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1.
Life Sci ; 241: 117137, 2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31809713

RESUMO

Hydrogel for various applications, such as cell encapsulation and controlled release of drugs, has attracted the field of biomaterials in the past decades. Specially, research on the surface-modified nanocellulose hydrogel has grown rapidly on account of the importance of target delivery in the anti-cancer therapy. In this work, surface-modified nanocellulose was mixed with hexadecyl amine as long chains to blend to build a network to produce hydrogel, which was successfully developed for controlled and targeted delivery of paclitaxel. The pH-stimuli surface-modified nanocellulose hydrogel was characterized and biological evaluated in vitro. The hydrogel was stable at pH 7.4 and paclitaxel was released by the shape change of hydrogel in an acidic environment (pH 5.5), and the sustained release of paclitaxel was observed at pH 5.5. The vitro cytotoxicity studies indicated that the drug accumulation and the inhibition of A549 and HepG2 cells was effectively increased by the surface-modified nanocellulose hydrogel as compared with free paclitaxel. The inhibitory effect of A549 cells was improved by nearly 30% as compared with free paclitaxel and the apoptosis rate was up to 90.5% after 12 h incubation. In addition, the inversion test and the results of a series of cell experiments in vitro demonstrated a good performance of the surface-modified nanocellulose hydrogel.


Assuntos
Celulose/química , Portadores de Fármacos/química , Hidrogéis/química , Nanopartículas/química , Paclitaxel/química , Paclitaxel/farmacologia , Células A549 , Antineoplásicos Fitogênicos/química , Antineoplásicos Fitogênicos/farmacologia , Sobrevivência Celular , Células Hep G2 , Humanos
2.
Ultrasonics ; 101: 106033, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31561207

RESUMO

The objective of this study was to use ultrasound in combination with nanoparticulate formulations of taxane drugs for an additive approach to overcome multidrug resistance (MDR). Polymeric nanoparticulate formulations containing both chemotherapeutic taxane drugs and a polymeric inhibitor (MePEG17-b-PCL5) of drug resistant proteins have been previously developed in an attempt to overcome MDR in cells. High frequency (>1 MHz) ultrasound has been shown to increase the uptake of cytotoxic drugs in MDR proliferating cells and has been suggested as a different way to overcome MDR, resensitize drug resistant cancer cells and allow for chemotherapeutic efficacy. MDCK-MDR cells were incubated with docetaxel (DTX) or paclitaxel (PTX) loaded, solid core, nanoparticles made from a 50:50 ratio of two diblock copolymers, MePEG114-b-PCL200 and MePEG17-b-PCL5 (PCL200/PCL5). The accumulation of drug in MDCK-MDR cells was measured using radiolabeled drug and the viability of cells was determined using an MTS cell proliferation assay. The effect of ultrasound (4 MHz, 32 W/cm2, 10 s, 25% duty cycle) on drug uptake and cell viability was studied. Using free DTX or PTX, MDCK-MDR cells were killed at sublethal doses of drug with the P-gp inhibitor (MePEG17-b-PCL5) present at a concentration of just 0.006% (m/v) and cell death began after just 3 h of incubation. Using sublethal incubation doses of PTX or DTX in PCL200/PCL5 nanoparticles for 90 min, followed by a second exposure to blank PCL200/PCL5 nanoparticles, cell viability dropped by approximately 60% at 24 h. Drug accumulation increased by 1.43-1.9 fold following five bursts of ultrasound applied at 90 min. Both, increased ultrasound exposure and increased concentrations of blank nanoparticles during the second incubation allowed for increased levels of cell death. The combined use of ultrasound with taxane and P-gp inhibitor loaded polymeric nanoparticles may allow for increased accumulation of drug and inhibitor which may then release both agents inside cells in a controlled manner to overcome drug resistance in MDR cells.


Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Antineoplásicos Fitogênicos/farmacologia , Docetaxel/farmacologia , Nanopartículas/química , Paclitaxel/farmacologia , Polietilenoglicóis/farmacologia , Ondas Ultrassônicas , Animais , Antineoplásicos Fitogênicos/química , Proliferação de Células/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/química , Cães , Sistemas de Liberação de Medicamentos , Resistência a Múltiplos Medicamentos , Resistencia a Medicamentos Antineoplásicos , Paclitaxel/química , Polietilenoglicóis/química , Polímeros/química , Polímeros/farmacologia , Células Tumorais Cultivadas
3.
Eur J Pharm Sci ; 140: 105071, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31525433

RESUMO

Multidrug resistance (MDR) is a major reason for anticancer chemotherapy failure, and P-glycoprotein (P-gp) over-expressing on tumor cells is considered as the important target to overcome MDR. Emerging reports have showed that vitamin E (VE) can cause significant reversal of MDR due to inhibition of ATPase activity. Accordingly, we synthesized hyaluronic acid (HA) conjugated vitamin E succinate (VES) polymer, which can self-assemble into micelles and thus achieve high drug (paclitaxel (PTX) used as model drug) encapsulation as well as tumor accumulation owing to the enhanced permeability and retention (EPR) effect and HA active targeting ability. In addition, the linker between HA and VES utilized in this work was disulfide bond with reduction-sensitive property, which would respond to high glutathione (GSH) concentration in tumor cytoplasmic environment and trigger HA-CYS-VES polymer disassociation and drug release. In vitro, PTX loaded HA-CYS-VES demonstrated enhanced cytotoxicity, high apoptosis-inducing activities and reversal effects of PTX on MCF-7/Adr cells, compared to PTX. Also, cellular uptake and intracellular PTX accumulation tests displayed that PTX loaded HA-CYS-VES could more efficiently enter tumor cells and selectively release drug in cytosol so as to facilitate its function on microtubule. More importantly, PTX loaded HA-CYS-VES showed better tumor targeting ability, improved antitumor efficacy and low adverse effects on tumor-bearing mice. In conclusion, PTX loaded HA-CYS-VES exhibited a great potential for reversing MDR in anticancer chemotherapeutics.


