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1.
Int J Nanomedicine ; 15: 137-149, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021170

RESUMO

Purpose: Traditional chemotherapy is accompanied by significant side effects, which, in many aspects, limits its treatment efficacy and clinical applications. Herein, we report an oxidative responsive polymersome nanosystem mediated by near infrared (NIR) light which exhibited the combination effect of photodynamic therapy (PDT) and chemotherapy. Methods: In our study, poly (propylene sulfide)20-bl-poly (ethylene glycol)12 (PPS20-b-PEG12) block copolymer was synthesized and employed to prepare the polymersome. The hydrophobic photosensitizer zinc phthalocyanine (ZnPc) was loaded in the shell and the hydrophilic doxorubicin hydrochloride (DOX·HCl) in the inner aqueous space of the polymersome. Results: Under the irradiation of 660 nm NIR light, singlet oxygen 1O2 molecules were generated from ZnPc to oxidize the neighbouring sulfur atoms on the PPS block which eventually ruptured the intact structure of polymersomes, leading to the release of encapsulated DOX·HCl. The released DOX and the 1O2 could achieve a combination effect for cancer therapy if the laser activation and drug release occur at the tumoral sites. In vitro studies confirmed the generation of singlet oxygen and DOX release by NIR irradiation. In vivo studies showed that such a combined PDT-chemotherapy nanosystem could accumulate in A375 tumors efficiently, thus leading to significant inhibition on tumor growth as compared to PDT (PZ group) or chemotherapy alone (DOX group). Conclusion: In summary, this oxidation-sensitive nanosystem showed excellent anti-tumor effects by synergistic chemophotodynamic therapy, indicating that this novel drug delivery strategy could potentially provide a new means for cancer treatments in clinic.


Assuntos
Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Melanoma Experimental/tratamento farmacológico , Fotoquimioterapia/métodos , Fármacos Fotossensibilizantes/administração & dosagem , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Humanos , Indóis/administração & dosagem , Indóis/química , Lasers , Masculino , Camundongos Endogâmicos BALB C , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Compostos Organometálicos/administração & dosagem , Compostos Organometálicos/química , Fármacos Fotossensibilizantes/química , Polietilenoglicóis/química , Polímeros/química , Oxigênio Singlete/farmacocinética , Sulfetos/química
2.
Int J Nanomedicine ; 15: 433-444, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32021189

RESUMO

Background: Carbon dots (CDs) have attracted extensive attention in recent years because of their high biocompatibility and unique optical property. But they could not be well applied in the drug delivery system to enable distribution in tumor sites with their low pH sensitivity. They are barriers for drug delivery. CDs as an imaging proper were conjugated with doxorubicin (DOX) lipid-coated calcium phosphate (LCP) nanoparticle, for a pH-sensitive nanocarrier and delivery of the antitumor drugs. Materials and Methods: CDs were prepared by one-step hydrothermal treatment of citric acid and ethylenediamine. The nanoparticles were simply prepared by using microemulsion technology to form calcium phosphate (CaP) core and further coated with cationic lipids. Results: The structure was characterized by FTIR, XRD and TEM. In vitro release study revealed that DOX-CDs@LCP was pH dependent. The cytotoxicity assay demonstrated that it exhibited enhanced efficiency compared to the control group (DOX-CDs), but weaker than free DOX. The cellular uptake revealed that these pH-sensitive nanoparticles could be taken up effectively and deliver DOX into the cytoplasm to reach antitumor effect. The fluorescence imaging indicated that DOX-CDs@LCP mostly distributed in the tumor region due to the enhanced permeability and retention effect (EPR) to reduce its systematical toxicity. Importantly, an antitumor activity study demonstrated that the DOX-CDs@LCP nanoparticles had higher antitumor activity than any other groups and lower toxicity. The results showed that LCP could significantly promote the release in tumor microenvironment due to pH-response. The DOX-CDs could enhance load capacity and reduce drug premature releasing; real-time tracking of efficacy as confocal imaging contrast agent. Thus, DOX-CDs@LCP had antitumor capacity and lower systematic toxicity in tumor therapy. Conclusion: DOX-CDs@LCP were proven as a promising tumor pH-sensitive and imaging-guided drug delivery system for liver cancer chemotherapy.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Fosfatos de Cálcio/química , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Animais , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Apoptose/efeitos dos fármacos , Carbono/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Células Hep G2 , Humanos , Concentração de Íons de Hidrogênio , Lipídeos/química , Masculino , Camundongos , Neoplasias Experimentais/diagnóstico por imagem , Distribuição Tecidual , Microambiente Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
3.
AAPS PharmSciTech ; 21(2): 42, 2020 Jan 02.
Artigo em Inglês | MEDLINE | ID: mdl-31897882

