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1.
Chem Pharm Bull (Tokyo) ; 67(8): 888-895, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31366838

RESUMO

New sugar hydrazones incorporating furan and/or 1,3,4-thiadiazole ring systems were synthesized by reaction of the corresponding hydrazide with different aldose sugars. Heterocyclization of the formed hydrazones afforded the derived acyclic nucleoside analogues possessing the 1,3,4-oxadiazoline as modified nucleobase via acetylation followed by the heterocyclization process. The anticancer activity of the synthesized compounds was studied against human liver carcinoma cell (HepG-2) and at human normal retina pigmented epithelium cells (RPE-1). High activities were revealed by compounds 3, 12 and 14 with IC50 values near to that of the reference drug doxorubicin.


Assuntos
Antineoplásicos/farmacologia , Doxorrubicina/farmacologia , Furanos/farmacologia , Oxidiazóis/farmacologia , Açúcares/farmacologia , Tiadiazóis/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Furanos/síntese química , Furanos/química , Células Hep G2 , Humanos , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Relação Estrutura-Atividade , Açúcares/síntese química , Açúcares/química , Tiadiazóis/síntese química , Tiadiazóis/química
2.
Pharm Res ; 36(10): 144, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31392417

RESUMO

PURPOSE: Boron neutron capture therapy (BNCT) has the potential to become a viable cancer treatment modality, but its clinical translation requires sufficient tumor boron delivery while minimizing nonspecific accumulation. METHODS: Thermal sensitive liposomes (TSLs) were designed to have a stable drug payload at physiological temperatures but engineered to have high permeability under mild hyperthermia. RESULTS: We found that TSLs improved the tumor-specific delivery of boronophenylalanine (BPA) and boronated 2-nitroimidazole derivative B-381 in D54 glioma cells. Uniquely, the 2-nitroimidazole moiety extended the tumor retention of boron content compared to BPA. CONCLUSION: This is the first study to show the delivery of boronated compounds using TSLs for BNCT, and these results will provide the basis of future clinical trials using TSLs for BNCT.


Assuntos
Compostos de Boro/química , Terapia por Captura de Nêutron de Boro , Lipossomos/química , Animais , Antineoplásicos/química , Compostos de Boro/administração & dosagem , Compostos de Boro/farmacocinética , Linhagem Celular Tumoral , Neoplasias do Sistema Nervoso Central/metabolismo , Doxorrubicina/química , Liberação Controlada de Fármacos , Feminino , Glioma/metabolismo , Humanos , Hipertermia Induzida , Camundongos Nus , Nitroimidazóis/administração & dosagem , Nitroimidazóis/química , Tamanho da Partícula , Fenilalanina/administração & dosagem , Fenilalanina/análogos & derivados , Fenilalanina/química , Fosfolipídeos/química , Temperatura Ambiente , Distribuição Tecidual
3.
Chem Commun (Camb) ; 55(72): 10654-10664, 2019 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-31418758

RESUMO

Some host-guest complexes of cucurbit[n]uril (CB[n]) host molecules act as supramolecular amphiphiles (SAs), which hierarchically self-assemble into various nanomaterials such as vesicles, micelles, nanorods, and nanosheets in water. The structures and functions of the nanomaterials can be controlled by supramolecular engineering of the host-guest complexes. In addition, functionalization at the periphery of CB[6] and CB[7] generates CB[n]-based molecular amphiphiles (MAs) that can also self-assemble into vesicles or micelle-like nanoparticles in water. Taking advantage of the molecular cavities of CBs and their strong guest recognition properties, the surface of the self-assembled nanomaterials can be easily decorated with various functional tags in a non-covalent manner. In this feature article, the two types (SAs and MAs) of CB-based amphiphiles, their self-assemblies and their applications for nanotherapeutics and theranostics are presented with future perspectives.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Doxorrubicina/farmacologia , Nanoestruturas/química , Tensoativos/farmacologia , Antibióticos Antineoplásicos/química , Hidrocarbonetos Aromáticos com Pontes/química , Proliferação de Células/efeitos dos fármacos , Doxorrubicina/química , Células HeLa , Humanos , Células KB , Tensoativos/química
4.
Chem Commun (Camb) ; 55(71): 10627-10630, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31429450

RESUMO

We report the synthesis of a novel hydroxyl-functionalised heteroleptic bis-NHC gold(i) complex that permits conjugation to various amines via carbamate bond formation. The resulting derivatives were studied in vitro using cell proliferation assays and fluorescent microscopic imaging of human cancer cell lines.


