Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 56
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
Soft Matter ; 15(44): 9011-9017, 2019 Nov 28.
Artigo em Inglês | MEDLINE | ID: mdl-31687734

RESUMO

A kind of lyotropic liquid crystal nanoparticle (LLC NPs) has been designed and prepared. LLC NPs are dSMO/OA/ß-casein/water quaternary systems, and their cubic or hexagonal microstructures have been characterized by cryogenic transmission electron microscopy (cryo-TEM) and small angle X-ray scattering (SAXS). The phase transition of LLC NPs takes place with ratio and pH adjustments. The properties, such as cytotoxicity, stability, drug encapsulation and release ability, have been investigated with MTT assay, cryo-TEM and UV-Vis spectroscopy. The results showed that LLC NPs were nontoxic to cells and stable to enzymatic degradation. Hydrophilic drug doxorubicin hydrochloride (DOX·HCl) could be effectively encapsulated in LLC NPs and its release rate could be regulated by pH. It was concluded that LLC NPs are potential nanocarriers in nanomedicine technologies. We hope that this work provides new guidelines for the rational design of LLC NP systems with lipopeptides for biomedical applications.

2.
ACS Appl Mater Interfaces ; 11(46): 42904-42916, 2019 Nov 20.
Artigo em Inglês | MEDLINE | ID: mdl-31657540

RESUMO

Potentiating systemic immunity against breast cancer is in the most urgent demand as breast cancer is less sensitive to immune checkpoint blockade. Although phototherapy and some chemotherapy can trigger immunogenic cell death (ICD) for T cell-mediated antitumor immune response, their immunotherapy efficacy is severely restricted by insufficient phototherapeutic capability and severe multidrug resistance (MDR). Inspired by both the hypersensitivity to phototherapy and the key role of MDR for mitochondria, a rationally engineered immunity amplifier via mitochondria-targeted photochemotherapeutic nanoparticles was, for the first time, achieved to fight against low-immunogenic breast cancer without additional immune agents. The newly synthesized task-specific mitochondria-targeted IR780 derivative (T780) was integrated with chemotherapeutic doxorubicin (DOX) to form multifunctional nanoparticles via an assembling strategy along with bovine serum albumin (BSA) as a biomimetic corona (BSA@T780/DOX NPs). The in situ enhancement in both phototherapy and MDR reversal by targeting mitochondria with BSA@T780/DOX NPs boosted highly efficient ICD toward excellent antitumor immune response. The newly developed strategy not only eradicated the primary tumor but also eliminated the bilateral tumors efficiently, as well as preventing metastasis and postsurgical recurrence, demonstrating great interest for fighting against low-immunogenic breast cancer.

3.
Langmuir ; 35(40): 13174-13181, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31532218

RESUMO

Novel lipopeptide vesicles are prepared from self-assembled nanomembranes through an extrusion method. The size of vesicles can be controlled by the pore diameter of the extrusion filter. The vesicles are rather stable because hydrogen bonds exist among the peptide headgroups. When doxorubicin hydrochloride (DOX·HCl) is encapsulated in the vesicles, it could be released sustainably, and its side effect would also be reduced due to encapsulation. The leakage rate of DOX·HCl depends on the pH via charge regulation. As drug carriers, lipopeptide vesicles have been proved to have nontoxicity to normal cells. A magnetic surfactant CH3(CH2)14CH2N(CH3)3+ [FeCl3Br]- (CTAFe) was mixed with lipopeptide to modify the vesicles. Also, the results demonstrated that the vesicles is endowed with magnetic property after the addition of CTAFe. We believe that the strategy of lipopeptide vesicle preparation would enrich the drug carrier family and expand the application of lipopeptide materials.