RESUMO

Mesoporous carriers have been widely used to deliver anticancer drugs due to their unique characteristics. In this work, mesoporous silica nanoparticles (MSN) and mesoporous carbon nanoparticles (MCN) with substantially similar and uniform particle size, specific surface area, and pore size were prepared to compare the photothermal effect, drug loading efficiencies (LE), and drug release properties. In order to improve the dispersion stability and biocompatibility of the carriers, MSN and MCN were grafted with PEG, respectively. The NIR-induced photothermal effect results indicated that MCN had a brilliant photothermal conversion efficiency due to its strong near-infrared absorption capacity, while MSN had no photothermal conversion capability. Moreover, LE of DOX in DOX/MCN-PEG reached 36.58%, higher than that in DOX/MSN-PEG, which was ascribed to non-covalent interaction of π-π stacking and electrostatic attraction. In addition, compared to DOX/MSN-PEG, DOX/MCN-PEG had a significantly increased release rate under NIR laser irradiation due to excellent photothermal conversion capability of MCN-PEG. Furthermore, cell viability assay and cellular uptake experiment results demonstrated that DOX/MCN-PEG showed a synergistic therapeutic effect in the combination of chemotherapy and phototherapy, with a combination index (CI) of 0.238.


Assuntos
Antineoplásicos/administração & dosagem , Antineoplásicos/química , Carbono/química , Nanopartículas/química , Dióxido de Silício/química , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Antineoplásicos/farmacocinética , Linhagem Celular , Doxorrubicina/administração & dosagem , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos , Composição de Medicamentos , Liberação Controlada de Fármacos , Excipientes , Hemólise/efeitos dos fármacos , Humanos , Tamanho da Partícula , Polietilenoglicóis , Porosidade , Coelhos
4.
Anal Bioanal Chem ; 411(27): 7087-7094, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31471684

RESUMO

Accurate measurement and understanding of therapeutic uptake and metabolism is key in the drug development process. This work examines the amount of doxorubicin that can penetrate into spheroids after being encapsulated in a liposomal configuration in comparison with free drug. Through a process known as serial trypsinization, three distinct cellular populations of a spheroid were successfully separated and a small molecule extraction was used to isolate the chemotherapeutic. Doxorubicin showed a time-dependent permeability into spheroids with the most drug accumulating in the core at 24 h of treatment. Entrapment of the chemotherapeutic delayed the permeability of the drug and resulted in reduced amounts quantified at the earlier time points. These findings validate the claim that liposomal therapeutics have the ability to alter the pharmacokinetics and pharmacodynamics profiles of a drug while also demonstrating the combined power of mass spectrometry and three-dimensional cell cultures to evaluate drug penetration and metabolism. Graphical abstract.


Assuntos
Antibióticos Antineoplásicos/metabolismo , Doxorrubicina/análogos & derivados , Esferoides Celulares/metabolismo , Antibióticos Antineoplásicos/farmacocinética , Doxorrubicina/metabolismo , Doxorrubicina/farmacocinética , Células HCT116 , Humanos , Espectrometria de Massas , Polietilenoglicóis/metabolismo , Polietilenoglicóis/farmacocinética , Tripsina/metabolismo
5.
Int J Hyperthermia ; 36(1): 817-826, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31451077

RESUMO

Objective: Thermosensitive liposomal doxorubicin (TSL-Dox) is a promising stimuli-responsive nanoparticle drug delivery system that rapidly releases the contained drug in response to hyperthermia (HT) (>40 °C). Combined with localized heating, TSL-Dox allows highly localized delivery. The goals of this study were to demonstrate that real-time fluorescence imaging can visualize drug uptake during delivery, and can predict tumor drug uptake. Methods: Nude mice carrying subcutaneous tumors (Lewis lung carcinoma) were anesthetized and injected with TSL-Dox (5 mg/kg dose). Localized HT was induced by heating tumors for 15, 30 or 60 min via a custom-designed HT probe placed superficially at the tumor location. In vivo fluorescence imaging (excitation 523 nm, emission 610 nm) was performed before, during, and for 5 min following HT. After imaging, tumors were extracted, drug uptake was quantified by high-performance liquid chromatography, and correlated with in vivo fluorescence. Plasma samples were obtained before and after HT to measure TSL-Dox pharmacokinetics. Results: Local drug uptake could be visualized in real-time during HT. Compared to unheated control tumors, fluorescence of heated tumors increased by 4.6-fold (15 min HT), 9.3-fold (30 min HT), and 13.2-fold (60 min HT). HT duration predicted tumor drug uptake (p = .02), with tumor drug concentrations of 4.2 ± 1.3 µg/g (no HT), 7.1 ± 5.9 µg/g (15 min HT), 14.1 ± 6.7 µg/g (30 min HT) and 21.4 ± 12.6 µg/g (60 min HT). There was good correlation (R2 = 0.67) between fluorescence of the tumor region and tumor drug uptake. Conclusions: Real-time in vivo fluorescence imaging can visualize drug uptake during delivery, and can predict tumor drug uptake.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Carcinoma Pulmonar de Lewis/diagnóstico por imagem , Carcinoma Pulmonar de Lewis/terapia , Doxorrubicina/análogos & derivados , Hipertermia Induzida , Imagem Óptica , Animais , Antibióticos Antineoplásicos/sangue , Antibióticos Antineoplásicos/farmacocinética , Carcinoma Pulmonar de Lewis/metabolismo , Doxorrubicina/administração & dosagem , Doxorrubicina/sangue , Doxorrubicina/farmacocinética , Sistemas de Liberação de Medicamentos , Feminino , Camundongos Endogâmicos BALB C , Camundongos Nus , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Temperatura
6.
Colloids Surf B Biointerfaces ; 182: 110325, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31301582