Assuntos
Antineoplásicos/química , Portadores de Fármacos/química , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ácido Hialurônico/química , Micelas , Paclitaxel/química , alfa-Tocoferol/química , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Animais , Apoptose/efeitos dos fármacos , Permeabilidade da Membrana Celular , Sobrevivência Celular/efeitos dos fármacos , Citosol/metabolismo , Preparações de Ação Retardada/química , Liberação Controlada de Fármacos , Resistência a Múltiplos Medicamentos/efeitos dos fármacos , Feminino , Humanos , Receptores de Hialuronatos/metabolismo , Células MCF-7 , Camundongos Endogâmicos BALB C , Camundongos Nus , Terapia de Alvo Molecular/métodos , Polímeros/química
4.
Eur J Med Chem ; 183: 111720, 2019 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-31553933

RESUMO

At present, chemo- and radiotherapies remain to be the mainstream methods for treating triple-negative breast cancer (TNBC), which is known for poor prognosis and high rate of mortality. Two types of novel dual-targeting TNBC liposomes (Fru-RGD-Lip and Fru+RGD-Lip) that actively recognize both fructose transporter GLUT5 and integrin αvß3 were designed and prepared in this work. Firstly, a Y-shaped Fru-RGD-chol ligand, where a fructose and peptide Arg-Gly-Asp (RGD) were covalently attached to cholesterol, was designed and synthesized. Then, the Fru-RGD-Lip was constructed by inserting Fru-RGD-chol into liposomes, while Fru+RGD-Lip was obtained by inserting both Fru-chol and RGD-chol (with the molar ratio of 1:1) into liposomes. The particle size, zeta potential, encapsulation efficiency and serum stability of the paclitaxel-loaded liposomes were characterized. The results indicated that the paclitaxel-loaded Fru-RGD-Lip had the strongest growth inhibition against GLUT5 and αvß3 overexpressed MDA-MB-231 and 4T1 cells. The cellular uptake of Fru-RGD-Lip on MDA-MB-231 cells and 4T1 cells was 3.19- and 3.23-fold more than that of the uncoated liposomes (Lip). The uptake of Fru+RGD-Lip was slightly lower, giving a 2.81- and 2.90-fold increase than that of Lip in two cell lines, respectively. The mechanism study demonstrated that the cellular uptake of both dual-targeting liposomes was likely to be recognized and mediated by GLUT5 and αvß3 firstly, then endocytosed through comprehensive pathways in an energy-dependent manner. Moreover, Fru-RGD-Lip displayed the maximum accumulation, which was 2.62-fold higher than that of Lip for instance, at the tumor sites compared to other liposomes using in vivo imaging. Collectively, the liposomes co-modified by fructose and RGD have enormous potential in the development of targeted TNBC treatment, especially the covalently modified Fru-RGD-Lip, making it a promising multifunctional liposome.


Assuntos
Antineoplásicos Fitogênicos , Transportador de Glucose Tipo 5/metabolismo , Integrina alfaVbeta3/metabolismo , Lipossomos , Paclitaxel , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Animais , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Linhagem Celular Tumoral , Feminino , Frutose/química , Humanos , Lipossomos/química , Camundongos Endogâmicos BALB C , Terapia de Alvo Molecular , Oligopeptídeos/metabolismo , Paclitaxel/administração & dosagem , Paclitaxel/química , Neoplasias de Mama Triplo Negativas/metabolismo
5.
Mater Sci Eng C Mater Biol Appl ; 104: 110001, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31500023

RESUMO

Paclitaxel is broad-spectrum anticancer drug which has been widely used in clinic. However, traditional drug delivery often suffers from the scarcity of resources and systemic toxic side effects caused by the localization to non-tumor areas, rendering cancer treatment extremely challenging. To address this problem, we developed a novel multifunctional drug delivery system of a poly(lactic-co-glycolic acid) (PLGA) drug-loaded magnetic Janus particles (DMJPs) using electrohydrodynamic (EDH) co-jetting. The DMJPs were loaded with three compartments each with distinct function, i.e. paclitaxel for killing cancer cell, Fe3O4 nanoparticles for target location, and rhodamine B for fluorescence tracing, respectively. The Janus structure of the DMJPs, as demonstrated by the loaded nano-quantum dots CdS/ZnS and CdSe/ZnS in different compartments, enhanced not only the drug loading and encapsulation efficiency but also the cumulative release rate of the loaded drugs from DMJPs in different media. More importantly, DMJPs exhibited specific and high toxicity only to human breast cancer cells (MDA-MB-231), but not to mouse embryonic fibroblasts (NIH-3 T3). Consistently, DMJPs induced the higher lethal effect on cancer cells than paclitaxel suspension of high concentrations. Under guidance of external magnetic field, DMJPs can readily target and accumulate on and inside cancer cells for cell elimination. The specific targetability, selectivity, and toxicity of DMJPs on cancer cells would greatly avoid any potential side effects and reduce the overdose of drugs for conventional drug delivery. This work hopefully provides a new drug delivery system for the development of anticancer drug systems for clinical and precision medicine treatment.