4.
Nano Lett ; 19(9): 6647-6657, 2019 09 11.
Artigo em Inglês | MEDLINE | ID: mdl-31409072

RESUMO

The antitumor immune response involves a cascade of three phases, namely, antigen presentation (Phase I), lymphocyte activation and proliferation/differentiation (Phase II), and tumor elimination (Phase III). Therefore, an ideal immunotherapy nanoplatform is one that can simultaneously execute these three phases. However, it is of great challenge to develop a single immunotherapy nanoplatform which can deliver individual immunoagent to their on-demand target sites for simultaneously tailoring three phases because of the different target sites restricted by three phases. Herein, for the first time we reported a three-in-one immunotherapy nanoplatform that can simultaneously execute these three phases. Chlorin e6 (Ce6)-conjugated hyaluronic acid (HC), dextro-1-methyl tryptophan (1-mt)-conjugated polylysine (PM) and anti-PD-L1 monoclonal antibodies (aPD-L1) were rationally designed as aPD-L1@HC/PM NPs via an assembling strategy. The step-by-step detachment of the antigen from near-infrared light irradiated HC component, the indoleamine-pyrrole 2,3-dioxygenase (IDO) pathway inhibitor 1-mt, and the anti-PD-L1 toward their on-demand target sites demonstrated the simultaneous tailoring of Phase I, Phase II, and Phase III, respectively, of the immunotherapy. The aPD-L1@HC/PM NPs were verified to be an excellent immunotherapy nanoplatform against tumor metastasis, relapse, and postsurgical regrowth because of the cascade-amplifying cancer-immunity cycle. The present all-immunity-phase-boosted immunotherapy strategy is of great interest for designing excellent immunotherapy treatments.

5.
ACS Appl Mater Interfaces ; 11(36): 32633-32646, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31429272

RESUMO

The concept of integrating immunogenic cell death (ICD) with tailoring the immunosuppressive tumor microenvironment (TME) is promising for immunotherapy. Photothermal therapy (PTT) could efficiently induce ICD, while an indoleamine 2,3-dioxygenase (IDO) inhibitor could convert the "cold" TME. Therefore, combination of PTT and the IDO inhibitor is an attractive approach for immunotherapy. Unfortunately, combination of PTT and the IDO inhibitor for tumor therapy is rarely reported. Herein, organic photothermal agent IR820 and IDO inhibitor 1-methyl-tryptophan (1MT) were, for the first time, designed to be an all-rolled-into-one molecule nanoplatform via a molecular engineering strategy. The designed IR820-1MT molecule could self-assemble into nanoparticles with remarkably high dual-therapeutic agent loading (88.8 wt %). Importantly, poor water solubility of 1MT and inadequate targeting and short lifetime of IR820 were all well solved within as-prepared IR820-1MT nanoparticles. The laser-triggered IR820-1MT nanoparticles remarkably enhanced accumulation of cytotoxic T cells, helper T cells, and memory T cells and simultaneously suppressed a proportion of regulatory T cells, resulting in excellent immunotherapy against tumor metastasis and recurrence. Our molecular engineering strategy provides a promising alternative option for design of a robust immunotherapy weapon against tumor metastasis and recurrence.

6.
J Colloid Interface Sci ; 547: 30-39, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-30933691

RESUMO

Chemo-photodynamic therapy is an attractive strategy against cancer. However, the combination of chemotherapeutic agent and photosensitizer is usually realized by physically embedding one or two agents in the carriers. In this case, batch to batch variation of drug contents increases the risk of composition uncertainty, limiting the clinical application of currently developed chemo-photodynamic therapy. Therefore, it is highly desirable for constructing chemo-photodynamic therapy nanoplatform with precisely controllable composition and drug loading content. Here, a precise chemo-photodynamic therapy nanoplatform is reported based on the chemical conjugation of both doxorubicin (DOX) and photosensitizer chlorin e6 (Ce6) to active targeting hyaluronic acid (HA). The achieved HA-DOX-Ce6 (HDC) conjugate can self-assemble into all-in-one nanoparticles (NPs) with properties of pH-response, self-targeting delivery, near-infrared (NIR) fluorescence imaging and chemo-photodynamic combination therapy. Because HDC conjugate holds precise components, the HDC NPs have a constant composition and drug loading content, endowing a precise chemo-photodynamic therapy nanoplatform. The HDC NPs show significantly higher cellular uptake and remarkably better tumor-targeted accumulation than free drugs. Moreover, HDC NPs with the laser irradiation exhibit enhanced anticancer activities both in vitro and in vivo. This work may open the door for design of all-in-one advanced nanoplatform toward chemo-photodynamic therapy with precisely controllable composition and drug loading content.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Ácido Hialurônico/farmacologia , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Porfirinas/farmacologia , Animais , Antibióticos Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Ácido Hialurônico/química , Concentração de Íons de Hidrogênio , Camundongos , Nanopartículas/química , Tamanho da Partícula , Fármacos Fotossensibilizantes/química , Porfirinas/química , Propriedades de Superfície , Células Tumorais Cultivadas
7.
J Colloid Interface Sci ; 545: 172-183, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-30878783