RESUMO

Targeting modifications and smart responsiveness of nanomedicines can enable anticancer drugs to be selectively delivered to and controllably released in tumour cells or tissues, which can reduce the treatment's toxicity and side effects. Good biocompatibility is crucial for the clinical application of any nanomedicine. In this study, a double-targeting molecule, an RGD peptide- and 4-(2-aminoethyl) morpholine-modified, doxorubicin (DOX)-loaded bovine serum albumin (BSA) nanomedicine, that can be controllably released by the high levels of autophagic lysosomes in tumour cells was developed. The size of the spherical BSA nanoparticles is approximately 60 nm. In vitro experiments indicated that the RGD peptide- and 4-(2-aminoethyl) morpholine-modified, DOX-loaded BSA nanomedicine has a better therapeutic effect than free DOX. In vivo experiments suggested that the BSA nanomedicine can successfully suppress the progression of PC9 xenograft tumours. This phenomenon may be attributable to the endocytosis of a relatively large amount of nanomedicine and the effective release of the loaded chemotherapeutic agent, as induced by high levels of autolysosomes. Collectively, the results of this study provide a smart approach for increasing therapeutic efficacy using a double-targeting molecule-modified BSA nanomedicine.


Assuntos
Antibióticos Antineoplásicos/farmacologia , Preparações de Ação Retardada , Doxorrubicina/farmacologia , Portadores de Fármacos , Neoplasias Pulmonares/tratamento farmacológico , Lisossomos/efeitos dos fármacos , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/química , Doxorrubicina/farmacocinética , Composição de Medicamentos/métodos , Liberação Controlada de Fármacos , Feminino , Humanos , Neoplasias Pulmonares/patologia , Lisossomos/metabolismo , Camundongos , Camundongos Nus , Morfolinas/química , Nanomedicina/métodos , Nanopartículas/administração & dosagem , Nanopartículas/química , Nanopartículas/ultraestrutura , Oligopeptídeos/química , Soroalbumina Bovina/química , Carga Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto
7.
J Colloid Interface Sci ; 554: 239-249, 2019 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-31301524

RESUMO

Thermochemotherapy has shown a synergistic anti-cancer efficiency and can enhance the therapeutic effect of simple chemotherapy. The photothermal conversion characteristics of carriers are vital in thermo-chemotherapy. Therefore, hollow mesoporous carbon (HMC) with excellent heating efficiency and a large specific surface area was used to ensure the high loading capacity. Next, approximately 4 nm spherical gold nanoparticles (NPs) were employed as gatekeepers of the tunnels of HMC by Au-S bonds, which have the same size as HMC mesopores. Additionally, the gold NPs could avoid the premature release of the drug and enhance the photothermal properties of the delivery system. The surface of the carriers was modified with polyethylene glycol (PEG) to increase the biocompatibility and dispersity of doxorubicin (DOX) loaded DOX/HMC-Au@PEG. DOX release was markedly accelerated in the presence of glutathione (GSH) and near-infrared (NIR), indicating that the system had redox and NIR dual-triggered drug release characteristics. Cytotoxicity experiments proved that combined therapy induced the highest cell killing level. Additionally, the combination index (CI) of DOX/HMC-Au@PEG was 0.452, indicating the synergistic effect of chemotherapy and photo-thermal therapy (PTT). In vivo antitumor experiments were also carried out and showed the same trend. In general, the results of this study indicated that DOX/HMC-Au@PEG has great potential in dual-triggered drug delivery and thermochemotherapy.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Preparações de Ação Retardada/química , Doxorrubicina/administração & dosagem , Ouro/química , Nanopartículas Metálicas/química , Animais , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapêutico , Carbono/química , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Liberação Controlada de Fármacos , Feminino , Camundongos , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Polietilenoglicóis/química , Porosidade
8.
Colloids Surf B Biointerfaces ; 182: 110375, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31351268