Assuntos
Antineoplásicos/química , Antineoplásicos/farmacologia , Neoplasias/tratamento farmacológico , Paclitaxel/química , Paclitaxel/farmacologia , Animais , Linhagem Celular Tumoral , Portadores de Fármacos/química , Sistemas de Liberação de Medicamentos , Humanos , Fenômenos Magnéticos , Magnetismo/métodos , Camundongos , Células NIH 3T3 , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química
6.
Pharm Res ; 36(11): 154, 2019 Sep 03.
Artigo em Inglês | MEDLINE | ID: mdl-31482205

RESUMO

PURPOSE: Conjugation of nanocarriers with antibodies that bind to specific membrane receptors that are overexpressed in cancer cells enables targeted delivery. In the present study, we developed and synthesised two PAMAM dendrimer-trastuzumab conjugates that carried docetaxel or paclitaxel, specifically targeted to cells which overexpressed HER-2. METHODS: The 1H NMR, 13C NMR, FTIR and RP-HPLC were used to analyse the characteristics of the products and assess their purity. The toxicity of PAMAM-trastuzumab, PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates was determined using MTT assay and compared with free trastuzumab, docetaxel and paclitaxel toward HER-2-positive (SKBR-3) and negative (MCF-7) human breast cancer cell lines. The cellular uptake and internal localisation were studied using flow cytometry and confocal microscopy, respectively. RESULTS: The PAMAM-drug-trastuzumab conjugates in particular showed extremely high toxicity toward the HER-2-positive SKBR-3 cells and very low toxicity towards to HER-2-negative MCF-7 cells. As expected, the HER-2-positive SKBR-3 cell line accumulated trastuzumab from both conjugates rapidly; but surprisingly, although a large amount of PAMAM-ptx-trastuzumab conjugate was observed in the HER-2-negative MCF-7 cells. Confocal microscopy confirmed the intracellular localisation of analysed compounds. The key result of fluorescent imaging was the identification of strong selective binding of the PAMAM-doc-trastuzumab conjugate with HER-2-positive SKBR-3 cells only. CONCLUSIONS: Our results confirm the high selectivity of PAMAM-doc-trastuzumab and PAMAM-ptx-trastuzumab conjugates for HER-2-positive cells, and demonstrate the utility of trastuzumab as a targeting agent. Therefore, the analysed conjugates present an promising approach for the improvement of efficacy of targeted delivery of anticancer drugs such as docetaxel or paclitaxel.


Assuntos
Antineoplásicos/química , Neoplasias da Mama/tratamento farmacológico , Dendrímeros/química , Docetaxel/química , Paclitaxel/química , Receptor ErbB-2/metabolismo , Trastuzumab/química , Antineoplásicos/farmacologia , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Docetaxel/farmacologia , Interações de Medicamentos , Liberação Controlada de Fármacos , Corantes Fluorescentes/química , Humanos , Paclitaxel/farmacologia , Propriedades de Superfície , Trastuzumab/farmacologia , Resultado do Tratamento
7.
ACS Appl Mater Interfaces ; 11(35): 31681-31692, 2019 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-31397163

RESUMO

In situ modulation of the surface properties on the micellar drug delivery nanocarriers offers an efficient method to improve the drug delivery efficiency into cells while maintaining stealth and stability during blood circulation. Light has been demonstrated to be a temporally and spatially controllable tool to improve cellular internalization of nanoparticles. Herein, we develop reactive oxygen species (ROS)-responsive mixed polymeric micelles with photoinduced exposure of cell-penetrating moieties via photodynamic ROS production, which can facilitate cellular internalization of paclitaxel (PTX) and chlorin e6 (Ce6)-coloaded micelles for the synergistic effect of photodynamic and chemotherapy. The thioketal-bond-linked block polymers poly(ε-caprolactone)-TL-poly(N,N-dimethylacrylamide) (PCL-TL-PDMA) with a long PDMA block are used to self-assemble into mixed micelles with PCL-b-poly(2-guanidinoethyl methacrylate) (PCL-PGEMA) consisting of a short PGEMA block, which are further used to coencapsulate PTX and Ce6. After intravenous injection, prolonged blood circulation of the micelles guarantees high tumor accumulation. Upon irradiation by 660 nm light, ROS production of the micelles by Ce6 induces cleavage of PDMA to expose PGEMA shells for significantly improved cellular internalization. The combination of photodynamic therapy and chemotherapy inside the tumor cells achieves improved antitumor efficacy. The design of ROS-responsive mixed polymeric nanocarriers represents a novel and efficient approach to realize both long blood circulation and high-efficiency cellular internalization for combined photodynamic and chemotherapy under light irradiation.