RESUMO

Graphene oxide (GO), as a drug delivery carrier, has attracted considerable attention because of its interesting properties. However, GO tends to aggregate in aqueous solution. Amphiphilic molecules are usually necessary to stabilize GO. The introduction of these non-functional macromolecules on the one hand reduces drug loading, but on the other hand may cause unpredictable side effects. This study proposes a new strategy for stabilizing GO with a functional photothermal agent, IR820 (new indocyanine green) derivative. IR820 derivative results from the conjugation of active targeted lactobionic acid (LA) with IR820 for the formation of IR820-LA. IR820-LA features central aromatic groups that can associate with the GO basal plane through π-π interactions. The flanking moiety of hydrophilic LA and sulfonic groups thus provides steric stabilization of GO in aqueous solution. Moreover, IR820-LA endows GO/doxorubicin (GO/DOX) nanovehicles with fluorescence imaging ability and actively targeted chemo-photothermal therapy. Experimental results both in vitro and in vivo have indicated its good chemo-photothermal therapeutic effect according to its active tumor targeting ability and pH-sensitive drug release characteristics. Therefore, our GO/DOX/IR820-LA nanohybrids can be excellent nanoplatforms for active tumor-targeted chemo-photothermal therapy with imaging guidance.


Assuntos
Dissacarídeos/metabolismo , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Corantes Fluorescentes/química , Grafite/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Transporte Biológico , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Preparações de Ação Retardada/química , Doxorrubicina/química , Liberação Controlada de Fármacos , Humanos , Camundongos , Terapia de Alvo Molecular/métodos , Imagem Óptica/métodos , Tamanho da Partícula , Fototerapia/métodos , Propriedades de Superfície
8.
Acta Biomater ; 84: 356-366, 2019 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-30502480

RESUMO

Self-assembled nanovehicles of chemotherapy drug with photothermal agent are regarded as intriguing chemo-photothermal therapy nanoplatform. However, most of the drugs and photothermal agents have poor water solubility and poor interactions to drive the formation of self-assembled nanovehicles, which is a bottleneck of co-assembled drug/photothermal agent for cancer therapy. Here, we proposed a versatile strategy to create self-assembled chemo-photothermal therapy nanoplatform based on the chemical modification of photothermal agent and drug. The IR-780 and camptothecin (CPT) were chosen as the studied models since they are important photothermal agent and anticancer drug, both of which have such poor water solubility with strong itself molecular interactions that they cannot co-assemble together. IR-780 was modified with an active targeting ligand lactobionic acid (LA) to result in amphiphilic IR780-LA while CPT was modified into redox-sensitive prodrug CPT-ss-CPT through a disulfide linkage to realize its assembly. Well-defined nanoparticles (NPs) could be created through the co-assembling of IR780-LA and CPT-ss-CPT. The IR780-LA/CPT-ss-CPT nanoparticles were demonstrated to be an excellent fluorescence imaging-guided, redox-responsive and enhanced synergistic chemo-photothermal therapy nanoplatform against tumors. Specifically, our chemical modification strategy offers a universal way to create self-assembled chemo-photothermal therapy nanoplatform, which solves the bottleneck of co-assembled drug/photothermal agent for cancer therapy. STATEMENT OF SIGNIFICANCE: Self-assembled nanoparticles of chemotherapeutics with photothermic drugs are regarded as intriguing chemo-photothermal therapy nanoplatform. However, most drugs have too poor solubility and interactions to form into self-assembled nanoparticles. We proposed a versatile strategy to create co-assembled chemo-photothermal therapy nanoparticles based on the chemical modification of common drugs. The IR-780 was modified with an active targeting ligand LA to result in amphiphilic IR780-LA molecules, while CPT was modified into redox-sensitive prodrug CPT-ss-CPT through disulfide linkage. Well-defined IR780-LA/CPT-ss-CPT nanoparticles were created through the co-assembling of IR780-LA and CPT-ss-CPT. The nanoparticles were demonstrated to be an excellent fluorescence imaging-guided, redox-responsive, active targeting chemo-photothermal therapy nanoplatform against tumors. Our strategy offers a versatile way to construct smart chemo-photothermal therapy nanoplatform from common drugs.