RESUMO

To overcome the limited drug loading capacity of magnetic nanopharmaceuticals arising from the relatively large mass of the metal core, a high-loading drug delivery system based on amino-functionalized Fe3O4 magnetic nanospheres modified by hyperbranched phenylboronic acid (HPBA-Fe3O4) were prepared for the first time. The obtained nanomaterials were characterized by transmission electron microscopy, Fourier transform infrared, zeta potential, elemental analysis, vibrating sample magnetometry and X-ray diffraction analysis, and the results showed that hyperbranched phenylboronic acid (HPBA) were successfully grafted onto the surface of the magnetic nanospheres. The polymerization conditions, adsorption and desorption performance, and tumor-targeting ability of HPBA-Fe3O4 was investigated in detail through chemical and biological experiments. The drug loading amount and capacity of HPBA-Fe3O4 are 271.3 mg/g and 27.13%, respectively, which are 2.26 and 3.27 times greater than those of PBA-Fe3O4 and PEI-Fe3O4, and the thermodynamic fitting results further demonstrate the high drug loading ability of HPBA-Fe3O4. In vitro studies performed in U-87 MG malignant glioma cells and astrocytes via light and fluorescence microscopy analyses, cell counting kit-8 assays, and HPLC tests confirm the pH-sensitive release and tumor-targeted drug delivery capabilities of HPBA-Fe3O4. The facile fabrication of hyperbranched magnetic nanomaterials could be an alternative solution for designing high-loading, tumor cell-targeting and pH-responsive DDSs with high-mass cores.


Assuntos
Ácidos Borônicos/química , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Óxido Ferroso-Férrico/química , Nanopartículas de Magnetita/química , Neoplasias/metabolismo , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Doxorrubicina/química , Doxorrubicina/farmacocinética , Humanos , Concentração de Íons de Hidrogênio , Nanopartículas de Magnetita/ultraestrutura , Camundongos , Microscopia Eletrônica de Transmissão , Neoplasias/tratamento farmacológico , Neoplasias/patologia , Espectroscopia de Infravermelho com Transformada de Fourier
9.
Colloids Surf B Biointerfaces ; 182: 110393, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31357128

RESUMO

In this work, photo-sensitive core/shell nanoparticles (NPs) based on biocompatible dextran-g-poly(o-nitrobenzyl acrylate) copolymers (Dex-g-PNBA), containing dextran as hydrophilic backbone and PNBA as photosensitive grafts, were formulated using two processes. In the first process (nanoprecipitation), NPs were prepared using preformed Dex-g-PNBA copolymers. Using the second process (emulsion/organic solvent evaporation), "clicked" or "unclicked" NPs were obtained carrying out (or not) an interfacial in situ click chemistry, respectively. Two model molecules, Nile Red (NR) and Doxorubicin (DOX), were encapsulated and their controlled release from NPs was investigated under UV irradiations to demonstrate the high potential of such photosensitive NPs in biomedicine applications as drug delivery nanocarriers. According to such irradiations, improved release was easily observed. Release kinetics depended on the formulation process and the NPs core chemistry, but not on the occurrence of the interfacial in situ click chemistry. More interesting, a stepped release of such model molecules may easily be obtained.


Assuntos
Acrilatos/química , Preparações de Ação Retardada/farmacologia , Dextranos/química , Doxorrubicina/farmacologia , Nanopartículas/química , Polímeros/química , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Células CACO-2 , Sobrevivência Celular/efeitos dos fármacos , Química Click , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Doxorrubicina/química , Doxorrubicina/farmacocinética , Portadores de Fármacos/química , Liberação Controlada de Fármacos/efeitos da radiação , Humanos , Interações Hidrofóbicas e Hidrofílicas , Nanopartículas/efeitos da radiação , Raios Ultravioleta
10.
Mater Sci Eng C Mater Biol Appl ; 103: 109803, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349440