Assuntos
Portadores de Fármacos , Nanopartículas , Neoplasias Experimentais , Paclitaxel , Fotoquimioterapia , Porfirinas , Animais , Portadores de Fármacos/química , Portadores de Fármacos/farmacocinética , Portadores de Fármacos/farmacologia , Células HeLa , Humanos , Camundongos , Micelas , Nanopartículas/química , Nanopartículas/uso terapêutico , Neoplasias Experimentais/tratamento farmacológico , Neoplasias Experimentais/metabolismo , Neoplasias Experimentais/patologia , Paclitaxel/química , Paclitaxel/farmacocinética , Paclitaxel/farmacologia , Porfirinas/química , Porfirinas/farmacocinética , Porfirinas/farmacologia
8.
Artif Cells Nanomed Biotechnol ; 47(1): 3465-3477, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31432702

RESUMO

Lung cancer is a kind of malignant tumour characterized as uncontrolled cell growth in lung. These malignant cell growth can spread beyond the lung by process of metastasis into other tissues or parts of the body. In this study, we developed dequalinium (DQA) modified paclitaxel plus ligustrazine micelles to destroy vasculogenic mimicry (VM) channels and inhibit tumour metastasis. In vitro assays showed that the targeting micelles with centralized particle size distribution showed not only vigoroso cytotoxicity on A549 cells but also strong inhibition on VM channels and tumour metastasis. Mechanism studies indicated that the DQA modified paclitaxel plus ligustrazine micelles could down-regulate the expressions of VEGF, MMP2, TGF-ß1 and E-cadherin in A549 cells. In vivo assays indicated that the targeting drug-loaded micelles could enhance the accumulation of chemotherapeutic drugs at tumour sites and exhibit strong tumour inhibitory activity with negligible toxicity. Hence, the DQA modified paclitaxel plus ligustrazine micelles developed in this study may provide a potential strategy for treatment of NSCLC.


Assuntos
Carcinoma Pulmonar de Células não Pequenas/patologia , Dequalínio/química , Portadores de Fármacos/química , Neoplasias Pulmonares/patologia , Paclitaxel/química , Paclitaxel/farmacologia , Células A549 , Animais , Apoptose/efeitos dos fármacos , Transporte Biológico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Adesão Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Liberação Controlada de Fármacos , Matriz Extracelular/efeitos dos fármacos , Matriz Extracelular/metabolismo , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Camundongos , Micelas , Invasividade Neoplásica , Metástase Neoplásica , Paclitaxel/metabolismo , Paclitaxel/uso terapêutico , Ensaios Antitumorais Modelo de Xenoenxerto
9.
Int J Biol Macromol ; 138: 207-214, 2019 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-31306708

RESUMO

In this work, paclitaxel was loaded into porous starch in the form of nanoparticles (PNPS), and the properties of PNPS were investigated by using raw paclitaxel and the system of paclitaxel directly loaded into porous starch (PPS) as control groups. According to the tested results, the drug loading (DL) and encapsulation efficiency (EE) of PNPS were 14.13%±0.27% and 73.92%±0.54%, higher than that of PPS (9.79%±0.31% and 71.17%±0.67%) respectively. Compared with raw paclitaxel and PPS, PNPS exhibited the more prominent dissolution rate and bioavailability, in which the bioavailability of PPS and PNPS were 2.94 and 5.42 times of that of raw paclitaxel respectively. In addition, the IC50 values of raw paclitaxel, PPS and PNPS on Lewis Lung Carcinoma (LLC) cells were 17,703.41±15.76µM, 95.10±5.32µM and 85.68±7.38µM respectively. Furthermore, the residues of acetone in PPS and PNPS were less than the ICH limit for acetone in class III solvents. To summarize, the preparation of PNPS was a potential method to improve the dissolution and bioavailability of paclitaxel.


Assuntos
Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel/química , Paclitaxel/farmacocinética , Amido/química , Disponibilidade Biológica , Linhagem Celular Tumoral , Humanos , Paclitaxel/farmacologia , Tamanho da Partícula , Porosidade , Solubilidade , Solventes/química
10.
Artigo em Inglês | MEDLINE | ID: mdl-31276955

RESUMO

In spite of having a remarkable anti tumor activity against a wide variety of cancers, the clinical effectiveness of the major chemotherapeutic drug paclitaxel is often limited by the issues of drug resistance that hampers the therapeutic effectiveness of the drug. The combination of proton pump inhibitor with paclitaxel is an effective approach to overcome therapeutic resistance caused by the acidic microenvironment (Warburg effect) in tumor. In the present study a new simple, precise and selective liquid chromatography tandem mass spectrometry method was developed for quantification of paclitaxel and lansoprazole using esomeprazole as an internal standard and applied for the pharmacokinetic study of investigational paclitaxel - lansoprazole loaded PLGA nanoparticles. The developed method quantifies both the drugs simultaneously irrespective of their dissimilar stability concerns. The detection was exercised with multiple reaction-monitoring mode in positive ionization that yielded highly intense response of parent-product (m/z) transition pair 854.4 → 286.1, 370.1 → 251.9 and 346 → 198 for paclitaxel, lansoprazole and Esomeprazole respectively. The chromatographic separation was achieved using phenomenex Kinetex 5 µ C18 100A 50 × 3.0 mm column and a gradient mobile phase combination of ammonium acetate in deionized water (pH 6.8, 2 mM, w/v) and acetonitrile spiked with formic acid (1:1000, v/v ). This method showed good linearity over a concentration range of 10-320 ng/mL and 100-3200 ng/mL with correlation coefficient (R2) 0.98 and 0.94 for paclitaxel and lansoprazole respectively. Using liquid liquid extraction process both the drugs were extracted from rat plasma. The intra- and inter-day precision and accuracy values were within the variability limits and both the analytes were found to be stable throughout the freeze-thaw, auto-sampler, bench top and long term stability studies. The liquid chromatography tandem mass spectrometry method was successfully validated in accordance with United States Food and Drug administration guidelines and the results were within the acceptable limits. The liquid chromatography tandem mass spectrometry method was successfully utilized for the pharmacokinetic investigation of experimental paclitaxel - lansoprazole loaded PLGA nanoparticles in rat plasma.