Assuntos
Aminas/química , Antineoplásicos/síntese química , Carbamatos/química , Complexos de Coordenação/síntese química , Corantes Fluorescentes/síntese química , Ouro/química , Células A549 , Antineoplásicos/farmacologia , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Complexos de Coordenação/farmacologia , Doxorrubicina/química , Humanos , Imagem Óptica , Tiorredoxina Dissulfeto Redutase/antagonistas & inibidores , Triazóis/química
5.
Chem Commun (Camb) ; 55(61): 9015-9018, 2019 Aug 07.
Artigo em Inglês | MEDLINE | ID: mdl-31290867
6.
J Nanobiotechnology ; 17(1): 83, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31291948

RESUMO

BACKGROUND: Macrophages with tumor-tropic migratory properties can serve as a cellular carrier to enhance the efficacy of anti neoplastic agents. However, limited drug loading (DL) and insufficient drug release at the tumor site remain the main obstacles in developing macrophage-based delivery systems. In this study, we constructed a biomimetic delivery system (BDS) by loading doxorubicin (DOX)-loaded reduced graphene oxide (rGO) into a mouse macrophage-like cell line (RAW264.7), hoping that the newly constructed BDS could perfectly combine the tumor-tropic ability of macrophages and the photothermal property of rGO. RESULTS: At the same DOX concentration, the macrophages could absorb more DOX/PEG-BPEI-rGO than free DOX. The tumor-tropic capacity of RAW264.7 cells towards RM-1 mouse prostate cancer cells did not undergo significant change after drug loading in vitro and in vivo. PEG-BPEI-rGO encapsulated in the macrophages could effectively convert the absorbed near-infrared light into heat energy, causing rapid release of DOX. The BDS showed excellent anti-tumor efficacy in vivo. CONCLUSIONS: The BDS that we developed in this study had the following characteristic features: active targeting of tumor cells, stimuli-release triggered by near-infrared laser (NIR), and effective combination of chemotherapy and photothermotherapy. Using the photothermal effect produced by PEG-BPEI-rGO and DOX released from the macrophages upon NIR irradiation, MAs-DOX/PEG-BPEI-rGO exhibited a significant inhibitory effect on tumor growth.


Assuntos
Antineoplásicos/química , Materiais Biomiméticos/química , Portadores de Fármacos/química , Macrófagos/metabolismo , Neoplasias da Próstata/tratamento farmacológico , Animais , Antineoplásicos/administração & dosagem , Linhagem Celular Tumoral , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Liberação Controlada de Fármacos , Grafite/química , Humanos , Hipertermia Induzida , Raios Infravermelhos , Lasers , Masculino , Camundongos Endogâmicos BALB C , Polietilenoglicóis/química , Polietilenoimina/análogos & derivados , Polietilenoimina/química , Distribuição Tecidual
7.
Chem Commun (Camb) ; 55(58): 8434-8437, 2019 Jul 25.
Artigo em Inglês | MEDLINE | ID: mdl-31259350

RESUMO

Phosphatidylcholine is the main component of liposomes and other phospholipid-based nanocarriers in drug delivery. However, the functions and applications of these nanocarriers are extremely limited by conventional phospholipids. Here we report novel disulfide phosphatidylcholines (SS-PCs) and SS-PC based liposomes (SS-LPs) used as alternatives to traditional phospholipids and liposomes.