RESUMO

Redox-responsive diselenide bond containing triblock copolymer Bi(mPEG-SeSe)-PCL,Bi(mPEG-SeSe)-PCL was developed for specific drug release in cancer cells. Initially, ditosylated polycaprolactone was prepared via the reaction between polycaprolactone diol (PCL-diol) and tosyl chloride (TsCl). Next, Bi(mPEG-SeSe)-PCL was synthesized via the reaction between ditosylated polycaprolactone and sodium diselenide initiated poly (ethylene glycol) methyl ether tosylate. The synthesized amphiphilic triblock copolymer could self-assemble into uniform nanoparticles in aqueous medium and disassemble upon redox stimuli. The Bi(mPEG-SeSe)-PCL nanoparticles showed a DOX loading content of 5.1 wt% and a loading efficiency of 49%. In vitro drug release studies showed that about 62.4% and 56% of DOX was released from the nanoparticles during 72 h at 37 °C in PBS containing 2 mg/mL (6 mM) GSH and 0.1% H2O2, respectively, whereas only about 30% of DOX was released in PBS under the same conditions. The cell viability (MTT assays) results showed that the synthesized material was biocompatible with above 90% cell viability, and that the DOX-loaded Bi(mPEG-SeSe)-PCL nanoparticles had a high antitumor activity against HeLa cells and low antitumor activity against HaCaT cells, following a 24-h incubation period. Three-dimensional (3D) spheroids of HeLa cells were established for the evaluation of localization of the DOX-loaded nanoparticles into spheroids cells and the successfully inhibition of 3D tumor spheroid growth. The results indicated that the synthesized material Bi(mPEG-SeSe)-PCL was biocompatible and it could be a potential candidate for anticancer drug delivery system.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Compostos de Selênio/química , Antibióticos Antineoplásicos/farmacocinética , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Células HeLa , Humanos , Peróxido de Hidrogênio/química , Nanopartículas/administração & dosagem , Oxirredução , Poliésteres/química , Polietilenoglicóis/química , Polímeros/síntese química , Polímeros/farmacocinética , Esferoides Celulares/efeitos dos fármacos , Compostos de Tosil/química
11.
Mater Sci Eng C Mater Biol Appl ; 103: 109738, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31349475

RESUMO

Recently, the emergence of cell-penetrating peptides (CPPs) like TAT has greatly improved the efficiency of cancer therapy by enhancing cellular uptake of nanomaterials. Here, we designed a near-infrared (NIR) triggered TAT-based targeted nanoplatform (cRGD@TAT-DINPs), which co-delivered anticancer drug doxorubicin (DOX) and biocompatible dye indocyanine green (ICG) to realize combined chemo/photothermal/photodynamic therapy of cancer in vitro. The resulting nanoparticles showed favorable monodispersity and colloidal stability. Impressively, the DOX could be released in a promoted manner once the nanoparticles were exposed to NIR light. Confocal laser scanning microscopy (CLSM) and flow cytometry analysis demonstrated an immensely enhanced cellular accumulation of DOX after the simultaneous introduction of targeted ligand cRGD and CPP TAT. In addition, the obtained nanoparticles exhibited explosive temperature elevation and reactive oxygen species (ROS) generation mediated by encapsulated ICG under NIR irradiation, and in vitro cytotoxicity assay confirmed the cRGD@TAT-DINPs had an increasing cytotoxicity and excellent synergistic inhibition capacity. Thus, TAT-based nanosystems provide a high-efficient drug delivery strategy for optimizing combined therapy efficiency of cancer.


Assuntos
Peptídeos Penetradores de Células/farmacocinética , Doxorrubicina/administração & dosagem , Sistemas de Liberação de Medicamentos/métodos , Nanopartículas/química , Produtos do Gene tat do Vírus da Imunodeficiência Humana/farmacocinética , Células A549 , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Peptídeos Penetradores de Células/química , Corantes/administração & dosagem , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Verde de Indocianina/administração & dosagem , Luz , Nanopartículas/uso terapêutico , Peptídeos Cíclicos/química , Peptídeos Cíclicos/farmacocinética , Fotoquimioterapia/métodos , Espécies Reativas de Oxigênio/metabolismo , Produtos do Gene tat do Vírus da Imunodeficiência Humana/química
12.
Nanoscale ; 11(24): 11709-11718, 2019 Jun 20.
Artigo em Inglês | MEDLINE | ID: mdl-31180099

RESUMO

Multimodal therapies have been regarded as promising strategies for cancer treatment as compared to conventional drug delivery systems that have various drawbacks in either low loading content, uncontrolled release, non-targeting or biotoxicity. We have developed a multifunctional three-dimensional tumor-targeting drug delivery system, Fe3O4@UIO-66-NH2/graphdiyne (FUGY), based on the hybridization of a novel two-dimensional material, graphdiyne (GDY), with a metal organic framework (MOFs) structure, Fe3O4@UIO-66-NH2 (FU). The FU MOF structure has superior ability for magnetic targeting, and was constructed by an in situ growth method in which it was surface-installed with GDY via amide bonds, as a carrier of anticancer drugs. The anticancer drug doxorubicin (DOX) was loaded onto FUGY and served as both an anticancer drug to treat the tumor and a fluorescence probe to ascertain the location of FUGY. The results show that FUGY exhibits a high drug loading content of 43.8% and an effective drug release around the tumor cells at pH 5.0. In particular, fluorescence imaging demonstrates that FUGY can deliver more anticancer drugs to tumor tissue than conventional drug delivery systems. Furthermore, FUGY exhibits superior therapeutic efficiencies with negligible side effects as compared to the direct administration of free DOX, both in vitro and in vivo. The obtained FUGY drug delivery system possesses ideal biocompatibility, sustained drug release, effective chemotherapeutic efficacy, and specific targeting abilities. Such a multimodal therapeutic system can facilitate new possibilities for multifunctional drug delivery systems.