Assuntos
Cromatografia Líquida de Alta Pressão/métodos , Lansoprazol/sangue , Paclitaxel/sangue , Espectrometria de Massas em Tandem/métodos , Animais , Composição de Medicamentos/métodos , Avaliação Pré-Clínica de Medicamentos , Feminino , Lansoprazol/química , Lansoprazol/farmacocinética , Masculino , Paclitaxel/química , Paclitaxel/farmacocinética , Ratos
11.
Nanoscale ; 11(27): 13069-13077, 2019 Jul 11.
Artigo em Inglês | MEDLINE | ID: mdl-31265023

RESUMO

Nanosized lipodisks with flat circular phospholipid bilayers surrounded by PEGylated edges have demonstrated promise in drug delivery. In the present work, a lipodisk-based paclitaxel and melittin co-delivery system functionalized with glycopeptide 9G-A7R (9G-A7R-Disk/PTX/melittin) was successfully constructed, in which melittin which was fully protected from proteolysis and hemolysis was effectively reduced. The ratio of paclitaxel to melittin in lipodisks could be accurately controlled through a film hydration-adsorption method. Paclitaxel combined with melittin showed synergism against U87 cells in vitro, and 9G-A7R-Disk/PTX/melittin demonstrated an enhanced anti-glioma effect in vivo, significantly prolonging the survival time of glioma-bearing mice. The results suggested a promising formulation for the co-delivery of paclitaxel/melittin and glioma-targeted therapy.


Assuntos
Neoplasias Encefálicas/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Glioma/tratamento farmacológico , Glicopeptídeos , Meliteno , Nanopartículas , Paclitaxel , Animais , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/patologia , Feminino , Glioma/metabolismo , Glioma/patologia , Glicopeptídeos/química , Glicopeptídeos/farmacologia , Humanos , Meliteno/química , Meliteno/farmacologia , Camundongos , Camundongos Nus , Nanopartículas/química , Nanopartículas/uso terapêutico , Paclitaxel/química , Paclitaxel/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto
12.
ACS Appl Mater Interfaces ; 11(33): 29536-29548, 2019 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-31333014

RESUMO

Previous reports from our team revealed the significant potential advantage of Mn-Zn ferrite nanoparticles (NPs) in magnetic resonance imaging (MRI), whereas anisotropic NPs reportedly increased the blood circulation time of nanocarriers. Thus, anisotropic Mn-Zn ferrite displayed a huge potential in cancer synchronous diagnosis and treatment, that is, enhanced MRI observation was performed simultaneously when drug-targeted delivery therapy was applied to the tumor. Here, we developed three shaped Mn-Zn ferrite (Mn0.63Zn0.37Fe2O4) MNPs used as cancer theranostic nanoagents and compared the effect of the three shaped MNPs on cancer theranostics. Compared to the monodisperse sphere MNPs (S-MNPs-PPR) and clustering MNPs (C-MNPs-PPR), worm-like Mn-Zn ferrite MNPs (W-MNPs-PPR) achieved better results in T2-weighted MRI and achieved more sustained drug release than S-MNPs-PPR and more complete drug release than C-MNPs-PPR in vitro. Additionally, polyethylene glycol (PEG) coating and RGD modification encouraged the three shaped MNPs to evade the recruitment of macrophages more easily and to target the integrin-enriched endothelial cells instead. Meanwhile, W-MNPs-PPR coupled with Paclitaxel (PTX) exhibited more delivery of PTX in the integrin-enriched cells than the other two shaped MNPs, and the content of PTX was far more than that of the wild-type Taxol control group. What is more, in vivo results demonstrated that PTX-coated W-MNPs-PPR not only gained good dual-mode imaging in the tumor (MRI and fluorescence images) but also achieved longer blood circulation time and more PTX-targeted delivery to the tumor, as well as more efficiency in tumor cell killing, which make the simultaneous diagnosis and treatment of tumors to be conducted. Therefore, our works further revealed the importance of the NP shape on its functionality and ultimately provided an alternative and efficient worm-like theranostic nanoagent for tumor theranostics.