9.
Small ; 14(52): e1802994, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30474224

RESUMO

Phototherapy as a promising cancer diagnostic and therapeutic strategy has aroused extensive attention. However, single-wavelength near-infrared (NIR) light-triggered combinational treatment of photothermal therapy (PTT) and photodynamic therapy (PDT) is still a great challenge. Herein, a multifunctional micelle activated by a single-wavelength laser for simultaneous PTT and PDT as well as fluorescence imaging is developed. Briefly, new indocyanine green (IR820) is conjugated to d-α-tocopheryl polyethylene glycol 1000 succinate (TPGS) via the linker 6-aminocaproic acid, and then, chlorin e6 (Ce6) is encapsulated into the micelles formed by TPGS-IR820 conjugates to fabricate TPGS-IR820/Ce6 micelles. As the well-designed TPGS-IR820 conjugate shares a similar peak absorption wavelength with Ce6, this micelle can be applied with a single NIR laser (660 nm). The stable micelles exhibit excellent photothermal conversion efficiency in vitro and in vivo as well as high singlet oxygen generation capacity in tumor cells. After efficient cellular internalization, the as-prepared micelles display outstanding anticancer activity upon single NIR laser irradiation in vitro and in vivo. Furthermore, TPGS-IR820/Ce6 micelles show negligible systemic toxicity. The highly safe and effective TPGS-IR820/Ce6 micelles can offer an innovative strategy to construct single NIR light-induced PTT and PDT combined phototherapy nanoplatforms via suitable modification of organic phototherapeutic agents.


Assuntos
Verde de Indocianina/análogos & derivados , Micelas , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/química , Polilisina/análogos & derivados , Porfirinas/química , Verde de Indocianina/química , Polilisina/química
10.
Int J Pharm ; 552(1-2): 111-118, 2018 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-30268848

RESUMO

Cytarabine (Ara-C) has become cornerstones for the treatment of hatmatological malignancies for several decades; however, it still faces serious challenges in clinical applications due to its side effects such as hand foot syndrome (HFS) and stomatitis. Therefore, considerable researchers have devoted to looking for the new derivative with desirable activity and low toxicity. A new prodrug based on the conjugation of cytarabine with lauric acid (LA-Ara) was synthesized in our group, and it could self-assemble into nanofibers (NFs) in aqueous solution with high drug loading (57 wt%). The lauric acid moiety protects NH2 group of from the enzymatic attachment and simultaneously raises the lipophilicity of Ara-C, thus obviously prolongs its plasma half-life. The oil/water partition coefficient (lg P) and the permeability of cell membrane of LA-Ara were obviously increased compared with Ara-C. Furthermore, the in vitro gastrointestinal stability results indicated the prodrug was suitable to be administrated orally. In the current study, the in vitro cytotoxicity and in vivo anti breast cancer experimental results indicate LA-Ara markedly improved antitumor activity compared with free Ara-C. The favorable safety evaluations elucidated its potentiality for oral alternative treatment to Ara-C. Importantly, LA-Ara can effectively decrease the incidence of toxic effects (HFS and stomatitis) of Ara-C, thereby exhibiting favorable skin safety profile. Overall, these results indicated the LA-Ara would be an excellent candidate for further clinical investigation and simultaneously highlight the prospects of Ara-C prodrug strategies in solid tumors therapy.


Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Citarabina/administração & dosagem , Portadores de Fármacos/administração & dosagem , Ácidos Láuricos/administração & dosagem , Nanofibras/administração & dosagem , Pró-Fármacos/administração & dosagem , Animais , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/química , Linhagem Celular Tumoral , Citarabina/efeitos adversos , Citarabina/química , Portadores de Fármacos/química , Feminino , Síndrome Mão-Pé , Humanos , Ácidos Láuricos/química , Camundongos Endogâmicos BALB C , Nanofibras/química , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Pró-Fármacos/química , Estomatite/induzido quimicamente , Carga Tumoral/efeitos dos fármacos
11.
ACS Appl Mater Interfaces ; 10(40): 34513-34523, 2018 Oct 10.
Artigo em Inglês | MEDLINE | ID: mdl-30215253