Assuntos
Antibióticos Antineoplásicos , Doxorrubicina , Portadores de Fármacos , Nanopartículas de Magnetita , Neoplasias Experimentais , Imagem Óptica , Animais , Antibióticos Antineoplásicos/química , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Preparações de Ação Retardada/química , Preparações de Ação Retardada/farmacocinética , Preparações de Ação Retardada/farmacologia , Doxorrubicina/química , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Células HeLa , Humanos , Concentração de Íons de Hidrogênio , Nanopartículas de Magnetita/química , Nanopartículas de Magnetita/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Neoplasias Experimentais/diagnóstico por imagem , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia
13.
Nano Lett ; 19(6): 3671-3675, 2019 06 12.
Artigo em Inglês | MEDLINE | ID: mdl-31062980

RESUMO

Nanocarriers-derived anticancer therapeutics typically suffers from poor tumor penetration and suboptimal antitumor efficacy. Although PEGylation improves the stability of nanoparticles and prolongs drug circulation, it further increases the size of nanoparticles and adversely affects the tumor penetration. Here, we developed a light-triggered PEGylation/dePEGylation strategy, whereby near-infrared (NIR)-/pH- dual responsive dePEGylation activates iRGD for tumor targeting. The embedded up-conversion nanoparticles (UCNPs) could efficiently convert NIR to UV-vis which cleaved the linker to remove PEG. NIR-induced dePEGylation remarkably improved vascular extravasation of drugs and deep tumor penetration. Therefore, the stimuli-responsive nanocarriers facilitated the tumor-targeted delivery of drugs through blood circulation and enhanced the antitumor effects.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Preparações de Ação Retardada/química , Doxorrubicina/administração & dosagem , Nanopartículas/química , Polietilenoglicóis/química , Animais , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular Tumoral , Doxorrubicina/farmacocinética , Sistemas de Liberação de Medicamentos , Humanos , Concentração de Íons de Hidrogênio , Raios Infravermelhos , Células MCF-7 , Camundongos , Nanopartículas/ultraestrutura , Neoplasias/tratamento farmacológico
14.
Bioconjug Chem ; 30(6): 1665-1676, 2019 06 19.
Artigo em Inglês | MEDLINE | ID: mdl-31045351

RESUMO

To reply to as yet unmet medical needs to treat osteosarcoma, a form of primary bone cancer, we conceived the 12b80 compound by covalently conjugating antineoplastic compound doxorubicin to a bone targeting hydroxybisphosphonate vector and turned it into a prodrug through a custom linker designed to specifically trigger doxorubicin release in acidic bone tumor microenvironment. Synthesis of 12b80 was thoroughly optimized to be produced at gram scale. 12b80 was evaluated in vitro for high bone support affinity, specific release of doxorubicin in acidic condition, lower cytotoxicity, and cellular uptake of the prodrug. In vivo in rodents, 12b80 displayed rapid and sustained targeting of bone tissue and tumor-associated heterotopic bone and permitted a higher doxorubicin payload in tumor bone environment compared to nonvectorized doxorubicin. Consequently, 12b80 showed much lower toxicity compared to doxorubicin, promoted strong antitumor effects on rodent orthotopic osteosarcoma, displayed a dose-response therapeutic effect, and was more potent than doxorubicin/zoledronate combination.


Assuntos
Antibióticos Antineoplásicos/química , Neoplasias Ósseas/tratamento farmacológico , Difosfonatos/química , Doxorrubicina/análogos & derivados , Osteossarcoma/tratamento farmacológico , Animais , Antibióticos Antineoplásicos/síntese química , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/uso terapêutico , Neoplasias Ósseas/patologia , Linhagem Celular Tumoral , Técnicas de Química Sintética , Difosfonatos/síntese química , Difosfonatos/farmacocinética , Difosfonatos/uso terapêutico , Doxorrubicina/síntese química , Doxorrubicina/farmacocinética , Doxorrubicina/uso terapêutico , Feminino , Camundongos Nus , Osteossarcoma/patologia , Ratos
15.
Drug Des Devel Ther ; 13: 1087-1098, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31118562