Assuntos
Compostos Férricos/química , Manganês/química , Nanopartículas/química , Nanomedicina Teranóstica/métodos , Zinco/química , Animais , Neoplasias da Mama/tratamento farmacológico , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Feminino , Células Endoteliais da Veia Umbilical Humana , Humanos , Marcação In Situ das Extremidades Cortadas , Espectroscopia de Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Paclitaxel/química , Paclitaxel/farmacologia , Paclitaxel/uso terapêutico , Polietilenoglicóis/química , Células RAW 264.7 , Espectroscopia de Luz Próxima ao Infravermelho
13.
Molecules ; 24(11)2019 Jun 08.
Artigo em Inglês | MEDLINE | ID: mdl-31181726

RESUMO

A series of novel 7,9-O-linked macrocyclic taxoids together with modification at the C2 position were synthesized, and their cytotoxicities against drug-sensitive and P-glycoprotein and ßIII-tubulin overexpressed drug-resistant cancer cell lines were evaluated. It is demonstrated that C-seco taxoids conformationally constrained via carbonate containing-linked macrocyclization display increased cytotoxicity on drug-resistant tumors overexpressing both ßIII and P-gp, among which compound 22b, bearing a 2-m-methoxybenzoyl group together with a five-atom linker, was identified as the most potent. Molecular modeling suggested the improved cytotoxicity of 22b results from enhanced favorable interactions with the T7 loop region of ßIII.


Assuntos
Compostos Macrocíclicos/síntese química , Compostos Macrocíclicos/farmacologia , Taxoides/síntese química , Taxoides/farmacologia , Hidrocarbonetos Aromáticos com Pontes/síntese química , Hidrocarbonetos Aromáticos com Pontes/química , Hidrocarbonetos Aromáticos com Pontes/farmacologia , Morte Celular/efeitos dos fármacos , Docetaxel/síntese química , Docetaxel/química , Docetaxel/farmacologia , Células HeLa , Humanos , Compostos Macrocíclicos/química , Simulação de Acoplamento Molecular , Paclitaxel/síntese química , Paclitaxel/química , Paclitaxel/farmacologia , Homologia Estrutural de Proteína , Taxoides/química , Tubulina (Proteína)/química
14.
Drug Deliv ; 26(1): 629-640, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31237149

RESUMO

Chemotherapeutic drugs often used as a first-line treatment of pancreatic cancer (PC) exhibit challenges due to resistance development, lack of selectivity, and tumor heterogeneity. Currently, combination chemo-photothermal therapy is known to enhance the therapeutic efficacy of chemotherapeutic drugs in PC. In this study, we develop adherent gold nanoparticles (GNPs) and paclitaxel (PTX)-loaded PLGA microspheres for the treatment of PC. Polydopamine (pD) was used as a linker to adhere GNPs to the surface of PLGA-Ms and characterized using TEM. Short-term cytotoxicity of GNPs-pD-PTX-PLGA-Ms with or without NIR treatment was evaluated using CCK-8 assays. ROS and western blot assay were performed to determine the intensity of ROS following the treatment of GNPs-pD-PTX-PLGA-Ms with or without NIR in Panc-1 cell line. Successful adhesion of GNPs on the microspheres was confirmed by TEM. CCK-8 assay revealed that GNPs-pD-PTX-PLGA-Ms with NIR showed three-fold higher cytotoxicity, compared to the group without NIR. Furthermore, ROS and western blot assay suggest that GNPs-pD-PTX-PLGA-Ms with NIR showed more ROS generation, followed by downregulation of the expression levels of antioxidant enzyme (SOD2 and CATALASE). These results suggest that the GNPs-pD-PTX-PLGA-Ms in combination with NIR irradiation can provide a synergistic chemo-photothermal therapy for the treatment of PC.


Assuntos
Ouro/química , Indóis/química , Nanopartículas Metálicas/química , Paclitaxel/química , Paclitaxel/farmacologia , Neoplasias Pancreáticas/tratamento farmacológico , Polímeros/química , Antioxidantes/química , Antioxidantes/farmacologia , Linhagem Celular Tumoral , Regulação para Baixo/efeitos dos fármacos , Humanos , Raios Infravermelhos , Microesferas , Fototerapia/métodos , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Espécies Reativas de Oxigênio/metabolismo
15.
J Biomed Nanotechnol ; 15(7): 1532-1545, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31196356

RESUMO

Not only dose oral administration have the highest safety, convenience and patient compliance, but also can improve patients' quality of life and reduce health care costs in many cases when compared to the parenteral route. However, many drugs, especially most anticancer drugs such as paclitaxel (PTX), are not orally bioavailable, which is attributed to low aqueous solubility, poor intestinal permeability, and the high level of P-glycoprotein (P-gp) efflux. In this study, we developed a nano-porous silica aerogel delivery system for oral administration of PTX that improved the bioavailability, reduced the side effects of the drug and inhibited tumor growth. The advantages of nano-porous silica aerogel include very high porosities, vast specific surface areas, high drug-loading rate, high biological safety, excellent biocompatibility, and biological inertia, which can also be applied to a variety of drugs. The aerogel delivery system is a universal pharmaceutical system that has huge potential in the field of pharmacy.