Assuntos
Dissulfetos/química , Portadores de Fármacos/química , Lipossomos/química , Fosfatidilcolinas/química , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Linhagem Celular Tumoral , Dissulfetos/síntese química , Dissulfetos/metabolismo , Doxorrubicina/química , Doxorrubicina/farmacologia , Doxorrubicina/uso terapêutico , Portadores de Fármacos/síntese química , Portadores de Fármacos/metabolismo , Humanos , Lipossomos/síntese química , Lipossomos/metabolismo , Camundongos , Oxirredução , Fosfatidilcolinas/síntese química , Fosfatidilcolinas/metabolismo
8.
J Phys Chem Lett ; 10(15): 4278-4284, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31318218

RESUMO

Silk continues to amaze: over the past decade, new research threads have emerged that include the use of silk fibroin for advanced pharmaceutics, including its suitability for drug delivery. Despite this ongoing interest, the details of silk fibroin structures and their subsequent drug interactions at the molecular level remain elusive, primarily because of the difficulties encountered in modeling the silk fibroin molecule. Here, we generated an atomistic silk model containing amorphous and crystalline regions. We then exploited advanced well-tempered metadynamics simulations to generate molecular conformations that we subsequently exposed to classical molecular dynamics simulations to monitor both drug binding and release. Overall, this study demonstrated the importance of the silk fibroin primary sequence, electrostatic interactions, hydrogen bonding, and higher-order conformation in the processes of drug binding and release.


Assuntos
Doxorrubicina/química , Portadores de Fármacos/química , Fibroínas/química , Animais , Bombyx/química , Cristalização , Liberação Controlada de Fármacos , Ligações de Hidrogênio , Simulação de Dinâmica Molecular , Conformação Proteica , Eletricidade Estática , Termodinâmica , Água/química
9.
Phys Chem Chem Phys ; 21(27): 15222-15232, 2019 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-31250877

RESUMO

Star-shaped polymers have received significant attention and have been widely developed for prospective applications in drug delivery owing to their topological structure and unique physiochemical characteristics. The anticancer drug doxorubicin (DOX) was used as a model drug, and four/six-arm star-shaped block polymeric micelles were employed as the carriers. The dissipative particle dynamics (DPD) method was adopted to simulate the formation of micelles, the effects of the hydrophobic/hydrophilic block ratio on the micellar structure and drug-loading performance, the effect of the drug loading content on the micellar morphology, and the effect of the pH-sensitive block ratio on the drug release properties. Under neutral conditions (pH = 7.4), increasing the hydrophobic block ratio reduces the stability of the micelle structure but could improve its drug loading performance. Increasing the pH-sensitive block (DEAEMA) ratio is beneficial to the drug loading performance of the mikto-arm star-shaped polymeric micelles and is detrimental to the drug loading performance of the herto-arm star-shaped polymeric micelles. After comparing the structural changes, radial distribution function (RDF) and mean square displacement (MSD) of the polymeric micelles with different pH-sensitive block ratios under weakly acidic conditions (pH = 5.0), the drug release properties of the drug-loaded micelles were systematically analysed. The results showed that the higher the proportion of the pH-sensitive block in the polymeric micelles, the better their pH-response performance, and the looser the structure of the micelles during the release process. A too high or too low ratio of pH-sensitive blocks in the polymeric micelles was detrimental to drug release performance. This study could provide theoretical support for the structural design and development of novel functional block polymers.


Assuntos
Antineoplásicos/administração & dosagem , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Micelas , Simulação de Dinâmica Molecular , Antineoplásicos/química , Preparações de Ação Retardada/administração & dosagem , Preparações de Ação Retardada/química , Doxorrubicina/química , Concentração de Íons de Hidrogênio , Polímeros/química
10.
Talanta ; 200: 212-217, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31036175