RESUMO

Purpose: Co-delivery of drugs to achieve the synergistic anticancer effect is a promising strategy for lung cancer therapy. The purpose of this research is to develop a doxorubicin (DOX) and ß-elemene (ELE) co-loaded, pH-sensitive nanostructured lipid carriers (DOX/ELE Hyd NLCs). Methods: In this study, DOX/ELE Hyd NLCs were produced by a hot homogenization and ultrasonication method and used for lung cancer treatment. In vitro and in vivo efficiency as well as toxicity of the system was evaluated on lung cancer cell lines and lung tumor-bearing mice. Results: DOX/ELE Hyd NLCs had a particle size of 190 nm, with a PDI lower than 0.2. DOX/ELE Hyd NLCs exhibited a significantly enhanced cytotoxicity (drug concentration causing 50% inhibition was 7.86 µg/mL), synergy antitumor effect (combination index lower than 1), and profound tumor inhibition ability (tumor inhibition ratio of 82.9%) compared with the non pH-responsive NLCs and single-drug-loaded NLCs. Conclusion: Since the synergistic effect of the drugs was found in this system, it would have great potential to inhibit lung tumor cells and tumor growth.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Doxorrubicina/uso terapêutico , Portadores de Fármacos/química , Lipídeos/química , Neoplasias Pulmonares/tratamento farmacológico , Nanoestruturas/química , Sesquiterpenos/uso terapêutico , Células A549 , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Linhagem Celular , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Doxorrubicina/administração & dosagem , Doxorrubicina/farmacocinética , Liberação Controlada de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Quimioterapia Combinada , Humanos , Concentração de Íons de Hidrogênio , Neoplasias Pulmonares/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/patologia , Sesquiterpenos/administração & dosagem , Sesquiterpenos/farmacocinética , Distribuição Tecidual
16.
Photochem Photobiol Sci ; 18(6): 1471-1478, 2019 Jun 12.
Artigo em Inglês | MEDLINE | ID: mdl-30964475

RESUMO

We conducted photo-activated delivery of drugs based on the fusion of liposomes with endocytic membranes, thus allowing the direct release of encapsulated drugs inside the cytoplasm. As described in our earlier works, liposomes can be photoresponsive and fusogenic following the incorporation of a malachite green derivative carrying a long alkyl chain (MGL) into the lipid membrane. We prepared MGL liposomes using 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphatidylcholine and encapsulated doxorubicin (DOX). Though the shape of MGL liposomes became elliptical after encapsulating DOX, UV irradiation did not enhance DOX leakage from MGL liposomes. We demonstrated the cellular uptake of MGL liposomes into murine cells derived from colon cancer (Colon 26 cells) using flow cytometry, and we found that the uptake was governed by a clathrin-dependent endocytosis pathway. Confocal fluorescence microscopic observations of Colon 26 cells treated with MGL liposomes encapsulating DOX revealed that DOX was localized in endosomes under dark conditions, while DOX was observed in the cytosol and nucleus after UV irradiation. The viability of Colon 26 cells treated with MGL liposomes encapsulating DOX was reduced by UV irradiation, indicating photo-induced enhancement of anti-cancer efficacy.


Assuntos
Antibióticos Antineoplásicos/farmacocinética , Neoplasias do Colo/tratamento farmacológico , Doxorrubicina/farmacocinética , Sistemas de Liberação de Medicamentos , Endossomos/química , Lipossomos/química , Corantes de Rosanilina/química , Animais , Antibióticos Antineoplásicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Neoplasias do Colo/metabolismo , Neoplasias do Colo/patologia , Relação Dose-Resposta a Droga , Doxorrubicina/química , Portadores de Fármacos/química , Ensaios de Seleção de Medicamentos Antitumorais , Camundongos , Estrutura Molecular , Relação Estrutura-Atividade , Células Tumorais Cultivadas , Raios Ultravioleta
17.
Bioconjug Chem ; 30(5): 1371-1384, 2019 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-30946570

RESUMO

Animal models are effective for assessing tumor localization of nanosystems but difficult to use for studying penetration beyond the vasculature. Here, we have used well-characterized HCT116 colorectal cancer spheroids to study the effect of nanoparticle (NP) physicochemical properties on penetration and uptake. Incubation of spheroids with Hoechst 33342 resulted in a dye gradient, which facilitated discrimination between the populations of cells in the core and at the periphery of spheroids by flow cytometry. This approach was used to compare doxorubicin and liposomal doxorubicin (Caelyx) and a range of model poly(styrene) nanoparticles of different sizes (30 nm, 50 nm, 100 nm) and with different surface chemistries (50 nm uniform plain, carboxylated, aminated and a range of NPs and polyethylene glycol modified NPs prepared from a promising new functionalized biodegradable polymer (poly(glycerol-adipate), PGA). Unmodified poly(styrene) nanoparticles (30 nm/50 nm) were able to penetrate to the core of HCT116 spheroids more efficiently than larger poly(styrene) nanoparticles (100 nm). Surprisingly, penetration of 30 and 50 nm particles was as good as clinically relevant doxorubicin concentrations. However, penetration was reduced with higher surface charge. PGA NPs of 100 nm showed similar penetration into spheroids as 50 nm poly(styrene) nanoparticles, which may be related to polymer flexibility. PEG surface modification of polymeric particles significantly improved penetration into the spheroid core. The new model combining the use of spheroids Hoechst staining and flow cytometry was a useful model for assessing NP penetration and gives useful insights into the effects of NPs' physical properties when designing nanomedicines.