Assuntos
Paclitaxel/química , Administração Oral , Materiais Biocompatíveis , Disponibilidade Biológica , Sistemas de Liberação de Medicamentos , Humanos , Porosidade , Qualidade de Vida , Dióxido de Silício
16.
Int J Biol Macromol ; 136: 266-274, 2019 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-31201909

RESUMO

Paclitaxel, an effective chemotherapeutic drug, is insoluble in aqueous solvents and is usually administered with excipients which have side effects. The use of this drug is also limited due to multi-drug resistance. In this study polysaccharide nanoparticles are used in the delivery of chemotherapeutic drug while minimizing side-effects, solubility issues and drug resistance. The use of biopolymers like galactoxyloglucan to synthesize nanoparticle makes it more biocompatible. This study involves the synthesis of PST-PTX nanoparticles using tamarind seed polysaccharide and Paclitaxel by epichlorohydrin crosslinking. The particles were further characterized by Dynamic Light Scattering (DLS), High-resolution transmission electron microscopy (HR-TEM) Fourier Transform Infrared Spectroscopy (FTIR) and UV-Visible spectroscopy. The cytotoxicity of PST-PTX nanoparticles in cancer cell lines and resistant cancer cell lines were determined by MTT assay. The quantitative analysis of cell death was determined by Annexin V dead cell assay, Caspase 3/7 assay and expression of pro-apoptotic protein Bax. The ability of the nanoparticle to overcome multi-drug resistance was evaluated by the expression of multidrug-resistant proteins P-glycoprotein (P-gp) and Breast cancer resistant protein (BCRP) in lung adenocarcinoma resistant cells (A549R). The present study provides evidence for the ability of PST-PTX nanoparticle to overcome multi-drug resistance and cause apoptotic cell death. The particle was found to be more effective than Paclitaxel in causing cell death in resistant cancer cells. Moreover, the particles were found to downregulate the expression of multi-drug resistant proteins P-gp and BCRP in resistant cell lines suggesting the ability of PST-PTX nanoparticles to overcome multi-drug resistance.


Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Galactose/química , Glucanos/química , Neoplasias Pulmonares/patologia , Nanopartículas/química , Paclitaxel/química , Paclitaxel/farmacologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP/metabolismo , Apoptose/efeitos dos fármacos , Transporte Biológico , Caspase 3/metabolismo , Caspase 7/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Portadores de Fármacos/química , Humanos , Linfócitos/citologia , Linfócitos/efeitos dos fármacos , Proteínas de Neoplasias/metabolismo , Paclitaxel/metabolismo
17.
Int J Biol Macromol ; 137: 20-31, 2019 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-31252010

RESUMO

The research was aimed to develop a liquisolid formulation of paclitaxel using novel, highly porous liquisolid carriers (modified polysaccharides) to enhance bioavailability of orally administered paclitaxel. Modified polysaccharides namely co-grinded treated guar gum (C-TGG), co-grinded treated tamarind kernel powder (C-TTKP) and co-grinded treated locust bean gum (C-TLBG) were developed by sequentially subjecting the corresponding polysaccharides to wetting, drying and co-grinding with mannitol (1:1). A total of 12 liquisolid systems of paclitaxel (LSP-1 to LSP-12) were formulated using non-volatile solvent (polysorbate 80/Solutol HS 15®), carrier material (C-TGG/C-TTKP/C-TLBG), and Aerosil® 200 as coating material, and evaluated for pre-compression parameters. The liquisolid systems were directly compressed to produce liquisolid tablets (LTP-1 to LTP-12) and assessed for post compression parameters, cytotoxic/cellular analysis and pharmacokinetics. The modified polysaccharides exhibited narrow symmetrical particle size distribution, high liquid absorption potential, diminutive swelling index, favorable in vitro biodegradability and compression amenability. Among the directly compressed liquisolid tabs, LTP-10 exhibited highest CDR of 98.70 ±â€¯2.68% and permeability of 61.59%. The IC50 of <20 mmol/L indicated remarkable cytotoxic potential on human gastro-enteric tumor cancerous cell lines (NCI-N87). Additionally, LTP-10 exhibited significantly high values for cell death 37.92 and 54.17% (P < 0.01) in early and late apoptosis and mitochondrial membrane potential regain (33%) in comparison to paclitaxel (P < 0.05) and 5-fluorouracil (P < 0.01). Pharmacokinetics revealed Cmax of 536.48 ±â€¯4.63 µg/L at 1.64 ±â€¯0.44 h for LTP-10 indicating enhancement in bioavailability (5.43 fold) of paclitaxel on oral administration.


Assuntos
Apoptose/efeitos dos fármacos , Ciclo Celular/efeitos dos fármacos , Portadores de Fármacos/química , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Paclitaxel/química , Paclitaxel/farmacologia , Polissacarídeos/química , Animais , Antineoplásicos/química , Antineoplásicos/metabolismo , Antineoplásicos/farmacocinética , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Liberação Controlada de Fármacos , Humanos , Paclitaxel/metabolismo , Paclitaxel/farmacocinética , Permeabilidade , Coelhos , Solubilidade , Distribuição Tecidual
18.
World J Microbiol Biotechnol ; 35(5): 74, 2019 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-31053977

RESUMO

In the present study, an endophytic fungal strain was isolated from its non-Taxus host plant Terminalia arjuna and identified as Alternaria brassicicola based on its morphological characteristics and internal transcribed spacer sequence analysis. This fungus was grown in potato dextrose broth and analyzed for the presence of taxol by using chromatographic and spectrometric techniques. The ethyl acetate extract of A.brassicicola was subjected to column chromatography. Among the different fractions, the fraction 7 showed positive to taxol, which was further confirmed by UV absorption, HPLC, FTIR spectra and LC-ESI-MS by comparing with the authentic taxol (Paclitaxel). The peaks of fraction 7 obtained by UV spectroscopy, FTIR and HPLC analysis were quite similar to that of standard taxol confirming the presence of taxol. A parent ion peak of m/z 854.95 was observed in the LC-ESI-MS spectrum which was similar to paclitaxel with reported m/z of 854 [M+H]+ ion. A. brassicicola produced about 140.8 µg/l taxol as quantified through HPLC. Present study results suggest that the endophytic fungus A.brassicicola serves as a potential source for the production of taxol isolated from non-Taxus plant.