RESUMO

Quercetin (QT) is one promising candidate for the treatment of various cancers with virtually no toxic side effects. However, its anticancer effect is severely restricted by its poor bioavailability, low water solubility, and chemical instability in the neutral and alkaline medium. Herein, zeolitic imidazolate framework-8 (ZIF-8) is first reported as the multifunctional nanoplatform to the codelivery of quercetin as an anticancer agent and CuS nanoparticles as a photothermal therapy (PTT) agent for synergistic combination of chemotherapy and PTT as well as overcoming the drawbacks of quercetin. Moreover, folic acid-bovine serum albumin (FA-BSA) conjugates are applied to stabilize the CuS@ZIF-8-QT to promote the bioavailability of quercetin and realize active-targeting drug delivery. Near-infrared (NIR) fluorescent imaging demonstrated the highly increased drug accumulations of FA-BSA/CuS@ZIF-8-QT in tumors, resulting from efficient internalization via FA-receptors-mediated endocytosis. The results of in vivo and in vitro anticancer experiments demonstrate that quercetin and PTT agent can work together efficiently under NIR irradiation, thus remarkably improving the anticancer effect. Therefore, our newly designed FA-BSA/CuS@ZIF-8-QT multifunctional drug delivery system might be a promising nanoplatform for cancer treatment.


Assuntos
Cobre , Sistemas de Liberação de Medicamentos/métodos , Hipertermia Induzida/métodos , Neoplasias Experimentais/terapia , Fototerapia/métodos , Quercetina , Sulfetos , Animais , Linhagem Celular , Cobre/química , Cobre/farmacocinética , Cobre/farmacologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/metabolismo , Quercetina/química , Quercetina/farmacocinética , Quercetina/farmacologia , Sulfetos/química , Sulfetos/farmacocinética , Sulfetos/farmacologia
12.
ACS Appl Mater Interfaces ; 10(37): 31674-31685, 2018 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-30133254

RESUMO

Photodynamic therapy (PDT) is a minimally invasive treatment for many diseases, including infections and tumors. Nevertheless, clinical utilization of PDT is severely restricted due to the shortcomings of the photosensitizers, especially their low water solubility and poor tumor selectivity. iRGD (internalizing RGD, CRGDKGPDC), a nine-unit cyclic peptide, was applied as an active ligand to realize tumor homing and tissue penetration. Herein, we innovatively fabricated a novel OFF-ON mode iRGD-based peptide amphiphile (PA) to self-assemble into spherical nanovesicles to enhance the tumor-targeting and tumor-penetrating efficacy of PDT. To introduce the self-assembling feature into iRGD, a hydrophilic arginine-rich sequence and hydrophobic alkyl chains were sequentially linked to the iRGD motif. A short proline sequence was selected to control the morphology of the self-assembled aggregates. Next, the photosensitizer hypocrellin B (HB) was encapsulated into PA vesicles with a high loading efficiency. The aggregation-caused quenching effect inactivated HB in the PA vesicles; however, the iRGD-peptide-based material was able to be selectively degraded in tumor cells. Thus, the HB fluorescence was recovered to achieve tumor-targeted imaging. This approach endows HB-loaded PA vesicles (HB-PA) with tumor-targeted activation, preferable tumor accumulation, and deep tumor penetration, thus leading to an excellent fluorescence-imaging-guided photodynamic efficacy both in vitro and in vivo. These amphiphilic iRGD aggregates provide a novel strategy for improving the accumulation, penetration, and imaging-guided photodynamic efficacy of photosensitizers.


Assuntos
Nanotecnologia/métodos , Oligopeptídeos/química , Fotoquimioterapia , Fármacos Fotossensibilizantes/farmacologia , Animais , Linhagem Celular Tumoral , Humanos , Camundongos , Células NIH 3T3 , Imagem Óptica
13.
ACS Appl Mater Interfaces ; 10(36): 30092-30102, 2018 Sep 12.
Artigo em Inglês | MEDLINE | ID: mdl-30118198

RESUMO

The short lifetime and easy quick elimination of the near-infrared (NIR) dye new indocyanine green (IR820) in the body restrict its practical application as a photothermal agent in cancer therapy. Meanwhile, the drawback of poor water solubility of the chemotherapeutic drug paclitaxel (PTX) largely restricts its clinical applications. Herein, we, for the first time, combined IR820 and PTX in an "all-in-one" fluorescence imaging-guided chemo-photothermal therapy (PTT) platform by a rational design of a novel pH- and enzyme-sensitive IR820-PTX conjugate assembly. Specifically, the IR820-PTX conjugate nanoparticles exhibit an extremely high therapeutic agent content (IR820 and PTX, 95.7%). Besides the good stability in bloodstream, the IR820-PTX nanoparticles can target tumors for high accumulation via the enhanced permeation and retention effect. Particularly, our IR820-PTX nanoparticles simultaneously solve the obstacles of PTX poor solubility and the short lifetime of IR820 for cancer therapy. The simultaneous release of the free drug and dye can efficiently kill tumor cells by the combination of PTT and chemotherapy via NIR irradiation. Furthermore, the combined therapy can be imaging-guided by measuring the NIR fluorescence imaging resulting from the IR820 component. Therefore, our rationally designed pH- and enzyme-sensitive IR820-PTX conjugate nanoparticles provide an alternative "all-in-one" option for an efficient combinational dual-therapy and imaging.