Assuntos
Neoplasias Colorretais/metabolismo , Nanopartículas , Esferoides Celulares/metabolismo , Animais , Antibióticos Antineoplásicos/administração & dosagem , Antibióticos Antineoplásicos/farmacocinética , Benzimidazóis/metabolismo , Doxorrubicina/administração & dosagem , Doxorrubicina/análogos & derivados , Doxorrubicina/farmacocinética , Corantes Fluorescentes/metabolismo , Células HCT116 , Humanos , Tamanho da Partícula , Polietilenoglicóis/administração & dosagem , Polietilenoglicóis/farmacocinética , Propriedades de Superfície
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.
Pharm Res ; 36(5): 66, 2019 Mar 13.
Artigo em Inglês | MEDLINE | ID: mdl-30868271

RESUMO

PURPOSE: Hypovascularization of cervical tumors, coupled with intrinsic and acquired drug resistance, has contributed to marginal therapeutic outcomes by hindering chemotherapeutic transport and efficacy. Recently, the heterogeneous penetration and distribution of cell penetrating peptide (CPP, here MPG) and polyethylene glycol (PEG) modified poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were evaluated as a function of tumor type and morphology in cervical cancer spheroids modeling hypovascularized tumor nodules. Building upon this work, this study investigates the efficacy imparted by surface-modified Doxorubicin-loaded NPs transported into hypovascularized tissue. METHODS: NP efficacy was measured in HeLa, CaSki, and SiHa cells. NP internalization and association, and associated cell viability, were determined in monolayer and spheroid models. RESULTS: MPG and PEG-NP co-treatment was most efficacious in HeLa cells, while PEG NPs were most efficacious in CaSki cells. NP surface-modifications were unable to improve efficacy, relative to unmodified NPs, in SiHa cells. CONCLUSIONS: The results highlight the dependence of efficacy on tumor type and the associated microenvironment. The results further relate previous NP transport studies to efficacy, as a function of surface-modification and cell type. Longer-term, this information may help guide the design of NP-mediated strategies to maximize efficacy based on patient-specific cervical tumor origin and characteristics.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Peptídeos Penetradores de Células/metabolismo , Doxorrubicina/administração & dosagem , Portadores de Fármacos/metabolismo , Nanopartículas/metabolismo , Neoplasias do Colo do Útero/tratamento farmacológico , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Peptídeos Penetradores de Células/química , Colo do Útero/irrigação sanguínea , Colo do Útero/efeitos dos fármacos , Colo do Útero/metabolismo , Colo do Útero/patologia , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Portadores de Fármacos/química , Feminino , Células HeLa , Humanos , Nanopartículas/química , Polietilenoglicóis/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/metabolismo , Neoplasias do Colo do Útero/irrigação sanguínea , Neoplasias do Colo do Útero/metabolismo , Neoplasias do Colo do Útero/patologia
20.
Pharm Dev Technol ; 24(6): 794-802, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-30907676

RESUMO

In this study, reduction-sensitive self-assembled polymer nanoparticles based on poly (lactic-co-glycolic acid) (PLGA) and chondroitin sulfate A (CSA) were developed and characterized. PLGA was conjugated with CSA via a disulfide linkage (PLGA-ss-CSA). The critical micelle concentration (CMC) of PLGA-ss-CSA conjugate is 3.5 µg/mL. The anticancer drug doxorubicin (DOX) was chosen as a model drug, and was effectively encapsulated into the nanoparticles (PLGA-ss-CSA/DOX) with high loading efficiency of 15.1%. The cumulative release of DOX from reduction-sensitive nanoparticles was only 34.8% over 96 h in phosphate buffered saline (PBS, pH 7.4). However, in the presence of 20 mM glutathione-containing PBS environment, DOX release was notably accelerated and almost complete from the reduction-sensitive nanoparticles up to 96 h. Moreover, efficient intracellular DOX release of PLGA-ss-CSA/DOX nanoparticles was confirmed by CLSM assay in A549 cells. In vitro cytotoxicity study showed that the half inhibitory concentrations of PLGA-ss-CSA/DOX nanoparticles and free DOX against A549 cells were 1.141 and 1.825 µg/mL, respectively. Therefore, PLGA-ss-CSA/DOX nanoparticles enhanced the cytotoxicity of DOX in vitro. These results suggested that PLGA-ss-CSA nanoparticles could be a promising carrier for drug delivery.


Assuntos
Antibióticos Antineoplásicos/administração & dosagem , Sulfatos de Condroitina/química , Doxorrubicina/administração & dosagem , Portadores de Fármacos/química , Nanopartículas/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/análogos & derivados , Células A549 , Antibióticos Antineoplásicos/farmacocinética , Antibióticos Antineoplásicos/farmacologia , Doxorrubicina/farmacocinética , Doxorrubicina/farmacologia , Liberação Controlada de Fármacos , Humanos , Neoplasias/tratamento farmacológico
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