RESUMO

A surface-enhanced Raman scattering (SERS) imaging probe and drug carrier based on zeolitic imidazolate framework (ZIF-8)-coated Au@Ag core-shell nanorod has been developed. Strong Raman signal is generated by a reporter molecule of 4-aminothiophenol (4-ATP) adsorbed on Au@Ag core-shell nanorod, endowing the probe with function of SERS imaging. Further coating of ZIF-8 on Au@Ag core-shell nanorod offered high loading capacity for anti-cancer drugs, doxorubicin (DOX), as well as improved the stability and biocompatibility of the SERS tag due to the protection of ZIF-8 shell. After immobilization of folic acid onto the Au@Ag NRs4-ATP@ZIF-8, the SERS probes were successfully applied to the targeted SERS imaging of HeLa, MCF-7, LNCaP, QGY-7703, HCT116 and MDA-MB-231 cells with low cytotoxicity, and further applied to the image of tumor tissue of human colon cancer. In vitro cell cytotoxicity confirmed that DOX-loaded SERS probes had potential therapeutic effect compared with the free drug. All of these original results contribute to develop potential biocompatible nanosystem integrating diagnosis and therapy.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Materiais Biocompatíveis/farmacologia , Doxorrubicina/farmacologia , Sistemas de Liberação de Medicamentos , Nanopartículas/química , Nanotubos/química , Zeolitas/farmacologia , Antibióticos Antineoplásicos/química , Materiais Biocompatíveis/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Relação Dose-Resposta a Droga , Doxorrubicina/química , Ensaios de Seleção de Medicamentos Antitumorais , Ouro/química , Ouro/farmacologia , Células HeLa , Humanos , Células MCF-7 , Imagem Óptica , Prata/química , Prata/farmacologia , Análise Espectral Raman , Relação Estrutura-Atividade , Propriedades de Superfície , Zeolitas/química
11.
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
12.
Sensors (Basel) ; 19(9)2019 May 05.
Artigo em Inglês | MEDLINE | ID: mdl-31060322

RESUMO

A new voltammetric DNA sensor has been developed for doxorubicin determination on the platform of a glassy carbon electrode (GCE) covered with electropolymerized Azure B film and physically adsorbed native DNA. The redox properties of polymeric Azure B were monitored at various pH and scan rates. DNA application decreased the peak currents related to polymeric and monomeric forms of the dye, whereas incubation in doxorubicin solution partially restored the peaks in accordance with the drug and DNA concentration. The relative shift of the cathodic peak current caused by doxorubicin depended on the nominal DNA concentration and its application mode. In optimal conditions, the DNA sensor makes it possible to determine between 0.1 µM to 0.1 nM doxorubicin (limit of detection 7×10-11 M). The DNA sensor was tested on commercial doxorubicin formulations and on artificial samples the mimicked electrolyte content of human serum.


Assuntos
Técnicas Biossensoriais , DNA/isolamento & purificação , Doxorrubicina/isolamento & purificação , Nanotubos de Carbono/química , Corantes Azur/química , DNA/química , Doxorrubicina/química , Técnicas Eletroquímicas/métodos , Humanos , Oxirredução , Polímeros/química
13.
J Mater Chem B ; 7(16): 2678-2687, 2019 04 28.
Artigo em Inglês | MEDLINE | ID: mdl-31073405

RESUMO

A drug delivery system (DDS) for combined therapy, based on a short oxidized multiwalled carbon nanotube, is reported. It was prepared exploiting a synthetic approach which allowed loading of two drugs, doxorubicin and metformin, the targeting agent biotin and a radiolabeling tag, to enable labeling with Ga-68 or Cu-64 in order to perform an extensive biodistribution study by PET/CT. The DDS biodistribution profile changes with different administration methods. Once administered at therapeutic doses, the DDS showed a marginal beneficial effect on 4T1 tumor bearing mice, a syngeneic and orthotopic model of triple negative breast cancer, with survival extended by 1 week and 2 days in 20% of the mice. This is encouraging given the aggressiveness of the 4T1 tumor. Furthermore our DDS was well tolerated, ruling out concerns regarding the toxicity of carbon nanotubes.