Assuntos
Tratamento Farmacológico/métodos , Verde de Indocianina/análogos & derivados , Raios Infravermelhos , Nanopartículas/química , Imagem Óptica , Paclitaxel/química , Fototerapia/métodos , Animais , Sobrevivência Celular/efeitos dos fármacos , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Verde de Indocianina/química , Verde de Indocianina/toxicidade , Células MCF-7 , Nanopartículas/toxicidade , Paclitaxel/toxicidade , Coelhos
14.
Mater Sci Eng C Mater Biol Appl ; 89: 15-24, 2018 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-29752084

RESUMO

Graphene oxide (GO) has shown great potential in drug delivery. However, the aqueous stability, non-specific drug release and slow release rate are major problems of the GO-based drug delivery system. Herein, we for the first time integrate the dispersant, stabilizing agent and active targeting carrier into a novel drug delivery system based on GO/PP-SS-DOX nanohybrids. The redox-sensitive PP-SS-DOX prodrug was obtained by conjugating mPEG-PLGA (PP) with doxorubicin (DOX) via disulfide bond. PEG-FA provided active targeting property for the constructed drug delivery system, GO/PP-SS-DOX/PEG-FA. In this demonstrated system, PP-SS-DOX markedly increases the stability in physiological solutions of GO and guarantees the DOX release in the reductive environment (cancerous cells). And PEG-FA helps target to cancerous tissues and induces FR-mediated endocytosis. In vitro drug release exhibited the obvious reductive sensitivity and the cumulative release amount was up to 90%, while 40% in previous reports within 72 h. The in vitro cytotoxicity of targeting nanohybrids was significantly cytotoxic than that of non-targeting nanohybrids. In vivo results displayed that the as-prepared targeting nanohybrids showed efficacious antitumor effect while it had nearly no systemic adverse toxicity on B16 tumor-bearing mice. Therefore, the in vitro and in vivo results indicate that our constructed GO/PP-SS-DOX/PEG-FA drug delivery system is a promising carrier in cancer therapy.


Assuntos
Portadores de Fármacos/química , Grafite/química , Pró-Fármacos/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Hemólise/efeitos dos fármacos , Humanos , Melanoma Experimental/tratamento farmacológico , Melanoma Experimental/patologia , Camundongos , Nanoestruturas/química , Óxidos/química , Poliésteres/química , Polietilenoglicóis/química , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Coelhos , Distribuição Tecidual
15.
Med Res Rev ; 38(5): 1485-1510, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29341223

RESUMO

Increasing numbers of disulfide linkage-employing polymeric drug carriers that utilize the reversible peculiarity of this unique covalent bond have been reported. The reduction-sensitive disulfide bond is usually employed as a linkage between hydrophilic and hydrophobic polymers, polymers and drugs, or as cross-linkers in polymeric drug carriers. These polymeric drug carriers are designed to exploit the significant redox potential difference between the reducing intracellular environments and relatively oxidizing extracellular spaces. In addition, these drug carriers can release a considerable amount of anticancer drug in response to the reducing environment when they reach tumor tissues, effectively improving antitumor efficacy. This review focuses on various disulfide linkage-employing polymeric drug carriers. Important redox thiol pools, including GSH/GSSG, Cys/CySS, and Trx1, as well as redox environments in mammals, will be introduced.


