ratios and negligible cytotoxicity and thus portends promising utility for systemic gene therapy applications.
Assuntos
DNA , Terapia Genética/métodos , Plasmídeos , Polietilenoglicóis , Ácidos Polimetacrílicos , Transfecção/métodos , Animais , DNA/química , DNA/farmacologia , Células HeLa , Humanos , Camundongos , Plasmídeos/química , Plasmídeos/farmacologia , Polietilenoglicóis/química , Polietilenoglicóis/farmacologia , Ácidos Polimetacrílicos/química , Ácidos Polimetacrílicos/farmacologiaRESUMO
Novel neutral-cationic brush block copolymer, poly[oligo(ethylene glycol) monomethyl ether methacrylate-co-folic acid methacrylate]-b-poly[2-(2-(2-(2-bromo-2-methylpropanoyloxy)-ethyl) disulfanyl) ethyl methacrylate-g-2-dimethylaminoethyl methacrylate], P(OEGMA-co-FAMA)-b-P(BSSMA-g-PDMAEMA), is synthesized via consecutive controlled radical polymerizations. Containing disulfide linkages bridging backbone and side chains in the cationic brush block and cancer cell-targeting ligands (folic acid) in the neutral hydrophilic block, the diblock copolymer is employed as a tumor-targeted redox-responsive degradable nonviral gene delivery vector. P(OEGMA-co-FAMA)-b-P(BSSMA-g-PDMAEMA) brush block copolymers can condense plasmid DNA (pDNA) efficiently via the formation of electrostatic polyplex micelles. Under reductive milieu, pDNA can be released due to the cleavage of disulfide linkages and accordingly pDNA-binding cationic PDMAEMA side chains. In addition, the brush block copolymer exhibits low cytotoxicity and the corresponding polyplex micelles show relatively high gene transfection efficiency.
Assuntos
Nanoestruturas/química , Polímeros/química , Materiais Biocompatíveis/síntese química , Materiais Biocompatíveis/química , Materiais Biocompatíveis/toxicidade , Sobrevivência Celular/efeitos dos fármacos , Técnicas de Transferência de Genes , Células HeLa , Humanos , Metacrilatos/química , Micelas , Nylons/química , Oxirredução , Plasmídeos/química , Plasmídeos/metabolismo , Polímeros/síntese química , Polímeros/toxicidadeRESUMO
Self-assembled nanostructures of amphiphilic and double hydrophilic block copolymers have been increasingly utilized as potent polymeric nanocarriers of therapeutic drugs, genes, bioactive molecules, and imaging/contrast agents due to improved water solubility, bioavailability, and extended blood circulation duration. Though passive and active targeted drug delivery strategies have long been proposed to promote desirable drug accumulation specifically at the disease sites, the introduction of stimuli-responsiveness into self-assembled block copolymer nanocarriers can additionally lead to controlled/triggered release of therapeutic/imaging agents into target pathological tissues and cells, with concomitant advantages of enhanced delivery efficiency and therapeutic efficacy. Appropriately designed stimuli-responsive block copolymer assemblies can exhibit chemical structure transformation, microstructural rearrangement and inversion, or even disassembly into unimers or smaller ones under external stimuli such as pH, temperature, ion strength, redox potential, light, electric, and magnetic fields, and specific bioactive molecules and metabolites. Compared to normal tissues, pathological sites such as tumor tissues typically exhibit vascular abnormalities, weak acidity (~pH 6.8), abnormal temperatures, over-expressed proteins and enzymes, hypoxia, high levels of metabolites and reactive small molecule species, etc. Moreover, upon cellular uptake, drug-loaded polymeric nanocarriers will be subjected to intracellular pH gradients (pH 5.9-6.2 in early endosomes and pH 5.0-5.5 in late endosomes and lysosomes) and redox and H2O2 gradients within different cell organelles and the cytosol. Thus, block copolymer nanocarriers responsive to the above described bio-relevant stimuli or biochemical signals characteristic of pathologic tissues and cells will provide an alternative type of "active targeting" strategy, which can be utilized to further boost therapeutic efficacy and imaging sensitivity via disease site-specific delivery and controlled release. A variety of extracellular or intracellular stimuli innate to disease sites, such as mildly acidic pH, temperature, enzymes (matrix metalloproteinase, ß-glucuronidase, and phosphatase), oxidative/reductive microenvironments, and abnormal levels of bioactive molecules or metabolites, have been utilized for this purpose. In this review, we summarize recent advances in stimuli-responsive block copolymer assemblies which are responsive to tumor and intracellular microenvironments and their applications in anticancer drug delivery and enhanced imaging sensitivity.
Assuntos
Portadores de Fármacos/química , Polímeros/química , Antineoplásicos/administração & dosagem , Antineoplásicos/química , Enzimas/metabolismo , Humanos , Concentração de Íons de Hidrogênio , Micelas , Nanopartículas/química , Neoplasias/diagnóstico , Neoplasias/tratamento farmacológico , OxirreduçãoRESUMO
Chemodynamic therapy (CDT), as a new type of therapy, has received more and more attention in the field of tumor therapy in recent years. By virtue of the characteristics of weak acidity and excess H2O2 in the tumor microenvironment, CDT uses the Fenton or Fenton-like reactions to catalyze the transformation of H2O2 into strongly oxidizing ËOH, resulting in increased intracellular oxidative stress for lipid oxidation, protein inactivation, or DNA damage, and finally inducing apoptosis of cancer cells. In particular, CDT has the advantage of tumor specificity. However, the therapeutic efficacy of CDT frequently depends on the catalytic efficiency of the Fenton reaction, which needs the presence of sufficient H2O2 and catalytic metal ions. Relatively low concentrations of H2O2 and the lack of catalytic metal ions usually limit the final therapeutic effect. The combination of CDT with immunotherapy will be an effective means to improve the therapeutic effect. In this review paper, the recent progress related to nanomedicine for the combination of CDT and immunotherapy is summarized. Immunogenic death of tumor cells, immune checkpoint inhibitors, and stimulator of interferon gene (STING) activation as the main immunotherapy strategies to combine with CDT are discussed. Finally, the challenges and prospects for the clinical translation and future development direction are discussed.