Assuntos
Alternaria/isolamento & purificação , Alternaria/metabolismo , Paclitaxel/química , Paclitaxel/isolamento & purificação , Plantas Medicinais/microbiologia , Terminalia/microbiologia , Alternaria/classificação , Cromatografia , Cromatografia Líquida de Alta Pressão , Endófitos/isolamento & purificação , Endófitos/metabolismo , Fermentação , Espectrometria de Massas , Espectrofotometria Ultravioleta , Espectroscopia de Infravermelho com Transformada de Fourier
19.
Int J Pharm ; 566: 149-156, 2019 Jul 20.
Artigo em Inglês | MEDLINE | ID: mdl-31129344

RESUMO

Lung cancer remains 23% of cancer-related death worldwide, ranking on first place for men and second place for women. Almost each cancer type has a great deal in common, overexpression of the apoptosis inhibitor survivin. Chemotherapy with anticancer drugs is leading to side effects. Drug targeting by the use of nanobubbles is a useful strategy to reduce side effects. Nanobubbles in cancer are one of the most investigated carriers in the last years. The size of nanobubbles (1-500 nm) is bigger than the pore size of healthy tissues, but smaller than the pores of cancer tissues. Thus, it is not possible for the drug to leave the blood stream and enter the tissue, but it can enter the cancer tissue through the pores, where it can accumulate. Therefore, the probability of undesired side effects decreases. For that reason, the development of nanobubbles containing paclitaxel and survivin inhibitor sepantronium bromide (YM155) were carried out. Characterization studies in terms of particle size, size distribution, zeta potential and morphology, and investigation of their effects on lung cancer cells were performed. To the best of our knowledge, there is no information in the literature about combining paclitaxel and YM155 loaded nanobubbles with ultrasound exposure.


Assuntos
Antineoplásicos Fitogênicos , Imidazóis , Neoplasias Pulmonares/tratamento farmacológico , Nanoestruturas , Naftoquinonas , Paclitaxel , Survivina/antagonistas & inibidores , Células A549 , Antineoplásicos Fitogênicos/administração & dosagem , Antineoplásicos Fitogênicos/química , Sobrevivência Celular/efeitos dos fármacos , Liberação Controlada de Fármacos , Humanos , Imidazóis/administração & dosagem , Imidazóis/química , Nanoestruturas/administração & dosagem , Nanoestruturas/química , Naftoquinonas/administração & dosagem , Naftoquinonas/química , Paclitaxel/administração & dosagem , Paclitaxel/química
20.
Carbohydr Polym ; 216: 129-139, 2019 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-31047049

RESUMO

A novel biotin and arginine modified hydroxypropyl-ß-cyclodextrin (biotin-Arg(pbf)-HP-ß-CD) was successfully synthesized. The hydroxyl groups of HP-ß-CD on the primary faces were coupled with carboxyl groups of biotin using arginine as the functional spacer. Using biotin-Arg(pbf)-HP-ß-CD as the carrier, paclitaxel (PTX)-loaded nanoparticles were developed by modified emulsion solvent evaporation method. The optimized PTX-loaded biotin-Arg(pbf)-HP-ß-CD nanoparticles had a mean diameter of 121.9 nm and zeta potential of -57.7 mV. Transmission electron microscopy (TEM) observation revealed that the nanoparticles were spherical in shape. XRD spectra confirmed the successful encapsulation of PTX. Moreover, in vitro and in vivo evaluations were performed to demonstrate the superior antitumor activity of the PTX-loaded nanoparticles. The cellular uptake study demonstrated the biotin receptor-mediated endocytosis of biotin-Arg(pbf)-HP-ß-CD nanoparticles and the increase of cellular uptake by introduction of biotin and arginine. It can be concluded that the biotin-Arg(pbf)-HP-ß-CD nanoparticles are efficient tumor-targeting drug delivery systems for PTX.


Assuntos
2-Hidroxipropil-beta-Ciclodextrina/química , Antineoplásicos/uso terapêutico , Portadores de Fármacos/química , Nanopartículas/química , Paclitaxel/uso terapêutico , 2-Hidroxipropil-beta-Ciclodextrina/síntese química , 2-Hidroxipropil-beta-Ciclodextrina/toxicidade , Animais , Antineoplásicos/química , Antineoplásicos/farmacologia , Arginina/análogos & derivados , Arginina/síntese química , Arginina/toxicidade , Biotina/análogos & derivados , Biotina/síntese química , Biotina/toxicidade , Carcinoma/tratamento farmacológico , Portadores de Fármacos/síntese química , Portadores de Fármacos/toxicidade , Feminino , Humanos , Células MCF-7 , Camundongos , Nanopartículas/toxicidade , Paclitaxel/química , Paclitaxel/farmacologia , Tamanho da Partícula , Neoplasias do Colo do Útero/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto
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