Assuntos
Doxorrubicina/química , Portadores de Fármacos/química , Metformina/química , Nanotubos de Carbono/química , Animais , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Radioisótopos de Cobre/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/síntese química , Radioisótopos de Gálio/química , Marcação por Isótopo , Metformina/farmacocinética , Metformina/farmacologia , Camundongos , Projetos Piloto , Tomografia Computadorizada com Tomografia por Emissão de Pósitrons , Distribuição Tecidual
14.
Nanoscale ; 11(18): 9201-9206, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31038497

RESUMO

Smart drug delivery nanosystems with integrated real-time monitoring capability have attracted great attention in recent years; however, they are still in a nascent stage due to a lack of proper imaging modalities. Herein, we present a novel pH-responsive drug delivery nanosystem in which a coordination complex of tannic acid and Cu2+ ions was successfully functionalized onto the surface of mesoporous silica-coated upconversion nanoparticles (UCNPs) to block premature release of the anti-cancer drug doxorubicin (DOX) from the mesopores of the particles. In addition, loading of the drug enables luminescence resonance energy transfer (LRET) from the UCNPs to DOX, which results in quenching of the emission of the UCNPs. The metal-phenolic networks are degraded in the acidic environment in living cells, leading to DOX release from the mesopores and thus to elimination of LRET. Therefore, the changes in upconversion luminescence enable monitoring of the pH-triggered drug release in real-time. This strategy will facilitate the design of smart drug delivery systems and theranostics.


Assuntos
Doxorrubicina/química , Portadores de Fármacos/química , Nanopartículas/química , Fenóis/química , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Transferência Ressonante de Energia de Fluorescência , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Microscopia Confocal , Porosidade
15.
Soft Matter ; 15(18): 3655-3658, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-31012474

RESUMO

We developed biocompatible ATP responsive DNA nanogels, by grafting DNA strands on carboxymethyl chitosan polymer chains, and then hybridizing with ATP aptamers to form core-shell nanogels. The DNA duplex structure could embed DOX in the G-C sequences, and realize simultaneous sol-gel transition and DOX release when suffering enrich ATP in tumor cells.


Assuntos
Trifosfato de Adenosina/metabolismo , Antineoplásicos/química , Materiais Biocompatíveis/química , DNA/química , Portadores de Fármacos/química , Nanoestruturas/química , Células A549 , Antineoplásicos/metabolismo , Transporte Biológico , Doxorrubicina/química , Doxorrubicina/metabolismo , Liberação Controlada de Fármacos , Géis , Humanos , Espaço Intracelular/metabolismo
16.
Chem Asian J ; 14(11): 1992-1999, 2019 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-30941908

RESUMO

Developing hierarchical supramolecular structures is important for better understanding of various biological functions and possibly generating new materials for biomedical applications. Herein, we report the first examples of functional vesicles derived from cationic spherical organic molecules (C1 -C3 ) which were readily synthesized by reacting a C3 -symmetric tris-benzimmidazole derivative (possessing a 1,3,5-ethyl substituted aromatic core) with 1,3,5-substituted tris-bromomethyl benzene derivatives. Vesicle formation by C1 -C3 was probed by high-resolution microscopy (TEM and AFM), dynamic light scattering (DLS) and fluorescence microscopic imaging of calcein-loaded vesicles. One of the vesicles [Vesicle(C3 )] displayed the ability to load the anticancer drug doxorubicin (DOX). The drug was subsequently released from DOX@Vesicle(C3 ) in a stimuli-responsive manner in presence of the well-known vesicle destroyer Triton X-100, as revealed by in vitro cell migration assay carried out on a highly aggressive human breast cancer cell line (MDA-MB-231).