Assuntos
Dissulfetos/metabolismo , Portadores de Fármacos/química , Mamíferos/metabolismo , Neoplasias/tratamento farmacológico , Polímeros/química , Animais , Humanos , Neoplasias/patologia , Oxirredução
16.
Colloids Surf B Biointerfaces ; 161: 449-456, 2018 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-29127937

RESUMO

Clinically, codelivery of chemotherapeutics has been limited by poor water-solubility and severe systemic toxicity. In this work, we developed a new reduction-sensitive mixed micellar system for self-codelivery of doxorubicin (DOX) and docetaxel (DTX). Biodegradable methoxy poly(ethylene glycol)-poly(ε-caprolactone) (mPEG-PCL) was coupled with DOX and DTX by a reduction-sensitive disulfide bond, resulting in mPEG-PCL-SS-DOX and mPEG-PCL-SS-DTX, respectively. mPEG-PCL-SS-DOX was mixed with mPEG-PCL-SS-DTX at a mole ratio of 1:1 in water, forming a mixed micellar system. The mixed micelles had a diameter of 223.7nm and a low critical micelle concentration. Reductive-triggered drug release revealed a "smart" characteristic of the mixed micelles. A cellular uptake and cytotoxicity assay in vitro showed that the mixed micelles could efficiently accumulate in MCF-7 cells and suppress the growth of tumour cells. The proposed reduction-sensitive mixed micelles assembled from amphiphilic prodrugs can be used as a promising drug codelivery system for cancer therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Micelas , Pró-Fármacos/administração & dosagem , Animais , Protocolos de Quimioterapia Combinada Antineoplásica/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Docetaxel , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Hemólise/efeitos dos fármacos , Humanos , Células MCF-7 , Oxirredução , Pró-Fármacos/química , Pró-Fármacos/farmacocinética , Coelhos , Taxoides/administração & dosagem , Taxoides/química , Taxoides/farmacocinética
17.
Adv Healthc Mater ; 6(24)2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-29076266

RESUMO

Herein, two careful selected anticancer drugs camptothecin (CPT) and cytarabine (Ara-C) with different biological action mechanisms and different water solubility are conjugated together through a glutathione (GSH) cleavable disulfide bond to construct a redox-sensitive drug-drug conjugate, which can self-assemble into nanoparticles, thus notably improving the water solubility of CPT and the cell membrane permeability of Ara-C. Compared with free drugs, the self-assembled CPT-ss-Ara nanoparticles can concentrate in tumor tissues through the enhanced permeability and retention (EPR) effect, then they can be rapidly internalized by tumor cells and degrade into free drugs for killing the tumor cells when exposed to the reductive environment (GSH) of tumor cells, thereby reducing the injury to normal cells. Meanwhile, the CPT-ss-Ara nanoparticles can effectively protect CPT and Ara-C molecules from biological inactivation before their arrival in tumor microenvironment since free CPT and Ara-C are easy to partly lose their therapy efficacy due to their structure degradation in blood circulation. The in vitro and in vivo anticancer experimental results indicate that simultaneous release of free CPT and Ara-C can realize synergistic chemotherapy effects, thus markedly improve their anticancer activity. Therefore, our designed carrier-free, redox-sensitive CPT-ss-Ara nanoparticles might have promising clinical application to combat cancers.


Assuntos
Antineoplásicos Fitogênicos/farmacologia , Camptotecina/farmacologia , Citarabina/farmacologia , Sistemas de Liberação de Medicamentos , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Apoptose/efeitos dos fármacos , Camptotecina/administração & dosagem , Linhagem Celular Tumoral , Citarabina/administração & dosagem , Modelos Animais de Doenças , Liberação Controlada de Fármacos , Sinergismo Farmacológico , Feminino , Glutationa/química , Células HT29 , Células Endoteliais da Veia Umbilical Humana , Humanos , Imagem por Ressonância Magnética , Camundongos , Nanopartículas/química
18.
ACS Appl Mater Interfaces ; 9(23): 19687-19697, 2017 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-28530401

RESUMO

Conventional organic and inorganic drug nanocarriers suffer from serious drawbacks such as low drug-storage capacity and uncontrolled release. Moreover, multidrug resistance (MDR) has been one of the primary causes leading to chemotherapy failure for cancers. The main reason for MDR is the overexpressed active efflux transporters such as P-glycoprotein. Here, zeolitic imidazolate framework ZIF-8, as one of the biocompatible metal organic frameworks (MOFs), is reported for the first time as the multidrug carrier to realizing the efficient codelivery of verapamil hydrochloride (VER) as the P-glycoprotein inhibitor as well as doxorubicin hydrochloride (DOX) as an anticancer drug to overcome the MDR in addition to realize the active targeted ability for an efficient anticancer effect. Uniform ZIF-8 nanoparticles encapsulating DOX and VER are achieved by a facile one-pot process, in which the VER is used to overcome the multidrug resistance. Furthermore, methoxy poly(ethylene glycol)-folate (PEG-FA) is used to stabilize the (DOX+VER)@ZIF-8 to realize prolonged circulations and an active targeting drug delivery. In particular, the ZIF-8 exhibits high drug loading content up to ∼40.9% with a pH-triggered release behavior. Importantly, the PEG-FA/(DOX+VER)@ZIF-8 shows enhanced therapeutic efficiencies with much safety compared with the direct administration of free DOX both in vitro and in vivo. Near infrared fluorescent (NIRF) imaging indicates that the PEG-FA/(DOX+VER)@ZIF-8 can increase the drug accumulations in tumors for targeted cancer therapy. Therefore, the PEG-FA/(DOX+VER)@ZIF-8 multidrug delivery system can be used as a promising efficient formulation in reversing the multidrug resistance for targeted cancer therapy.