Assuntos
Antineoplásicos/química , Doxorrubicina/química , Portadores de Fármacos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacologia , Derivados de Benzeno/química , Linhagem Celular Tumoral , Movimento Celular/efeitos dos fármacos , Doxorrubicina/metabolismo , Doxorrubicina/farmacologia , Portadores de Fármacos/síntese química , Liberação Controlada de Fármacos , Fluoresceínas/química , Humanos , Microscopia de Fluorescência , Água/química
17.
Chem Pharm Bull (Tokyo) ; 67(4): 367-371, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30930441

RESUMO

Formulation of a drug as liposomes facilitates its delivery to the disease target. Rightly, liposomes are gaining popularity in the medical field. In order for the drug to show efficacy, release of the encapsulated drug from the liposome at the target site is required. However, the release is affected by the permeability of the lipid bilayer of the liposome, and it is important to examine the effect of the surrounding environment on the permeability. In this study, we showed the usefulness of fluorescence analysis, especially fluorescence fingerprint, for a rapid and simple monitoring of release of an encapsulated anticancer drug (doxorubicin) from its liposomal formulation (DOXIL). Our result indicated that the release is accelerated by the existence of membrane permeable ions, such as tris(hydroxymethyl)aminomethane, and blood proteins like albumin. Hence, monitoring of doxorubicin release by fluorescence analysis is useful for the efficacy evaluation of DOXIL in a biomimetic environment.


Assuntos
Doxorrubicina/sangue , Lipossomos/química , Doxorrubicina/química , Doxorrubicina/metabolismo , Composição de Medicamentos , Liberação Controlada de Fármacos , Humanos , Albumina Sérica/química , Espectrometria de Fluorescência
18.
Int J Nanomedicine ; 14: 2069-2089, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30988609

RESUMO

Purpose: Melanoma is the most aggressive form of skin cancer. Chemotherapy at a late stage fails due to low accumulation in tumors, indicating the need for targeted therapy. Materials and methods: To increase drug uptake by tumor cells, we have targeted doxorubicin-containing liposomes using a T-cell receptor (TCR)-like antibody (scFv G8 and Hyb3) directed against melanoma antigen A1 (MAGE-A1) presented by human leukocyte antigen A1 (M1/A1). With the use of flow cytometry and confocal microscopy, we have tested our formulation in vitro. In vivo pharmacokinetics was done in tumor-free nu/nu mice, while biodistribution and efficacy study was done in nu/nu mice xenograft. Results: We demonstrated two to five times higher binding and internalization of these immunoliposomes by M1+/A1+ melanoma cells in vitro in comparison with nontargeted liposomes. Cytotoxicity assay showed significant tumor cell kill at 10 µM doxorubicin (DXR) for targeted vs nontargeted liposomes. In vivo pharmacokinetics of nontargeted and targeted liposomes were similar, while accumulation of targeted liposomes was 2- to 2.5-fold and 6.6-fold enhanced when compared with nontargeted liposomes and free drug, respectively. Notably, we showed a superior antitumor activity of MAGE-A1-targeted DXR liposomes toward M1+/A1+ expressing tumors in mice compared with the treatment of M1-/A1+ tumors. Our results indicate that targeted liposomes showed better cytotoxicity in vitro and pharmacokinetics in vivo. Conclusion: Liposomes decorated with TCR-mimicking scFv antibodies effectively and selectively target antigen-positive melanoma. We showed that DXR-loaded liposomes coupled to anti-M1/-A1 scFv inflict a significant antitumor response. Targeting tumor cells specifically promotes internalization of drug-containing nanoparticles and may improve drug delivery and ultimately antitumor efficacy. Our data argue that targeting MAGE in A1 context, by nanosized carriers decorated with TCR-like antibodies mimicking scFv, can be used as a theragnostic platform for drug delivery, immunotherapy, and potentially imaging, and diagnosis of melanoma.


Assuntos
Apresentação do Antígeno/imunologia , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos , Antígeno HLA-A1/imunologia , Lipossomos/administração & dosagem , Melanoma/tratamento farmacológico , Nanopartículas/administração & dosagem , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/química , Doxorrubicina/farmacocinética , Humanos , Lipossomos/química , Lipossomos/imunologia , Melanoma/imunologia , Camundongos Nus , Nanopartículas/química , Receptores de Antígenos de Linfócitos T/imunologia , Anticorpos de Cadeia Única/imunologia , Distribuição Tecidual , Células Tumorais Cultivadas
19.
ACS Appl Mater Interfaces ; 11(18): 16285-16295, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-30986025

RESUMO

Engineering multiple theranostic modalities into a single nanoscale entity holds great potential to rejuvenate cancer treatments; however, enabling the sophisticated spatiotemporal control of each component for maximizing theranostic improvement and minimizing side effects concurrently remains a challenge. Herein, an intelligent detachable "nanorocket" is developed to sequentially manipulate and optimize multitheranostic processes for magnetic resonance-assisted ultrasound-drug combined therapy (MR-HIFU-Drug). The "nanorocket" is constructed by integrating multicomponent (MnCO3, doxorubicin, silica) on the pH-sensitive CaCO3 nanoparticles step by step via cation exchange and controlled heterogeneous nucleation, in which doxorubicin is encapsulated in both carbonates and silica component. The "nanorocket" can initiate sequential detachment in the acidic tumor microenvironment. Specifically, carbonates decompose instantly, releasing Mn2+ as the MR contrast agent and leaving hollow silica nanostructure behind as the HIFU synergistic agent. Consequently, burst release of drug is also triggered, further triggering the degradation of silica, which in turn regulates the slow release of drug from the silica matrix. Thus, efficient tumor inhibition is achieved by enhanced HIFU ablation and biphase release of doxorubicin with a stepwise clearance of Mn and Si. This work establishes a system for the systematic spatiotemporal dispatch of diverse theranostic components for the balance of efficacy and safety in cancer theranostics.


Assuntos
Doxorrubicina/administração & dosagem , Nanopartículas/administração & dosagem , Neoplasias/tratamento farmacológico , Nanomedicina Teranóstica/métodos , Animais , Carbonato de Cálcio/química , Linhagem Celular Tumoral , Doxorrubicina/química , Liberação Controlada de Fármacos , Humanos , Concentração de Íons de Hidrogênio , Imagem por Ressonância Magnética , Camundongos , Nanopartículas/química , Neoplasias/diagnóstico por imagem , Neoplasias/patologia , Ratos , Dióxido de Silício/química , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
20.
ACS Appl Mater Interfaces ; 11(18): 16412-16420, 2019 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-30990307

RESUMO

Metal ion synergistically enhanced chemotherapy is a promising strategy for cancer treatment. However, targeting delivery of ions toward cancer cells remains challenging for decades. Herein, we developed a novel folic acid-nanogel (termed as FA-nanogel) with alkane chains as diffusion barriers for targeted transmembrane delivery of calcium ions into cancer cells. With the aid of hydrophobic diffusion barriers, the FA-nanogel showed a reduced and sustained speed for release of calcium ions, significantly prolonging the ion effect. Moreover, a pH-sensitive injectable hydrogel-loaded FA-nanogel and chemotherapeutic drug 5-fluorouracil (5-Fu) was synthesized for investigating the synergistic effect of nanogel on chemotherapy. Both in vitro and in vivo experiments confirmed that the intracellular calcium ions were continuously increased because of the targeted delivery ability and ion sustained release ability of the smart FA-nanogel, and the tumor growth was effectively inhibited by the ion synergistic chemotherapy. This study not only provides a powerful nanoplatform for sustained transmembrane delivery of ions into malignant cells but also creates better conditions for improving the therapeutic efficacy of chemotherapy.


Assuntos
Cálcio/administração & dosagem , Hidrogéis/administração & dosagem , Nanopartículas Metálicas/administração & dosagem , Neoplasias/tratamento farmacológico , Animais , Cálcio/química , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Portadores de Fármacos/administração & dosagem , Portadores de Fármacos/química , Fluoruracila/administração & dosagem , Fluoruracila/química , Ácido Fólico/administração & dosagem , Ácido Fólico/química , Células HeLa , Humanos , Hidrogéis/síntese química , Hidrogéis/química , Concentração de Íons de Hidrogênio , Íons/administração & dosagem , Íons/química , Nanopartículas Metálicas/química , Camundongos , Neoplasias/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
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