Assuntos
Estruturas Metalorgânicas/química , Doxorrubicina , Resistência a Múltiplos Medicamentos , Humanos , Neoplasias , Verapamil
19.
Colloids Surf B Biointerfaces ; 155: 51-60, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28407531

RESUMO

PTX and DOX have different anticancer mechanisms. The combination of the two anticancer drugs could synergically enhance their anticancer effect, but simultaneously accompanied by severe side effects. In the present study, we constructed a mixed micelle system based on redox-sensitive mPEG-SS-PTX and mPEG-SS-DOX conjugate. The drug delivery system has a fixed and high drug loading content of 24.2% (PTX∼14.8% and DOX∼9.4%) with a precise ratio of PTX and DOX to realize the synchronized and controlled release. The mixed micelle has an average size of 93.3nm with a narrow distribution, suitable for passive targeting to tumor tissues by the EPR effect. In vitro release profile and in vitro anticancer results show the mixed micelles have obvious redox-sensitive release properties in reducing environment and have a significant cytotoxicity to A549 and B16 cells. Importantly, in vivo study shows the mixed micelles have no obvious side effect on mice compared to free PTX/DOX samples during the treatment. Therefore, the constructed redox-sensitive mixed micelle is a promising drug delivery system for cancer therapy.


Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Portadores de Fármacos , Composição de Medicamentos/métodos , Melanoma Experimental/tratamento farmacológico , Paclitaxel/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Células A549 , Animais , Antineoplásicos/química , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Quimioterapia Combinada , Humanos , Injeções Intravenosas , Masculino , Melanoma Experimental/patologia , Camundongos , Micelas , Oxirredução , Paclitaxel/química , Polietilenoglicóis/química , Neoplasias Cutâneas/patologia
20.
Colloids Surf B Biointerfaces ; 151: 119-127, 2017 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-27988472

RESUMO

The clinical usage of docetaxel (DTX) has been blocked in the clinic because of its poor solubility and tumour multi-drug resistance (MDR). The dominating mechanism of MDR is the over-expression of p-gp on tumour cells. Traditional nano-medicines, such as nanoparticles and micelles, have been used to physically entrap DTX to improve their solubility, while the drug loading content was very low and the tumour resistance was neglected. In this study, the synthesized reduction-sensitive mPEG-PLGA-SS-DTX conjugate was utilized to load the p-gp inhibitor veraparmil (VRP) to prepare DTX and VRP co-delivered mPEG-PLGA-SS-DTX/VRP (PP-SS-DTX/VRP) multi-functional micelles to reverse MDR and enhance the anti-tumour effect of DTX. The micelles had a high drug loading content and showed an obvious reduction-sensitive release property for both DTX and VRP. In addition, an in vitro anti-tumour assay revealed that the micelles markedly inhibited the efflux activity of p-gp and accelerated cell apoptosis, resulting in the improvement of anti-tumour activity and reversal of MDR. The PP-SS-DTX micelles markedly enhanced the in vivo circulation time and increased the drug accumulation in tumour tissues. Therefore, the PP-SS-DTX/VRP micelle is a desirable drug delivery system for multi-drug resistance therapy of DTX and is very promising for clinical usage.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Poliésteres/química , Polietilenoglicóis/química , Succinimidas/química , Taxoides/administração & dosagem , Taxoides/química , Verapamil/administração & dosagem , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/química , Animais , Apoptose , Neoplasias da Mama/genética , Sobrevivência Celular , Docetaxel , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Concentração Inibidora 50 , Células MCF-7 , Micelas , Microscopia Eletrônica de Transmissão , Ratos , Ratos Wistar , Solubilidade , Verapamil/química
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA